Dengue

Dengue is a viral disease transmitted by mosquitoes (especially Aedes aegypti), most commonly in tropical regions. Most individuals with dengue are asymptomatic or have mild symptoms of fever, headache, and rash. Severe illness is rare; manifestations include pleural effusions, ascites, and hemorrhage. The typical course consists of the febrile phase, the critical phase, and the recovery phase; most affected individuals improve during the critical phase, but some develop severe dengue. Patients are risk-stratified, with hospitalization indicated for patients who have or are at risk of severe dengue. Treatment is supportive. Insect bite prevention methods are indicated to prevent further spread of disease and are recommended for all individuals who live in and/or travel to endemic areas.

• Distribution
  • Tropical regions worldwide, particularly Asia (e.g., Thailand) and the Americas
  • In the US, dengue is:
    • Endemic in some territories (e.g., Puerto Rico, American Samoa, the US Virgin Islands) ^[1]
    • Occasionally locally transmitted in Florida, California, Texas, Hawaii, and Arizona ^[2]
• Incidence
  • Most common viral disease affecting tourists in tropical regions
  • ∼ 400 million infections per year worldwide
  • Severe dengue occurs in ∼ 2% of cases. ^[3]

References:^[4]

Epidemiological data refers to the US, unless otherwise specified.

• Pathogenic
  • Dengue virus (Serotype: DENV 1–4)
  • RNA virus of the genus Flavivirus
• Transmission route ^[5]
  • Vector-borne; : mosquitoes most commonly from the species Aedes aegypti
• Incubation period: 4–10 days ^[6][7]

A fifth dengue subtype (DENV 5), similar to varieties that normally infect wildlife, was recorded in Malaysia in 2013. Further research is needed to confirm this finding. ^[8]

References: ^[9]

Most infected individuals are asymptomatic or have mild symptoms. ^[7]

Febrile phase of dengue ^[6][10]

• Typically lasts 2–7 days
• Fever (may be a biphasic fever)
• Severe headache
• Retro-orbital pain
• Rash ^[11]
  • Initial flushing over the face, neck, and chest within 48 hours
  • Second generalized morbilliform rash may appear on days 3–5.
• Severe arthralgia and myalgia (hence the colloquial term “breakbone fever”)
• Anorexia and nausea ^[10]
• Positive tourniquet test
• Dengue with warning signs may develop in the late febrile phase and suggests progression to severe dengue.

Consider dengue if symptoms develop within 2 weeks of returning from a dengue-endemic region. ^[2]

Critical phase of dengue ^[6][7][10]

• Occurs after defervescence
• Typically lasts 24–48 hours
• Increased hematocrit and capillary permeability can lead to plasma leakage, manifesting as: ^[7]
  • Pleural effusion
  • Ascites
  • Signs of shock
• Most improve during this phase; some develop severe dengue.

Severe dengue can occur in the absence of warning signs. ^[7]

Recovery phase of dengue ^[6][10]

• Typically lasts 48–72 hours
• General clinical improvement
• Resorption of extravasated fluids leads to hemodynamic stability and diuresis.

Probable dengue ^[7]

Fever with ≥ 2 of the following features, in an individual who lives in or has traveled to an endemic area:

• Nausea or vomiting
• Rash
• Aches
• Positive tourniquet test
• Leukopenia
• Warning signs for dengue

Dengue with warning signs ^[7]

• Probable dengue or laboratory confirmed dengue with:
  • Abdominal pain
  • Persistent vomiting
  • Hemorrhagic manifestations: petechiae, epistaxis, gingival bleeding
  • Extravascular fluid accumulation (e.g., pleural effusion and/or ascites)
  • Lethargy and/or restlessness
  • Liver enlargement > 2 cm below the costal margin
  • Laboratory results indicating ↑ hematocrit; measured on ≥ 2 consecutive blood tests with ↓ platelets ^[7][12]
• Features typically manifest in the late febrile phase of dengue and suggest progression to severe dengue. ^[6][7][12]

Severe dengue (formerly dengue hemorrhagic fever) ^[6][7]

• Greatly increased vascular permeability
  • Severe pleural effusion causing respiratory distress
  • Pronounced ascites causing abdominal pain
  • Severely ↑ or ↓ Hct
• Severe hemorrhagic symptoms due to thrombocytopenia
  • Melena
  • Hematemesis
  • Purpura
  • Ecchymoses
• Significant organ involvement
  • Changes in mental status (e.g., confusion)
  • Liver failure with AST or ALT ≥ 1000 IU/L ^[13]
  • Cardiomyopathy
• Dengue shock syndrome: hypovolemic shock in the presence of other symptoms of severe dengue

Second infection with a different dengue serotype (especially serotype 2) is a risk factor for severe dengue, as it may cause an antibody-dependent reaction. ^[6][7]

Expanded dengue syndrome ^[14]

