eMedicine Specialties > Infectious Diseases > Gastrointestinal Tract and Intra-abdominal Infections

Yellow Fever

Author: Mary T Busowski, MD, Fellow, Infectious Diseases, Orlando Health
Coauthor(s): Mark Raymond Wallace, MD, Infectious Disease Fellowship Director, Orlando Regional Healthcare; Clinical Professor of Medicine, Florida State University; Janelle L Robertson, MD, Staff Physician, Department of Infectious Diseases, Wilford Hall Medical Center
Contributor Information and Disclosures

Updated: Apr 17, 2009

Introduction

Background

Yellow fever is a mosquito-borne, viral hemorrhagic illness. A flavivirus infection, yellow fever can manifest as a spectrum of presentations, ranging from asymptomatic illness to acute-onset viral hepatitis and hemorrhagic fever.

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.¹ Benjamin Rush described the epidemic and, based on the science of the time, sought to contain the devastating illness. Yellow fever did not discriminate by gender, race, occupation, or socioeconomic status. Yellow fever may have played a part in shaping the decision to move the nation's capital out of Philadelphia.¹ 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 man's struggle with yellow fever has shaped world history. The French effort to develop the Panama Canal was not lost in engineering failures, but by disease. Frenchmen died of yellow fever in alarming numbers, leading to Panama being coined "the white man's graveyard." It was not until 1900 that US Army Major Walter Reed, following the lead of Dr. Carlos Finlay, demonstrated that the mosquito was the carrier of yellow fever. The viral causation would not be described until 1928. US Army colonel William Crawford Gorgas was ordered by President Theodore Roosevelt to rid Panama of yellow fever. Gorgas had success in Cuba during the Spanish-American War, and his team would make a lasting mark, not only on the Canal Zone but also on the history of medicine.²

Monkeys serve as animal reservoirs and several species of mosquitoes as vectors. Aedes aegypti is an effective vector in urban settings. Other Aedes species and Haemagogus mosquitoes play a major role in sporadic cases of yellow fever in rain forests. Transmission cycles include the sylvatic, intermediate, and urban. The sylvatic, or jungle, cycle is maintained by monkeys infected by mosquitoes. Infected wild mosquitoes infect humans who enter the rain forest.

Intermediate transmission cycles occur in semihumid savannas of Africa. Semidomestic mosquitoes infect both monkeys and humans. Urban-type epidemics of yellow fever can arise when unvaccinated humans come into contact with domestic mosquitoes.

The appropriate mix of domestic mosquitoes with a dense unvaccinated population can lead to large epidemics of urban yellow fever. Monkeys are not involved in disease transmission. A aegypti can breed in urban water containers, allowing mosquito transmission of virus from human to human.

Large vaccination campaigns and A aegypti control programs have decreased the incidence of yellow fever worldwide. Despite the availability of an effective live-attenuated 17D vaccine, yellow fever has reemerged across Africa and South America. The populations at highest risk for the illness are those in the poorest countries in the world that lack funding or infrastructure to support a widespread vaccination program. A aegypti mosquitoes are now present in the Americas, and there is a concern that large yellow fever outbreaks could occur.

Flaviviruses, including those that cause yellow fever, also have a potential use as a biologic weapon.³ For more information, see the article CBRNE - Viral Hemorrhagic Fevers in eMedicine’s Emergency Medicine volume.

Pathophysiology

Yellow fever virus is a positive-sense, single-stranded, 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 follows.

The virus gains entrance through receptor-mediated endocytosis. RNA synthesis occurs in the cytoplasm and protein synthesis in the endoplasmic reticulum. Virions are released through the cell membrane. Its 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 is a minor glycoprotein.
• E proteins initiate infection and mediate viral entry.
• Nonstructural protein 1 (NS1) may play a role in RNA replication.
• NS2A protein is 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.

The infection quickly disseminates to 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.

Liver involvement is a late manifestation of the infection. Direct viral effects lead to apoptotic cell death of the midzonal hepatic cells. Vitamin K–depleted clotting factors and disseminated intravascular coagulation lead to coagulopathy and bleeding. Hepatic involvement is associated with higher risk of mortality.

