Approach Considerations
Dengue fever usually is a self-limited illness. There is no specific antiviral treatment available for dengue fever. The World Health Organization (WHO) has provided a number of free publications about dengue.
Supportive care with analgesics, fluid replacement, and bed rest usually is sufficient. Acetaminophen may be used to treat fever and relieve other symptoms. Aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), and corticosteroids should be avoided. Management of severe dengue requires careful attention to fluid management and proactive treatment of hemorrhage.
Single-dose methylprednisolone showed no mortality benefit in the treatment of dengue shock syndrome in a prospective, randomized, double-blind, placebo-controlled trial. [84] The Novartis Institute for Tropical Diseases (NITD) in Singapore is carrying out research to find inhibitors of dengue viral target proteins to reduce the viral load during active infection. [65]
Suspected Dengue
Oral rehydration therapy is recommended for patients with moderate dehydration caused by high fever and vomiting. Patients with known or suspected dengue fever should have their platelet count and hematocrit measured daily from the third day of illness until 1-2 days after defervescence. Patients with clinical signs of dehydration and patients with a rising hematocrit level or falling platelet count should have intravascular volume deficits replaced under close observation. Those who improve can continue to be monitored in an outpatient setting, and those who do not improve should be admitted to the hospital for continued hydration.
Patients who develop signs of dengue hemorrhagic fever warrant closer observation. Admission for intravenous fluid administration is indicated for patients who develop signs of dehydration, such as the following:
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Tachycardia
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Prolonged capillary refill time
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Cool or mottled skin
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Diminished pulse amplitude
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Altered mental status
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Decreased urine output
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Rising hematocrit
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Narrowed pulse pressure
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Hypotension
Severe Dengue
Successful management of severe dengue requires careful attention to fluid management and proactive treatment of hemorrhage. Admission to an intensive care unit is indicated for patients with dengue shock syndrome.
Patients may need a central intravenous line for volume replacement and an arterial line for accurate blood pressure monitoring and frequent blood tests. Exercise caution when placing intravascular catheters because of the increased bleeding complications of dengue hemorrhagic fever. Urethral catheterization may be useful to strictly monitor urine output.
Intravascular volume deficits should be corrected with isotonic fluids such as Ringer lactate solution. Boluses of 10-20 mL/kg should be given over 20 minutes and may be repeated. If this fails to correct the deficit, the hematocrit value should be determined. If it is rising, limited clinical information suggests that a plasma expander may be administered. Starch, dextran 40, or albumin 5% at a dose of 10-20 mL/kg may be used. One study has suggested that starch may be preferable because of hypersensitivity reactions to dextran. [85]
If the patient does not improve after infusion of a plasma expander, blood loss should be considered. Patients with internal or gastrointestinal bleeding may require transfusion, and patients with coagulopathy may require fresh frozen plasma.
After patients with dehydration are stabilized, they usually require intravenous fluids for no more than 24-48 hours. Intravenous fluids should be stopped when the hematocrit falls below 40% and adequate intravascular volume is present. At this time, patients reabsorb extravasated fluid and are at risk for volume overload if intravenous fluids are continued. Do not interpret a falling hematocrit value in a clinically improving patient as a sign of internal bleeding.
Platelet and fresh frozen plasma transfusions may be required to control severe bleeding. A case report demonstrated good improvement following intravenous anti-D globulin administration in 2 patients. The authors proposed that, as in immune thrombocytopenic purpura from disorders other than dengue, intravenous anti-D produces Fcγ receptor blockade to raise platelet counts. [86]
Patients who are resuscitated from shock rapidly recover. Patients with dengue hemorrhagic fever or dengue shock syndrome may be discharged from the hospital when they meet the following criteria:
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Afebrile for 24 hours without antipyretics
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Good appetite, clinically improved condition
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Adequate urine output
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Stable hematocrit level
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At least 48 hours since recovery from shock
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No respiratory distress
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Platelet count greater than 50,000 cells/μL
Pregnant patients
Dengue in pregnancy must be carefully differentiated from preeclampsia. An overlap of signs and symptoms, including thrombocytopenia, capillary leak, impaired liver function, ascites, and decreased urine output may make this clinically challenging. Pregnant women with dengue fever respond well to the usual therapy of fluids, rest, and antipyretics. However, 3 cases of maternal death due to dengue fever in the third trimester have been reported. An awareness of the clinical and laboratory manifestations of dengue in pregnancy should allow its early recognition and the institution of appropriate treatment. If the mother acquires infection in the peripartum period, newborns should be evaluated for dengue with serial platelet counts and serologic studies. [87, 88]
Diet and Activity
No specific diet is necessary for patients with dengue fever. Patients who are able to tolerate oral fluids should be encouraged to drink oral rehydration solution, fruit juice, or water to prevent dehydration from fever, lack of oral intake, or vomiting. Return of appetite after dengue hemorrhagic fever or dengue shock syndrome is a sign of recovery.
