Yellow Fever 

Updated: Jun 21, 2019
Author: Dana M Blyth, MD; Chief Editor: John L Brusch, MD, FACP 

Overview

Practice Essentials

Yellow fever is a mosquito-borne disease that is endemic to tropical South America and Sub-Saharan Africa (see the image below). Its presentation can range from asymptomatic illness to acute-onset viral hepatitis and hemorrhagic fever.[1, 2]

This female Aedes aegypti mosquito is shown after This female Aedes aegypti mosquito is shown after landing on a human host. The A aegypti mosquito is a known transmitter of dengue fever and yellow fever. A aegypti is sometimes referred to as the yellow fever mosquito. The viruses are transferred to the host when he or she has been bitten by a female mosquito. Image courtesy of the CDC/World Health Organization (WHO).

See 11 Travel Diseases to Consider Before and After the Trip, a Critical Images slideshow, to help identify and manage infectious travel diseases.

Signs and symptoms

History

Yellow fever is usually a mild, self-limited illness consisting of fever, headache, myalgia, and malaise. It is typically divided into three stages: the period of infection, period of remission, and period of intoxication.

More serious illness presents with the abrupt onset of the following during the period of infection:

  • General malaise

  • Fever

  • Chills

  • Headache

  • Lower back pain

  • Nausea

  • Dizziness

This is followed by a period of remission, when the virus is cleared and when many infected individuals fully recover.

In 15%-25% of individuals with yellow fever, symptoms recur during the period of intoxication and can progress to fatal illness. This period is marked by the following:

  • Fever

  • Vomiting

  • Abdominal pain

  • Renal failure

  • Hemorrhage

Physical examination

Physical findings in yellow fever include the following:

  • Fever

  • Relative bradycardia for the degree of fever (Faget sign)

  • Conjunctival injection

  • Skin flushing

As the disease progresses, additional physical findings include the following:

  • Scleral icterus

  • Jaundice

  • Epigastric tenderness

  • Hepatomegaly

The following is also often apparent in severe disease:

  • Petechiae

  • Purpura

  • Mucosal bleeding

  • Gastrointestinal bleeding (gross or occult)

Organ ischemia, which primarily affects the kidneys and central nervous system, leads to altered mental status and/or signs of volume overload. In the late stages of yellow fever, patients present with the following:

  • Tachycardia

  • Hypothermia or hyperthermia

  • Hypotension

Individuals who are severely hypoperfused appear mottled and cyanotic; they are also often obtunded. Tachypnea and hypoxia with impending respiratory failure may develop as a consequence of sepsis and acute respiratory distress syndrome (ARDS).

See Clinical Presentation for more detail.

Diagnosis

Laboratory studies

  • Complete blood count (CBC)

  • Chemistries

  • Liver function tests (LFTs): Elevated levels of transaminases precede the appearance of jaundice, and the degree of liver dysfunction in the acute phase may be predictive of the clinical course.
  • Coagulation studies

  • Urinalysis

Imaging studies

Chest radiography is used to evaluate the extent of pulmonary edema, to reveal secondary bacterial pulmonary infections, and to aid in ventilator management if intubation is required.

Specific tests for yellow fever

  • Rapid detection methods (eg, polymerase chain reaction assay)

  • Serologic tests (eg, enzyme-linked immunosorbent assay)

  • Immunohistochemical tissue staining - To identify the yellow fever antigen

See Workup for more detail.

Management

No specific treatment exists for yellow fever; however, supportive care is critical. Severely ill patients should be treated in an intensive care setting. The required management consists of the following:

  • Vasoactive medications

  • Fluid resuscitation

  • Ventilator management

  • Treatment of disseminated intravascular coagulation (DIC), hemorrhage, secondary infections, and renal and hepatic dysfunction

Additional supportive care recommendations for patients with yellow fever include the following:

  • A nasogastric or orogastric tube may be required to provide nutritional support

  • Patients with renal failure or refractory acidosis may require dialysis

  • Salicylates should be avoided because of the increased risk of bleeding secondary to platelet dysfunction

Prevention

The currently available yellow fever vaccine confers near lifelong immunity in 95% of patients.[3]

See Treatment and Medication for more detail.

Background

Yellow fever is one of many causes of viral hemorrhagic fever. It is a member of the flavivirus family (group B arbovirus). The Flavivirus genus is composed of more than 70 viruses, most of which are arthropod-borne, with 30 that are known to cause human disease. Other flaviviral infections include dengue, Japanese encephalitis, West Nile, Zika, and tick-borne encephalitis. It is important to consider this group of viruses in the clinical differential of CNS infection, hemorrhagic fever, and acute febrile illnesses with arthropathy. Yellow fever virus is shown in the image below. (See Etiology.)

Yellow fever virus. Image courtesy of the Centers Yellow fever virus. Image courtesy of the Centers for Disease Control and Prevention.

A mosquito-borne disease, yellow fever can manifest on a wide spectrum, ranging from asymptomatic illness to acute-onset viral hepatitis and hemorrhagic fever. (See Clinical and Workup.)

From 1793-1822, yellow fever was one of the most dreaded diseases in US port cities. Yellow fever outbreaks in the United States shaped American history and influenced important national decisions. In the 1780s, yellow fever outbreaks in Philadelphia were responsible for killing one tenth of the city's population.[4]

The disease may have played a part in shaping the decision to move the nation's capital out of Philadelphia.[4] The disease had such an impact on the local economies that, in 1803, Napoleon, with his troops decimated by yellow fever, had few reservations about selling the affected Louisiana and western territories to the US government.

Fascinating accounts document how humankind's struggle with yellow fever has shaped world history. The French effort to develop the Panama Canal was not lost through engineering failures, but by disease. Frenchmen died of yellow fever in alarming numbers, leading to Panama being coined "the white man's graveyard."[5]

In the early 20th century, Carlos Findlay and Walter Reed's discovery of Aedes aegypti as a source of yellow fever transmission led to the eradication of yellow fever in parts of Latin America. Isolation of the virus and later development of the 17D vaccine by Max Theiler helped to eliminate A aegypti and yellow fever from countries in Africa and the Americas during the mid 20th century.[6]

Yellow fever is transmitted by tree-hole breeding mosquitoes (Haemagogus and Aedes species) during the tropical wet season and early dry season.[1] Genomic sequence analyses suggest that yellow fever evolved from other mosquito-borne viruses about 3000 years ago in Africa. It is surmised that the yellow fever virus was introduced to the Americas from West Africa by Dutch slave traders during the 17th century.

