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Yellow fever: Epidemiology, clinical manifestations, and

diagnosis
Author: Annelies Wilder-Smith, MD, PhD
Section Editor: Martin S Hirsch, MD
Deputy Editor: Elinor L Baron, MD, DTMH

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Oct 2020. | This topic last updated: Dec 02, 2019.

INTRODUCTION

Yellow fever is a mosquito-borne viral hemorrhagic fever with a high case-fatality rate. Clinical
manifestations include hepatic dysfunction, renal failure, coagulopathy, and shock. Travelers to
tropical regions of South America and sub-Saharan Africa where the disease is endemic are at
risk for acquisition of infection and require immunization.

Issues related to virology, pathogenesis, epidemiology, clinical manifestations, and diagnosis of

yellow fever will be reviewed here. Issues related to the treatment and prevention of yellow
fever are discussed separately. (See "Yellow fever: Treatment and prevention".)

VIROLOGY, PATHOGENESIS, AND HISTOPATHOLOGY

Yellow fever is the prototype member of the family Flaviviridae, a group of small (40 to 60 nm),
enveloped, positive-sense, single-stranded RNA viruses that replicate in the cytoplasm of
infected cells. Yellow fever virus is a single serotype and is antigenically conserved, so the
vaccine protects against all strains of the virus. At the nucleotide sequence level, it is possible to
distinguish seven major genotypes representing West Africa (two genotypes), Central-East
Africa and Angola (three genotypes), and South America (two genotypes) [1,2].

The yellow fever virus re-emerged in large outbreaks in Africa (2015 to 2016) and Brazil (2016 to
2018). Phylogenetic studies demonstrated that the 2016 strains were similar to Angola 1971
strains and only three amino acid changes were new to other lineages [3]. In Brazil,
cocirculation of two distinct yellow fever virus clades occurring in humans and nonhuman
primates suggests multiple sylvatic transmission cycles [4].

Humans are highly susceptible to infection and disease. Most nonhuman primate species are
susceptible to infection, and some species of nonhuman primates develop clinical
manifestations.

An infected female mosquito inoculates approximately 1000 to 100,000 virus particles

intradermally during blood feeding. Virus replication begins at the site of inoculation, probably
in dendritic cells in the epidermis, and spreads through lymphatic channels to regional lymph
nodes. Lymphoid cells, particularly monocyte-macrophages and large histiocytes, appear to be
the preferred cell types for primary replication. The virus reaches other organs via the lymph
and then the bloodstream, seeding other tissues. Large amounts of virus are produced in the
liver, lymph nodes, and spleen and are released into the blood. During the viremic phase (days
three to six), infection may be transmitted to blood-feeding mosquitoes.

Yellow fever is characterized by hepatic dysfunction, renal failure, coagulopathy, and shock [5-
8]. The midzone of the liver lobule is principally affected, with sparing of cells bordering the
central vein and portal tracts [9]. Viral antigen localizes to the midzone, indicating that it is the
site of direct viral injury. Very high virus loads have been found in the liver and spleen of fatal
cases [10].

Injury to hepatocytes is characterized by eosinophilic degeneration with condensed nuclear

chromatin (Councilman bodies) rather than by the ballooning and rarefaction necrosis seen in
viral hepatitis. Liver cell death is due to apoptosis. Hepatocytes in the midzone of the liver
lobule express Fas ligand, and lymphocytes infiltrating the liver mediate apoptosis.
Inflammatory cells, mainly CD4+ cells, are present in low numbers; smaller numbers of NK and
CD8+ cells are present [11,12]. There is no disruption of the reticular architecture of the liver. In
nonfatal cases, healing is complete without postnecrotic fibrosis. In fatal cases, approximately
80 percent of hepatocytes undergo coagulative necrosis.

Renal damage is characterized by eosinophilic degeneration and fatty change of renal tubular
epithelium without inflammation. These findings are believed to be a result of both direct viral
injury and nonspecific changes due to hypotension and the hepatorenal syndrome [7].

Focal injury to the myocardium, characterized by cell degeneration and fatty change, is the
result of viral replication.

The hemorrhagic diathesis in yellow fever is due to decreased synthesis of vitamin K-dependent
coagulation factors by the liver, disseminated intravascular coagulation, and platelet
dysfunction.