• Uncommon atypical presentation
• Isolated severe organ involvement (e.g., liver, kidney, heart, eyes, or brain)
• Can occur in the absence of plasma leakage
• May result from prolonged shock

Diagnostics occur alongside initial management of dengue. ^[15]

Approach ^[15][16][17]

• Choose diagnostic tests according to number of days since symptom onset.
  • ≤ 7 days: IgM antibodies plus NAAT or NS1 antigen test
  • > 7 days: IgM ELISA ^[17]
• Order diagnostics for Zika infection if the patient was in an area where both dengue and Zika are present. ^[15]
• Obtain additional studies to assess for hematological and organ dysfunction.
• Further studies may be necessary depending on symptoms, e.g.:
  • Diagnostics for shock
  • Chest x-ray for suspected pleural effusion
  • Abdominal ultrasound for ascites
  • Type and screen in dengue shock syndrome

Interpret results with caution in patients with previous exposure to dengue or other flaviviruses (including through vaccination) because of the risk of false positives. ^[17]

Dengue is a nationally notifiable disease in the US; report all suspected cases to the health department. ^[2]

Confirmatory studies

≤ 7 days after symptom onset ^[15][16][17]

• IgM antibodies ; ^[15][16][17]
  • Positive from approximately day 3 of illness; may remain positive for months ^[15]
  • Typically combined with NAAT or an NS1 antigen test
  • False positives may occur if patients have been previously exposed (via infection or vaccination) to:
    • Other serotypes of dengue
    • Other flaviviruses (e.g., Zika, tickborne encephalitis)
  • If a false positive is suspected in a patient with previous flavivirus exposure, order a plaque reduction neutralization test. ^[15]
• NAAT ^[17]
  • Perform if the patient presents within 7 days of infection. ^[17]
  • High sensitivity and specificity
  • Can be used to determine serotype
• NS1 antigen test ^[17]
  • ELISA detection of the dengue NS1 antigen ^[18]
  • Levels wane ∼7 days after symptom onset.
  • Cannot be used to determine serotype

> 7 days after symptom onset ^[15][17]

• Preferred test: ELISA to detect IgM antibodies
• NAAT can be used to confirm but cannot rule out dengue infections. ^[17]

Alternative tests

• If standard confirmatory studies are not available, use paired IgM and IgG serology, taken during the acute and convalescent phases.
• A 4-fold increase in IgG suggests infection.
• Previous exposure to dengue or other flavaviruses (including through vaccination) may cause false-positive results; interpret results with caution.

Additional studies

The following laboratory findings support a diagnosis of dengue infection:

• CBC ^[12]
  • Leukopenia
  • Progressive increase in hematocrit
  • Thrombocytopenia
• Complete metabolic panel: renal failure and/or electrolyte and glucose disturbances. ^[10]
• Liver chemistries: AST or ALT ≥ 10,000 IU/L ^[12][13]
• PT and/or INR: abnormal parameters
• Blood gas: acid-base disorders

For further information on management in pregnant individuals and children, see “Special patient groups.”

Approach ^[10][13]

• Consult infectious diseases early.
• Start supportive therapy.
  • Immediate stabilization for patients with severe dengue or dengue with warning signs
    • IV fluid resuscitation
    • Blood transfusion for management of hemorrhagic shock
  • Acetaminophen for pain and fever (for dosages, see “Oral analgesics”)
  • Oral hydration with oral rehydration solution (up to 3 L/day) for patients able to drink
• Assess for admission criteria for patients with dengue, and initiate inpatient or outpatient management of dengue accordingly.
• Prevent further spread of disease using insect bite prevention methods.

Avoid NSAIDs, including aspirin, as they may worsen hemorrhage and gastritis. ^[10][16]

Steroids, immunoglobulins, and antivirals are not indicated in the treatment of dengue. ^[12][16]

Immediate stabilization for patients with dengue

• Aims to prevent deterioration in patients with severe dengue or dengue with warning signs
• A higher level of care is frequently required; consult intensive care early.
• Monitor fluid intake and urinary output, and repeat CBC at regular intervals. ^[13]

IV fluid therapy ^[13]

• Initial resuscitation with IV crystalloids.
  • Dengue shock syndrome: 20 mL/kg over 15–30 minutes
  • Severe dengue or dengue with warning signs: 10 mL/kg over 1 hour
• Reassess
  • Re-examine and repeat CBC.
  • Any of the following findings: Repeat the initial fluid bolus up to 2 more times.
    • Urine output has increased by < 1 mL/kg/hr
    • Clinical status has not improved
    • Hematocrit has increased
• Escalate: if no improvement
  • Consider boluses of IV colloids.
  • Refer to intensive care for vasopressors.
  • See “Management of shock” for further details.
• Maintenance: for patients who have improved with IV fluid resuscitation
  • Dengue shock syndrome
    • Reduce the intensity of fluid resuscitation of isotonic saline to 10 mL/kg over 1–2 hours.
    • Continuous improvement: Provide a stepwise decrease in fluid resuscitation therapy.
  • Severe dengue or dengue with warning signs: Provide a stepwise decrease in fluid resuscitation therapy.