The first documented epidemic occurred in the Yucatan Peninsula and spread through the Caribbean basin. This was the result of ship travel and the continued importation of slaves from West Africa. Vessels infested with A aegypti mosquitoes brought yellow fever into New England and several port cities throughout North America.

Large vaccination campaigns and A aegypti control programs have decreased the incidence of yellow fever worldwide. Nonetheless, yellow fever has reemerged across Africa and South America, despite the availability of an effective live-attenuated 17D vaccine. The populations at highest risk for the illness are those in countries that lack the funding and infrastructure to support a widespread vaccination program. (See Epidemiology and Treatment.)[7, 8]

Flaviviruses, including those that cause yellow fever, also have a potential use as biologic weapons.[9]

Transmission

As an arthropod-borne virus (ie, arbovirus), yellow fever is transferred from host to host by contaminated mouthparts of mosquitoes. Different species of the Aedes and Haemagogus genus breed in unique habitats (peridomestically versus within the forest canopy). Consequently, these vectors transmit the virus in 3 ways: (1) between monkeys, (2) from monkeys to humans, and (3) from person to person.[10, 11] This variability has led to 3 types of transmission cycles: sylvatic (jungle), intermediate (savannah), and urban. (See the diagram below.)

Transmission cycles of yellow fever in Africa and Transmission cycles of yellow fever in Africa and South America. Adapted from Annu Rev Entomol. 2007. 52:209-29.

Sylvatic (jungle) cycle

In tropical rainforests, yellow fever virus is endemic among lower primates. Infected monkeys pass the virus to canopy-dwelling mosquitoes that feed on them. Persons who subsequently enter the forest (often workers, eg, loggers, and travelers) are infected following the bite of an infected mosquito. In Africa, the principal vector of the jungle cycle is A africanus; in South America, Haemagogus species are the primary vector for jungle transmission. Nonhuman primates remain the preferred host and reservoir in this setting.

Intermediate (savannah) cycle

In moist and semihumid areas of Africa, mosquitoes, which breed in the wild and around households, feed primarily on monkeys but will also feed on humans when the opportunity arises. This cycle likely reflects the evolution of yellow fever into an epidemic human disease and is also known as the zone of emergence. It is the most common cycle present in Africa and frequently leads to small-scale outbreaks in villages. However, transmission can potentially lead to large-scale epidemics if an infected individual carries the disease into an urban region. This cycle has not been identified in South America.

Urban cycle

A aegypti is responsible for the transmission of urban yellow fever in Africa and South America (see image below). A aegypti is well adapted as an urban vector: breeding in man-made water containers, feeding primarily on humans, biting multiple individuals during a single blood meal, and transmitting yellow fever efficiently in its saliva. Thus, A aegypti can infect large populations of unvaccinated individuals. Urban outbreaks were rare in South America, yet have been increasingly reported in both South America and Africa, with concern for potential of further spread.[12]

This female Aedes aegypti mosquito is shown after This female Aedes aegypti mosquito is shown after landing on a human host. The A aegypti mosquito is a known transmitter of dengue fever and yellow fever. A aegypti is sometimes referred to as the yellow fever mosquito. The viruses are transferred to the host when he or she has been bitten by a female mosquito. Image courtesy of the CDC/World Health Organization (WHO).

Patient education

Recommend yellow fever vaccination for international travelers going to endemic regions. Current information, including new outbreaks and information for travelers, can be obtained online from the World Health Organization and the Centers for Disease Control and Prevention.

Etiology

Yellow fever virus is a positive-sense, single-stranded, ribonucleic acid (RNA) ̶ enveloped flavivirus with a diameter of about 50-60 nm. The virus is transmitted via the saliva of an infected mosquito. Local replication of the virus takes place in the skin and regional lymph nodes. Viremia and dissemination follow.

The virus gains entrance through receptor-mediated endocytosis. RNA synthesis occurs in the cytoplasm and protein synthesis takes place in the endoplasmic reticulum. Virions are released through the cell membrane. The viral envelope contains a lipid bilayer taken from the infected cell. Virulence factors include the following:

  • Capsid protein C - Facilitates viral binding
  • Membrane protein M - A minor glycoprotein
  • E proteins - Initiate infection, mediate viral entry, and serve as principal targets for host immune response
  • Nonstructural protein 1 (NS1) - May play a role in RNA replication and immune evasion
  • NS2A protein - Involved in RNA replication and packaging
  • NS2B and NS3 - Form a complex and are involved in polyprotein processing and replication of RNA
  • NS5 - Has a major role in RNA replication

The E protein interacts with the cellular receptor, and virions are endocytosed into the dendritic cells. Subsequently, epidermal dendritic cells and lymph channels disseminate virions. After invasion in the host, Kupffer cells (fixed liver macrophages) are infected within 24 hours.[13] Yellow fever is primarily viscerotropic, with the liver being the most affected organ.[14]

The infection quickly disseminates to the kidneys, lymph nodes, spleen, and bone marrow. Renal failure occurs as renal tubules undergo fatty change and eosinophilic degeneration, likely due to direct viral effect, hypotension, and hepatic involvement.

The liver is the most important organ affected in yellow fever. The disease was labeled "yellow" based on the profound jaundice observed in affected individuals. Hepatocellular damage is characterized by lobular steatosis and necrosis, with recent data indicating apoptosis as the primary mechanism of cell death in the liver, corresponding with subsequent formation of Councilman bodies (degenerative eosinophilic hepatocytes).[13, 14]

The kidneys also undergo significant pathologic changes. Albuminuria and renal insufficiency evolve secondary to the prerenal component of yellow fever; consequently, acute tubular necrosis develops in advanced disease. Hemorrhage and erosion of the gastric mucosa lead to hematemesis, popularly known as black vomit. Fatty infiltration of the myocardium, including the conduction system, can lead to myocarditis and arrhythmias.

Central nervous system (CNS) findings can be attributed to cerebral edema and hemorrhages compounded on metabolic disturbances. The bleeding diathesis of this disease is secondary to reduced hepatic synthesis of clotting factors, thrombocytopenia, and platelet dysfunction.

