Chapter 3Infectious Diseases Related To Travel
Kay M. Tomashek, Harold S. Margolis
Dengue is caused by infection with any 1 of 4 related positive-strand RNA viruses of the genus Flavivirus, dengue viruses (DENV) 1, 2, 3, or 4.
Transmission occurs through the bite of an infected Aedes mosquito, primarily Aedes aegypti and Ae. albopictus. Humans are the main host and the primary source of virus for female mosquitoes, which become infective after an extrinsic incubation period of 8–12 days and can then transmit DENV for the rest of their approximately 1-month lifespan.
Because of the approximately 7-day viremia in humans, bloodborne transmission is possible through exposure to infected blood, organs, or other tissues (such as bone marrow). In addition, perinatal DENV transmission occurs, and the highest risk appears to be among infants whose mothers are acutely ill around the time of delivery. It is not known if DENV is transmitted through breast milk.
Dengue is endemic throughout the tropics and subtropics and is a leading cause of febrile illness among travelers returning from the Caribbean, South America, and South and Southeast Asia, according to an analysis of data collected by the GeoSentinel Surveillance Network. Dengue occurs in >100 countries worldwide (Maps 3-01, 3-02, and 3-03), including Puerto Rico, the US Virgin Islands, and US-affiliated Pacific Islands. Sporadic outbreaks with local transmission have occurred in Florida, Hawaii, and along the Texas-Mexico border. Although the geographic distribution of dengue is similar to that of malaria, dengue is more of a risk in urban and residential areas than is malaria. The DengueMap (www.healthmap.org/dengue/index.php) shows areas of ongoing transmission.
About 75% of all DENV infections are asymptomatic. Symptomatic infection (dengue) most commonly presents as a mild to moderate, nonspecific, acute, febrile illness. However, as many as 5% of all dengue patients develop severe, life-threatening disease. Early clinical findings are nonspecific but require a high index of suspicion, because recognizing early signs of shock and promptly initiating intensive supportive therapy can reduce risk of death among patients with severe dengue from 10% to <1%. See Box 3-01 for information regarding the new World Health Organization (WHO) guidelines for classifying dengue.
Dengue begins abruptly after an incubation period of 4–7 days (range, 3–14 days), and the course follows 3 phases: febrile, critical, and convalescent. Fever typically lasts 2–7 days and can be biphasic. Other signs and symptoms may include severe headache; retroorbital pain; muscle, joint and bone pain; macular or maculopapular rash; and minor hemorrhagic manifestations, including petechiae, ecchymosis, purpura, epistaxis, bleeding gums, hematuria, or a positive tourniquet test result. Some patients have injected oropharynx and facial erythema in the first 24–48 hours after onset. Warning signs of progression to severe dengue occur in the late febrile phase around the time of defervescence and include persistent vomiting, severe abdominal pain, mucosal bleeding, difficulty breathing, signs of hypovolemic shock, and rapid decline in platelet count with an increase in hematocrit (hemoconcentration).
The critical phase of dengue begins at defervescence and typically lasts 24–48 hours. Most patients clinically improve during this phase, but those with substantial plasma leakage develop severe disease as a result of a marked increase in vascular permeability. Initially, physiologic compensatory mechanisms maintain adequate circulation, which narrows pulse pressure as diastolic blood pressure increases. Patients with severe plasma leakage have pleural effusions or ascites, hypoproteinemia, and hemoconcentration. Patients may appear to be well despite early signs of shock. However, once hypotension develops, systolic blood pressure rapidly declines, and irreversible shock and death may ensue despite resuscitation. Patients can also develop hemorrhagic manifestations, including hematemesis, bloody stool, melena, or menorrhagia, especially if they have prolonged shock. Dengue patients can have atypical manifestations, including hepatitis, myocarditis, pancreatitis, and encephalitis.
As the plasma leakage subsides, the patient enters the convalescent phase and begins to reabsorb extravasated intravenous fluids and pleural and abdominal effusions. As a patient’s well-being improves, hemodynamic status stabilizes (although he or she may manifest bradycardia), and diuresis ensues. The patient’s hematocrit stabilizes or may fall because of the dilutional effect of the reabsorbed fluid, and the white cell count usually starts to rise, followed by a slow recovery of platelet count. The convalescent-phase rash may desquamate and be pruritic.
Laboratory findings commonly include leucopenia, thrombocytopenia, hyponatremia, elevated aspartate aminotransferase and alanine aminotransferase, and a normal erythrocyte sedimentation rate.
Data are limited on health outcomes of dengue in pregnancy and effects of maternal DENV infection on the developing fetus. Perinatal DENV transmission can occur, and peripartum maternal infection may increase the likelihood of symptomatic disease in the newborn. Of the 34 perinatal transmission cases described in the literature, all developed thrombocytopenia and all but 1 had fever in the first 2 weeks after birth. Nearly 40% had a hemorrhagic manifestation, and one-fourth had hypotension. Transplacental transfer of maternal IgG anti-DENV (from a previous maternal infection) may increase risk for severe dengue among infants infected at 6–12 months of age.
Box 3-01. New guidelines for classifying dengue
In November 2009, World Health Organization (WHO) issued a new guideline that classifies symptomatic cases as dengue or severe dengue.
