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 (YF) is a mosquito-borne viral infection endemic to Africa and South America. It is characterized by variable symptoms ranging from a minimal flulike illness to one that may be complicated by a toxic phase characterized by hemorrhage, hepatic failure, proteinuria, renal failure, and death. The mortality rate is 20-50%. YF virus, an arbovirus, is the type species for the family Flaviviridae and is a single, positive-stranded, enveloped RNA virus. The envelope consists of a lipid bilayer containing an envelope glycoprotein and a matrix protein. The single RNA is complexed with a capsid protein.

Immediately report all suspected or confirmed cases of YF to local and state health departments, which then report immediately to the Division of Global Migration and Quarantine (telephone: 1-404-498-1600) or Division of Vector-Borne Infectious Diseases (telephone: 1-970-221-6400), Centers for Disease Control and Prevention (CDC). If local or state health departments cannot be reached, contact the CDC directly.

All travelers going to destinations in the tropics or developing countries should at least see a health provider who is familiar with traveler's health recommendations from public health agencies. One source of such recommendations is the Traveler's Health page of the CDC.

History and epidemiology

Diseases described in texts as old as 400 years match YF. Major 18th- and 19th-century epidemics occurred in Africa, the Caribbean, Central America, Europe, North America, and South America. In 1793, an epidemic in Philadelphia resulted in the death of approximately 10% of the city's population. In 1881, Carlos Finlay proposed the mosquito-borne transmission of YF. In 1900, Walter Reed and colleagues observed that the infectious agent, a filterable virus, was transmitted by means of a mosquito bite. General Gorgas acted on this information, rapidly eliminating YF from Havana with a mosquito-eradication program. In 1905, the last major YF outbreak occurred; this was in New Orleans. In 1927, YF virus from a viremic man from Ghana was isolated in Rhesus monkeys. Viral strains from South America are closely related to those from West Africa. This observation supports the supposition that YF virus originated in West Africa.

In the 1930s, French and American investigators independently developed effective and safe vaccines. In 1932, a jungle transmission cycle was demonstrated. (See Transmission for a discussion of the 3 types of YF transmission cycle.) Vigorous measures of mosquito control (primary) and vaccination (secondary) led to the elimination of YF during the early 20th century from all areas of the world except parts of Africa, South America, and the Caribbean. In 1942, the last major urban epidemic in the Western Hemisphere (Brazil) occurred. However, jungle transmission persists. With the new reinfestation of Aedes aegypti mosquitoes in South America, the threat of epidemic transmission has resurfaced. Urban and jungle transmissions persist in Africa (West, Central, and East), with periodic large outbreaks.

Reemergence has occurred since 1985, as reflected in the number of cases per year officially reported to the World Health Organization (WHO) (see Frequency). Urban reemergence in South America may occur because of 3 factors: (1) The reinvasion of A aegypti since 1980 is probably related in part to a reduction in mosquito-control measures (see Transmission). (2) The juxtaposition of areas of jungle transmission and areas of A aegypti infestation allow the latter to become reinfected. (3) The lack of YF vaccination in densely populated areas outside of the traditional jungle transmission zone creates huge populations at risk.

Areas of endemic YF

In Africa, YF occurs in areas between 15° north and 10° south of the Equator, a region encompassing 34 countries with a total population of nearly 500 million people.

Yellow fever is also transmitted in Panama south of the canal zone and in Trinidad.

In South America and the Caribbean, enzootic countries include Bolivia, Brazil, British Guyana, Colombia, Ecuador, French Guyana, Panama (south of the Canal Zone), Peru, Surinam, Trinidad, and Venezuela. Human cases were reported in the 1990s in Bolivia, Brazil, Colombia, Ecuador, and Peru.

In Asia, although conditions currently exist for the transmission of YF in Asia, no documented transmission has occurred there. Evidence suggests that previous infection with another flavivirus (eg, those causing dengue) may confer protection from YF. This has been cited as the reason why YF has not been observed in Asia.

Although the conditions exist for the transmission of yellow fever on the Indian subcontinent, no such transmission is reported.

Transmission

Jungle (sylvatic) cycle

The mosquito transmits the virus to wild nonhuman primates (or possibly an incidental human host), and then it is transmitted to another mosquito. This cycle is confined to rain forests, and human hosts are usually males working in the forests clearing trees. In Africa, Aedes species not including A aegypti are implicated, while Haemagogus species are involved in South America.

Urban cycle

The mosquito transmits the virus to a human host, and then it is transmitted to another mosquito. Confined to urban areas, A aegypti, a domestic mosquito that breeds in human-made containers, is the primary vector.

Intermediate cycle

The mosquito transmits the virus to wild nonhuman primates and human hosts, and then it is transmitted to another mosquito. Confined to moist savannas and forest savanna ecotones of Africa, this is the most common cycle for outbreaks in Africa. Many villages in a given area are affected simultaneously. Mortality appears to be lower with these outbreaks. Semidomestic mosquitoes that live in and outside of villages are the primary vectors. This cycle may act as a bridge between the jungle and urban areas, leading to spread to urban centers where, if contact is made between domestic mosquitoes and an unvaccinated human population, an urban epidemic can result.

