AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Yellow fever is a viral hemorrhagic fever (VHF) caused by the Flavivirus yellow fever virus. Currently, 3 genotypes in Africa and 2 in South America have been isolated. Yellow fever can present with a spectrum of disease, from asymptomatic illness to acute-onset viral sepsis, fever, myalgias, jaundice, and bleeding dyscrasias. Half of affected individuals who advance to the toxic phase die from the disease. At-risk areas include 33 countries in Africa, 9 countries in South America, and several Caribbean islands.

The animal reservoirs for yellow fever are monkeys, and the vectors include several different species of mosquitoes. Aedes aegypti is an effective vector in urban settings. Other Aedes species and Haemagogus mosquitoes play a major role in sporadic disease in rain forests. Transmission cycles include sylvatic, intermediate, and urban. The sylvatic cycle (jungle cycle) is maintained by monkeys infected by mosquitoes. Humans are incidentally introduced into the cycle when logging and agricultural activities encroach in these areas.

Intermediate transmission cycles occur in African areas where monkey habitats abut human villages. The mosquitoes are semi-domestic, breeding in tree holes, and the local populations are seasonally exposed.

The cycle can extend into an urban cycle with the appropriate mix of domestic mosquitoes and an unvaccinated population. A aegypti breeds in urban water containers, allowing mosquito transmission of virus from human to human. During the dry season, the virus survives in mosquito ova, with new progeny hatching during the subsequent rainy season.

In addition to current outbreaks, the illness has a rich history. The earliest mention of yellow fever was in 1648, in a Mayan manuscript that described sickness affecting Guadeloupe and the Yucatan peninsula. The virus is believed to have originated in Africa 3000 years ago. "Yellow Jack" caused outbreaks through the Atlantic shipping lanes. The disease had such an impact on the local economies that, in 1803, Napoleon, with troop populations decimated by yellow fever, had few reservations about selling the affected Louisiana and western territories to the US government.

Many waves of epidemics occurred in the United States: Philadelphia had 20; New York, 15; Boston, 8; and Baltimore, 7. The famous Philadelphia epidemic of 1793 was described by Benjamin Rush, who mistakenly attributed it to rotting coffee left on the Arch Street wharf. At the time, Philadelphia had a population of approximately 50,000, with 11,000 infected and 5,000 subsequent deaths.

Yellow fever decimated American troop populations in the Spanish-American War, prompting the appointment of a Yellow Fever Commission. Dr. Walter Reed (for whom the famous army hospital is named) was named to head it. In September 1900, his commission concluded the virus vector was the mosquito and that yellow fever could be experimentally transmitted from one human via infected blood. Without an animal model, the studies relied on human volunteers. Although the commission was actively attempting to infect humans with potentially lethal doses of virus, they were pioneers in the first forms of informed consent.

In 1848, Josiah Clark Nott suggested mosquitoes as the source of infection, but CJ Finlay published his theory of mosquito transmission in 1881. In 1927, Drs. Bauer and Mahaffy (also of the Yellow Fever Commission) discovered that the cause of yellow fever was a filterable virus. In 1937, Dr. Theiler at the Rockefeller Institute created the still-used live attenuated virus (17D) vaccine.

After large vaccination campaigns and A aegypti control programs decreased yellow fever numbers, the disease saw a resurgence in the late 1980s. Vaccination programs in the poorest at-risk countries fell short, with outbreaks in West Africa and Peru occurring from 1994-1995. According to the World Health Organization (WHO), in 1996, only 5 of 34 African countries had yellow fever vaccine coverage.

The highly effective, live, attenuated 17D vaccine has been used for 65 years with few complications. Less than 5% of patients develop low-grade fevers, general malaise, myalgias, and injection site reactions. The serious reactions of yellow fever vaccine–associated neurotropic disease (YEL-AND) and yellow fever–associated viscerotropic disease (YEL-AVD) are rare but do occur.

YEL-AND presents as a postvaccination encephalitis and is described in scattered case reports. Most of these cases occurred early in the vaccination's usage in infants, before the restriction of the vaccine to patients older than 9 months. YEL-AVD appears as a wild-type infection after primary vaccination in a nonimmune patient. The mortality rate is similar to that of wild-type infection obtained in South America. The estimated incidence is 2.2 per million in the general population but increases with age. Patients older than 70 years have a 13-fold increased risk of serious adverse event over young healthy adults. International health regulations require vaccination at 10-year intervals; however, the immunity afforded by the vaccination likely lasts for 30-35 years, perhaps for life.