Consider a reduced fluid resuscitation regimen for patients at higher risk of fluid overload (e.g., heart failure, older adults, pregnant individuals). ^[13]

Management of hemorrhage ^[13]

• Asses for signs of concealed hemorrhage (e.g., rapid decrease in hematocrit).
• Administer packed red blood cells or whole blood.
  • Packed red cells: 5–10 mL/kg
  • Whole blood: 10–20 mL/kg
• Avoid administering platelets or fresh frozen plasma unless there is life-threatening bleeding. ^[12]

Admission criteria for patients with dengue ^[12][13]

• Dengue with warning signs
• Severe dengue
• Dyspnea
• Unable to tolerate oral fluids
• Acute renal failure
• Coagulopathy
• Pregnancy
• Comorbid conditions (e.g., peptic ulcer disease, CKD, taking anticoagulant medications) ^[13]
• BMI ≥ 30 kg/m^{2 [13]}
• Barriers to follow-up
• Infant or age > 65 years ^[7][13]

• For patients with severe dengue or dengue with warning signs, start immediate stabilization for patients with dengue.
• For all other patients: Provide fluid resuscitation.
  • If tolerating oral fluids: Encourage oral fluids (e.g., up to 3000 mL of water per day with oral rehydration salts). ^[12]
  • If not tolerating oral fluids: Administer IV saline at 2–4 mL/kg/hr. ^[13]
• Monitor patients regularly for signs of deterioration and escalate care if present. ^[13]
  • Measure fluid intake and urinary output.
  • Repeat CBC at regular intervals. ^[13]
  • Examine for features of dengue with warning signs or severe dengue.
• Continue monitoring until 4–6 hours after the end of the critical phase of dengue. ^[13]
• Discharge when all of the following criteria are met: ^[10][13]
  • Normal vital signs for 48 hours
  • Tolerating oral nutrition and fluids
  • Stable hematocrit and adequate urine output (0.5–1.5 mL/kg/hr) without IV fluids ^[13]
  • No evidence of bleeding
  • Resolving thrombocytopenia

Routine laboratory monitoring for renal, hepatic, and clotting dysfunction is typically unnecessary in the absence of suggestive symptoms. ^[7]

• Advise patients to monitor for dengue with warning signs and symptoms of severe dengue. ^[13][15]
• Initiate outpatient monitoring with daily CBC. ^[10][12][13]
• Encourage oral hydration with oral rehydration solution (up to 3 L/day). ^[12]
• Admit for inpatient care if any of the following develop: ^[12][13]
  • Laboratory findings of:
    • Progressive increase in hematocrit
    • Thrombocytopenia
    • Leukopenia
  • Features of dengue with warning signs or severe dengue

• Chikungunya fever and other viral hemorrhagic fevers
• Malaria
• Zika virus infection
• Oropouche virus disease

Severe hemorrhagic manifestations with shock and death as well as decreased neutrophil and platelet counts are more indicative of dengue fever than chikungunya fever.

The differential diagnoses listed here are not exhaustive.

• Ensure insect bite prevention (e.g., mosquito repellent, bed nets). ^[16]
• Dengue vaccination (with live-attenuated tetravalent vaccines) is recommended as part of routine vaccination for children living in dengue-endemic areas. ^[19][20][21]

Dengue in infants and children ^[10]

• Clinical features
  • Similar to clinical features of dengue in adults ^[13][22]
  • Children (including infants) are at higher risk of severe dengue than adults. ^[7]
• Diagnostics: similar to dengue diagnostics in adults
• Management is similar to that in adults, with the following exceptions:
  • Admit infants. ^[13]
  • Provide supportive care for pediatric fever.
  • Inpatient: Calculate maintenance IV fluids using the Holliday-Segar formula. ^[13]
  • Outpatient: Calculate oral hydration using the Holliday-Segar formula plus 5%. ^[12]

Children are at increased risk of severe dengue compared to adults. ^[7]

Dengue in pregnancy ^[10][13][22]

• Clinical features
  • Similar to clinical features of dengue in nonpregnant adults
  • Severe dengue is more common (especially in the third trimester) than in nonpregnant individuals. ^[12]
• Diagnostics: similar to dengue diagnostics in nonpregnant adults
• Management is similar to that in nonpregnant adults, with the following modifications:
  • Admit all pregnant individuals with suspected or confirmed dengue. ^[12][13]
  • Refer to obstetrics for shared care.
  • Consider lower doses of IV crystalloids if fluid resuscitation is required. ^[13]
  • Use antepartum fetal surveillance to assess for fetal distress. ^[12]
  • Monitor neonates for symptoms; dengue may be transmitted vertically, particularly if symptomatic during late pregnancy or delivery. ^[10][22]
  • See also “Management of high-risk pregnancies.” ^[13]