The terminal event of shock can be attributed to a combination of direct parenchymal damage and a systemic inflammatory response. This cytokine storm has been characterized by increased levels of interleukin (IL)-6, IL-1 receptor antagonist, interferon-inducible protein-10, and tumor necrosis factor (TNF)–alpha. Viral antigens are found diffusely in kidneys, myocardium, and hepatocytes. In individuals who survive yellow fever, the recovery is complete, with no residual fibrosis.

Epidemiology

Occurrence in the United States

Reports of yellow fever in the United States are exceedingly rare, with the last outbreak reported in New Orleans in 1905. It was a rare cause of illness in returning travelers; between 1970 and 2002, 9 cases of yellow fever were reported in unimmunized travelers from the United States and Europe. In these individuals, the disease was acquired in Brazil, Senegal, Venezuela, Ivory Coast, Gambia, and West Africa. Seven of these cases were fatal.[11, 3]

World Health Organization (WHO) data suggest that the rate of yellow fever transmission is increasing, especially in sub-Saharan Africa. In addition, the number of US residents traveling to South America and Africa is also increasing. The WHO estimates that travelers from the United States to endemic areas has doubled since 1988.[15] Without proper precautions, including vaccination, these travelers are at risk of contracting yellow fever.

Less fervent mosquito control efforts in the United States have led to the reemergence of Aedes aegypti in the last 30 years. A aegypti has been found in 23 states in the southeastern US. It is still a common mosquito in subtropical regions of southeastern Florida and along the Gulf of Mexico.[10, 16]

After 21st century outbreaks of dengue fever in Hawaii and along the Texas-Mexico border, it has been hypothesized that yellow fever could reemerge in the United States.[17] Virology research has isolated Flaviviridae strains from mosquitoes in eastern Texas, making transmission of urban yellow fever a potential threat for the United States in the future.[18] Failure to sustain vector control campaigns has led to the reinvasion of A aegypti across the Americas, as evidenced by the recent chikungunya and Zika outbreaks.[12]

International occurrence

After adjustment for underreporting, broadly quoted estimates are that 200,000 cases of yellow fever occur annually in 47 countries, with 30,000 deaths per year.[10, 19] Accurate incidence reporting is limited by the occurrence of asymptomatic disease, underreporting of the disease, and lack of diagnostic capabilities in endemic areas.[3] A recent modeling study estimated that yellow fever may infect up to 1.8 million individuals in Africa annually, resulting in 180,000 cases and 78,000 deaths.[12]

Ninety percent of reported cases occur in Africa,[20] where Aaegypti is rampant. Transmission occurs in largely unvaccinated populations of sub-Saharan Africa. The countries at greatest risk lie within a band from 15° north to 15° south of the equator.[21] This region includes 34 countries in sub-Saharan Africa. (See the image below).[10]

Global distribution of yellow fever. Image courtes Global distribution of yellow fever. Image courtesy of the Centers for Disease Control and Prevention.

Thirty-four countries in Africa are at risk. Transmission in Africa is facilitated by the close proximity of vector mosquito populations to unvaccinated human populations.[20] The case-fatality rate of yellow fever in Africa approximates 20%. Infants and children are at highest risk.[22]

In South America, the rate of transmission of yellow fever is lower than in Africa. Historically, yellow fever outbreaks in South America occurred in the Amazon region.[3] The Haemagogus species of mosquitoes transmitted the virus in this area; affected individuals developed the sylvatic form of yellow fever.[21] Most of these cases occurred in young men via occupational exposures in forested areas.

The incidence of yellow fever in South America is lower than in Africa because the infected monkeys in the rain forest canopy do not often come in contact with human populations. Indigenous human populations have immunity as a part of mass immunization campaigns.[22]

Recent outbreaks in urban areas of South America have been due to deforestation (leading to ground-level biting activity of canopy-dwelling vectors), unvaccinated population migration into endemic areas, and the resultant emergence of A aegypti species. Currently, 13 endemic countries within South America have been identified, with Bolivia, Brazil, Columbia, Ecuador, and Peru at greatest risk.[10, 14]

The range of yellow fever continues to expand, now including areas in which it previously was believed to be eradicated (eg, eastern and southern African countries). Outbreaks of yellow fever have not been reported in Asia, but this region remains at risk because of the presence of competent vector mosquitoes and nonhuman primates.[20] During the recent yellow fever outbreak in Angola, 11 imported cases were documented in China. These were the first yellow fever cases reported in Asia and have led to high levels of concern for potential introduction and urbanization of yellow fever in Asia. The scenario in Angola, which has a large community of nonimmune foreign Asian nationals (home to approximately 100,000 Chinese workers often working in the bush and building roads), coupled with high volumes of air travel to an area conducive to transmission in Asia with a susceptible population of 2 billion people and limited responsive infrastructure, is unprecedented.

The prior failure of yellow fever to become established in Asia-Pacific, in contrast to similar hyperendemic dengue, suggests local factors may have prevented yellow fever from gaining a foothold in the region. This may be related to local vector characteristics, preceding high levels of cross-immunity from dengue and other flaviviruses, prior low risk of importation of viremic travelers, and regional differences in yellow fever geographic strains. However the recent chikungunya and Zika experience has illustrated that a shared vector and prior population exposure do not necessarily constrain the entry of a new arbovirus into dengue-endemic regions. The experience in South America has illustrated 4 main conditions to support yellow fever introduction into a new population, as follows:[12]

  • Intense and sustained migratory flow of viremic individuals
  • High density of competent vectors in receptive ecological conditions
  • Susceptible or partially susceptible human and monkey populations
  • Inadequate surveillance and delayed recognition and ineffective vaccination programs

A traveler's risk of acquiring yellow fever depends on the location of travel, immunization status, season, duration of travel, and types of occupational or recreational activities. US travel data from 1996-2004 describes the overall risk for serious illness and death due to yellow fever to be 0.05-0.5 per 100,000 travelers to yellow fever–endemic areas.[22] Although transmission rates vary by year and season, it is estimated that an unvaccinated traveler spending 2 weeks in sub-Saharan Africa carries a 1:267 risk of contracting yellow fever, with a 1:1333 risk of death from illness. For travelers, the risk of illness and death due to yellow fever is estimated to be 10 times greater in West Africa than in South America.[22, 23]

Sex-related demographics

South American cases of yellow fever are sporadic and usually occur in the population exposed to tropical rain forests. Men aged 14-45 years are most often infected through occupational exposure.[21]

In African cases, in which undervaccination of endemic populations has led to higher infection rates in children, yellow fever is slightly more common in males.

