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Dengue

(Breakbone Fever; Dandy Fever)

By

Thomas M. Yuill

, PhD, University of Wisconsin-Madison

Last full review/revision Mar 2020| Content last modified Mar 2020
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Dengue is a mosquito-borne disease caused by a flavivirus. Dengue fever usually results in abrupt onset of high fever, headache, myalgias, arthralgias, and generalized lymphadenopathy, followed by a rash that appears with a 2nd temperature rise after an afebrile period. Respiratory symptoms, such as cough, sore throat, and rhinorrhea, can occur. Dengue can also cause potentially fatal hemorrhagic fever with a bleeding tendency and shock. Diagnosis involves serologic testing and polymerase chain reaction (PCR). Treatment is symptomatic and, for dengue hemorrhagic fever, includes meticulously adjusted intravascular volume replacement.

Dengue is endemic to the tropical regions of the world in latitudes from about 35° north to 35° south. Outbreaks are most prevalent in Southeast Asia but also occur in the Caribbean, including Puerto Rico and the US Virgin Islands, Oceania, and the Indian subcontinent; more recently, dengue incidence has increased in Central and South America. Each year, only about 100 to 200 cases are imported to the US by returning tourists, but an estimated 50 to 100 million cases occur worldwide, with about 20,000 deaths. Limited local transmission has occurred most recently in Hawaii, Florida, and Texas.

The causative agent, a flavivirus with 4 serogroups, is transmitted by the bite of Aedes mosquitoes. The virus circulates in the blood of infected humans for 2 to 7 days; Aedes mosquitoes may acquire the virus when they feed on humans during this period.

Symptoms and Signs

After an incubation period of 3 to 15 days, fever, chills, headache, retro-orbital pain with eye movement, lumbar backache, and severe prostration begin abruptly. Extreme aching in the legs and joints occurs during the first hours, accounting for the traditional name of breakbone fever. The temperature rises rapidly to up to 40° C, with relative bradycardia. Bulbar and palpebral conjunctival injection and a transient flushing or pale pink macular rash (particularly of the face) may occur. Cervical, epitrochlear, and inguinal lymph nodes are often enlarged.

Fever and other symptoms persist 48 to 96 hours, followed by rapid defervescence with profuse sweating. Patients then feel well for about 24 hours, after which fever may occur again (saddleback pattern), typically with a lower peak temperature than the first. Simultaneously, a blanching maculopapular rash spreads from the trunk to the extremities and face.

Sore throat, gastrointestinal symptoms (eg, nausea, vomiting), and hemorrhagic symptoms can occur. Some patients develop dengue hemorrhagic fever. Neurologic symptoms are uncommon and can include encephalopathy and seizures; some patients develop Guillain-Barré syndrome.

Mild cases of dengue, usually lacking lymphadenopathy, remit in < 72 hours. In more severe disease, asthenia may last several weeks. Death is rare. Immunity to the infecting strain is long-lasting, whereas broader immunity to other strains lasts only 2 to 12 months.

More severe disease may result from antibody-dependent enhancement of infection, in which patients have a non-neutralizing antibody from a previous infection with one dengue serotype and then have another infection with a different dengue serotype.

Diagnosis

  • Acute and convalescent serologic testing

Dengue fever is suspected in patients who live in or have traveled to endemic areas if they develop sudden fever, severe retro-orbital headache, myalgias, and adenopathy, particularly with the characteristic rash or recurrent fever. Evaluation should rule out alternative diagnoses, especially malaria and leptospirosis.

Diagnostic studies include acute and convalescent serologic testing, antigen detection, and virus genome detection by polymerase chain reaction (PCR) of blood. Serologic testing involves hemagglutination inhibiting or complement fixation tests using paired sera, but cross-reactions with other flavivirus antibodies, especially to Zika virus, are possible. Plaque-reduction neutralization tests are more specific and are considered the gold standard for serologic diagnosis. Antigen detection is available in some parts of the world (not in the US), and PCR is usually done only in laboratories with special expertise.

Although rarely done and difficult, cultures can be done using inoculated Toxorhynchites mosquitoes or specialized cell lines in specialized laboratories.

Complete blood count may show leukopenia by the 2nd day of fever; by the 4th or 5th day, the white blood cell count may be 2000 to 4000/mcL with only 20 to 40% granulocytes. Urinalysis may show moderate albuminuria and a few casts. Thrombocytopenia may also be present.

Treatment

  • Supportive care

Treatment of dengue is symptomatic. Acetaminophen can be used, but NSAIDs (nonsteroidal anti-inflammatory drugs), including aspirin, should be avoided because bleeding is a risk. Aspirin increases the risk of Reye syndrome in children and should be avoided for that reason.

Prevention

People in endemic areas should try to prevent mosquito bites. To prevent further transmission by mosquitoes, patients with dengue should be kept under mosquito netting until the 2nd bout of fever has resolved.

