Dengue

Section Contents

Key Points
Background & Epidemiology
Pathophysiology
Natural History of Symptomatic Dengue
Clinical Spectrum of Dengue
Diagnosis
Treatment & Management
Prevention
Other Media Resources (Optional)
References

Key Points

Dengue is a mosquito-borne disease caused by 4 serotypes of the dengue virus.
Most patients are either asymptomatic or go through a self-limited acute febrile illness, although a small subset of patients may progress to severe dengue.
Severe dengue is characterized by exaggerated plasma leakage, severe bleeding, end-organ damage, and shock.
Infection induces lifelong immunity against one serotype, but there is a potential increased risk of severe dengue with heterotypic infections.
Supportive care is the cornerstone therapy for dengue, as there is no specific antiviral available.

Background & Epidemiology

Dengue is a mosquito-borne disease caused by the dengue virus (DENV) of the genus Flavivirus. DENV has 4 antigenically distinct serotypes (numbered 1-4), that are transmitted by the Aedes mosquito in tropical and subtropical areas worldwide. The main vector for DENV is Aedes aegypti, and less commonly Aedes albopictus (see Table 1 below).

	Aedes aegypti	Aedes albopictus
Behavior	Anthropophilic	Zoophilic > Anthropophilic
Habitat	Urban areas/Peri-urban	Peri-urban/Rural areas
Local distribution	Indoor = Outdoor	Outdoor > Indoor

Figure 1. Aedes aegypti

DENV is endemic in most tropical and subtropical areas, and due to geographical extension of the Aedes mosquito, certain areas in the United States and Europe have also reported endogenous cases. Please click here to see areas at risk of dengue fever.

Note: Medically relevant Flaviviruses

Dengue virus
Yellow fever virus
Japanese/St Louis encephalitis virus
Powassan virus
West Nile virus
Zika virus

Pathophysiology

Life Cycle: transmission of dengue occurs through the Aedes mosquito. Rare reports of transmission via transfusion or transplant, perinatal acquisition or laboratory accidents have been documented. Vectorial transmission starts when a female mosquito takes a blood meal during an active DENV viremia in an infected human. Once the virus is ingested by the vector, it travels to the midgut where it matures, and goes to the mosquito’s salivary glands. Now, it can be reintroduced with the saliva when it takes a blood meal in another host. This process takes approximately 10 days.

Dengue immunity 101: infection with one serotype will induce lifelong immunity against that serotype, but NOT against others. Hosts can still get re-infected with the remaining serotypes (called heterotypic infection). During a heterotypic infection (more commonly during a second episode) through a very complex set of immunologic pathways, there is an increased risk of severe dengue infection.

Although the exact mechanisms are unknown, it is thought that non-neutralizing antibodies produced during the primary infection paradoxically enhance viral and T-cell replication, leading to an uncontrolled cytokine production, endothelial dysfunction, and plasma leakage. This phenomenon is called antibody-dependent enhancement and is relevant in both naturally-acquired heterotypic infection, and infections occurring in previously immunized individuals (more in Prevention).

Natural History of Symptomatic Dengue

After an incubation period of 3-14 days (average 7 days), symptomatic patients often go through three distinct phases as part of the natural history of dengue fever:

Febrile or acute phase

Febrile or acute phase → typically starts acutely and lasts 2-7 days (correlates with the duration of the viremia). During this phase, patients may present with either of the following: fever, malaise, retro-orbital pain, headache, nausea, vomiting, myalgias, arthralgias, facial flushing or maculopapular rash. Patients can have mild hemorrhagic events (i.e., petechiae, mucosal bleeding), generalized lymphadenopathy, pharyngeal and/or conjunctival erythema.

Laboratories → leukopenia starts before thrombocytopenia. Elevated liver enzymes are common.

Note: Just like in malaria, dengue can present with many non-specific symptoms. Any of these symptoms in a patient living or coming from a dengue-endemic area should make you think of dengue!

Critical phase

Critical phase → typically begins once the fever is coming down, and less commonly while the patient is still febrile. The critical phase lasts for 1-2 days, and it is characterized by plasma leakage. While most have minimal plasma leakage (not clinically apparent) and recover, some patients can progress to clinical fluid accumulation (ie., pleural effusion), circulatory collapse, severe bleeding, shock with severe organ damage. Thus, during the critical phase is when warning signs are most apparent (more in Clinical Spectrum).

Laboratories → progressive thrombocytopenia with further rise in hematocrit. Leukopenia is common.
Complications → shock, severe bleeding. Rarely, encephalitis, myocarditis.

Note: Remember two things about the critical phase: i) thrombocytopenia goes against the direction of hematocrit; AND ii) once the fever is winding down, is when you need to keep the closest eye on alarm signs!