Pathophysiology

Yellow fever is a positive-sense, single-stranded, RNA-enveloped Flavivirus with a diameter of about 50-60 nm. The virus enters the cell by receptor-mediated endocytosis and, after RNA synthesis in the cytoplasm and protein synthesis in the endoplasmic reticulum, the virions are released through the cell membrane. Its viral envelope contains a lipid bilayer taken from the infected cell. It has various structures that aid in virulence and viral replication.

• Capsid protein C forms the nucleocapsid, and its charged ends are likely involved in binding viral RNA to the membrane.
• Membrane protein M is a minor glycoprotein that may act as a chaperonelike protein, aiding in the folding of E proteins.
• E proteins initiate infection and mediate viral entry, and antibodies to the E epitope interfere with internalization of the virus.
• Nonstructural protein 1 (NS1) is found in infected cells as a secreted protein and on the surface of cells. It may have 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 large role in RNA replication and may be the polymerase.

At the site of the mosquito bite, viral replication begins. 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 of the body, 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 one of the last stages to occur; the midzonal hepatic cells undergo apoptotic cell death. The virus is recoverable from these midzonal areas, indicating that the damage is due to direct viral effect. In fatal cases, up to 80% of hepatocytes are involved. As the liver is increasingly damaged, coagulopathies develop because of a decreased synthesis of vitamin K–dependent clotting factors and disseminated intravascular coagulation.

Viral antigens are found diffusely in kidneys, myocardium, and hepatocytes. If patients survive, recovery is complete with no residual fibrosis. 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)–a.

Frequency

United States

Reports of yellow fever in the United States are exceedingly rare and involve travelers who have returned from endemic areas. The last US outbreak was in 1905 in New Orleans.

International

Annually, up to 5000 cases are reported in Africa and 300 in South America, but, because of significant underreporting, the actual number of cases is much higher. The WHO estimates the number of cases at 200,000 cases per year, with the highest proportion in sub-Saharan Africa.

Mortality/Morbidity

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

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

Race

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

Sex

• South American cases are sporadic and usually occur in the population exposed to tropical rain forests. Most of the laborers engaged in logging and clearing land are males aged 14-45 years.
• In African cases, in which undervaccination of endemic populations has led to higher infection rates in children, a slight predilection exists for males.

Age

• African cases occur seasonally in villages with contact with semi-domestic 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

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

A travel history is critical in these patients, specifically targeting travel to tropical areas of Africa, South America, Trinidad, and Tobago in the Caribbean within the prior several weeks. Also important is vaccination against yellow fever within 10 years of presentation and a history of yellow fever, leptospirosis, or malaria infection.

• Once infected by the bite of a mosquito, the incubation period is 3-6 days, followed by a spectrum of disease that ranges from mild illness to hemorrhagic fever and death. Most patients develop this mild illness, presenting with mild fever and malaise.
• More serious illness develops in 15% of cases and presents with abrupt onset of general malaise, fever, chills, headache, lower back pain, nausea, and dizziness. The patients have pulse-fever dissociation (Faget sign), conjunctival injection, and facial flushing. The fever lasts for 3-4 days. Laboratory studies are usually significant for 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. Patients may either recover or, in up to half of patients, progress to fatal illness.
• The return of symptoms is called the period of intoxication. At this time, viremia decreases and humoral responses are seen. This stage is marked by fever, vomiting, abdominal pain, renal failure, and hemorrhage. Patients may form petechiae, ecchymoses, and epistaxis and may ooze blood from gums and venipuncture sites. Bleeding can worsen to include melena, hematemesis, and metrorrhagia. Jaundice worsens as the transaminitis increases, with serum aspartate aminotransferase (AST) levels typically higher than alanine aminotransferase (ALT) levels secondary to direct viral injury to skeletal muscle tissue and myocardium. This myocardial injury is seen in ST-T wave abnormalities, or occasionally by dilated cardiomyopathy. As the liver incurs more damage and consumption coagulopathy develops, patients have 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%; death usually occurs 7-10 days after the illness begins. The fatal end stage of the disease includes delirium, stupor, and coma, as patients have hypotension, hypoglycemia, hypothermia, and metabolic acidosis. Patients develop cerebral edema and microscopic perivascular hemorrhage. Those that survive to convalesce are weak and fatigued for weeks.
• The fever pattern is biphasic and is called a dromedary pattern, reflecting the 3 phases of the illness described above. In the acute phase, fevers may be high, with relative bradycardia. The saddle occurs during the secondary stage, when temperatures normalize. In the intoxication phase, fevers recur.