Biology of the mosquito spreading YF

Feeding habits

These mosquitos are diurnal feeders, and only females feed on blood. In humans, YF virus is transmitted to the mosquito from an ill human only during the initial 3-4 days of illness. If the female is interrupted while feeding, it may seek another host on which to feed, leading to multiple transmissions during a feeding cycle. The extrinsic incubation period (interval from infection of the mosquito with YF virus until the mosquito can transmit YF to another host) is 12-21 days.

Vertical transmission

YF virus enters the ovum in the female mosquito and survives there during the dry season. Less than 1% of female mosquito progeny are infected. This is important for survival of the virus during the dry season.

Horizontal transmission

Uninfected female mosquitoes bite infected hosts, providing for viral amplification. This is essential for survival of the virus. Approximately 3-10 virions are necessary to infect a mosquito.

Breeding habits

Mosquitoes breed in stagnant water, including rainwater in tree holes, human-made water storage vessels, used vehicle tires, and in other collections of water in and about dwellings, such as broken coconut shells, flower vases, gutters, tin cans, and water drums. Seasonal transmission occurs, with peak transmission usually being the time of peak humidity and rainfall. In Africa, this is the mid rainy season to the early dry season. In South America, this occurs from January to March. However, transmission is not limited to the peak season.

Pathophysiology

YF virus is transferred from the infected female mosquito's salivary gland by means of saliva introduced into a bite wound during a blood meal. The virus replicates in local tissues and regional lymph nodes. The virus can then infect a feeding mosquito during the initial 3-4 days of the illness. No human-to-human transmission is known. Hematogenous spread to the bone marrow, kidney (probable), liver (main target), myocardium, and spleen ensues, where further replication occurs. Cerebral edema and cerebral petechial hemorrhages result from secondary factors. In the hemorrhagic diathesis that may follow, disseminated intravascular coagulation (DIC) involves decreased synthesis of coagulation factors, altered platelet function, and bleeding from the GI mucosa and abdominal/pleural serosa.

Myocardial fiber injury occurs secondary to direct virus activity, with cloudy swelling and fatty change. Shock and death can result from YF. Multiple organ insult involves the liver, kidney, brain, and heart. Other effects are hemorrhage and secondary effects of vasoactive cytokines. In an immune response, viral neutralizing antibodies are present by the end of the first week, and the virus is rapidly cleared. Immune response confers lifelong immunity. The role of immune response in pathogenesis has not yet been established.

Frequency

United States

Since 1996, 3 fatal cases of YF have been reported in American travelers to the Amazon. None of the patients were immunized against YF. The CDC estimates that YF immunization of travelers to YF endemic areas has declined 50% from 1992-1998. The first 2 did receive other pretravel vaccinations, including the hepatitis A vaccine. The third person did not receive a medical consultation, YF vaccine, or malaria prophylaxis before traveling.

Because patients with YF can present with a mild influenza-like illness, YF may not be recognized and go unreported. In addition, the outfitter of the 1 of the individuals stated, "The International medical community suggests yellow fever and malaria prophylaxis for the Amazon region. This is not a requirement to enter Brazil, but merely a suggestion." The brochure of a travel agent stated, "We do not suggest any inoculations of any kind for this trip...But to make sure you are worry free, consult with your personal physician." These cases illustrate that some outfitters, travel agents, and physicians may underestimate health risks of travelers.

In 1996, a 45-year-old man spent 9 days in the jungles of Brazil. He returned to the United States with headache, myalgias, arthralgias, and chills. During an initial visit to an emergency department, he had fever, leukopenia, thrombocytopenia, and mild elevations in hepatic transaminase values. He subsequently developed jaundice and hemorrhagic manifestations and died 10 days after developing symptoms. YF virus was isolated from tissue specimens.

In 1999, a 48-year-old man returned to the United States after a 10-day trip to a forested area of Venezuela. During his trip, he received multiple mosquito bites. On the day of his return, he developed fever, chills, headache, photophobia, myalgias, arthralgias, nausea, vomiting, constipation, upper abdominal discomfort, and weakness. He developed hemorrhagic manifestations and died 9 days after developing symptoms. YF viral antigens were isolated from postmortem liver specimens by using immunohistochemical methods.

In 2002, a 47-year-old man traveled to the Brazilian Amazon to fish. He slept in an air-conditioned boat and wore clothing impregnated with N, N-diethyl-m-toluamide (DEET). He returned to Texas and presented to an emergency department the same day, complaining of 4 days of crampy abdominal pain, 1 day of fever (102.8°F [39.3°C]), and severe headache. He was treated for presumed rickettsial infection and sent home. Two days later, he was admitted for intractable vomiting.

On initial evaluation, he had leukopenia (WBC count 2.3 X 10⁹ [2300/µL]), coagulopathy, hepatic failure, and renal failure. He was treated for malaria. Bacterial cultures of blood, urine, and CSF were negative, as were malaria smears. On the fourth day, he developed shock and seizures. On the fifth day, he died. Serum tests for immunoglobulin G (IgG) and immunoglobulin M (IgM) were negative for YF on days 2-7. Reverse-transcriptase polymerase chain reaction (PCR) assay of serum samples obtained on days 4, 5, and 7 and a postmortem liver specimen demonstrated YF virus RNA.

