An Overview of Yellow Fever Virus Disease

Yellow fever virus (YFV) is a potential deadly mosquito-borne flavivirus currently endemic in parts of equatorial Africa and South America, with previous circulation in parts of North America.^1,2 It can be transmitted to humans through the bites of certain Aedes or Haemagogus species of mosquitoes and has distinct transmission cycles in the jungle (sylvatic cycle), in the African savannah (intermediate cycle), and in cities (urban cycle).^1,2 Within urban areas, YFV can rapidly spread due to mosquito–human–mosquito transmission (usually involving Aedes aegypti mosquitoes).^1,2 Recently, there have been deadly outbreaks of YFV disease in Angola (2016), in the Democratic Republic of the Congo (2016), and in Brazil (2017).³

Clinically, many people infected with YFV are asymptomatic.^1,3 Others develop symptoms including sudden fever, chills, headache, low back pain, myalgia, nausea, vomiting, and/or fatigue after an incubation period of approximately 3 to 6 days.^1,3 Most with YFV disease improve within 3 to 4 days.³ However, roughly 15% go on to develop a more severe form of YFV disease with high fever, bleeding diatheses, abdominal pain, renal failure, cardiovascular instability, and/or liver failure and jaundice (hence the name “yellow fever”), and 20% to 50% of these patients may die.^1-3 Additionally, neurologic complications may occur in those with YFV disease including headache, photophobia, agitation, seizures, encephalopathy, or rarely cerebral edema and coma.² Interestingly, cerebrospinal fluid (CSF) pleocytosis and brain tissue inflammation in these patients are largely absent, suggesting systemic derangements as the cause rather than central nervous system (CNS) viral invasion or neuroinflammation.²

Yellow fever virus infection can be diagnosed molecularly by detecting YFV RNA using reverse transcription polymerase chain reaction tests or serologically by detecting YFV-specific immunoglobulin M antibodies followed by confirmatory neutralizing antibody tests.^1,3,4

Treatment for YFV disease is supportive as there are no disease-modifying therapies currently. Observation, rest, fluids, and acetaminophen for pain and fever are recommended.^1,4 Nonsteroidal anti-inflammatory drugs and aspirin should be avoided, given the risk of hemorrhagic shock. Persons with YFV disease should be protected from mosquito bites for 5 days after fever onset to avoid infecting naive mosquitoes and help break the transmission cycle.¹ Those who recover likely have long-lasting immunity.¹

To prevent mosquito bites that may lead to YFV disease, people in endemic areas should wear long-sleeved shirts and pants while outside when feasible, apply insect repellant when going outdoors, and use window screens or air-conditioning to keep mosquitoes outside.¹ There is also a live YFV vaccine (17D) available for those living in or traveling to endemic areas (travelers can find vaccine recommendations at https://wwwnc.cdc.gov/travel/), with >99% of vaccinated persons developing protective neutralizing antibodies within 4 weeks across most studies.^2,4 Rarely, serious adverse events have been associated with the vaccine (estimated at 4.7 events per 100 000 doses) including anaphylaxis, “viserotropic” multi-organ disease, and neurologic complications such as meningitis, encephalitis, myelitis, acute disseminated encephalomyelitis, cranial neuropathies, or Guillain-Barré syndrome.^2,4,5 Such YFV vaccine-associated neurologic disease (YFV-AND) occurs approximately at 0.8 events per 100 000 vaccine doses, with higher rates in those over age 60.^2,4,5 As opposed to natural YFV infection, CSF pleocytosis can often be seen with some types of YFV-AND, suggesting CNS viral invasion or neuroinflammation may play a role.² Treatment for any YFV-AND should be tailored to the specific clinical neurologic syndrome.⁴

Neurologists should consider YFV disease in those with the appropriate clinical syndrome who live in or have recently traveled to YFV endemic areas and should be aware of potential adverse neurologic events associated with the YFV vaccine. Suspected cases should be reported to local public health authorities. The latest information on YFV (and its vaccine) can be found in the Centers for Disease Control and Prevention’s Website.¹