Age-related demographics

African cases of yellow fever occur seasonally in villages in contact with semidomestic mosquitoes. In these populations, nonimmunized children are at the highest risk.

Sylvatic disease primarily affects individuals aged 15-45 years who work outdoors in agriculture and forestry. Urban yellow fever and intermediate yellow fever, which occurs primarily in the humid savannas of Africa, affect individuals of all ages.[21]

Prognosis

Yellow fever ranges in severity from a self-limited infection to life-threatening hemorrhagic fever. About 15-25% of affected individuals develop a more severe phase of disease that involves fever, jaundice, and liver and renal failure. Case-fatality rates in South America are reportedly higher than in West Africa.[3] Mortality is a function of patient susceptibility and of the virulence of the infecting strain.[13] In those who become symptomatic but recover, weakness and fatigue can last for months.[22]

The case-fatality rate for yellow fever has been reported at 5%-70%. In recent outbreaks, the fatality rate was approximately 20% among patients with jaundice. The mortality risk in patients who present in the toxic stage of yellow fever is up to 50%.[24]

Death usually follows within 7-10 days of the onset of the toxic phase of yellow fever.[13] Infancy and age older than 50 years are associated with increased severity of illness and lethality.[3]

Unvaccinated travelers entering endemic regions have a greater risk of developing symptomatic disease than natives who have developed significant immunity.[1] An association has been made between recurrent outbreaks in West Africa and a unique strain in that region, suggesting potential strain-specific virulence.[20]

The rare cases of postvaccination neurologic and viscerotropic disease have infrequently led to death. Most individuals diagnosed with yellow fever vaccine–associated neurologic disease (YEL-AND) recover without sequelae; the case-fatality rate has been reported as less than 5%. Even fewer cases of fatal yellow fever vaccine–associated viscerotropic disease (YEL-AVD) have been documented.[3, 25]

Complications

Complications include:

  • Liver failure

  • Renal failure

  • Pulmonary edema

  • Myocarditis

  • Secondary bacterial infections

  • Hemorrhage or disseminated intravascular coagulation

  • Encephalitis (rare)

  • Shock or death

Secondary bacterial infections are frequent complications in patients who survive the critical period of illness.

 

Presentation

History

To arrive at a diagnosis, consider the patient's clinical features, destination and dates of travel, time of year, immunizations, and activities.[26]

After an incubation period of 3-6 days, most individuals with yellow fever have a mild, self-limited illness consisting of fever, headache, myalgia, and malaise. The clinical presentation is divided into 3 stages: the period of infection, the period of remission, and, if it progresses, the period of intoxication.

Period of infection

More serious illness develops in 15% of cases and presents with the abrupt onset of general malaise, fever, chills, headache, lower back pain, nausea, and dizziness. Physical findings include pulse-fever dissociation (Faget sign), conjunctival injection, and facial flushing. Significant laboratory findings usually include leukopenia with relative neutropenia. Transaminase levels may rise 48-72 hours after initial symptoms appear.

Period of remission

Following the period of infection, symptoms and temperature normalize for up to 24 hours. During this time, virus is cleared by antibodies and cellular immune response. The patient may then either recover, as is seen in self-limited illness, or progress to fatal illness during the next stage.

Period of intoxication

In approximately 15%-25% of cases, remission is followed by the return of symptoms. Viremia is reduced, and humoral-mediated reactions are responsible for marked physical illness.[11] This stage is marked by fever, vomiting, abdominal pain, renal failure, and hemorrhage. Petechiae, ecchymoses, epistaxis, and bleeding from gums and venipuncture sites can progress to melena, hematemesis, and metrorrhagia.

Jaundice worsens as the levels of transaminases increase, with serum aspartate aminotransferase (AST) levels typically higher than those of alanine aminotransferase (ALT) owing to direct viral injury to skeletal muscle tissue and myocardium. Progressive liver involvement and humoral-mediated responses can lead to consumption coagulopathy. Prolonged clotting and prothrombin times and reduced levels of fibrinogen and clotting factors II, V, VII, VIII, IX, X occur; also, fibrin split products appear.

Hepatorenal disease carries a mortality rate of 20%-50%; with death occurring 7-10 days after onset of symptoms. The terminal phase is marked by delirium, stupor, and coma due to cerebral edema and microscopic perivascular hemorrhage.

Physical Examination

Physical examination findings during early yellow fever include fever, relative bradycardia for the degree of fever (Faget sign), conjunctival injection, and skin flushing.

Other physical findings, such as scleral icterus, jaundice, epigastric tenderness, and hepatomegaly, develop as disease progresses. Early appearance of jaundice indicates a poor prognosis.

Disseminated intravascular coagulation (DIC), induced by liver dysfunction, leads to consumption of platelets and clotting factors. This process clinically presents as a combination of a bleeding diathesis and organ ischemia secondary to fibrin deposition throughout the microcirculation. Petechiae, purpura, mucosal bleeding, and gastrointestinal bleeding (gross or hemoccult) will often be apparent.

Ischemia primarily affects the kidneys and central nervous system leading to altered mental status and/or signs of volume overload (jugular venous distension, presence of rales, and S3 gallop, or edema).

Late stages

In late stages of disease, shock and multiorgan dysfunction syndrome (MODS) dominate the clinical picture. These septic patients present with tachycardia, hypothermia or hyperthermia, and hypotension. Individuals who are severely hypoperfused appear mottled and cyanotic. They are also often obtunded.

Tachypnea and hypoxia with impending respiratory failure may develop as a consequence of sepsis and acute respiratory distress syndrome (ARDS).