International

Each year, an estimated 200,000 cases of YF occur in Africa and South America combined, causing 20,000-30,000 deaths. The number of total cases reported to the WHO each year from Africa and South America ranges from hundreds to a few thousand. The true incidence is estimated to be at least 40 times more than this in Africa and 10 times more than this in South America.

Underreporting occurs because many cases are mild or asymptomatic, because cases occur in remote regions, because populations are moving or displaced, and/or because the public health infrastructure is nonexistent, particularly in Africa where regional conflicts are ongoing.

Since 1980, YF has been reemerging, with more cases being reported now than in the late 1940s. This trend is evident in Africa, where the number of countries reporting cases and the number of small-scale outbreaks have increased, where large populations are losing immunity (due to the end of mass-prevention campaigns in the early1960s), and where vectors are present in urban areas. In addition, urban population are markedly increasing by 4.8% per year), populations are migrating (forced and unforced), and vaccine cannot be procured because of the expense.

In South America, A aegypti is now present in urban areas. A aegypti is the vector of urban YF. It breeds in domestic and peridomestic containers. In the past 30 years, A aegypti has reinfested most countries, where its eradication was previously accomplished.

In 1998, A aegypti was present in the southern United States, Central America, the Caribbean, most major urban centers in tropical South America, the Indian subcontinent, Southeast Asia, Oceania, and northeast Australia. A legitimate concern is that YF could be reintroduced into these areas at any time because of global travel and trade and because of migrating populations.

Travel to countries where YF is endemic poses a threat to the unimmunized traveler. Each year, an estimated 9 million travelers from North America, Europe, and Asia travel to endemic countries. At least one third of these travelers are exposed to areas where active transmission is known or unknown to be occurring. Since 1979, at least 9 cases of traveler-related YF have been reported. Seven individuals, all unimmunized, died. Of the 2 survivors, 1 had been immunized. All traveled to rural areas, where no epidemics were known to be occurring.

The overall risk to an unimmunized traveler in Africa who is entering an area with epidemic activity is 1:267 for YF illness and 1:1333 for YF death during a 2-week trip. If the area is undergoing a silent period (ie, existing surveillance methods fail to detect active transmission), the risk is 1:2000 for YF illness and 1:10,000 for YF death for a 2-week trip. In the South America the risk is estimated to be one tenth as much.

In West Africa, the most dangerous time of year is July-October. In Brazil, it is January-March. In South America, Iguarzú Falls on the Argentine-Brazil border is not considered a high risk destination, but the risk is not zero. For example, in 1996 and 2001, risk increased because of epizootic expansion. This example illustrates how the status of YF transmission in endemic countries is constantly shifting and unpredictable.

Mortality/Morbidity

• Mortality rates due to the toxic form of disease vary from 25-50%, but the mortality rate has been reported to be as low as 1%. The number of reported deaths from YF among travelers over the past 10 years has increased, and more can be expected unless YF vaccine is most appropriately used.
• Morbidity is minimal unless complications develop from the toxic form of the disease.
• Recovery from the disease confers long-lasting immunity.

Race

No racial predilection is known.

Sex

No sex predilection is known. More men than women are infected in jungles and forests because of occupational exposure.

Age

No age predilection is known. However, most infections in endemic countries occur in persons younger than 15 years because that is the largest population of nonimmune individuals. Occupational or recreational exposure may be increased among children as well.

CLINICAL

Section 3 of 10  

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

History

The clinical spectrum of YF ranges from a minimally symptomatic flulike illness to a catastrophic illness complicated by hemorrhage and organ failure (primarily the liver and kidney). Several distinct phases of YF are outlined below.

• Incubation period (3-6 d): No prodromal symptoms occur.
• Period of infection (3-4 d)
• • Viremia is present. Susceptible biting mosquitoes can be infected with YF.
  • Symptoms typically begin abruptly with fever, chills, malaise, prostration, headache, dizziness, myalgia (particularly lumbosacral area), anorexia, nausea, and vomiting.
• Period of remission (2-24 h): Symptoms and fever abate.
• Abortive phase (>1 d): Recovery occurs without further symptoms.
• Period of intoxication (3-5 d): Liver failure, hemorrhagic diathesis, and kidney failure occur.
• • This period develops in approximately 15% of all cases.
  • This stage is fatal in 1-50% of cases that develop toxicity.
  • Previous symptoms and new symptoms include fever with high temperatures, chills, anxiety, confusion, lethargy, prostration, jaundice, epistaxis, anorexia, epigastric pain, nausea, vomiting, hematemesis, melena, lumbosacral pain, and decreased urine output.
  • Complications include bacterial pneumonia and sepsis.
• Period of convalescence (days to weeks)
• • The patient completely recovers without sequelae.
  • Complications may include protracted weakness and fatigability.

Physical

The Pan American Health Organization has published a case definition for YF to aid in surveillance.