Convalescent or Recovery phase

Convalescent or Recovery phase → usually lasts 2-3 days and it is characterized by resorption of the extravascular fluid that leaked during the critical phase. Patients may experience a desquamating convalescent rash (“white islands in a sea of red”) after the fever is over (can be pruritic!).

Laboratories → improvement in platelets, hematocrit & white blood cells.
Complications → volume overload can occur if excess fluids were given during the critical phase to compensate for the plasma leakage.

Clinical Spectrum of Dengue

The presentation of dengue ranges from asymptomatic infection (up to 80%) to severe dengue. According to the WHO, there are three distinct clinical syndromes, which illustrate the spectrum of disease:

Dengue with NO warning signs

Dengue with NO warning signs → these patients go through an acute/febrile phase and develop no or minimal plasma leakage, and recover with minimal complications. Patients can have a positive tourniquet test (which is not a sign of severity!).

Note: El tourniquet test is one of those “test questions”, that is not that helpful clinically. It is a surrogate for capillary fragility. It consists in inflating a blood pressure cuff at a point between the systolic and the diastolic BP, and leaving it inflated for 5 minutes. After two minutes, if more than 10 petechiae are seen within a square inch then the test is positive. Sensitivity is slightly over 50%.

Dengue with warning signs

Dengue with warning signs → these subset of patients develop initial signs of plasma leakage, which starts between the end of the febrile phase and beginning of the critical phase. These patients are not severe YET, but they may progress to severe disease. Thus, patients need closer monitoring and possibly hospitalization.

The seven warning signs to look out for are:

Abdominal pain or tenderness
Persistent vomiting
Clinical fluid accumulation
Mucosal bleeding
Lethargy or restlessness
Liver enlargement >2 cm
An increased hematocrit level that is accompanied by a decreased platelet count.

Severe dengue

Figure 2. Clinical spectrum of Dengue fever

Diagnosis

As with all diseases, diagnosis starts with a clinical suspicion in the right epidemiological context (Ask yourself: What is the presentation? Who is the host?). Definitive diagnosis can be supported through the following:

Antigen detection → Non-structural protein 1 (NS1) can be detected from the start of symptoms up to 9-10 days after symptom onset. It is therefore more useful during the febrile/acute phase. Sensitivity is over 90%.
Antibody detection → IgM can be detected ~5 days after symptom onset and can remain elevated up to 3 months. Can cross-react with other flaviviruses (i.e., West Nile Virus). IgG can be detected usually after 7 days after symptom onset and can remain elevated for decades. Antibodies are not suitable for early diagnosis since it takes 5-7 days to become positive.
PCR → can be detected from the start of symptoms up to ~5 days after symptom onset. Highly specific and can different between serotypes. Not widely available.

Note: Dengue is clinically indistinguishable from MANY infections (ie., streptococcal pharyngitis, leptospirosis, acute cholecystitis) - including arboviruses (ie., Zika, Chikungunya). However, during dengue epidemics, clinical diagnosis is occasionally made but it requires a high-degree of experience.

Figure 3. Most common diagnostic modalities used in Dengue

Treatment & Management

There is no specific antiviral agent available for dengue & management is entirely supportive. Here are some management pearls you should keep in mind:

How to manage the symptoms in dengue fever?

Symptomatic treatment → acetaminophen/paracetamol are preferred to manage symptoms of fever, malaise, and body aches. AVOID non-steroidal antiinflammatory drugs (NSAIDs) as they can increase risk of bleeding.
Return precautions → most patients (~90-95%) will recover from dengue with no complications. Patients should be instructed about alarm symptoms and should be closely monitored until the end of the critical phase.

How to decide outpatient v. inpatient management?

It all comes down to understanding the three main clinical syndromes:

Group A → this is for patients with dengue with NO warning signs who have no other significant comorbidities and laboratories (Hemoglobin/Hematocrit, Platelets) are stable. These individuals can be managed in the outpatient setting.
Group B → this is for patients with dengue with warning signs or those with NO warning signs BUT with comorbidities that increase the risk for severe disease (ie., pregnancy, decompensated organ failure, diabetes). These individuals need very close monitoring and/or hospitalization.
Group C → this is for patients with severe dengue. These individuals will need hospitalization and some will need intensive care!

How to manage fluid resuscitation in Dengue?

Fluid management in dengue can get complicated! We will mention basic concepts in management, but if you’re looking for a more comprehensive review, please click here (page 13).

Group A → these patients should be encouraged to get proper oral hydration
Group B → typically IV fluids are favored during the critical phase. Once patients’ urine output, oral intake and hematocrit values are normal, IVF should be reduced. Use the hematocrit to guide your decisions!
1. 1. Remember that fluids you give during the critical phase will get reabsorbed during the convalescent phase so be careful in inducing hypervolemia!
Group C → these patients are in shock. For a comprehensive algorithm on shock management click here (page 16).

