Dengue

Introduction

Infectious agent

Dengue, an acute febrile illness, is caused by infection with any of 4 related single-stranded RNA viruses of the genus Flavivirus, dengue virus 1, 2, 3, or 4 (DENV1–4). Infection with any of the 4 DENV confers long-term immunity to that virus but only short-lived protection against the other 3 dengue viruses. Severe dengue can be caused by any of the 4 DENV. The risk for severe dengue is greater during a second DENV infection, but severe dengue also can occur during the first or any subsequent infection.

Transmission

Almost all DENV transmission occurs through the bite of infected Aedes species mosquitoes, primarily Aedes aegypti and Aedes albopictus. Because of the approximate 7-day viremia in humans, blood-borne transmission is possible through exposure to infected blood, organs, or other tissues (e.g., bone marrow). Transmission through needlestick injury and mucocutaneous exposure in hospital and research settings has been reported. In addition, perinatal DENV transmission occurs when the mother is infected near the time of birth; infection occurs via microtransfusions as the placenta detaches or through mucosal contact with maternal blood during birth. No cases of congenital transmission have been documented, but it has been suggested. DENV has been detected in breast milk and transmission through this route could be possible; however, suspending breastfeeding among mothers with dengue is not recommended. DENV also has been detected in vaginal secretions and semen; sexual transmission has been reported but is considered rare.

Epidemiology

Dengue is endemic throughout the tropics and subtropics and occurs in >100 countries and destinations worldwide, including Puerto Rico, the U.S. Virgin Islands, and U.S.-affiliated Pacific Islands. The incidence of dengue among travelers to the tropics has increased in recent years, and dengue burden continues to grow in Sub-Saharan Africa, Latin America, and Asia, with estimates of 390 million DENV infections and 96 million symptomatic cases per year.

During 2010–2021, a total 7,528 travel-related dengue cases were reported in the United States; a total of 3,135 patients required hospitalization, and 19 died. The most frequently reported regions of travel among U.S. cases were the Caribbean, Central America, and Asia. Travel-associated dengue case numbers also increased during 2019, and 2022–2024, with >1,400 cases reported each year, compared to a previous peak of 919 cases in 2016.

Sporadic outbreaks with limited local transmission have occurred in Florida, Hawaii, and Texas. In addition, new areas have documented locally acquired dengue cases, including Arizona in 2022 and California in 2023. Although the geographic distribution of dengue is similar to that of malaria, dengue is more of a risk in urban and residential areas than malaria.

Clinical presentation

An estimated 40%–80% of DENV infections are asymptomatic. Symptomatic dengue most commonly presents as a mild to moderate, nonspecific, acute febrile illness; ≤5% of all people experiencing symptoms from dengue develop severe, life-threatening disease. Early clinical findings are nonspecific and require a high index of suspicion. Recognizing early signs of shock and promptly initiating intensive supportive therapy can reduce risk for death among patients with severe dengue by ≥20-fold. See Figure 4.4.1 for the current World Health Organization clinical classification criteria of dengue: dengue without warning signs, dengue with warning signs, and severe dengue. Patients with dengue with warning signs or severe dengue require strict observation and inpatient management.

Figure 4.4.1

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A diagram related to dengue fever, differentiating between cases with, without warning signs, and severe dengue. It lists symptoms and criteria for severe dengue, such as abdominal pain, persistent vomiting, severe bleeding, and organ involvement. The diagram emphasizes the importance of recognizing warning signs in individuals living in or traveling to endemic areas. Additionally, it outlines methods for laboratory confirmation of dengue fever through molecular techniques or seroconversion testing. Tags associated with the image include text, screenshot, font, and design.

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Phases of symptomatic dengue

Symptomatic dengue begins abruptly after an incubation period of 5–7 days (range 3–10 days) and has a 3-phase clinical course: febrile, critical, and convalescent.

Febrile phase

Fever typically lasts 2–7 days and can be biphasic. Other signs and symptoms include severe headache; retro-orbital pain; bone, joint, or muscle pain; macular or maculopapular rash; and minor hemorrhagic manifestations, including ecchymosis, epistaxis, bleeding gums, hematuria, petechiae, purpura, or a positive tourniquet test result. Some patients have an injected oropharynx or facial erythema in the first 24–48 hours after onset. Warning signs of progression to severe dengue usually occur in the late febrile phase around the time of defervescence (i.e., temperature 38°C [<100.4°F]), but they can present during the febrile or critical phase and should be evaluated in all patients with dengue during any medical encounter. Warning signs include severe abdominal pain, persistent vomiting, extravascular fluid accumulation, mucosal bleeding, progressive increase in hematocrit (hemoconcentration), postural hypotension, lethargy or restlessness, and liver enlargement.

Critical phase

The critical phase of dengue begins at defervescence and typically lasts 24–48 hours. Most patients improve clinically during this phase, but those with plasma leakage from increased vascular permeability may progress to severe dengue. Severe dengue manifestations are most frequently seen during the critical phase. Patients with substantial plasma leakage can develop ascites or pleural effusions, hemoconcentration, and hypoproteinemia. Physiologic compensatory mechanisms narrow the pulse pressure as diastolic blood pressure increases, initially maintaining adequate circulation; patients might appear well despite early signs of shock.

