Introduction
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 68 arthropod transmitted viruses, of which 30 are known to cause human disease. Other flaviviral infections include dengue, Japanese encephalitis, 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. Image courtesy of the Centers for Disease Control and Prevention.
Yellow fever is transmitted by tree-hole breeding mosquitoes (Haemagogus janthinomys, Haemagogus species, Sabethes chloropterus, and Aedes species) during the tropical wet season and early dry season.1 Genomic sequence analyses suggest that it 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 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 continued importation of slaves from West Africa. Vessels infested with Aedes aegypti (mosquitoes) brought yellow fever into New England and several port cities throughout North America.
In the early 20th century, Carlos Findlay and Walter Reed's discovery of A aegypti as the source of 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 eliminate A aegypti and yellow fever from countries in Africa and the Americas during the mid 20th century.2
A resurgence of yellow fever occurred in South America and sub-Saharan Africa in the late 1980s.3 This was likely the result of fragmentary vaccine implementation, deforestation, urbanization, and climate change.4 Today, outbreaks occur regularly in Africa and South America, with significant variation in annual incidence by country and region.3
Pathophysiology
Seventy-three species of flaviviruses have been identified; yellow fever virus was the first to be isolated (1927) and grown in vitro (1932).1 It is a small (40-60 nm), single-stranded, RNA virus. Although 7 strains exist, there is only one serotype; this enables one vaccine to protect against all strains.3 After a bite from an infected mosquito, the virus replicates initially in local lymph nodes, followed by blood-borne spread and subsequent replication in regional lymph tissue, spleen, and bone marrow. It later spreads to the liver, lungs, and adrenal glands.
The liver is the most important organ affected in yellow fever. Hepatocellular damage is characterized by lobular steatosis, necrosis, and apoptosis with subsequent formation of Councilman bodies (degenerative eosinophilic hepatocytes).5 The kidneys also undergo significant pathologic changes. Albuminuria and renal insufficiency evolve secondary to the prerenal component of yellow fever; resultantly, 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.
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.
Frequency
United States
The last epidemic of yellow fever in North America occurred in New Orleans in 1905. However, during 1970-2002,9 cases of yellow fever were reported in unimmunized travelers from the United States and Europe—disease was acquired in Brazil, Senegal, Venezuela, Ivory Coast, Gambia, and West Africa. Seven of these cases were fatal.3,6
After the 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.7 Recent virology research has isolated Flaviviridae strains from mosquitoes in eastern Texas, making transmission of yellow fever a potential threat for the United States in the future.8
International
Approximately 200,000 cases of yellow fever occur annually, with about 30,000 deaths.9 Accurate incidence reporting is limited by the occurrence of asymptomatic disease, underreporting of the disease, and the lack of diagnostic capabilities in endemic areas.3 Ninety percent of reported cases occur in Africa,6 where A aegypti species is rampant. Transmission occurs in largely unvaccinated populations of sub-Saharan Africa. The countries at greatest risk lie within a band from 15°N to 10°S of the equator.9
Global distribution of yellow fever. Image courtesy of the Centers for Disease Control and Prevention.
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In South America, the rate of transmission of yellow fever is lower than in Africa, this is in part due to greater vaccine coverage throughout the continent. 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 (also known as jungle) form of yellow fever.9,10 The majority of these cases occurred in young men working in the forests.
In early 2008, Paraguay and Brazil reported their first cases of yellow fever in 30 years.3 Recent outbreaks in urban areas of South America have been due to deforestation, population migration, and the resultant emergence of A aegypti species.10 Countries considered at greatest risk include Bolivia, Brazil, Colombia, Ecuador, and Peru. 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). Although yellow fever has never been reported in Asia, this region is at risk because the appropriate primates and mosquitoes are present.9
Though 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 1:1333 risk of death from illness. The corresponding risks for persons traveling to South America are about 10% lower.11
Mortality/Morbidity
Yellow fever ranges in severity from a self-limited infection to life-threatening hemorrhagic fever. About 15-25% of affected individuals enter into a more severe phase of disease that involves fever, jaundice, and liver and renal failure. Overall mortality ranges from 20-50%.4 Case-fatality rates in South America are reportedly higher than in West Africa.3
Mortality is a function of both host susceptibility and the virulence of the infecting strain.5 Infancy and age older than 50 years is associated with increased severity of illness and lethality.3 Transaminase levels increase relative to the degree of hepatic injury. Early appearance of jaundice indicates a poor prognosis.
Race
No known racial predilection is known in the transmission or contraction of yellow fever.
Sex
Sylvatic (jungle) yellow fever, which is primarily acquired by forest workers,9 is most common among healthy young males because of occupational risk.
Age
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.9
Clinical
History
To arrive at a diagnosis of yellow fever, consider the patient's clinical features and his or her places and dates of travel, including the epidemiologic history of the places visited, immunizations, and activities.
- An incubation period of 3-6 days indicates that travelers may be viremic before demonstrating symptoms.
- Clinical symptoms manifest in 1:20 partially immune patients and 1:5 immunologically naive patients.
- Initial symptoms correspond to the viremic phase (ie, period of infection). They have an abrupt onset and are followed by a transient (up to 48 h) remission:3
- Fever and chills
- Severe headache
- Back pain
- Myalgia
- Nausea
- Prostration
- The toxic phase (ie, period of intoxication) of yellow fever develops as the fever returns. This phase occurs in approximately 15% of cases.
- Clinical symptoms include high fever, headache, lumbosacral back pain, nausea, vomiting, abdominal pain, and somnolence.
- Hepatic-induced coagulopathy produces hemorrhagic manifestations, including the characteristic black vomit (hematemesis), epistaxis, gum bleeding, and petechial and purpuric hemorrhages.
- Systemic manifestations include deepening jaundice and albuminuria.
- In the late stages of disease hypotension, shock, metabolic acidosis, acute tubular necrosis, myocardial dysfunction, and arrhythmia dominate the clinical picture.
- Confusion, seizure, and coma distinguish the late CNS manifestations of the disease. Death usually follows within 7-10 days of onset.
- Secondary bacterial infections are frequent complications in patients who survive the critical period of illness.
Physical
Physical findings of yellow fever are as follows:
- Altered mental status
- Fever
- Relative bradycardia for the degree of fever (Faget sign)
- Conjunctival injection
- Other physical findings such as jaundice, epigastric tenderness, and hepatomegaly develop as disease progresses.
- Hemorrhagic PE findings as described in History
- Shock, multiorgan system dysfunction, acute respiratory distress syndrome (ARDS)
Causes
Early signs of disease are likely due to the innate immune response to infection. The release of proinflammatory mediators initiates a cascade of events leading to apoptosis. Additionally, clearance of infected cells by cytotoxic T lymphocytes contributes to the production of oxygen free radicals and subsequent cell damage. The terminal events of shock and multiorgan failure are believed to be due to a combination of direct parenchymal damage and a systemic inflammatory response. With similar cytokines and chemoattractant proteins, the syndrome seen in end-stage yellow fever closely resembles that of overwhelming sepsis.5
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Further Reading
Keywords
yellow fever symptoms, yellow fever vaccine, flavivirus, Aedes aegypti, group B arbovirus, attenuated 17D vaccine, flaviviral infections, dengue, Japanese encephalitis, tick-borne encephalitis, hemorrhagic fever, acute febrile illnesses with arthropathy