 

DDx

Diagnostic Considerations

Based on its clinical presentation, yellow fever may be mistaken for other infectious diseases present in tropical regions; however, failure to consider this illness in a febrile traveler could have a grave outcome.[26] Leptospirosis and louse-borne relapsing fever most closely mimic yellow fever and can manifest as jaundice, hemorrhage, and DIC in severe cases. Other viral hemorrhagic fevers (with dengue and Crimean-Congo hemorrhagic fever being the most similar in presentation) also remain among the differential diagnoses for severe yellow fever during the intoxication period and are important to consider, as they require unique isolation precautions. Malaria is also important to consider because of the overlapping distribution, a mosquito vector, and the potential for a fatal outcome without targeted therapy.

Important diagnostic considerations include other flaviviruses circulating in the area, as these can have similar presentations and can cross-react on diagnostic testing (ie, on ELISA). Noninfectious causes of DIC and acute liver failure are also important to consider.

Differential Diagnoses

  • Acute Liver Failure

    A broad differential diagnosis, including noninfectious causes such as like acute fatty liver of pregnancy and toxin-mediated hepatitis.

  • Disseminated Intravascular Coagulation

  • Flavivirus

    Many other flaviviruses share some clinical features and geographic distributions and can complicate diagnosis because of cross-reactivity on ELISA testing.

  • Hemorrhagic Fevers

    While most viral hemorrhagic fevers (VHF) do not result in jaundice, dengue and Crimean-Congo hemorrhagic fever can occasionally present with similar features.

    -- Dengue Hemorrhagic Fever

    -- Rift Valley Fever

    -- South American VHF: Venezuelan Hemorrhagic fever, Bolivian Hemorrhagic fever, Argentine Hemorrhagic fever

    -- Lassa Fever

    -- Crimean-Congo Hemorrhagic Fever

    -- Marburg Hemorrhagic Fever

    -- Ebola Hemorrhagic Fever

  • Hepatitis E

    Viral hepatitis should remain among the differential diagnoses, especially hepatitis E virus, which can occur in outbreaks.

  • Leptospirosis

    One of two pathogens that can most closely mimic the presentation of yellow fever, which can present with jaundice, hemorrhage, and DIC in severe cases

  • Malaria

    Especially important to screen for as presentations are both protean and can be nonspecific, and malaria can be fatal without targeted treatment.

  • Multiple Organ Dysfunction Syndrome in Sepsis

  • Relapsing Fever

    Louse-borne relapsing fever (Borrelia recurrentis) is one of the two pathogens that can most closely mimic the presentation of severe yellow fever with jaundice, hemorrhage, and DIC in severe cases

  • Typhoid Fever

  • Typhus

  • Viral Encephalitides

    Especially including other flaviviruses such as West Nile virus and Japanese encephalitis (which does not currently have geographic overlap)

 

Workup

Approach Considerations

Laboratory abnormalities during the initial viremic phase of yellow fever include leukopenia, often present at the onset of illness, and elevation of direct bilirubin and hepatic transaminases on days 2-3 of the illness.[3, 20] Transaminase levels increase relative to the degree of hepatic injury.

In the toxic phase, end-organ dysfunction is reflected by laboratory values, as follows:

  • Prothrombin time, activated partial thromboplastin time, international rationalized ratio (INR), and clotting times are invariably prolonged

  • Diminished levels of factor VIII, fibrinogen, and platelets, along with the presence of fibrin split products, indicate presence of DIC

  • Albuminuria usually is noted via urinalysis studies; proportional rises in blood urea nitrogen (BUN) and creatinine will be present in serum

Complete blood count

Findings in a complete blood count (CBC) for patients with yellow fever include the following:

  • Leukopenia with relative neutropenia in the first week of infection, which can progress to leukocytosis during the second week
  • Thrombocytopenia as part of a consumptive coagulopathy
  • Initial hemoconcentration, increased hemoglobin and hematocrit levels
  • Subsequent hemorrhage and hemodilution resulting in decreasing complete blood cell counts

Coagulation studies

Coagulation studies reveal the following in patients with yellow fever:

  • Reduced fibrinogen and clotting factors II, V, VII, VIII, IX, and X and the presence of fibrin split products indicate disseminated intravascular coagulation
  • Decreased synthesis of clotting factors may result in an elevated prothrombin time (PT) and partial thromboplastin time (PTT)
  • Prolonged clotting times may be found

Chemistries

Chemistry studies in patients with yellow fever show the following:

  • Elevated serum creatinine level and blood urea nitrogen (BUN), with a BUN level of more than 100 mg/mL associated with death
  • Hypoglycemia secondary to hepatic dysfunction

Urinalysis

Urinalysis in patients with yellow fever reveals the following:

  • Elevated urinary protein levels (3-20 g/L)

  • Albuminuria is a constant feature and aids in differentiating yellow fever from other viral hepatitides

  • Elevated urobilinogen levels

Imaging studies

Chest radiography is used to evaluate the extent of pulmonary edema, to reveal secondary bacterial pulmonary infections, and to aid in ventilator management if intubation is required.

When mental status changes occur late in the illness, a brain computed tomography (CT) scan is helpful in determining whether intracranial hemorrhage is the cause.

ECG and cardiac monitoring

Electrocardiography (ECG) may identify prolongation of PR and QT intervals.[1] Arrhythmias are commonly due to myocarditis. Cardiac involvement by yellow fever is evidenced by ST-T wave abnormalities.

Electrolyte abnormalities, hypoxia, and hypoperfusion states also are common causes of arrhythmias in patients who are severely ill.

Specific Tests for Yellow Fever Virus

Preliminary diagnosis is based on clinical features and risk determined by history.

Rapid detection methods

Rapid detection methods include the following:

  • Detection of yellow fever antigen using monoclonal enzyme immunoassay in serum specimens
  • Detection of viral genome sequences in tissue or in blood or other body fluid using reverse-transcription polymerase chain reaction (RT-PCR) assay: Useful in early illness only (first 3-4 days). By the time overt symptoms are present, viral RNA is undetectable. Current recommendations are to test blood samples collected within the first 10 days of symptom onset. [27]

Serologic testing methods

Serologic tests, such as enzyme-linked immunosorbent assay (ELISA), aid in making an exact diagnosis. Confirmation is difficult because of cross-reactivity with other viruses, particularly in Africa, where multiple flaviviruses exist. Ruling out other flaviviruses is often aided by a detailed travel history.[3]

Immunoglobulin M (IgM) antibody-capture enzyme-linked immunosorbent assay (MAC-ELISA) is used to detect the specific IgM for yellow fever; a single positive serum titer in the late acute or early convalescent period is diagnostic. This assay is 95% sensitive when serum specimens are collected 7-10 days after the onset of illness. During the acute phase of the illness, 3-10 days from onset of symptoms, a positive IgM ELISA result provides a presumptive diagnosis.