Several tetravalent vaccine candidates are being evaluated. One tetravalent vaccine, Dengvaxia®, was licensed in Mexico in December 2015 and subsequently in the Philippines and a number of other countries for use in people aged 9 to 45 years living in endemic areas (which in the US includes the territories of American Samoa, Guam, Puerto Rico, and the US Virgin Islands). The vaccine decreases the risk of hospitalization and severe disease in seropositive recipients. However, vaccinating children who have never had dengue appears to result in risk of more severe disease if the children become infected with dengue later; this effect led Philippine health authorities to halt dengue vaccination in that country. The World Health Organization (1) and the US Food and Drug Administration recommend doing pre-vaccination screening for serologic evidence of previous dengue infection and vaccinating only seropositive patients. Three doses are given at 6-month intervals.

Prevention reference

Key Points

  • The dengue virus is transmitted by the bite of Aedes mosquitoes.

  • Dengue fever typically causes sudden fever, severe retro-orbital headache, myalgias, adenopathy, a characteristic rash, and extreme aching in the legs and joints during the first hours.

  • Dengue fever can cause a potentially fatal hemorrhagic fever with a bleeding tendency and shock (dengue hemorrhagic fever and dengue shock syndrome).

  • Suspect dengue fever if patients who live in or have traveled to endemic areas if they have typical symptoms; diagnose using serologic tests, antigen tests, or PCR of blood.

Dengue Hemorrhagic Fever

(Philippine, Thai, or Southeast Asian Hemorrhagic Fever; Dengue Shock Syndrome)

Dengue hemorrhagic fever with dengue shock syndrome is a variant presentation that occurs primarily in children < 10 years living in areas where dengue is endemic. Dengue hemorrhagic fever frequently requires prior infection with the dengue virus.

Dengue hemorrhagic fever is an immunopathologic disease; dengue virus–antibody immune complexes trigger release of vasoactive mediators by macrophages. The mediators increase vascular permeability, causing vascular leakage, hemorrhagic manifestations, hemoconcentration, and serous effusions, which lead to circulatory collapse (ie, dengue shock syndrome).

Symptoms and Signs

Dengue hemorrhagic fever often begins with abrupt fever and headache and is initially indistinguishable from classic dengue. Warning signs that predict possible progression to severe dengue include

  • Severe abdominal pain and tenderness

  • Persistent vomiting

  • Hematemesis

  • Epistaxis or bleeding from the gums

  • Black, tarry stools (melena)

  • Edema

  • Lethargy, confusion, or restlessness

  • Hepatomegaly, pleural effusion, or ascites

  • Marked change in temperature (from fever to hypothermia)

Shock and increasing illness may develop rapidly 2 to 6 days after onset.

Bleeding tendencies manifest as follows:

  • Usually as purpura, petechiae, or ecchymoses at injection sites

  • Sometimes as hematemesis, melena, or epistaxis

  • Occasionally as subarachnoid hemorrhage

Bronchopneumonia with or without bilateral pleural effusions is common. Myocarditis can occur.

Mortality is usually < 1% in experienced centers but otherwise can range to up 30%.

Diagnosis

  • Clinical and laboratory criteria

Dengue hemorrhagic fever is suspected in children with World Health Organization–defined clinical criteria for the diagnosis:

  • Sudden fever that stays high for 2 to 7 days

  • Hemorrhagic manifestations

  • Hepatomegaly

Hemorrhagic manifestations include at least a positive tourniquet test and petechiae, purpura, ecchymoses, bleeding gums, hematemesis, or melena. The tourniquet test is done by inflating a blood pressure cuff to midway between the systolic and diastolic blood pressure for 15 minutes. The number of petechiae that form within a 2.5-cm diameter circle are counted; > 20 petechiae suggests capillary fragility.

Complete blood count, coagulation tests, urinalysis, liver tests, and dengue serologic tests should be done. Coagulation abnormalities include

  • Thrombocytopenia (≤ 100,000 platelets/mcL)

  • A prolonged prothrombin time (PT)

  • Prolonged activated partial thromboplastin time (PTT)

  • Decreased fibrinogen

  • Increased amount of fibrin split products

There may be hypoproteinemia, mild proteinuria, and increases in aspartate aminotransferase (AST) levels. Complement fixation antibody titers against flaviviruses are usually high (demonstration of a 4-fold or greater change in reciprocal IgG or IgM antibody titers to ≥ 1 dengue virus antigens in paired serum samples).

Patients with World Health Organization-defined clinical criteria plus thrombocytopenia ( 100,000/mcL) or hemoconcentration (Hct increased by 20%) are presumed to have the disease (see the Centers for Disease Control and Prevention's Dengue Virus: Clinical Guidance).

Treatment

  • Supportive care

Patients with dengue hemorrhagic fever require intensive treatment to maintain euvolemia. Both hypovolemia (which can cause shock) and overhydration (which can cause acute respiratory distress syndrome) should be avoided. Urine output and the degree of hemoconcentration can be used to monitor intravascular volume.

No antivirals have been shown to improve outcome.

Key Points

  • Dengue hemorrhagic fever occurs primarily in children < 10 years living in areas where dengue is endemic and requires prior infection with the dengue virus.

  • Dengue hemorrhagic fever may initially resemble classic dengue fever, but certain findings (eg, severe abdominal pain and tenderness, persistent vomiting, hematemesis, epistaxis, melena) indicate possible progression to severe dengue.

  • Diagnose based on specific clinical and laboratory criteria.

  • Maintaining euvolemia is crucial.

More Information

Drugs Mentioned In This Article

Drug Name Select Trade
TYLENOL
No US brand name
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