• The clinical case definition is as follows: An illness characterized by acute onset of fever followed by jaundice within 2 weeks of onset of first symptoms plus 1 of the following:
• • Bleeding from the nose, gums, GI tract, or skin
  • Death within 3 weeks of illness onset
• A case of YF is classified as suspected if it meets the clinical definition or if other causes of fever or jaundice are excluded.
• A suspected YF case can be confirmed by laboratory criteria or when it is epidemiologically linked to a laboratory-confirmed case or outbreak.
• Data to be reported to public health authorities include patient-specific identifier, age or date of birth, location, laboratory results, vaccination history, outcome of infection (alive, dead, unknown), case classification, and date of death (if dead).
• Physical examination findings are nonspecific and may include the following:
• • Fever
  • Pulse - Slow, inversely proportional to temperature (Faget sign)
  • Anxiety, lethargy, prostration, confusion, coma
  • Facies - Flushed
  • Conjunctival injection
  • Abdominal tenderness
  • Hemorrhagic manifestations - Epistaxis, gingival bleeding, hematosis, melena, hematuria
  • Urine output - Decreased
  • Shock

Causes

See Pathophysiology

DIFFERENTIALS

Section 4 of 10  

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

Other Problems to be Considered

Arboviral infections - Lassa fever, chikungunya
Carbon tetrachloride poisoning
Influenza
Hepatitis E
Sepsis
Typhoid fever
West Nile virus infection (with hepatitis)

WORKUP

Section 5 of 10  

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

Lab Studies

• Laboratory diagnosis
• • Diagnosis of YF involves any 1 of the following:
  • • Isolation of YF virus
    • Isolation of YF virus–specific IgM
    • 4-fold or more rise in serum IgG
    • Positive findings on postmortem liver histopathology
    • Detection of YF antigen in tissues by immunohistochemistry
    • Detection of YF viral genomic sequences by polymerase chain reaction
  • For guidance on specimen collection and detection of YF virus, contact the CDC (see Background).
• CBC determination
• • Leukopenia with neutropenia may be observed during the initial stage of YF infection.
  • Thrombocytopenia may be observed during the toxic stage of YF infection.
• Electrolyte, BUN, creatinine, and glucose measurements
• • Results may reveal azotemia.
  • Hypoglycemia may occur because of a lack of oral intake and hepatic dysfunction.
  • Hyperkalemia may be secondary to renal dysfunction.
• Liver function tests
• • Elevated transaminase and bilirubin levels are observed during the toxic stage of illness.
  • Transaminase levels may remain elevated for as long as 2 months after recovery.
• Coagulation studies: During the toxic stage of illness, an abnormal pattern resembling DIC may occur.
• Urinalysis: Clinically significant proteinuria often occurs.
• Blood, urine, and CSF cultures to exclude other infections: CSF findings may be typical of YF, with increased pressure, elevated protein levels, cell counts in the reference range, or pleocytosis.
• Malaria smears
• • Findings may exclude concurrent malaria.
  • Thick smears are needed to diagnose malaria.
  • Thin smears are used to speciate the parasite.
• Analysis of acute and convalescent sera: Samples are obtained for viral isolation and diagnosis. Send samples to CDC National Center for Infectious Diseases, Division of Vector-Borne Infectious Diseases (see Background).

Imaging Studies

• In general, no specific studies are indicated for the diagnosis and management of YF. Use imaging to diagnose other primary or secondary conditions.
• Chest radiography is important early in the illness to diagnose primary infection. It is indicated to exclude pneumonia in a patient whose condition deteriorates.

Other Tests

• ECG may show nonspecific ST-segment and T-wave changes.
• ECG may also show arrhythmias.

Procedures

• Peripheral intravenous cannulation for hydration and the administration of medications, including antibiotics as needed
• Central venous catheterization to achieve hydration and to monitor central venous pressure in critically ill patients
• Arterial catheterization to monitor blood pressure in patients who are critically ill and to serially measure blood gases
• Bladder catheterization to monitor urine output and to monitor renal function, particularly proteinuria

Histologic Findings

YF virus is viscerotropic. Histology of infected liver tissue may reveal initial infection of the Kupffer cells, followed by coagulation necrosis of the midzone (zone 2) hepatocytes, which spares zones adjacent to the central vein and portal triad. Intracellular hyaline deposits (Councilman bodies) are present with eosinophilic degeneration of hepatocytes, Torres bodies, intranuclear inclusions, microvesicular fat accumulation, deposition of eosinophilic pigment, and minimal mononuclear inflammatory infiltrate.

Recovery leads to complete healing without cirrhosis. When renal involvement occurs, the kidney is generally edematous, and the cells of the tubular epithelium and glomerular endothelium are swollen. Mesangial proliferation occurs. Viral antigen is found in the glomeruli and tubules. Acute tubular necrosis occurs secondary to circulatory collapse. Heart tissue may demonstrate myocardial cell degeneration and fatty infiltration.

TREATMENT

Section 6 of 10  

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

Medical Care

No specific treatment for YF exists. Monitor for signs of organ failure and other infections and be prepared to manage them.

• Supportive care is the mainstay of management.
• • Monitor fluid status and hydrate to maintain organ perfusion.
  • Monitor electrolyte status and promptly correct any abnormalities.
  • Monitor and be prepared to manage organ failure secondary to direct organ injury from YF virus leading to cardiogenic shock, hepatic coma, and renal failure requiring dialysis.
  • Monitor coagulation profile and correct abnormalities. Blood products may be required. Anticipate DIC.
• Anticipate secondary bacterial infections, particularly pneumonia.
• Exclude concurrent malaria.
• Indicators of poor prognosis include the following:
• • Early onset of bilirubinemia
  • Marked albuminuria
  • Prothrombin time increased by more than 25%
  • Severe hemorrhage
  • Shock
  • Intractable hiccough (hiccup)

Consultations

• Infectious diseases specialist
• • Additional training in tropical medicine is preferred.
  • Diagnose and manage YF.
  • Diagnose and manage concurrent malaria.
  • Diagnose and manage concurrent tropical disease other than malaria or YF.
• Critical care specialist
• • Consultation is preferred early in the course of illness in order to anticipate problems.
  • Manage organ failure.
  • Manage hemorrhagic diathesis.
• Nephrologist, if dialysis is required

Diet

Diet is based on the patient's general status, the presence of any organ failure, and the development of a hemorrhagic diathesis.