Physical

In the acute phase of the illness, clinical signs may be nonspecific. Fever, bilious vomiting, relative bradycardia, and conjunctival injection may be the only findings.

• In the toxic phase of illness, other findings develop, including jaundice.
• Hepatomegaly and right upper quadrant tenderness to palpation may be noted.
• Signs of bleeding dyscrasias with petechiae, ecchymoses, epistaxis, and oozing from gums and venipuncture sites may be observed.
• Arrhythmias are common, as are hypotension and shock that are frequently unresponsive to fluid resuscitation.
• Late clinical signs include delirium, stupor, and coma.
• The patient may become hypothermic.

Causes

Travel into endemic area without prior vaccination and a subsequent bite by an infected mosquito is the cause of yellow fever.

• International travelers and local residents in yellow fever–endemic areas should be vaccinated.
• To reduce the risk of exposure to infected mosquitoes, proper insect netting and repellant should be used.
• Local control programs against A aegypti were successful in the past, but, with funding lapses, this mosquito has reinfected many areas previously cleared of the vector.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Louse-borne relapsing fever
Hemorrhagic fevers (dengue hemorrhagic, Rift Valley, Venezuelan, Bolivian, Argentine, Lassa, Crimean-Congo, Marburg, and Ebola fevers)
Liver failure (other causes)
Toxic hepatitis

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Complete blood cell count
• • Leukopenia with relative neutropenia can occur.
  • Thrombocytopenia can occur as part of a consumptive coagulopathy.
  • Initial hemoconcentration is present, with increased hemoglobin and hematocrit levels.
  • Subsequent hemorrhage and hemodilution results in decreasing complete blood cell counts.
• Coagulation studies
• • Reduced fibrinogen and clotting factors II, V, VII, VIII, IX, and X and the presence of fibrin split products indicate disseminated intravascular coagulation.
  • An elevated prothrombin time may develop secondary to decreased synthesis of clotting factors.
  • Patients have prolonged clotting times.
• Chemistries
• • Renal damage is evidenced by significant azotemia.
  • Serum creatinine can be 3-8 times the reference range.
  • Hypoglycemia develops as severe liver damage occurs.
  • Because of vomiting, volume status, and renal failure, acid-base disorders are common.
• Urinalysis
• • Renal damage is evidenced by markedly elevated levels of urinary protein.
  • Elevated urobilinogen levels are also frequently present.
• Liver function tests
• • Transaminitis precedes the appearance of jaundice, and the degree of liver dysfunction in the acute phase may be predictive of the clinical course.
  • Serum aspartate transferase (AST) levels exceed alanine transferase (ALT) levels.
  • Direct bilirubin levels are elevated.
• Serum albumin: Albuminuria, decreased synthesis, and extravasation of albumin through damaged capillary endothelium cause reductions in serum albumin levels.
• Specific tests for yellow fever virus
• • Rapid detection methods include the following:
  • • Detection of yellow fever antigen by monoclonal enzyme immunoassay in serum specimens
    • Detection of viral genome sequences in tissue or blood using polymerase chain reaction (PCR)
  • Yellow fever virus is isolated from viral culture with the following:
  • • Intracerebral inoculation of suckling mice, inoculation of mosquito cell cultures (Aedes pseudoscutellaris AP61), or intrathoracic inoculation of mosquitos are the most sensitive media for virus isolation.
    • Mammalian cell cultures (Vero, SW13, BHK-21) combined with PCR of immunostaining can also be used.
  • Serologic studies include the following:
  • • Immunoglobulin M (IgM) antibody-capture enzyme-linked immunosorbent assay (MAC-ELISA) is used to detect the specific presence of IgM for yellow fever; a single positive serum titer is diagnostic.
    • IgM appears 7-10 days following infection.
    • A 4-fold rise in hemagglutination inhibition, complement fixation, or neutralization of antibodies in acute and convalescent phases is diagnostic.
    • Yellow fever virus and other flaviviruses cross-react, complicating serological diagnoses.
  • Other diagnostic methods include the following:
  • • Histopathologic lesions compatible with those of yellow fever or detection of virus in tissue using immunohistochemical staining
    • Indirect fluorescent antibody tests are used to detect monoclonal antibodies to yellow fever virus and flaviviruses in AP61 cells in tissue culture.