Dengue is defined by a combination of ≥2 clinical findings in a febrile person who traveled to or lives in a dengue-endemic area. Clinical findings include nausea, vomiting, rash, aches and pains, a positive tourniquet test, leukopenia, and the following warning signs: abdominal pain or tenderness, persistent vomiting, clinical fluid accumulation, mucosal bleeding, lethargy, restlessness, and liver enlargement. The presence of a warning sign may predict severe dengue in a patient.
Severe dengue is classified as dengue with any of the following: severe plasma leakage leading to shock or fluid accumulation with respiratory distress; severe bleeding; or severe organ impairment such as elevated transaminases ≥1,000 IU/L, impaired consciousness, or heart impairment.
From 1975 through 2009, symptomatic dengue virus infections were classified according to the WHO guidelines as dengue fever, dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS, the most severe form of DHF). The case definition was changed to the 2009 clinical classification after reports that the case definition of DHF was both too difficult to apply in resource-limited settings and too specific, as it failed to identify a substantial proportion of severe dengue cases, including cases of hepatic failure and encephalitis. Many dengue experts felt that the original case definitions, which were developed based on data from pediatric cases in Southeast Asia, were not applicable to other regions and populations. The 2009 clinical classification has been criticized because it is felt to be overly inclusive, as it allows several different ways to qualify for severe dengue, and nonspecific warning signs are used as diagnostic criteria for dengue. Last, the new guidelines have been criticized because they do not define the clinical criteria for establishing severe dengue (with the exception of providing laboratory cutoff values for transaminase levels), thereby leaving severity determination up to individual clinical judgment.
Clinicians should consider dengue in a patient who was in an endemic area within 2 weeks before symptom onset. All suspected cases should be reported to the local health department, because dengue is a nationally reportable disease. Laboratory confirmation can be made from a single acute-phase serum specimen obtained early (≤5 days after fever onset) in the illness by detecting DENV genomic sequences with RT-PCR or DENV nonstructural protein 1 (NS1) antigen by immunoassay. Later in the illness (≥4 days after fever onset), IgM anti-DENV can be detected with ELISA. For patients presenting during the first week after fever onset, diagnostic testing should include a test for DENV (PCR or NS1) and IgM anti-DENV. For patients presenting >1 week after fever onset, IgM anti-DENV is most useful, although NS1 has been reported positive up to 12 days after fever onset.
Presence of DENV by PCR or NS1 antigen in a single diagnostic specimen is considered laboratory confirmation in patients with a compatible clinical and travel history. IgM anti-DENV in a single serum sample suggests a probable, recent DENV infection. IgM anti-DENV seroconversion in acute- and convalescent-phase serum specimens is considered laboratory confirmation of dengue.
IgG anti-DENV by ELISA in a single serum sample is not useful for diagnostic testing, because it remains elevated for life after any DENV infection and can be falsely positive in people with antibodies to other flaviviruses (such as West Nile, yellow fever, Japanese encephalitis).
Dengue diagnostic testing (molecular and immunoassay) is available from several commercial reference diagnostic laboratories, state public health laboratories, and CDC (www.cdc.gov/Dengue/clinicalLab/index.html). Consultation on dengue diagnostic testing can be obtained from CDC at 787-706-2399.
No specific antiviral agents exist for dengue. Patients should be advised to stay well hydrated and to avoid aspirin (acetylsalicylic acid), aspirin-containing drugs, and other nonsteroidal anti-inflammatory drugs (such as ibuprofen) because of their anticoagulant properties. Fever should be controlled with acetaminophen and tepid sponge baths. Febrile patients should avoid mosquito bites to reduce risk of further transmission. For those who develop severe dengue, close observation and frequent monitoring in an intensive care unit setting may be required. Prophylactic platelet transfusions in dengue patients are not beneficial and may contribute to fluid overload.
No vaccine is available, although several are in clinical trials; no chemoprophylaxis is available to prevent dengue. Travelers to dengue-endemic areas are at risk of getting dengue; risk increases with longer duration of travel and disease incidence in the travel destination (such as during dengue season and during epidemics). Travelers should be advised to avoid mosquito bites by taking the following preventive measures:
- Select accommodations with well-screened windows and doors or air conditioning when possible. Aedes mosquitoes typically live indoors and are often found in dark, cool places, such as in closets, under beds, behind curtains, and in bathrooms. Travelers should be advised to use insecticides to get rid of mosquitoes in these areas.
- Wear clothing that adequately covers the arms and legs, especially during the early morning and late afternoon, when risk of being bitten is the highest.
- Use insect repellent (see Chapter 2, Protection against Mosquitoes, Ticks, & Other Insects & Arthropods).
- For long-term travelers, empty and clean or cover any standing water that can be mosquito-breeding sites in the local residence (such as water storage tanks or flowerpot trays).
CDC website: www.cdc.gov/dengue
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- Schwartz E, Weld LH, Wilder-Smith A, von Sonnenburg F, Keystone JS, Kain KC, et al. Seasonality, annual trends, and characteristics of dengue among ill returned travelers, 1997–2006. Emerg Infect Dis. 2008 Jul;14(7):1081–8.
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- World Health Organization. Dengue: guidelines for diagnosis, treatment, prevention and control. Geneva: World Health Organization; 2009.
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