Activity

Activity is based on the patient's general status, the presence of any organ failure, and the development of a hemorrhagic diathesis.

MEDICATION

Section 7 of 10  

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

No specific medication is indicated in the treatment of YF. Medication selection is based on the control of symptoms, secondary infections, and organ failure.

Drug Category: Analgesic and antipyretic agents

Antipyretics should be used only with caution, if at all, because of their metabolic effects on the liver and kidney. Do not use acetaminophen in the presence of hepatic compromise. Do not use ibuprofen in the presence of hepatic or renal compromise.

Drug Name	Ibuprofen (Advil, Motrin)
Description	Drug of choice (DOC) for mild-to-moderate pain; also used to reduce fever. Inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis.
Adult Dose	200-400 mg PO q4-6h while symptoms persist; not to exceed 3.2 g/d
Pediatric Dose	<6 months: Not established 6 months to 12 years: 4-10 mg/kg PO q6-8h >12 years: Administer as in adults
Contraindications	Documented hypersensitivity; peptic ulcer disease; recent GI bleeding or perforation; renal insufficiency; high risk of bleeding
Interactions	Coadministration with aspirin increases risk of inducing serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; monitor prothrombin time (PT) closely (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Category D in third trimester of pregnancy; caution in congestive heart failure, hypertension, and decreased renal and hepatic function; caution in anticoagulation abnormalities or during anticoagulant therapy

Drug Category: Vaccines

Active immunization increases resistance to infection. Vaccines consist of microorganisms or cellular components, which act as antigens. Administration of the vaccine stimulates the production of antibodies with specific protective properties.

FOLLOW-UP

Section 8 of 10  

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

Further Inpatient Care

• Base management decisions on the presence of dehydration, electrolyte imbalance, organ failure, concurrent infections, secondary infections, hemorrhagic diathesis, and generalized symptoms.
• The managing physician must be thoroughly versed in critical care management to coordinate the various interventions to the maximum benefit of the patient.

Further Outpatient Care

• Patients who recover do so with minimal end-organ damage.
• In addition, they develop life-long immunity from further infection with YF virus.

In/Out Patient Meds

• No specific medication is required for the treatment of YF.
• Antipyretics may have limited use, if no hepatic or renal compromise exists.
• In addition, comorbid conditions may exist that require medication, and the risks and benefits of such medications must be considered before continuing them during the acute phase of illness.

Transfer

• Transfer patients with YF to another institution when the necessary clinical expertise, monitoring capability, and treatment modalities are not available at the current institution.
• The patient must be stable enough for transfer.
• Physicians with experience in pediatric medicine, infectious or tropical diseases, pediatric critical care, and nephrology should be readily available at the institution to which the patient is being transferred.
• An attending physician at that institution must accept the patient in transfer.