A confirmed case of yellow fever infection is defined as a clinically compatible case and 4-fold rise in antibody titer in a patient who has no history of a recent yellow fever vaccination and cross-reactivity to other flaviviruses has been excluded. A rise in yellow fever–specific antibody titer in paired acute and convalescent samples confirms a laboratory diagnosis. Because of potential cross-reactivity, positive ELISA results should be confirmed with plaque-reduction neutralization testing if patients were exposed in an area with other potential flavivirus exposures.

Immunohistochemical staining of tissues

Immunohistochemical staining of tissues (liver, heart, or kidneys) for the yellow fever antigen can also provide a definitive diagnosis.[3] One should not attempt a liver biopsy during infection because of the risk of complications from hemorrhage.

Liver Function Tests

Elevated liver function test results precede the appearance of jaundice, and the degree of liver dysfunction in the acute phase may be predictive of the clinical course.

Liver function tests also reveal the following:

  • Serum AST levels - Exceed ALT levels secondary to the accompanying muscle damage. In a case series in Brazil, the prognosis was guarded when AST levels exceeded 1500 IU or ALT levels exceeded 1200 IU. [14]
  • Direct bilirubin levels - Elevated, typically 5-10 mg/dL
  • Hypoalbuminemia - Albuminuria, decreased synthesis, and extravasation of albumin through damaged capillary endothelium

Histologic Findings

In the acute phase of yellow fever, gross examination of liver biopsy reveals a mottled yellow (boxwood) color and friable texture. With the availability of serology to provide diagnosis, a liver biopsy is likely not necessary to provide diagnostic confirmation of infection, and the risks versus benefits of a liver biopsy need to be carefully considered. During acute illness, a liver biopsy should be avoided because of the increased risk of bleeding.

Histopathologic changes consistent with yellow fever include midzonal necrosis with sparing of cells around the central vein and portal tracts, steatosis, and Councilman bodies. Councilman bodies are acidophilic inclusion bodies resulting from apoptotic death of hepatocytes; they are characteristic of viral hemorrhagic fevers and other acute viral hepatitis. Late in the illness, biopsy may reveal only severe, nonspecific necrotic changes.

 

Treatment

Approach Considerations

There is mandated reporting to the WHO of all suspected or confirmed yellow fever cases within 24 hours of detection. Cases should also immediately be reported to the local health department.

No specific treatment exists for yellow fever; however, supportive care is critical. Severely ill patients should be treated in an intensive care setting. The required management consists of vasoactive medications, fluid resuscitation, ventilator management, and treatment of disseminated intravascular coagulation, hemorrhage, secondary infections, and renal and hepatic dysfunction. Salicylates should be avoided because of the increased risk of bleeding secondary to platelet dysfunction.

In 2001, an expert panel recommended the following common-sense recommendations (although these have never been validated in clinical studies):[28]

  • Maintenance of nutrition and prevention of hypoglycemia
  • Nasogastric suction to prevent gastric distension and aspiration
  • Gastric acid suppression to prevent gastric bleeding
  • Treatment of hypotension with fluid resuscitation and vasoactive drugs (dopamine)
  • Administration of oxygen
  • Correction of metabolic acidosis
  • Treatment of bleeding with fresh frozen plasma
  • Dialysis if indicated by renal failure
  • Treatment of secondary bacterial infections with indicated antimicrobials

Clinical studies are ongoing, but no specific treatment is currently available. Administration of interferon-α (or possibly IVIG) would be a reasonable postexposure prophylactic treatment in an unvaccinated laboratory or hospital worker exposed to yellow fever or blood of an acutely ill (potentially viremic) patient with yellow fever if administered within 24 hours. A long list of novel small molecules have shown activity against yellow fever and other flaviviruses in vitro or in animal models, but none is currently available clinically. In studies of nonhuman primates, ribavirin treatment did not prolong survival.[14]

In a retrospective analysis of patients with yellow fever vaccine–associated viscerotropic disease accompanied by shock, 75% of those treated with stress-dose steroids survived, compared with 29% of those not treated with stress-dose steroids.[14]

Transmission prevention

Because viremic patients bitten by mosquitoes can transmit the virus to other patients, the patient should be isolated with mosquito netting in areas with potential vector mosquitoes.

Yellow fever virus is not transmitted person to person, but other infections in the differential diagnoses can be transmitted; thus, the patient should be isolated until a definitive diagnosis is made.

Adherence to universal precautions is mandatory to prevent transmission to health care workers. One case of infection of a health care worker (a phlebotomist) has been reported. However, no documented needlesticks or blood splashes explained the transmission in this case.

Emergency Department Care

Treatment of yellow fever principally is symptomatic and preventative. Closely monitor patients for hypovolemia, oliguria, hypoxia, acidosis, and electrolyte imbalance. Hypotension and hypoxia may aggravate hepatic and renal injury.

Intravascular volume may decrease secondary to sequestration in the extravascular space and fluid loss through insensible losses, vomiting, and capillary leak. Invasive arterial blood pressure monitoring may be warranted.

Monitor central venous pressure, peripheral blood pressure, as well as surrogates for organ perfusion and regional blood flow (eg, capillary refill, urinary output, ScvO2). Monitor acid-base disturbances and metabolic acidosis via arterial blood gas sampling.

Replacement of red blood cells and clotting components will be necessary to treat hemorrhage and shock. Consider vasopressor support for those patients who remain hypotensive despite volume resuscitation and further management of shock.

Patients with respiratory failure, acute respiratory distress syndrome (ARDS), or both may require endotracheal intubation and mechanical ventilation. In those cases, nasogastric suction is essential to prevent gastric distention and aspiration of gastric contents.