Once hypotension develops, however, systolic blood pressure rapidly declines, and irreversible shock and death can ensue despite resuscitation efforts. Particularly in cases of prolonged shock, patients can develop severe hemorrhagic manifestations, including hematemesis, melena, or menorrhagia. Uncommon manifestations during this phase include encephalitis, hepatitis, myocarditis, or pancreatitis. Laboratory findings commonly include leukopenia, lymphopenia, thrombocytopenia, elevated aspartate aminotransferase and alanine aminotransferase, hyponatremia, and a normal erythrocyte sedimentation rate (Figure 4.4.2).

Figure 4.4.2

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SOURCE:

Paz-Bailey, G., Adams, L. E., Deen, J., Anderson, K. B., & Katzelnick, L. C. (2024). Dengue. The Lancet, 403(10427), 17–23.

This diagram shows clinical and laboratory findings by day of illness in dengue patients, with day of illness 1 through 10 on the x-axis (febrile phase 0-7 days, critical phase (1-2 days) risk of shock and hemorrhage, recovery phase). The fever and laboratory findings (top section of the table) has flow lines for temperature (dark blue line), WBC (yellow line), hematocrit (red line), and platelets (light blue line)). The virus and antibody response levels (bottom section of the table) has flow lines for NS1 (yellow line), Viral RNA (red line), IgM (light blue line), IgG primary (dark blue line), IgG secondary (dark blue dotted line).

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Notes

Abbreviations: NS1, nonstructural protein 1; WBC, white blood cells; IgM, immunoglobulin M; IgG, immunoglobulin G.

DENV RNA and NS1 are detectable during the first week of illness. DENV IgM is detectable starting approximately 4 days after illness onset. Although most cases only have detectable DENV IgM for 14–20 days after illness onset, in some cases IgM might be detectable for up to 90 days. Routine testing of DENV IgG with a single sample is not useful in identifying patients with dengue.

Convalescent/recovery phase

As plasma leakage subsides, patients enter the convalescent phase and well-being improves; extravasated intravenous fluids and abdominal and pleural effusions are reabsorbed, hemo­dynamic status stabilizes (although bradycardia could manifest), and diuresis ensues. The patient's hematocrit stabilizes (or falls because of the dilutional effect of the reabsorbed fluid), and the white cell count usually starts to rise, after which the platelet count recovers. A confluent rash with spared areas of normal skin, called "islands of white in a sea of red" rash, can appear during this phase and might desquamate and be extremely pruritic.

During the clinical evaluation of patients with dengue, both the dengue clinical classification (presence of warning signs or severe dengue) and the phase of disease (febrile, critical, or convalescent) should be assessed because they are both used to guide patient monitoring and management decisions.

Dengue in pregnancy

Data are limited on health outcomes of dengue in pregnancy and effects of maternal infection on the developing fetus. DENV infection has been associated with a higher risk for abortion if infection occurs during the first trimester, as well as a higher risk for low-weight and preterm birth.

Vertical transmission should be considered for mothers who are symptomatic late in pregnancy or at delivery. Signs and symptoms in perinatally infected neonates typically present during the first week of life and include fever, thrombocytopenia, ascites or pleural effusions, hemorrhagic manifestations, or hypotension. Placental transfer of maternal IgG against DENV from a previous maternal infection might increase risk for severe dengue among infants infected at 6–12 months of age when the protective effect of antibodies wanes.

Diagnosis

Dengue is a nationally notifiable disease in the United States; report all suspected cases to the state or local health department. Consider dengue in the differential diagnosis of patients who develop onset of symptoms ≤14 days after returning from an endemic area.

Diagnosis of DENV infection during the acute phase can be achieved using whole blood, plasma, or serum. Dengue testing is ideally performed during the first 7 days of illness, when the sensitivity of nucleic acid amplification tests (e.g., RT-PCR) and antigen tests (DENV non-structural protein 1; NS1) is high. However, samples collected after day 7 can also be tested using these methods because positive results can be obtained for some patients for an additional 7 days. The detection of IgM antibodies from day 4 to approximately 12 weeks after symptom onset through serologic testing can also be used to diagnose dengue (Figure 4.4.2).

Presence of virus by RT-PCR or DENV NS1 antigen in a single diagnostic specimen is considered laboratory confirmation of dengue in patients with a compatible clinical and travel history. IgM in a single serum sample suggests a probable recent DENV infection. If a patient's travel history includes locations where other potentially cross-reactive flaviviruses circulate, perform both molecular and serologic diagnostic testing to detect DENV and other flaviviruses.

ELISA IgG in a single serum sample is not useful for routine diagnostic testing because IgG remains detectable for life after infection. In addition, people infected with or vaccinated against other flaviviruses (e.g., Japanese encephalitis virus, yellow fever virus) might produce cross-reactive flavivirus antibodies, yielding false-positive serologic dengue diagnostic test results. Rapid tests can be an important tool for the early diagnosis of dengue; immunochromatographic tests that combine IgM and NS1 detection have the best performance. Rapid tests for dengue are not widely available in the United States.