Deterrence/Prevention

• Immunization
• • Administration of the YF vaccine
  • • Individuals aged 9 months or older (>6 mo during epidemics) who are traveling to or living in South America or Africa in a country with known YF endemicity should be immunized with the YF vaccine.
    • In the United States, live, attenuated YF vaccine is available against the 17D-204 strain YF-VAX (Sanofi Pasteur, Swiftwater, PA). It is grown in chick embryos. The vaccine should be stored at 35-46ºF (2-8ºC) until it is reconstituted with sterile, physiologic sodium chloride solution. If not used within 1 hour after reconstitution, it should be discarded because its immunizing potency decreases. The dose is 0.5 mL of reconstituted vaccine administered subcutaneously to all individuals of ages who qualify to receive the vaccine.
    • The biologic duration of immunity is 30-35 years, probably for life after a single immunization. The International Certificate of Vaccination for YF is good for 10 years. After this period, a booster must be obtained to maintain a valid certificate.
    • Immunization induces neutralizing antibodies (mediator of protection) in 90% of individuals by 10 days after vaccination and in 99% by 30 days. Data from clinical trials suggest a primary vaccine failure rate of 1-5%. This failure is not absolute because revaccination may produce neutralizing antibodies. A couple reported cases describe deaths due to YF in vaccinated individuals. However, whether the vaccination procedure was compromised in a way that might have affected immunity is unknown. Overall, the vaccine is considered safe and highly effective.
    • YF vaccine is grossly under utilized. Many individuals are traveling at substantial risk for acquiring YF. Each year, approximately 9 million individuals travel to countries where YF is endemic (see Frequency) from Asia, Europe, and North America combined. In 2004, almost 3 million trips at least a 1-night stay were made from the United States to Africa and South America (Department of Commerce, 2005; see U.S. Resident Travel Abroad Historical Visitation: Outbound 1994-2004 [One or More Nights]). Some of these trips were repeat trips made by the same individual.
    • Each year approximately 900,000 doses of YF-VAX are distributed in the United States: 600,000 to the military sector and 300,000 to the civilian sector (Khromava, 2005).
    • From mathematic models, the estimated percentage of individuals immunized against YF who traveled to YF-endemic countries decreased from 64% in 1992 to 31% in 1998 when 1 in 3 individuals were considered to be at risk, and the percentage decreased from 21% to 10% over the same period when all individuals were considered to be at risk.
    • The number of reported deaths from YF among travelers over the past 10 years has increased, and more can be expected unless YF vaccine is most appropriately used.
    • For an updated list of YF-endemic countries, visit the CDC Web site. Regardless of the stated requirement for YF immunization for the listed countries, all individuals traveling to any portion of an endemic area where YF transmission has been known to occur should receive the vaccine unless its use is contraindicated or unless the individual can clearly demonstrate that he or she will not be entering an area where YF transmission is occurring. As an alternative, personal protective measures can be used to reduce the risk. However, these measures do not eliminate the risk, as illustrated in 1 case of YF in the United States (see Frequency). Avoiding travel to the area should be strongly considered.
  • Adverse reactions to the of the YF vaccine
  • • Mild reactions (£25%; 1% recipients curtail usual activities), hypersensitivity reactions (1 per 130,000-250,000 immunizations), and serious reactions (>1.6 per 100,000) are reported. Mild reactions include local injection-site reactions characterized by erythema and pain, as well as systemic reactions characterized by low-grade fever, mild headaches, malaise, and myalgia. These last as long as 5-10 days. In infants, the intensity of the reactions is less than or similar to that in adults.
    • Hypersensitivity reactions most often occur in patients with egg allergies (those unable to eat eggs and egg products). YF-VAX contains gelatin (a stabilizer), which may contribute to hypersensitivity, as it does with other vaccines. If the patient has a history of egg intolerance, skin testing can be performed with scratch testing then intradermal injection with increasing concentrations of the vaccine, as outlined in the YF-VAX package insert. If the result is positive, full immunization doses should be avoided, and neutralizing antibodies should be measured >14 days after testing. (Contact the state health department to submit serum. Neutralizing-antibody assay is the only reliable test to measure seroconversion.) If seroconversion has not occurred, desensitization can be accomplished before administration of the full dose of vaccine is given by following the procedure outlined in the package insert.
    • Serious reactions are rare and defined as any adverse event occurring after the administration of any vaccine dose that results in death, life-threatening illness, inpatient hospitalization, prolongation of existing hospitalization, and persistent or clinically significant disability. Two types of serious reactions are as follows:
    • • YF vaccine–associated neurotropic disease: This is a newer term for postvaccinal encephalitis and consists of meningismus, mental status change, paresis, seizures, and CSF positive for WBCs and elevated protein levels.
      • YF vaccine–associated viscerotropic disease: This consists of multiorgan system failure including (but not limited to) fever, disseminated intravascular coagulation, hepatic failure, jaundice, myocarditis, renal failure, and respiratory failure.
    • For all individuals aged 9 months or older, the estimated incidence of both diseases is >0.3 per 100,000. For those older than 60 years, rates are >1.8 per 100,000 for both diseases and >5.3 per 100,000 for all serious reactions.
    • Since 1945, at least 29 cases (1 death) of YF vaccine-associated neurotropic disease have been reported. Of these 29 cases, 13 were aged 5 weeks to 3 months, 1 was aged 6 months, 1 was aged 7 months, 1 was aged 3 years, 3 were aged 13-19 years, 4 were aged 29-59 years, and 1 was aged 71 years. Only 6 cases were reported in the United States (1 aged 10 wk, 1 aged 3 y, 4 aged 16-71 y). Most of the US cases were reported to the Vaccine Adverse Event Reporting System (VAERS). These cases have been closely associated (clinical onset within 2-21 d of vaccination in the absence of another probable cause) or proven to be caused by the YF vaccine using serological and virological evidence.
    • In addition, since 1990, other reported neurological sequelae have been thought to be secondary to YF vaccination, including 4 cases of Guillain-Barré syndrome and 3 cases of acute demyelinating syndrome. Other rare case reports that may have a causal association with YF vaccination include ataxia, Bell palsy, bursitis, chronic lymphocytic leukemia, diabetic ketoacidosis, malaria recrudescence, mononeuritis, multiple sclerosis, and optic neuritis.
    • The estimated US incidence of YF vaccine–associated neurotropic disease has been calculated. Rates per 100,000 immunizations were 0.4 in those aged 1-18 years, about 0 in those aged 19-39 years, 0.5 in those aged 40-49 years, 0.3 in those aged 50-59 years, 1.6 in those aged 60-60 years, and 1.1 in those older than 7 years. These findings highlight the fact that increasing age increases the risk (see Frequency). Because of the significant risk, vaccination is absolutely contraindicated in neonates and infants younger than 4 months. Vaccination is relatively contraindicated in infants aged 6-9 months unless they are traveling to an area undergoing an epidemic of YF.