Other points to remember include the following:

  • Renal failure may necessitate dialysis

  • H2-receptor antagonists and proton pump inhibitors may be valuable in preventing gastric bleeding

  • Use of cooling blankets and tepid sponging can reduce fever and, thus, oxygen consumption

  • Hypothermia frequently occurs late in the disease course and is corrected with gradual rewarming

  • Consider parenteral alimentation; hypoglycemia can be prevented by infusion of 10-20% glucose solution

Deterrence and Prevention

Prevention remains the cornerstone to minimizing the risk of yellow fever. Travelers to endemic areas and local populations should be vaccinated. The currently available vaccine confers near lifelong immunity in 99% of patients.[3, 29]

In 2015, the CDC's Advisory Committee on Immunization Practices and the World Health Organization (WHO) updated recommendations that a single lifetime dose of yellow fever vaccine is sufficient for most people traveling to endemic areas (based on increasing data that prolonged immunity [upwards of 30-35 years in some studies] was noted following a single vaccination). The CDC also recommends that some high-risk groups may receive a booster dose after 10 years or an additional dose before traveling to an endemic area.[30, 31]

An additional dose is recommended for the following populations:

  • Women who were pregnant (regardless of trimester) when they received their initial dose of yellow fever vaccine should receive 1 additional dose before their next travel that puts them at risk for yellow fever virus infection.
  • Persons who have undergone hematopoietic stem cell transplantation after receiving a dose of yellow fever vaccine and who are sufficiently immunocompetent to be safely vaccinated should be revaccinated before their next travel that puts them at risk for yellow fever virus infection.

A booster dose is recommended for the following high-risk populations after 10 years:

  • A booster dose may be given to travelers who received their last dose of yellow fever vaccine at least 10 years previously and who will be in a higher-risk setting based on season, location, activities, and duration of their travel.
  • Persons who were infected with HIV when they received their last dose of yellow fever vaccine should receive a dose every 10 years.
  • Travelers who plan to spend a prolonged period in endemic areas or those traveling to highly endemic areas such as rural West Africa during peak transmission season or an area with an ongoing outbreak should receive a booster dose.
  • Laboratory workers who routinely handle wild-type yellow fever virus should have yellow fever virus–specific neutralizing antibody titers measured at least every 10 years to determine if they should receive additional doses of the vaccine.
  • For laboratory workers who are unable to have neutralizing antibody titers measured, yellow fever vaccine should be given every 10 years as long as they remain at risk.

International Health Regulations allow countries to require proof of vaccination before allowing travelers to enter or leave. Travelers should have a completed International Certificate of Vaccination or Prophylaxis (ICVP). Only the most recent ICVP form CDC 731 complies with the International Health Regulations. For specific information regarding vaccination, see the CDC's Traveler's Health Web site.[22]

Preventive measures also include staying in air-conditioned or properly screened sleeping quarters and wearing protective clothing, long sleeves, and long pants. Travelers should consider using DEET (N,N -diethyl-meta-toluamide)-containing insect repellent spray.

Because of ongoing concerns for vaccination shortages, work is ongoing to develop alternate dosing, administration, or vaccine options to expand the vaccination supply.[32, 33, 34, 35] In the United States, only one vaccine is licensed by the Food and Drug Administration (FDA), YF-VAX (Sanofi-Pasteur). Manufacturing issues in the process of transitioning to a new vaccine production facility triggered YF-VAX shortages and order restrictions in 2015. Subsequently, the FDA accepted use of an alternate vaccine, Stamaril (produced in France and distributed to more than 70 countries with a similar efficacy and safety profile to YF-VAX), through an Investigational New Drug (IND) protocol in an Expanded Access Program. There are 250 US clinic sites spread throughout the country. However, vaccine recommendations for the Stamaril IND differ from YF-VAX in that breastfeeding women and children aged 6-8 months are excluded from enrollment.[36] Sites where Stamaril is available are listed at www.cdc.gov/travel/page/search-for-stamaril-clinics.[19]

In June 2016, the WHO Strategic Advisory Group of Experts on Immunization approved the use of fractional vaccine (one-fifth the standard dose) in emergency response when vaccine supplies are limited. Until long-term immunity is proven with fractional dosing, this does not meet requirements for International Health Regulations proof of vaccination; revaccination with full-dose vaccine is required, when available.[37] In the United States, fractional dosing is not recommended owing to limited efficacy data.[36]

Eradication challenges

Yellow fever will likely not be eradicated in the near future. Various mosquito species transmit the sylvatic form via nonhuman primates in the jungles and moist savannas;[6] this ongoing life cycle does not require humans for the spread of disease. Additionally, urbanization and deforestation have reintroduced the virus into areas of previous inactivity. New outbreaks and epidemics continue to reemerge in regions of Africa and South America previously not considered at risk.

At present, the burden of disease internationally is greater than the resources available for proper surveillance and mass vaccination.[8] Yellow fever also carries the potential threat of use as a bioterrorist agent;[1] however, other viral hemorrhagic fevers pose a greater risk because of their lack of prophylactic protection.

 

Medication

Medication Summary

Prior to the development of a vaccine, passive immunization was utilized in the prevention and management of yellow fever. This posed many challenges because of difficulty in obtaining sufficient amounts of human serum and subsequent serum sickness; its use was discontinued in 1936.

Present day supplies of intravenous immunoglobulin (IVIG) have been found to contain high titers of yellow fever antibodies. In 2000, an unpublished case of a patient being treated with IVIG to prevent illness prior to a trip to the Amazon was reported. Vaccination was contraindicated in this individual, who had chronic lymphocytic leukemia. Despite this event, no published reports exist of off-label use of IVIG in the treatment of yellow fever.

Currently, no approved antiviral drug against yellow fever is available. To date, nonclinical testing of antiviral agents has yielded modest results. Ribavirin, given at high doses to hamsters challenged with yellow fever, has been shown to reduce mortality when administered as late as 120 hours after infection. However, in studies of nonhuman primates, ribavirin treatment did not prolong survival. Interferon-α has also been found to reduce mortality when administered to monkeys with yellow fever; however, it was only effective when given within 24 hours of infection. A long list of novel small molecules have shown activity against yellow fever and other flaviviruses in vitro or in animal models, but none is currently available clinically.[14] These findings suggest that antiviral therapies may only be effective early in the course of disease, when clinical symptoms are nonspecific and indistinguishable from other viral infections.

