Clinical & Laboratory Evaluation

In its mildest form, yellow fever is a self-limited infection characterized by sudden onset of fever and headache without other symptoms. Other patients experience an abrupt onset of a high fever (up to 104°F [40°C]), chills, severe headache, generalized myalgias, lumbosacral pain, anorexia, nausea, vomiting, and dizziness. The patient appears acutely ill, and examination might demonstrate bradycardia in relation to the elevated body temperature (Faget’s sign). The patient is usually viremic during this period, which lasts for approximately 3 days. Many patients have an uneventful recovery, but in approximately 15% of infected persons, the illness recurs in more severe form within 48 hours following the viremic period. Symptoms include fever, nausea, vomiting, epigastric pain, jaundice, renal insufficiency, and cardiovascular instability. Viremia generally is absent during this phase of symptom recrudescence. A bleeding diathesis can occur, with hematemesis, melena, metrorrhagia, hematuria, petechiae, ecchymoses, epistaxis, and oozing blood from the gingiva and needle-puncture sites. Physical findings include scleral and dermal icterus, hemorrhages (e.g., hematemesis, melena, petechiae, ecchymoses), and epigastric tenderness without hepatic enlargement.

Multiple laboratory abnormalities can be observed in patients with yellow fever; these can vary depending on the severity and stage of illness. In the first week of the illness, leukopenia might occur; however, leukocytosis also can occur during the second week of the disease. Bleeding dyscrasias also can occur, together with elevated prothrombin and partial thromboplastin times, decreased platelet count, and presence of fibrin-split products. Hyperbilirubinemia might be present as early as the third day but usually peaks toward the end of the first week of illness. Elevations of serum transaminase levels occur in severe hepatorenal disease and might remain elevated for up to 2 months after onset.

Preliminary diagnosis is based on the patient’s clinical features, vaccination status, and travel history, including destination, time of year, and activities. Laboratory diagnosis generally is accomplished by testing serum to detect virus-specific immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies by serologic assays. It is important to obtain a yellow fever vaccination history, as IgM antibodies to yellow fever vaccine virus can persist for several years following vaccination. Serologic cross-reactions occur with other flaviviruses (e.g., West Nile or dengue viruses), so positive results should be confirmed with a more specific test (e.g., plaque-reduction neutralization test). Early in the illness (during the first 3-4 days), yellow fever virus or yellow fever virus RNA often can be detected in the serum by virus isolation or nucleic acid amplification testing (e.g., reverse transcription-polymerase chain reaction [RT-PCR]). However, by the time overt symptoms are recognized, the virus or viral RNA usually is undetectable. Therefore, negative virus isolation and RT-PCR results cannot rule-out the diagnosis of yellow fever. Immunohistochemical staining of formalin-fixed material can detect yellow fever virus antigen in histopathologic specimens. Healthcare providers should contact their state or local health department and CDC (at telephone 1-970-221-6400) for assistance with diagnostic testing. Get more information on diagnostic testing from the yellow fever diagnostic testing page.