How do I know the patient is getting better?

What is the overall prognosis in dengue?

Prevention

Vector avoidance → avoid outdoor spaces during the day (highest activity of the Aedes mosquito is dawn and dusk), apply mosquito repellent, use metallic fabric in doors and windows, spray insecticides in the rooms overnight, avoid dengue endemic zones (particularly if pregnant), use clothes that covers exposed areas, use of mosquito nets + insecticide-treated nets;
Vector control → use of larvicides, destruction of breeding sites (i.e., artificial containers that contain water), DDT (used in the past, but use was waned due to cost and environmental consequences);
Vaccination → there are three live attenuated licensed vaccines for the prevention of dengue, summarized in the table below. Some general concepts of each vaccine are displayed:
1. CYD-TDC (Dengvaxia ®) → this was the first dengue vaccine that became available and it is FDA-approved for individuals aged 9-16 living in endemic areas, with previous laboratory confirmation of dengue infection.
  1. Controversies: after the introduction of CYD-TDV in 2015 there were excess hospitalizations with severe dengue among vaccine recipients in Asia and Latin America. A potential theory is that the vaccine provides only partial immunity to dengue and upon a subsequent natural dengue infection, this mimicked the antibody dependent enhancement mechanism increasing the risk of severe dengue. For this reason, Dengvaxia® is the only vaccine that requires laboratory-confirmed previous dengue for its administration to avoid this risk.
2. TAK-003 (Qdenga®) → this was approved in 2022 regardless of their serostatus. According to the WHO, it is recommended as part of routine immunization programs in locations with high transmission of dengue. The indications are country specific (i.e., Indonesia: 6-45 years; European Union: 4 years or older; Brazil: 4-60 years). Overall efficacy is around 75% at dengue prevention, and 95% at preventing hospitalization, among seronegative individuals.
3. Butatan-DV → has not been yet approved but results of Phase III trial were published in 2024. Efficacy against symptomatic DENV-1, DENV-2 close to 80%.

	Mechanism of action	Dose series	Covered serotypes	Requires previous serostatus
CYD-TDV	Live attenuated	Three doses	DENV 1-4	Yes
TAK-003	Live attenuated	Two doses	DENV 1-4*	No
Butantan-DV	Live attenuated	Single dose	DENV 1-4*	No

* Efficacy-risk profile still being studied for serotypes DENV 3 and DENV 4

Other Media Resources (Optional)

Podcast Recording

References

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Tayal, A., Kabra, S. K., & Lodha, R. (2022). Management of Dengue: An Updated review. The Indian Journal of Pediatrics, 90(2), 168–177.
Guzman, M. G., Gubler, D. J., Izquierdo, A., Martinez, E., & Halstead, S. B. (2016). Dengue infection. Nature Reviews Disease Primers, 2(1).
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Halstead, S. B. (2015). Pathogenesis of Dengue: Dawn of a new era. F1000Research, 4, 1353.
Flipse, J., Diosa-Toro, M. A., Hoornweg, T. E., Van De Pol, D. P. I., Urcuqui-Inchima, S., & Smit, J. M. (2016). Antibody-Dependent Enhancement of Dengue Virus Infection in Primary Human Macrophages; Balancing Higher Fusion against Antiviral Responses. Scientific Reports, 6(1).
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Biswal, S., Reynales, H., Saez-Llorens, X., Lopez, P., Borja-Tabora, C., Kosalaraksa, P., Sirivichayakul, C., Watanaveeradej, V., Rivera, L., Espinoza, F., Fernando, L., Dietze, R., Luz, K., Da Cunha, R. V., Jimeno, J., López-Medina, E., Borkowski, A., Brose, M., Rauscher, M., . . . Wallace, D. (2019). Efficacy of a tetravalent dengue vaccine in healthy children and adolescents. New England Journal of Medicine, 381(21), 2009–2019.
Sridhar, S., Luedtke, A., Langevin, E., Zhu, M., Bonaparte, M., Machabert, T., Savarino, S., Zambrano, B., Moureau, A., Khromava, A., Moodie, Z., Westling, T., Mascareñas, C., Frago, C., Cortés, M., Chansinghakul, D., Noriega, F., Bouckenooghe, A., Chen, J., . . . DiazGranados, C. A. (2018). Effect of dengue serostatus on dengue vaccine safety and efficacy. New England Journal of Medicine, 379(4), 327–340.
Vaccines and immunization: Dengue. (n.d.). https://www.who.int/news-room/questions-and-answers/item/dengue-vaccines
Dengue Clinical Case Management. (n.d.). https://www.cdc.gov/dengue/training/cme/ccm/page53133.html

This lesson was last updated September 4 2025