Bed rest is recommended for patients with symptomatic dengue fever, dengue hemorrhagic fever, or dengue shock syndrome. Permit the patient to gradually resume their previous activities, especially during the long period of convalescence.
Prevention
The only way to truly prevent dengue virus acquisition is to avoid being bitten by a vector mosquito. Although this can be accomplished by avoiding travel to areas where dengue is endemic, that is not an ideal strategy because it would require a person to avoid most tropical and subtropical regions of the world, many of which are popular travel and work destinations. Other measures are as follows:
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Wear N,N-diethyl-3-methylbenzamide (DEET)–containing mosquito repellant
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Wear protective clothing, preferably impregnated with permethrin insecticide
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Remain in well-screened or air-conditioned places
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The use of mosquito netting is of limited benefit, as Aedes are day-biting mosquitoes
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Eliminate the mosquito vector using indoor sprays
The most widely used mosquito-control technique, spraying cities to kill adult mosquitoes, is not effective. Efforts should target the larval phase with larvicides and cleaning up larvae habitats. Poor sanitation and poor refuse control provide excellent conditions for mosquito larvae to grow. Hurricanes and other natural disasters increase the habitat for mosquito growth in urban areas by increasing rubble and garbage, which act as water reservoirs.
Breeding of vector mosquitoes can be reduced by eliminating small accumulations of stagnant water around human habitats (eg, disposing of old tires, covering water receptacles, and changing water in birdbaths daily. Support community-based vector control programs (including source reduction) and the use of vectoricidal agents, including predatory copepods as biological control agents. [89, 90, 91, 92]
In 2011, an Australian research effort infected Aedes aegypti mosquitoes with the intracellular bacterium Wolbachia in the laboratory. Maternally inherited Wolbachia prevents dengue virus from replicating within mosquitos. They then released these mosquitos into the wild to mate with wild mosquitos and pass the Wolbachia along to their offspring. After releasing approximately 10 mosquitos/house/week for 10 weeks, they found that greater than 80% of collected wild mosquitos had Wolbachia infection. Infected mosquitos laid fewer eggs and exhibited shorter life spans. The research group plans further field trials in Vietnam, Indonesia, and Brazil. If successful, this would provide a practical biological approach to dengue suppression. [93]
Outbreaks of dengue increasingly will cross common borders of endemic and disease-free countries unless the following measures are undertaken:
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Increased health surveillance
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Prompt reporting of new cases
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Heightened professional awareness
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Public education
Vaccine Development
One vaccine is approved for the prevention of dengue infection. Sanofi Pasteur registered Dengvaxia (CYD-TDV), a live recombinant tetravalent vaccine, in several countries in late 2015-2016, with Mexico being the initial country to register the vaccine in December 2015. The vaccine is given in 3 doses at age 0, 6, and 12 months. It underwent testing in more than 30,000 volunteers and reduced the risk for severe illness and hospitalization by as much as 30% in individuals previously infected with 1 or more strains. The vaccine proved less effective in persons who were not previously exposed to dengue and in areas with a lower burden of disease. [94] Owing to concern that the vaccine may act like an initial dengue infection in this second group of individuals not previously infected with the virus, with additional exposure to a second serotype placing these individuals at increased risk for severe dengue, the WHO released a position paper in July 2016 stating that countries should consider introduction of vaccine as a part of an comprehensive dengue control strategy only where epidemiologic data indicate a high burden of disease. [95]
In April 2018, the WHO’s Strategic Advisory Group of Experts recommended that rapid diagnostic tests to establish serostatus be developed so that prevaccination screening might be used to assess serostatus before CYD-TDV vaccine is administered. [96] As of late 2018, the CYD-TDV vaccine had been approved for use and was being marketed in European endemic areas to persons aged 9-45 years with prior exposure to the disease. [97]