The late phase of the disease is characterized by circulatory shock. The underlying mechanism
may be cytokine dysregulation, as in the sepsis syndrome. In a series of patients with fatal
yellow fever, levels of proinflammatory cytokines (interleukin [IL]-6, IL-1 receptor antagonist,
tumor necrosis factor [TNF]-alpha, and interferon-inducible protein-10) were elevated compared
with patients with nonfatal yellow fever [13]. Patients dying of yellow fever have cerebral edema
at autopsy, probably the result of microvascular dysfunction. Large amounts of complement-
fixing antigen (presumably NS1) have been found in blood of severely ill yellow fever patients
[14].

Some nonhuman primate species develop fatal infection with features similar to the disease in
humans [7]. A model of yellow fever infection in hamsters has been described [15,16]. Clinical,
immunologic, and pathologic features resemble human infection, suggesting that this model
might serve to increase the understanding of the pathogenesis of infection and to explore
possible treatments. Interferon-alpha/beta receptor-deficient mice are also susceptible to
viscerotropic infection [17].

EPIDEMIOLOGY

Geographic distribution — Yellow fever occurs in tropical regions of sub-Saharan Africa and

South America; it is an epidemic disease problem of considerable magnitude [18,19]. The
incidence of endemic disease is not well established, but approximately 1 percent of individuals
with severe hepatitis in endemic areas of Africa may be caused by yellow fever [20]. An estimate
from serologic and epidemiologic data concluded that there were 130,000 cases with
viscerotropic disease and 78,000 deaths in Africa in 2013 [21].

The incidence of yellow fever in Africa varies widely, and the disease occurs in epidemics [18]. A
large Aedes aegypti–borne epidemic occurred in Angola and neighboring Democratic Republic of
the Congo in south/central Africa between December 2015 and July 2016 with over 2930
confirmed or suspected cases and 253 deaths and resulting in the emergency distribution of 30
million doses of vaccine [22-24]. Mosquito-borne epidemics in Africa occur where large human
populations reside in high density and immunization coverage is low. The highest number of
outbreaks has occurred in West Africa, but this situation is changing due to a concerted effort
to undertake mass immunization campaigns in that region. Human-to-human transmission in
the absence of the mosquito has not been reported.

Fewer cases occur in South America than in Africa because transmission occurs from enzootic
sources (principally from monkey to human via mosquito vectors), the vector density is
relatively low, and vaccination coverage is relatively high (80 to 90 percent in endemic areas of
South America). In typical years, there are several hundred cases officially notified, but in
epidemic years up to 5000 cases are reported. Between 2016 and 2018, rapid expansion of a
severe sylvatic yellow fever virus outbreak occurred in southeastern Brazil. This outbreak
reached one of the most populated metropolitan areas in Brazil that had been yellow fever-free
for more than 70 years [25]. Between January and March 2018, one report noted 79 patients
with severe yellow fever in Sao Paolo required intensive care [26].

In Africa and South America, only a small proportion of cases is officially recorded because the
disease often occurs in remote areas, recognition of outbreaks is delayed, and diagnostic
facilities are limited. In Africa, reports of outbreaks in the 1980s noted the incidence of yellow
fever infection to be 20 to 40 percent, the incidence of severe disease to be 3 to 5 percent, and
the case-fatality rate to be 20 to 30 percent. In contrast, case-fatality rates in South America are
consistently 50 to 60 percent. It is uncertain whether these disparities reflect reporting artifact,
a real difference in virus strain virulence, and/or differing genetic susceptibility of the human
populations. A racial difference in susceptibility is likely, supported by an analysis of
epidemiologic data from an 1878 epidemic in Tennessee, in which yellow fever attack rates were
similar in the Caucasian and non-Caucasian populations of the city, but the case-fatality rate
was 6.8-fold higher in Caucasians [27].

Yellow fever epidemics have never been reported in Asia, and introduction to that region could
have devastating effects since there is no background of specific immunity, and the urban
vector (Aedes aegypti) is prevalent. In the context of the 2016 yellow fever outbreak in Angola, at
least 11 Chinese workers developed yellow fever upon travel home to China, illustrating the
danger of introduction and potential secondary spread [28].