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 head CT scan of the brain is helpful in determining whether intracranial hemorrhage is the cause.

Other Tests

• ECG and cardiac monitoring
• • Arrhythmias are common because of myositis.
  • Cardiac involvement by yellow fever is evidenced by ST-T wave abnormalities.
  • Electrolyte abnormalities, hypoxia, or hypoperfusion states also are common causes of arrhythmias in patients who are severely ill.

Procedures

• Liver biopsy can aid in diagnosis; however, it should not be performed premortem because of the significant risk of hemorrhage.

Histologic Findings

Liver biopsy: In the acute phase of illness, the liver grossly has a mottled yellow (boxwood) color and is friable. The typical changes due to yellow fever include midzonal necrosis with sparing of cells around the central vein and portal tracts, steatosis, and eosinophilic degeneration of hepatocytes, with condensed nuclear chromatin. These condensed chromatin particles are called Councilman bodies. Late in the illness, biopsy may reveal only severe, nonspecific necrotic changes.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

No specific treatment exists for yellow fever.

• 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.
  • Endotracheal intubation may be required in patients with significant hemorrhage, pulmonary edema, secondary bacterial infections, and shock.
  • Central venous access may be required for vasopressors andmedications when patients enter the toxic stage of the illness.
  • To manage the coagulopathy, various recommendations have been made, as follows:
  • In actively bleeding patients, administer fresh frozen plasma to maintain prothrombin time at 25-30 seconds.
  • In patients with disseminated intravascular coagulation, heparin has been recommended for treatment.
  • 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.
• Because viremic patients bitten by mosquitos can transmit the virus to other patients, the patient should be isolated with mosquito netting in areas with potential vector mosquitos.
• Yellow fever 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.
• 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.

Surgical Care

No surgical care changes the course of yellow fever. In addition, liver biopsy is contraindicated in living patients given the risk of hemorrhage.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: Vaccines

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. 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.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Deterrence/Prevention

• Because treatment for yellow fever is supportive, the most important part of yellow fever care is prevention. Travelers entering into endemic areas and local residents in endemic areas should be vaccinated. Many countries require proof of yellow fever vaccination before visitors are allowed to enter the country.
• Local control programs against A aegypti that remove breeding sites were successful in the past, but, with funding lapses, this mosquito has reinfected many areas previously cleared of the vector.
• Protective clothing, insect repellent, and mosquito netting should be used in endemic areas.

Complications

• Liver failure
• Renal failure
• Pulmonary edema
• Myocarditis
• Secondary bacterial infections
• Hemorrhage or disseminated intravascular coagulation
• Encephalitis (rare)
• Shock or death

Prognosis

• Patients who present in the toxic stage face a mortality rate of up to 50%.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to diagnose specific treatable conditions resembling yellow fever may prove fatal for the patient.
• Failure to recommend yellow fever vaccination for international travelers going to endemic regions may be a source of liability.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Baker TD. Yellow fever and Maryland physicians. Md Med J. Oct 1989;38(10):801-3. [Medline].
• McFarland JM, Baddour LM, Nelson JE, et al. Imported yellow fever in a United States citizen. Clin Infect Dis. Nov 1997;25(5):1143-7. [Medline].
• Peters CJ. Infections caused by arthropod- and rodent-borne viruses. In: Braunwald E, ed. Harrison's Principles of Internal Medicine. 14th ed. New York, NY: McGraw Hill, Inc;. 1998:1133-46.
• Robertson SE, Hull BP, Tomori O, et al. Yellow fever: a decade of reemergence. JAMA. Oct 9 1996;276(14):1157-62. [Medline].
• Thompson C, O''Leary JP. Yellow fever in New Orleans. Am Surg. May 1996;62(5):424-6. [Medline].
• Tsai TF. Yellow fever virus. In: Gorbach SL, Bartlett JG, Blacklow NR, eds. Infectious Diseases. 2nd ed. Philadelphia, Pa: WB Saunders and Co;. 1998:2234-37.
• Van der Stuyft P, Gianella A, Pirard M, et al. Urbanisation of yellow fever in Santa Cruz, Bolivia. Lancet. May 8 1999;353(9164):1558-62. [Medline].
• Woodward TE. The fever pattern as a diagnostic aid. In: Mackowiak PA, ed. Fever: Basic Mechanisms and Management. 2nd ed. Philadelphia, Pa: Lippincott-Raven;. 1997:215-35.

Article Last Updated: Aug 11, 2006