Investigations
1st investigations to order
FBC
Test
Leukopenia with predominant neutropenia is common, but not specific for yellow fever.
Result
leukopenia (WBC count <2500/microlitre), neutropenia
liver function tests
coagulation screen
Test
Coagulation abnormalities with elevated PT, thrombocytopenia, and fibrinogen split products define disseminated intravascular coagulation (DIC).
Result
elevated PT, reduced platelets, fibrinogen split products in DIC
reverse transcription polymerase chain reaction (RT-PCR)
Test
Preferred test for diagnosis of patients with suspected yellow fever infection. Viral RNA can be detected within 10 days of symptom onset. Occasionally, it can be detected for longer than 10 days (detection up to 14 days has been reported), particularly in severe cases.[34]
A positive result confirms the diagnosis and no further testing is required. If the result is negative, subsequent serological testing is recommended.[34]
The Centers for Disease Control and Prevention recommends RT-PCR should not be used to rule out a diagnosis of yellow fever as viral RNA may be undetectable by the time symptoms are recognised.[10]
Result
positive for yellow fever virus RNA
serology
Test
IgM ELISA (or any other immunoassay such as indirect immunofluorescence) is recommended from day 6 onwards in patients with a negative RT-PCR result. Laboratory confirmation requires seroconversion in paired acute and convalescent samples (collected at least one week apart) with a more than 4-fold increase in antibody titres between samples.[34]
A positive IgM result should be followed by differential IgM testing appropriate for the area (including dengue and Zika). A positive differential test result indicates recent flavivirus infection, but does not rule out yellow fever. A negative differential test result indicates a probable yellow fever case; however, a positive IgM test in a single sample is not confirmatory.[34]
A negative IgM result on a sample collected ≥8 days from symptom onset excludes a diagnosis of yellow fever. A negative IgM result on a sample collected <8 days from symptom onset is considered inconclusive and a second sample should be tested.[34]
Significant cross-reactivity of yellow fever IgM assays with other flaviviruses can occur, especially in secondary flavivirus infections.
Results should be interpreted carefully in areas where active vaccination campaigns are ongoing, as detection of vaccine-induced antibodies can occur.
IgG ELISA and plaque reduction neutralisation test (PRNT) may also be used. PRNT offers greater specificity compared with IgM and IgG detection, but requires a specialised laboratory and cross-reactivity with other flaviviruses is still an issue.
There are currently no commercial IgM ELISA kits available; however, a new trial version of an ELISA kit (ELISA YF MAC HD) has been launched.[38]
Result
positive for yellow fever virus antibodies
Investigations to consider
ECG
Test
While neither specific nor sensitive, yellow fever is more likely to be associated with myocardial involvement than some of the other diseases in the differential.
Result
ST-T changes indicate myocardial damage
histopathology
Test
Histopathological analysis on liver sections (and other tissues) is recommended for diagnosis in fatal cases only.
Result
typical features of yellow fever infection
Emerging tests
virus isolation
Test
Direct detection of virus in tissue cultures (Vero, AP-61, SW-13, BHK-21 cell lines), brain tissue (intracerebral inoculation of suckling mice), or mosquito cells is both sensitive and specific. Not commercially available and requires specialised referral laboratory.[15][35]
Result
isolation of yellow fever virus
isothermal nucleic acid amplification assays
Test
There have been promising efforts to develop isothermal protocols for yellow fever genome detection, which could be used in resource-limited settings where standard PCR with thermocycling is not feasible.[36]
Result
positive for yellow fever virus RNA
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