Prior to the reports among travelers from Angola, yellow fever in expatriates and travelers to
and from Africa and South America had been rare; since the introduction of vaccination after
World War II, ten cases had been recorded up to the time of the 2016 Angolan outbreak [10,29-
33]. During the Angola outbreak, 11 Chinese construction workers were infected while working
in Angola and subsequently exported the virus upon return to China; this was the first
documented exportation of yellow fever into Asia. Subsequent analyses showed that the
majority of Chinese workers in Angola had not been vaccinated [34]. The outbreak in Brazil
resulted in more exportation of yellow fever via travelers than in the previous decades [35]. (See
'Outbreak in South America' below.)

Changes in human demography, particularly expansion of urban populations throughout the

tropics, expansion of air travel, and rapid spread of other viruses (dengue, Zika, chikungunya)
transmitted between humans by urban Ae. aegypti throughout the southern hemisphere
illustrate the global dangers associated with exportation and spread of yellow fever.

Outbreak in South America — An ongoing yellow fever outbreak in Brazil began in

December 2016 [35-37]. Between July 1, 2017, and February 16, 2018, 464 confirmed human
cases of yellow fever were reported in Brazil, including 154 deaths [38]. In March 2018, the
Brazilian health ministry issued a recommendation for universal yellow fever vaccination in
Brazil [39].

Since January 2018, 10 travel-related cases have been reported in international travelers
returning from Brazil, including four deaths; none of the 10 travelers had received yellow fever
vaccination [35]. In March 2018, the United States Centers for Disease Control and Prevention
issued an advisory which expanded the regions within Brazil for which travelers should receive
yellow fever vaccine [40-42]. In 2018, five countries in the Americas reported confirmed cases of
yellow fever: Bolivia, Brazil, Colombia, French Guiana, and Peru. As of September 2019, three
countries in the Region of the Americas reported yellow fever (Bolivia, Brazil, and Peru) [43].

Transmission cycles — The primary transmission cycle involves monkeys and daytime biting
mosquitoes (Aedes species in Africa, Haemagogus species in South America).

In Africa, a wide array of Aedes vectors is responsible for transmission. During the rainy season,
the virus circulates via mosquitoes in the savanna vegetational zone in proximity to human
settlements. Both humans and nonhuman primates can be hosts in the transmission cycle, and
the rate of virus transmission may accelerate to reach epidemic levels. Aedes aegypti, a common
domestic mosquito that can breed in containers used to store potable water in heavily settled
areas, is capable of serving as an epidemic vector with humans as the intermediate viremic
hosts (so-called "urban yellow fever").

In South America, the larval development of mosquitoes occurs in areas such as tree holes
containing rainwater. Persons entering forested areas are at risk of infection (so-called "jungle
yellow fever"); this accounts for the predominance of cases among young males engaged in
forest clearing and agriculture. In the 1970s, the Aedes aegypti mosquito reinvaded areas of
South America where it previously had been eradicated, increasing the risk that urban yellow
fever may re-emerge. The first well-documented instance of an urban-cycle epidemic since 1942
occurred in Paraguay in 2008 [44].

CLINICAL MANIFESTATIONS

The clinical spectrum of yellow fever includes [45]:

 ● Subclinical infection
● Abortive, nonspecific febrile illness without jaundice
● Life-threatening disease with fever, jaundice, renal failure, and hemorrhage

Yellow fever affects all ages, but disease severity and lethality is highest in older adults. The
onset of illness appears abruptly three to six days (median 4.3 days) after the bite of an infected
mosquito [46]. The classical illness is characterized by three stages:

● Period of infection
● Period of remission
● Period of intoxication

Period of infection — The period of infection consists of viremia, which lasts for three to four
days. The patient is febrile and complains of generalized malaise, headache, photophobia,
lumbosacral pain, pain in the lower extremities, myalgia, anorexia, nausea, vomiting,
restlessness, irritability, and dizziness [47]. Symptoms and signs are relatively nonspecific; at
this phase, it is virtually impossible to distinguish yellow fever from other acute infections.

On physical examination, the patient appears acutely ill with flushed skin, reddening of the
conjunctivae and gums, and epigastric tenderness. Enlargement of the liver with tenderness
may be present. The tongue is characteristically red at the tip and sides with a white coating in
the center. The pulse rate is slow relative to the height of the fever (Faget's sign). The
temperature is typically 39ºC but may rise as high as 41ºC.