Molecular and serologic DENV diagnostic testing are available from several commercial reference diagnostic laboratories, state public health laboratories, and CDC's Dengue Branch. Healthcare professionals can obtain consultation on dengue diagnostic testing from CDC at 787-706-2399 or by emailing [email protected].

Treatment

No specific antiviral agents exist for dengue. Depending on the clinical manifestations, patients might need only ambulatory care or might require hospitalization (see CDC dengue case management recommendations and clinical care of dengue). Pregnant women with dengue should always be hospitalized.

Advise ambulatory patients to stay well hydrated and to avoid medications with anticoagulant properties, including aspirin (acetylsalicylic acid), aspirin-containing drugs, and other nonsteroidal anti-inflammatory drugs (e.g., ibuprofen). To control fever, advise patients to use acetaminophen and tepid sponge baths. Caution febrile patients to avoid mosquito bites to reduce risk for further community transmission by using insect repellents approved by the U.S. Environmental Protection Agency (EPA).

Patients who develop severe dengue require hospitalization and close observation; monitoring in an intensive care unit might be required. Intravenous fluid therapy is the mainstay of treatment when plasma leakage is recognized (Box 4.4.1). Prophylactic platelet transfusions in patients with dengue are not beneficial and can contribute to fluid overload. Packed red blood cells or whole blood are the recommended products for transfusion in patients with dengue experiencing active bleeding. Similarly, administration of corticosteroids has no demonstrated benefit and is potentially harmful. Avoid use of corticosteroids except in cases of autoimmune-related complications.

Box 4.4.1

Prevention

Dengue vaccines

There are currently no dengue vaccines recommended for travelers in the United States.

Dengvaxia

Dengvaxia is recommended for children aged 9–16 years with laboratory-confirmed previous DENV infection who are living in areas of the United States where dengue is endemic. These areas include the U.S. territories of American Samoa, Puerto Rico, and the U.S. Virgin Islands, as well as freely associated states, including the Federated States of Micronesia, the Republic of Marshall Islands, and the Republic of Palau.

In people who have not already been infected with DENV, Dengvaxia can increase the risk for severe illness and hospitalization if the person gets dengue after vaccination. Serologic diagnostic tests with acceptable performance (≥75% sensitivity and ≥98% specificity) are recommended by CDC to test people for evidence of previous DENV infection for vaccine eligibility purposes. Only people who have laboratory-confirmed evidence of a previous DENV infection and live in endemic areas are eligible for vaccination with Dengvaxia. While the vaccine is highly effective, there is a low risk that some vaccinated people can still get infected with dengue. In 2024, the manufacturer announced that Dengvaxia will be discontinued due to a lack of demand in the global market.

Qdenga

In 2023, the WHO Strategic Advisory Group of Experts on Immunization recommended Qdenga for children aged 6–16 years in settings with high dengue disease burden (i.e., dengue seroprevalence >60% by age 9 or peak in dengue hospitalizations among people <16 years). Qdenga has been authorized by the European Medicine Agency, and has been approved in several countries, including Argentina, Brazil, Indonesia, and Thailand. Since 2023, it has been administered as part of immunization programs in several countries, including Argentina and Brazil. As of 2023, the manufacturer voluntarily withdrew Qdenga's vaccine application for approval to the U.S. Food and Drug Administration, and Qdenga is not available or recommended for use in the United States.

TV003

TV003 is a single-dose dengue vaccine developed by the National Institutes of Health. It has been licensed to several manufacturers globally, including Merck & Co in the United States and the Instituto Butantan in Brazil. In 2024, preliminary results from the phase 3 trial showed that the overall efficacy against virologically confirmed dengue after 3.7 years was 77% among seropositive people and 60% among seronegative people. Additional results of phase 3 trials are pending.

Non-vaccine preventions

No specific medication is available to prevent dengue. Risk increases with duration of travel and disease incidence in the travel destination (e.g., during local epidemics or the rainy season). Travelers going to the tropics for any length of time should take steps to prevent mosquito bites by using the preventive measures listed below (see also Mosquitoes, Ticks, and Other Arthropods chapter).

• Select accommodations with well-screened windows and doors or air conditioning, when possible. While Aedes albopictus mosquitoes live mainly outdoors, Aedes aegypti mosquitoes live indoors and outdoors. Aedes aegypti mosquitoes often are found in dark, cool places (e.g., in closets, under beds, behind curtains, in bathrooms, on porches).
• Wear long-sleeved clothing that covers the arms and legs, especially during the early morning and late afternoon, when risk of being bitten by Aedes species mosquitoes is greatest.
• Use EPA-approved insect repellent.
• For longer-term travelers, empty and clean or cover any standing water that can be a mosquito-breeding site in the local residence (e.g., water storage tanks, flowerpots).

CDC does not recommend that travelers with a history of previous DENV infection avoid travel to dengue endemic areas but instead recommends that they use mosquito bite prevention measures for the duration of travel.