Finally, circulatory shock develops secondary to cytokine storm, with evidence of increased levels of interleukin (IL)–6, IL-1 receptor antagonist, inferno-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.

Frequency

United States

• Reports of yellow fever in the United States are exceedingly rare, with the last outbreak reported in New Orleans in 1905. It is a rare cause of illness in returning travelers. In 1999, he Centers for Disease Control and Prevention (CDC) reported a case of fatal yellow fever in a previously healthy California man who had returned from a 10-day trip to Venezuela. A second case of fatal yellow fever was reported in 1996 in a US resident returning from South America. Prior to these reports, the last case was reported in 1924. Neither patient had received a yellow fever vaccine prior to travel.⁴
• 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 1988.⁴ Without proper precautions, including vaccination, these travelers are at risk of contracting yellow fever.
• A aegypti mosquitoes are present in the southeastern United States, making the outbreak of yellow fever in that region a potential risk.⁵

International

• After adjustment for underreporting, an estimated 200,000 cases of yellow fever occur annually, with 30,000 deaths per year.⁵
• Thirty-three countries in Africa are at risk. Transmission in Africa is facilitated by the close proximity of vector mosquito populations to unvaccinated human populations.⁶ The case-fatality rate of yellow fever in Africa approximates 20%. Infants and children are at highest risk.⁷
• Yellow fever is endemic in 9 South American countries and several Caribbean islands. Bolivia, Brazil, Ecuador, and Peru are considered at highest risk.⁵ 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.⁷ Yellow fever occurs most frequently in young men through occupational exposure in forested areas.
• 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.⁵
• 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. For travelers, the risks of death and illness due to yellow fever is estimated to be 10 times greater in West Africa than in South America.⁷
• US travel data from 1996-2004 describes the overall risk for serious illness and death due to yellow fever estimated to be 0.05-0.5 per 100,000 travelers to yellow fever–endemic areas.⁷

Mortality/Morbidity

The case-fatality rate of yellow fever has been reported at 5%-70%.

• In recent outbreaks, the fatality rate was approximately 20% among patients with jaundice.
• Up to 50% of patients who progress to the toxic phase die.

Race

Yellow fever has no specific racial predilection; however, affected areas include 9 countries of South America, tropical areas of Africa, and several of the Caribbean islands.

Sex

• 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.
• 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

• African cases of yellow fever occur seasonally in villages in contact with semidomestic mosquitoes. In these populations, nonimmunized children are at the highest risk.
• In South American populations, young adults and adult forced-labor populations are at the highest risk.

Clinical

History

A correct diagnosis of yellow fever requires a high degree of suspicion based on a history of travel to an endemic area, as well as a vaccination history.

• After an incubation period of 3-6 days, most individuals with yellow fever have a mild, self-limiting illness consisting of fever, headache, myalgia, and malaise.
• 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. This is followed by a period of remission, with normalization of symptoms and temperature for up to 24 hours. The patient may then either recover or progress to fatal illness (up to half of cases).
• Remission followed by the return of symptoms is classified as the period of intoxication. Viremia is reduced, and humoral-mediated reactions are responsible for marked physical illness.³ 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 fibrinogen and clotting factors II, V, VII, VIII, IX, X, and 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

In the acute phase of yellow fever, clinical signs may be nonspecific, including fever, bilious vomiting, relative bradycardia, and conjunctival injection.

• The toxic phase of yellow fever is characterized by fever, headache, lumbosacral back pain, profound weakness, somnolence, and jaundice.
• Hepatomegaly and right upper quadrant pain may occur.
• Signs of bleeding dyscrasias develop, with petechiae, ecchymoses, epistaxis, and oozing from gums and venipuncture sites.
• Arrhythmias are common, as are hypotension and shock, frequently unresponsive to fluid resuscitation.
• Late clinical signs include hypothermia, delirium, stupor, and coma.

Causes

• Yellow fever is caused by infection with yellow fever virus, which is transmitted by the bite of vector mosquitoes.
• Despite a highly effective vaccine developed over 60 years ago, yellow fever is a re-emerging infection owing to decreased vector-control strategies and decreased use of vaccines in endemic areas.
• Large susceptible nonimmune populations in tropical countries with ongoing virus life-cycle in the rain forests are constantly at risk for yellow fever outbreaks.⁸

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