Adjunctive measures include nonhepatotoxic antipyretics to reduce fever and pain and gastric acid suppression to prevent gastric bleeding. Use of heparin for documented cases of DIC is controversial. In a retrospective analysis of patients with yellow fever vaccine–associated viscerotropic disease accompanied by shock, 3 of 4 (75%) case-patients who received stress-dose steroids survived, compared with 2 of 7 (29%) patients who did not receive stress-dose steroids.[14]

Drugs to avoid include the following:

  • Drugs that act centrally, including phenothiazines, barbiturates, and benzodiazepines, because they may precipitate or aggravate encephalopathy
  • Drugs dependent on hepatic metabolism
  • Salicylates because of risk of bleeding

Vaccines

Class Summary

The live attenuated virus (17D) vaccine was created by serial passages of yellow fever virus through chick and mouse embryo cells. Dr. Max Theiler of the Rockefeller Institute developed this vaccine in 1937. Since 1945, more than 200,000,000 doses have been administered.

The WHO, United Nations Children's Fund (UNICEF), and the World Bank have recommended that yellow fever vaccine be added to the routine Expanded Program on Immunization in developing nations. However, poor financing remains a problem and a major reason for low vaccination rates among residents of endemic areas. In the United States, the yellow fever vaccine is available at designated state health departments and selected travel clinics.

Up-to-date information on yellow fever vaccination and travel requirements may be obtained by contacting Health Information for Travelers, Centers for Disease Control and Prevention, Atlanta, GA 30333, fax (404) 332-4265, document number 220022#, phone (404) 332-4559.

Yellow fever vaccine (YF-VAX)

This vaccine should be administered to residents of and travelers to endemic areas. The seroconversion rate for adults and children receiving the vaccine is 99%. Protective antibodies form within 7-10 days, and protection lasts for at least 10 years. The vaccine is safe and effective in asymptomatic adult patients with HIV and CD4 counts of greater than 200/μL. The vaccine appeared ineffective when administered to 1-year-old infants who were HIV positive (CD4 count >200/μL).

The yellow fever vaccine has been regarded as one of the safest and most effective vaccines in use. Nonetheless, the live-attenuated 17D vaccine has been shown to cause wild-type disease in a subset of patients.[12] Between 1952 and 1959, 15 cases of postvaccination encephalitis were reported after administration of vaccine[7] ; since 1945 a total of 28 cases have been reported. Sixteen of these cases occurred in infants younger than 6 months. This resulted in the restriction of vaccine use in children younger than age 6 months and in limited use in patients aged 6-9 months.

The syndrome of YEL-AND is characterized by fever, headache, and focal or generalized neurologic dysfunction. YEL-AND has been described in primary vaccinees with a reported rate of 0.25-0.8/100,000 vaccine doses. Symptomatic onset ranges from 4-23 days after vaccination. In addition to encephalitis, cases of disseminated encephalomyelitis and Guillain-Barré syndrome have been reported. Case-fatality rates are less than 5%; most individuals recover from YEL-AND without sequelae.[3, 22]

YEL-AVD is characterized by fever, jaundice, and multiorgan system failure similar to the wild-type strain. YEL-AVD has been described in primary vaccinees with a reported rate of 0.25-0.4/100,000 vaccine doses. Symptoms begin 2-5 days after immunization; they are usually mild but can be fatal. As of August 2006, more than 30 cases of YEL-AVD had been described worldwide; it has occurred only in nonimmune, first-time vaccinees. Unlike YEL-AND, YEL-AVD has been reported primarily in individuals of advanced age.[3]

The proposed cause of vaccine-associated disease is an unsuited host response to the live-attenuated 17D vaccine. Individuals younger than age 6 months and those older than age 60 years, persons with a history of thymic disease (eg, DiGeorge syndrome, thymomas, and post-thymectomy), and those with a cell-mediated immunodeficiency status (eg, cancer, transplant, human immunodeficiency virus [HIV]) are all considered to be at a greater risk of developing YEL-AND and YEL-AVD with its subsequent sequelae.[27] A careful medical history to exclude the above should be obtained before the vaccine is administered.

Histamine H2 antagonists

Class Summary

These agents are useful as an adjunctive therapy to prevent gastric bleeding. H2-receptor antagonists are highly selective, do not affect the H1 receptors, and are not anticholinergic agents. These are potent inhibitors of all phases of gastric acid secretion. They inhibit secretions caused by histamine, muscarinic agonists, and gastrin.

Ranitidine (Zantac)

Ranitidine competitively inhibits histamine at the H2 receptor of gastric parietal cells, resulting in reduced gastric acid secretion, reduced gastric volume, and reduced hydrogen concentrations.

Famotidine (Pepcid)

Famotidine competitively inhibits histamine at the H2 receptor of the gastric parietal cells, resulting in reduced gastric acid secretion, reduced gastric volume, and reduced hydrogen concentrations.

Nizatidine (Axid)

Nizatidine competitively inhibits histamine at the H2 receptor of gastric parietal cells, resulting in reduced gastric acid secretion, reduced gastric volume, and reduced hydrogen concentrations.

Cimetidine (Tagamet HB)

Cimetidine competitively inhibits histamine at H2 receptors of the gastric parietal cells, resulting in reduced gastric acid secretion, reduced gastric volume, and reduced hydrogen ion concentration.

Proton Pump Inhibitors

Class Summary

Gastric acid suppression, using H2 receptor antagonists or proton pump inhibitors, is recommended to decrease the risk of gastric bleeding.

Pantoprazole (Protonix)

Proton pump inhibitors suppress gastric acid secretion by inhibiting the parietal cell H+/K+ ATP pump

Esomeprazole (Nexium 24HR, Nexium)

Proton pump inhibitors suppress gastric acid secretion by inhibiting the parietal cell H+/K+ ATP pump

Omeprazole (Prilosec, Prilosec OTC)

Proton pump inhibitors suppress gastric acid secretion by inhibiting the parietal cell H+/K+ ATP pump

Antipyretics

Class Summary

Treatment of yellow fever is symptomatic and supportive. Bed rest and mild analgesic-antipyretic therapy often help to relieve associated lethargy, malaise, and fever. Salicylates should be avoided because of bleeding risk.

Acetaminophen (Tylenol, Aspirin-Free Anacin, FeverAll, Cetafen)

Acetaminophen inhibits the action of endogenous pyrogens on heat-regulating centers. It reduces fever by direct action on the hypothalamic heat-regulating centers, which, in turn, increase dissipation of body heat via sweating and vasodilation.