Discussion
Dengue virus is a single-stranded, nonsegmented RNA virus in the Flaviviridae family. Four major subtypes exist: DEN-1, DEN-2, DEN-3, and DEN-4. Lifelong serotype-specific immunity is conferred following infection. The virus is transmitted by the female Aedes aegypti mosquito, which is found worldwide but has a predilection for tropical and subtropical regions. The Aedes aegypti mosquito remains an effective vector secondary to its diurnal feeding habit and nearly imperceptible bite.1,3
The viral incubation period for dengue is typically 3 to 7 days4; therefore, dengue is highly unlikely in patients whose symptoms begin more than 2 weeks after departure from an endemic area. Replication primarily occurs in the regional lymph nodes and disseminates through the lymphatic system and bloodstream.1
The 1997 WHO guidelines previously classified dengue into three categories: undifferentiated fever, dengue fever, and dengue hemorrhagic fever (which was further classified by four severity grades, with grades III and IV defined as dengue shock syndrome). However, changes in epidemiology of the disease and reports of difficulty applying the criteria in the clinical setting led to reclassification of dengue on a continuum from dengue to severe dengue in the WHO’s updated 2009 guidelines.4
Signs and Symptoms
The ramifications of dengue infection can range from asymptomatic (typically in young, immunocompetent patients) to lethal. Key symptoms of dengue fever include nausea, vomiting, fever, respiratory symptoms, morbilliform or maculopapular rash, and headache or retro-orbital pain. In addition, arthralgia (hence the colloquial name for dengue of “breakbone fever”), myalgia, and conjunctivitis may exist.3,4 Fever usually lasts 5 to 7 days and can be biphasic, with a return of symptoms after the initial resolution as seen in case report 1.4 Severe dengue is characterized by capillary leakage, hemorrhage, or end-organ damage.3-5 The most common bleeding sites are the skin, nose, and gums.
Diagnosis
Bedside evaluation for dengue can be performed with the TT—one of the WHO’s case definitions for dengue.6 This is accomplished by placing a manual blood pressure (BP) cuff on the arm and inflating it to halfway between systolic and diastolic BP for 5 minutes. The test is positive for dengue if more than 10 petechiae appear per 1-inch (2.5-cm) square below the antecubital fossa.7 Of note, the test has poor sensitivity (51.6%, 95% confidence interval [CI], 33-69), but good specificity (82.4%, 95% CI, 76-87).7,8 A positive TT combined with leukopenia increases the sensitivity to 93.9%, [95% CI, 89-96].7 While not specific to dengue infection, in the right clinical scenario, the TT is a simple bedside test to help confirm the diagnosis and is extremely useful in resource-limited settings.
During the initial days of illness, the virus may be detected by PCR, as viremia and fever usually correlate. Once defervescence occurs, IgM and then IgG antibodies become detectable. When using these antibody tests to evaluate for dengue, clinicians should be aware of cross-reactivity with other flavivirus infections, such as yellow fever or Japanese encephalitis (including immunological cross-reactivity).1 New diagnostic modalities include enzyme immunoassays that can detect dengue viral RNA within 24 to 48 hours, and viral antigen-detection kits, which can yield results in less than 1 hour.4
Aside from advanced laboratory testing, worsening thrombocytopenia in light of a rising hematocrit can be highly suggestive of dengue. Leukopenia with lymphopenia and mild elevation of hepatic enzymes (typically 2 to 5 times the upper limits of the normal reference range) are also often seen in active infections.1 The occurrence of these signs in conjunction with a rapid reduction in the platelets often signals transition to the critical phase of plasma leakage.1,4
Treatment
Treatment of dengue consists of supportive care and transfusion when necessary. The WHO recommends strict observation of patients with suspected dengue who have warning signs of severe disease (eg, abdominal pain, persistent vomiting, mucosal bleeding, lethargy, hepatomegaly, rapid increase in hematocrit with concomitant drop in platelet count). Inpatient treatment centers on judicious fluid management, trending blood count parameters, and monitoring for signs of plasma leakage and hemorrhage. Fluid resuscitation is titrated to optimize central and peripheral circulation and end-organ perfusion. Blood-product administration should be reserved for suspected or severe bleeding.4
While dengue fever was the final diagnosis in both of our case presentations, these cases also highlight key diagnostic and treatment dilemmas associated with dengue. The patient in the first case report demonstrated the characteristic biphasic fever seen with dengue—resolution of symptoms on day 3, but then return of fever and symptoms on day 4. Often the dengue-specific antibodies are not formed until after the resolution of fever. This patient represents a classic example of dengue as the serologic studies sent on day 4 of the patient’s illness were negative but then turned positive on day 7, illustrating the need for high clinical suspicion and underscoring the importance of initiating treatment despite laboratory confirmation.