Laboratory abnormalities include leukopenia (1500 to 2500 per microL) with relative
neutropenia; leukopenia occurs rapidly after the onset of illness. Serum transaminase levels
start to rise 48 and 72 hours after onset of illness, prior to the appearance of jaundice. The
degree of liver enzyme abnormalities at this stage may predict the severity of hepatic
dysfunction later in the illness [48].

Period of remission — A period of remission lasting up to 48 hours may follow the period of
infection, characterized by the abatement of fever and symptoms. Patients with abortive
infections recover at this stage. Approximately 15 percent of individuals infected with yellow
fever virus enter the third stage of the disease.

Period of intoxication (severe yellow fever) — The period of intoxication begins on the third
to sixth day after the onset of infection with return of fever, prostration, nausea, vomiting,
epigastric pain, jaundice, oliguria, and hemorrhagic diathesis. The viremia disappears at this
stage and antibodies appear in the blood, although ongoing viremia has also been reported
[49]. Patients with viral loads of ≥5.1 log copies/mL had an extremely high mortality in the
Brazilian experience [49]. This phase is characterized by variable dysfunction of multiple organs
including the liver, kidneys, and cardiovascular system. Multiorgan failure in yellow fever is
associated with high levels of proinflammatory cytokines similar to that seen in bacterial sepsis
and systemic immune response syndrome (SIRS) [31].

Hepatic dysfunction — Hepatic dysfunction due to yellow fever differs from other viral
hepatitides in that serum aspartate aminotransferase (AST) levels exceed those of alanine
aminotransferase (ALT). This may be due to concomitant viral injury to the myocardium and
skeletal muscle. The levels are proportional to disease severity. In one study, the mean AST and
ALT levels in fatal cases were 2766 and 660 U, respectively, while in surviving patients with
jaundice, the mean levels were 929 and 351 U [50]. Alkaline phosphatase levels are normal or
only slightly elevated. Direct bilirubin levels are typically between 5 and 10 mg/dL, with higher
levels in fatal than in nonfatal cases [51].

Renal dysfunction — Renal damage is characterized by oliguria, azotemia, and very high

levels of protein in the urine. Serum creatinine levels are three to eight times normal. In some
patients who survive the hepatitic phase, renal failure predominates [52]. Death is preceded by
virtually complete anuria.

Hemorrhage — Hemorrhage is a prominent component of the third phase of illness,

including coffee-grounds hematemesis, melena, hematuria, metrorrhagia, petechiae,
ecchymoses, epistaxis, oozing of blood from the gums, and bleeding from needle puncture
sites. Gastrointestinal hemorrhage may contribute to circulatory collapse. Laboratory
abnormalities include thrombocytopenia, prolonged prothrombin time, and global reductions
in clotting factors synthesized by the liver (factors II, V, VII, IX, and X). Some patients have
findings suggesting disseminated intravascular coagulation, including diminished fibrinogen
and factor VIII and the presence of fibrin split products.

Myocardial injury — The clinical significance of myocardial injury is poorly understood and

probably has been underestimated in clinical studies. In some cases, acute cardiac enlargement
has been documented during the course of infection [53]. The electrocardiogram may show
sinus bradycardia without conduction defects, ST-T abnormalities, particularly elevated T waves,
and extrasystoles [54]. Bradycardia and myocarditis may contribute to hypotension, reduced
perfusion, and metabolic acidosis in severe cases. Arrhythmia has been suggested to explain
the rare reports of late death during convalescence.

Central nervous system dysfunction — Patients exhibit variable signs of central nervous

system (CNS) dysfunction including delirium, agitation, convulsions, stupor, and coma. In severe
cases, the cerebrospinal fluid is under increased pressure and may contain elevated protein but
no cells. Pathologic changes include microscopic perivascular hemorrhages and edema. Given
the absence of inflammatory changes suggesting viral neuroinvasion and encephalitis, CNS
alterations are probably due to metabolic encephalopathy. True yellow fever viral encephalitis is
exceedingly rare.

Pancreatitis — Among patients with severe yellow fever reported from the 2018 Brazilian
epidemic, the incidence of pancreatitis was 58 percent [26].