    • In 1996, 4 cases of YF vaccine–associated viscerotropic disease were reported in the United States. Two additional cases (unpublished) were identified in the United States, and several other cases were reported from Australia, Brazil, and Europe. The estimated US incidence of YF vaccine–associated neurotropic disease per 100,000 immunizations is about 0 in persons aged 1-18 years, 0.2 in those aged 19-29 years, about 0 in those aged 30-49 years, 0.3 in those aged 50-59 years, 1.1 in those aged 60-69 years, and 3.2 in those older than 70 years. Thesedata highlight the fact that increasing age increases the risk (see Frequency).
    • Recent reports suggest that 3.5% of vaccine recipients have a mild, subclinical elevation in liver enzyme levels about 10 days after vaccination. These changes resolve without sequelae. Any patient who develops febrile illness within 10 days of vaccination should be evaluated with liver function tests (LFTs). If results are elevated, the patient should be admitted for observation and further testing. Procedures should include serial collection and analysis of serum samples to quantitate viremia and antibody titers, preservation of buffy coat cells for future genetic studies, and submission of a report to VAERS.
    • All serious or unusual reactions to any vaccine should be reported to the VAERS (telephone 1-800-822-7967). See also the Vaccine Safety and Adverse Event Reports page of the CDC. The VAERS is designed to accept all reports of adverse events after the administration of any US-licensed vaccine in all age groups. For contact information for the CDC, see the Background section above.
  • Administration of the YF vaccine with other vaccines, immunoglobulin, and/or chloroquine
  • • The YV-VAX can be administered concomitantly or at intervals of 1-30 days with the following vaccines or agents: bacille Calmette-Guérin (BCG) vaccine; oral cholera vaccine chloroquine (inhibits YF virus replication in vitro, but does not interfere with antibody response to YF vaccine); diphtheria-pertussis-tetanus (DPT) vaccine; hepatitis A vaccine; hepatitis B vaccine; immunoglobulin; measles vaccine (YF vaccine given at weekly intervals after measles vaccine does not alter immunity.) ; meningococcal polysaccharide vaccine (Menomune); measles, mumps, and rubella (MMR) vaccine; polio vaccine (oral and inactivated); smallpox vaccine (vaccinia); and typhoid vaccine (Typhim Vi).
    • Data regarding concurrent administration of YF-VAX and the following are lacking: Japanese encephalitis, pneumococcal, rabies and varicella vaccines. Interference is considered unlikely.
    • When concurrent vaccines are live, some experts recommend administration at different sites (eg, not in the same arm) if they are done simultaneously or administration 4 weeks apart. In theory, the close administration of 2 doses of the same or different live virus vaccines can interference with the development of immunity. Simultaneous administration does not cause any known or demonstrated interference. If circumstances do not permit adhering to this recommendation, live virus vaccines can be administered at <4 weeks. One exception to this recommendation is the oral polio vaccine, which can be administered at any interval with the MMP and oral typhoid vaccines. This exception and other research data suggest that further study of immune interference is warranted.
  • Altered immune status and administration of the YF vaccine
  • • In theory, administering live virus vaccines may pose a risk to individuals with compromised immune systems because of HIV infection, leukemia, lymphoma, other malignancies, medication or radiation-induced immunosuppression.
    • In 1 study, 3 of 18 (17%) infants with HIV infection who simultaneously received the 17D YF and measles vaccines developed neutralizing antibodies versus 42 of 57 (74%) without HIV infection (Sibailly, 1997). In 33 adults with HIV and a CD4⁺ level >200/mm³, 23 (70%) developed neutralizing antibodies (Goujon, 1995). Titers for neutralizing antibodies to YF should be checked in HIV-infected people receiving YF-VAX vaccine before they travel to endemic or epidemic areas. YF vaccine should not be given to patients with leukemia, lymphoma, or other cancer that is not in remission (3-mo minimum) or to patients undergoing chemotherapy, radiation therapy, or both. Low-dose corticosteroids (prednisone <20 mg/d or equivalent), for <2 weeks, or intra-articular, bursa, tendon are not considered to have significant immunosuppression and, therefore, can receive the YF vaccine.
    • Any questions regarding administration of YF vaccine to a potentially compromised host can be directed to a travel medicine provider, the state health department, or the CDC (see Background).
  • Pregnancy and lactation and YF vaccination
  • • In theory, vaccination of the pregnant women may pose a risk to the fetus.
    • In 2 series of 81 infants whose mothers received the YF vaccine during pregnancy, YF 17D was detected in only 1 fetus (1.2%) (Nasidi, 1993; Nishioka, 1998).
    • To the authors' knowledge, congenital anomalies secondary to YF vaccination of the mother during pregnancy has not been reported.
    • The risk for miscarriage is not significantly different after YF vaccination than without vaccination.
    • In general, pregnant women who must travel to an area where YF is endemic or epidemic should be vaccinated, and their infants should be followed up closely. Also, levels of YF-neutralizing antibody should be checked in pregnant women who are vaccinated because their levels are substantially lower than normal.
• Personal protective measures
• • The purpose of these measures is to avoid being bitten by mosquitoes and thereby avoid exposure to YF and many other insect-borne diseases, such as malaria and dengue.
  • Clothing
  • • Individuals should wear proper clothing. Wear long pants, long-sleeved shirts, hat (one without vents that allow mosquitoes in), socks, and closed-toed shoes to decrease area of skin exposed.
    • They should choose colors (khaki, tan, pale green) that do not attract mosquitoes and avoid dark colors (blue, black, red) that attract mosquitoes. Loose-fitting, breathable synthetics or cotton are the best fabrics.
• • Insect repellents
  • • DEET concentrations should not exceed 30% in cream-based products applied directly to skin. Two commercial formulations with maximum protection and minimal absorption when applied to skin are the Sawyer Long Acting and Ultrathon products. Washing off any residual repellent once daily is best to minimize the risk of toxicity, which has occurred in only a few cases among hundreds of millions of applications. DEET products can damage synthetics, except nylon. Damage is observed mostly with concentrations >50%.
    • Permethrin is applied by spraying or impregnating clothing and mosquito nets to maximize their benefit. It should not be applied to sheets on which someone will sleep to avoid potential, theoretical toxicity.
  • Protected sleeping quarters
  • • Individuals should reduce their exposure by sleeping in air-conditioned quarters or by preparing non–air-conditioned quarters.
    • They should sleep in rooms with adequate screens and mosquito-proof the room. The closed-up room should be sprayed with insect repellant around the edges of ceilings, up high behind curtains, and high in closets in the evening when the person will not be in the room for 2-3 hours. He or she should then air out the room before sleeping in it. They should sleep under a permethrin-impregnated mosquito net.
• Mosquito-eradication programs: These programs eliminate mosquito breeding sites by covering water storage containers and eliminating areas of stagnant water and human-made containers that pool stagnant water, such as tires, vases, clay pots, and discarded cans.