Dengue vaccine was approved in the United States by the FDA in 2019 for prevention of dengue disease caused by dengue virus serotypes 1, 2, 3, and 4 in individuals aged 9-16 years with laboratory-confirmed previous dengue infection who live in endemic areas. It is approved only in individuals previously infected by any dengue virus serotype or in whom this information is unknown. Persons not previously infected are at an increased risk for severe dengue disease when vaccinated and subsequently infected with dengue virus. The efficacy, limitations of giving the vaccine due to having to perform dengue serological testing beforehand, and the repeated doses (3 doses 6 months apart) in a population / setting with 50% seropositivity, are among the many considerations of the context for the appropriate use of the dengue vaccine. [98]
The approval was based on data from 2 placebo-controlled studies in patients (n > 35,000) living in dengue-endemic areas. Patients were randomized in a 2:1 ratio to receive either the vaccine or saline placebo and monitored for symptomatic virologically confirmed dengue (VCD) starting at Day 0. Vaccine efficacy was assessed beginning 28 days after the third vaccination for 12 months. The vaccine was approximately 76% effective in preventing symptomatic VCD disease among patients aged 9-16 years who were seropositive for dengue at baseline. [99]
Immunity to a single dengue strain is the major risk factor for severe dengue; as such, a vaccine must provide high levels of immunity to all 4 dengue strains to be clinically useful. [100] Seroconversion alone does not predict protection. [101]
TAK-003 made by Takeda is another candidate dengue vaccine being actively studied for use in dengue endemic countries as well as possibly for travellers to areas endemic with dengue. Takeda’s tetravalent dengue vaccine candidate (TAK-003) is based on a live-attenuated dengue serotype 2 virus, which provides the genetic “backbone” for all 4 vaccine viruses. Efficacy varied by serotype in the studies conducted thus far, and results demonstrated TAK-003 generally was well tolerated, and there have been no important safety risks observed to date. More information should be forthcoming about this candidate dengue vaccine.
Consultations
Consultation with an infectious diseases specialist may be helpful in guiding decisions regarding diagnosis and treatment. Consultation with a critical care medicine specialist may be helpful when treating patients with dengue hemorrhagic fever or dengue shock syndrome and severe hemorrhagic manifestations or shock.
Telephone consultation may be obtained from the Centers for Disease Control and Surveillance (800-232-4636, 8am-8pm ET/Monday-Friday).
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Drawing of Aedes aegypti mosquito. Courtesy of the Centers for Disease Control and Prevention (CDC).
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Aedes albopictus. Courtesy of the Centers for Disease Control and Prevention (CDC).
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Worldwide distribution of dengue in 2000. Courtesy of the Centers for Disease Control and Prevention (CDC).
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Worldwide distribution of dengue in 2003. Courtesy of the Centers for Disease Control and Prevention (CDC).
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Worldwide distribution of dengue in 2005. Courtesy of the Centers for Disease Control and Prevention (CDC).
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Increasing rates of dengue infection by regions of the world. Courtesy of the World Health Organization (WHO).
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Dengue transmission cycle. Courtesy of the Centers for Disease Control and Prevention (CDC).
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Reinfestation by Aedes aegypti in the Americas after the 1970 (left) mosquito eradication program and most recent distribution as of 2002 (right). Courtesy of the Centers for Disease Control and Prevention (CDC).
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A child with dengue hemorrhagic fever or dengue shock syndrome may present severely hypotensive with disseminated intravascular coagulation (DIC), as this severely ill pediatric ICU patient did. Crystalloid fluid resuscitation and standard DIC treatment are critical to the child's survival.
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Delayed capillary refill may be the first sign of intravascular volume depletion. Hypotension usually is a late sign in children. This child's capillary refill at 6 seconds was delayed well beyond a normal duration of 2 seconds.
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Signs of early coagulopathy may be as subtle as a guaiac test that is positive for occult blood in the stool. This test should be performed on all patients in whom dengue virus infection is suspected.
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Aedes aegypti mosquito. Courtesy of Wikimedia Commons (https://commons.wikimedia.org/wiki/File:Aedes_aegypti.jpg; author Muhammad Mahdi Karim).
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Global map of dengue risk. Frequent or continuous risk = frequent outbreaks or ongoing transmission. Sporadic or uncertain risk = variable and unpredictable risk, country-level data are unavailable. Courtesy of the Centers for Disease Control and Prevention (CDC) (https://www.cdc.gov/dengue/areaswithrisk/around-the-world.html).