Outcome — The outcome is determined during the second week after onset, at which point the
patient either dies or rapidly recovers. Approximately 20 to 50 percent of patients who enter the
period of intoxication succumb to the disease. Poor prognostic signs include anuria, shock,
hypothermia, agitation, delirium, intractable hiccups, seizures, hypoglycemia, hyperkalemia,
metabolic acidosis, Cheyne-Stokes respirations, stupor, and coma. A study in a tertiary hospital
setting in Brazil identified the following predictive factors for progression to severe yellow fever:
older age, male sex, elevated leukocyte and neutrophil counts, elevated alanine
aminotransferase, aspartate transaminase (AST), bilirubin, creatinine, prolonged prothrombin
time, and higher yellow fever virus RNA plasma viral load. In a multivariate regression model,
older age, elevated neutrophil count, increased AST, and higher viral load were independently
associated with death [49].

Convalescence may be associated with fatigue lasting for several weeks. In some cases,
jaundice and serum transaminase elevations may persist for months, although such patients
may have yellow fever superimposed on other hematologic or hepatic diseases. The outcome of
yellow fever appears to be comparable in patients with or without hepatitis B surface
antigenemia.

Complications of yellow fever include bacterial superinfections, such as pneumonia, parotitis,

and sepsis. Late deaths during convalescence occur rarely and have been attributed to
myocarditis, arrhythmia, or heart failure.

DIAGNOSIS

Diagnosis is made by serology, detection of viral genome by polymerase chain reaction (PCR),
by viral isolation or histopathology, and immunohistochemistry on postmortem tissues.

Serology — Serologic diagnosis is best accomplished using an enzyme-linked immunosorbent

assay (ELISA) for immunoglobulin (Ig)M. The presence of IgM antibodies in a single sample
provides a presumptive diagnosis; confirmation is made by a rise in titer between paired acute
and convalescent samples or a fall between early and late convalescent samples.
Persistence of antibodies from earlier receipt of the live-attenuated vaccine can complicate
interpretation of IgM results [55]. In addition, cross-reactions with other flaviviruses complicate
the diagnosis of yellow fever by serologic methods, particularly in Africa where multiple
flaviviruses circulate. The neutralization test is more specific but requires a specialized
laboratory.

Rapid diagnostic tests — Rapid diagnostic tests include PCR to detect viral genome in the
blood or tissue and ELISA for determination of IgM antibody [10]. Next-generation sequencing
of RNA directly amplified from blood has been used to confirm the diagnosis and compare the
patient’s strain to known geographic clades of the virus. These tools are increasingly available in
national and regional laboratories in the endemic areas. A reverse-transcription loop-mediated
isothermal amplification (RT-LAMP) yellow fever diagnostic test, which does not require
thermocycling equipment and can be read visually, has shown promise as a sensitive and rapid
test for use in field conditions [56].

Virus isolation — Virus isolation is accomplished by inoculation of mosquito or mammalian cell

cultures, intracerebral inoculation of suckling mice, or intrathoracic inoculation of mosquitoes.
The virus may also be recovered from postmortem liver tissue. During a yellow fever outbreak
in Ivory Coast in 1982 including 90 confirmed cases, 30 percent were diagnosed by virus
isolation from the blood; the majority of patients had detectable virus prior to onset of jaundice
[57].

Pathology — Liver biopsy during illness due to yellow fever should never be performed, since
fatal hemorrhage may ensue. Postmortem histopathologic examination of the liver often
demonstrates the typical features of yellow fever including midzonal necrosis. A definitive
postmortem diagnosis may be made by immunocytochemical staining for yellow fever antigen
in the liver, heart, spleen, or kidney [58-60]. (See 'Virology, pathogenesis, and histopathology'
above.)

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of yellow fever includes:

● Viral hepatitis (hepatitis A, B, C, D, and E) – These entities are characterized by elevated

transaminases; hepatitis A and E are acute infections transmitted most frequently by the
fecal-oral route, whereas hepatitis B, C, and D can present acutely or chronically and are
transmitted by body fluids. In Africa, severe and fatal hepatitis E in pregnancy has
frequently been misdiagnosed as yellow fever. (See related topics.)
 ● Influenza – Influenza is associated with fever, headache, malaise, and myalgias. It is not
generally associated with severe hepatic involvement or jaundice. The diagnosis is
established by viral detection. (See "Seasonal influenza in adults: Transmission, clinical
manifestations, and complications".)

