Key points
- Yellow fever is a mosquito-borne illness endemic to tropical and subtropical areas of Africa and South America.
- Yellow fever can be a mild febrile illness to severe, sometimes fatal disease, with hepatitis and hemorrhagic manifestations.
- Molecular and serologic testing for yellow fever can be performed at CDC.
- Contact your state or local health department to request testing if you have a patient with suspected yellow fever. Obtain a yellow fever vaccination history prior to testing.
Clinical considerations
Yellow fever virus is a mosquito-borne flavivirus endemic in tropical areas of Africa and South America. Although most infections are asymptomatic, clinical disease ranges from a mild febrile illness to severe disease with hepatitis and hemorrhagic manifestations. Preliminary diagnosis of yellow fever is based on the patient’s clinical features, vaccination status, and travel history, including destination, time of year, and activities.
Signs and symptoms
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 recover uneventfully, 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.
Diagnostic testing
Laboratory diagnosis of yellow fever generally is accomplished by testing serum to detect virus-specific immunoglobulin (Ig) M and neutralizing antibodies. 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 and available tests cannot differentiate antibodies raised against wild-type virus and vaccine. 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 viral 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 is not detectable. Viral RNA can be detected a little longer, typically in the first week after illness onset. Because of the transient viremia, negative virus isolation and RT-PCR results does not rule-out the diagnosis of yellow fever. Immunohistochemical staining of formalin-fixed material can detect yellow fever virus antigen in histopathologic specimens.
In fatal cases, nucleic acid amplification, histopathology with immunohistochemistry, and virus culture of biopsy or autopsy tissues can be positive. Only a few state laboratories or other specialized laboratories, including those at CDC, are capable of doing these specialized tests.
To submit specimens for testing, please contact your state or local health department. They can assist you with determining if samples should be sent to the CDC Arbovirus Diagnostic Laboratory for further testing. Specimens should be submitted to CDC through state health departments. All results will be sent from CDC to the appropriate state health department.
- Staples JE, Davis E, Monath TP, Barrett ADT. Yellow fever vaccines. In: Plotkin SA, Orenstein WA, Offit PA, Edwards KM, eds. Plotkin's Vaccines. 8th ed. Elsevier; Philadelphia, PA; 2023:1251–1321.