● Dengue – Dengue and yellow fever are similar in that both are associated with fever,
headache and body aches, and hemorrhagic manifestations. Hepatic involvement can
occur in the setting of severe dengue infection [61]. The diagnosis of dengue is established
by serology. (See "Dengue virus infection: Clinical manifestations and diagnosis".)

● Malaria – Malaria is characterized by fever and anemia; clinical manifestations include

jaundice due to hemolysis. The diagnosis of malaria is established by visualization of
parasites on peripheral smear. (See "Malaria: Clinical manifestations and diagnosis in
nonpregnant adults and children".)

● Typhoid – Manifestations of typhoid fever include fever and gastrointestinal symptoms.

Abnormal liver function tests are observed but jaundice is not a typical clinical feature. The
diagnosis is established by culture. (See "Epidemiology, microbiology, clinical
manifestations, and diagnosis of enteric (typhoid and paratyphoid) fever".)

● Leptospirosis – Leptospirosis is a bacterial infection characterized by fever, myalgia,

headache, and conjunctival suffusion. Modest elevation of hepatic transaminases may be
observed. The diagnosis is established by serology. (See "Leptospirosis: Epidemiology,
microbiology, clinical manifestations, and diagnosis".)

● Q fever – Q fever occurs as a result of infection with Coxiella burnetii; hepatic involvement
includes elevated transaminases, hepatomegaly without jaundice, and granulomas on liver
biopsy. The diagnosis is established by serology. (See "Clinical manifestations and diagnosis
of Q fever".)

● Hemorrhagic fever – Yellow fever may be distinguished from other viral hemorrhagic fevers
(Lassa fever, Marburg virus, Ebola virus, Bolivian and Argentine hemorrhagic fevers) in that
these other viral hemorrhagic fevers are not usually associated with jaundice. However,
Congo-Crimean hemorrhagic fever may be associated with severe liver damage; Rift Valley
fever and dengue hemorrhagic fever may present with this complication as well. (See
related topics.)

SUMMARY AND RECOMMENDATIONS

 ● Yellow fever is a mosquito-borne viral hemorrhagic fever with a high case-fatality rate.
Travelers to tropical regions of South America and sub-Saharan Africa are at risk for
acquisition of infection and require immunization. (See 'Introduction' above.)

● Mosquito-borne epidemics in Africa occur where human populations reside in high density
and immunization coverage is low (so-called "urban yellow fever"). Fewer cases occur in
South America than in Africa because transmission occurs principally from monkey to
human via mosquito vectors, the vector density is relatively low, and vaccination coverage
is relatively high (so-called "jungle yellow fever"). (See 'Epidemiology' above.)

● Yellow fever is characterized by three stages: periods of infection, remission, and

intoxication. The period of infection consists of viremia with nonspecific symptoms and
signs including fever, malaise, headache, joint pain, nausea, and vomiting. This is followed
by a period of remission with abatement of fever and symptoms lasting up to 48 hours. The
subsequent period of intoxication is characterized by hepatic dysfunction, renal failure,
coagulopathy, and shock. (See 'Clinical manifestations' above.)

● Diagnosis may be made by serology, by detection of viral genome by polymerase chain

reaction in serum, by virus isolation, or by histopathology and immunocytochemistry
(postmortem samples only). Serologic diagnosis is best accomplished using an enzyme-
linked immunosorbent assay for immunoglobulin (Ig)M. The presence of IgM antibodies in
a single sample provides a presumptive diagnosis; confirmation is made by a rise in titer
between paired acute and convalescent samples or a fall between early and late
convalescent samples. More specific neutralization tests may be performed but require a
specialized laboratory. (See 'Diagnosis' above.)

ACKNOWLEDGMENTS

The editorial staff at UpToDate would like to acknowledge Thomas Monath, MD, FACP, FASTMH,
and Edward T Ryan, MD, DTMH, who contributed to an earlier version of this topic review.

Use of UpToDate is subject to the Subscription and License Agreement.

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Topic 3032 Version 53.0

Contributor Disclosures
Annelies Wilder-Smith, MD, PhD Nothing to disclose Martin S Hirsch, MD Nothing to disclose Elinor L
Baron, MD, DTMH Nothing to disclose

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