Complications

• Organ failure
• • Liver - Secondary to hepatic necrosis
  • Kidney - Secondary to parenchymal injury and acute tubular necrosis
  • Heart - Secondary to parenchymal injury
• Hemorrhagic diathesis
• • The YF virus directly injures the liver, kidney, and heart.
  • A hemorrhagic diathesis progressing to DIC is not uncommon in the toxic form of the disease because of hepatic damage, thrombocytopenia, and perhaps other factors.
• Secondary infections, particularly bacterial pneumonia

Prognosis

• If death does not occur, recovery without sequelae is the rule.
• Recovery from YF confers life-long immunity to reinfection.

Patient Education

• Increased public awareness is important.
• All travel to YF-endemic areas warrants a consultation with a travel health specialist.
• Even if the WHO does not have a requirement for YF vaccination for travel to a country, a traveler may still be exposed and concern may be warranted.

MISCELLANEOUS

Section 9 of 10  

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

Medical/Legal Pitfalls

• Failure to suspect YF in a patient with a compatible clinical history of fever and jaundice who lives in or has recently traveled to a YF-endemic area
• Failure to notify public health authorities of a suspected case of YF
• Failure to consider other potential causes of the patient's condition and to treat them until they are excluded

Special Concerns

• Concurrent infections: The patient's itinerary and activities, coupled with a knowledge of the endemic diseases in the country visited, allows the managing physician to make a list of possible concurrent infections for consideration.
• • Malaria
  • Hepatitis
  • Typhoid fever
  • Others (see Differentials)
• Medical community education
• • All travel to YF-endemic areas warrants a consultation with a travel health specialist.
  • Travel from one YF-endemic country to another country may necessitate proof of YF vaccination status with a properly completed International Certificate of Vaccination, even if a certificate was not required to enter the first country.
  • Even if the WHO does not have a requirement for YF vaccination for travel to a country, a traveler may still be exposed and concerned may be warranted.

REFERENCES

Section 10 of 10

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

• CDC. Fatal yellow fever in a traveler returning from Venezuela, 1999. MMWR Morb Mortal Wkly Rep. Apr 14 2000;49(14):303-5. [Medline]. [Full Text].
• CDC. Travelers' Health: Yellow Book. Health Information for International Travel, 2005-2006. Chapter 4 - Prevention of Specific Infectious Diseases: Yellow Fever. Atlanta, GA: CDC. [Full Text].
• CDC. Fatal yellow fever in a traveler returning from Amazonas, Brazil, 2002. MMWR Morb Mortal Wkly Rep. Apr 19 2002;51(15):324-5. [Medline]. [Full Text].
• CDC. Travelers' Health: Yellow Book. Health Information for International Travel, 2005-2006. Yellow Fever. Chapter 5 - Yellow Fever Vaccine Requirements and Information on Malaria Risk and Prophylaxis, all Countries (yellow pages). Atlanta, GA: CDC. [Full Text].
• Cetron MS, Marfin AA, Julian KG, et al. Yellow fever vaccine. Recommendations of the Advisory Committee on Immunization Practices (ACIP), 2002. MMWR Recomm Rep. Nov 8 2002;51(RR-17):1-11; quiz CE1-4. [Medline].
• Department of Commerce. U.S. Resident Travel Abroad Historical Visitation: Outbound 1994-2004 (One or More Nights). Department of Commerce, International Trade Administration, Office of Travel and Tourism Industries. 2005. [Full Text].
• Goujon C, Tohr M, Feuille V. Good tolerance and efficacy of yellow fever vaccine among subjects who are carriers of human immunodeficiency virus. In: Abstracts, 4th International Conference on Travel Medicine, Acapulco, Mexico. 1995.
• Khromava AY, Eidex RB, Weld LH, et al. Yellow fever vaccine: an updated assessment of advanced age as a risk factor for serious adverse events. Vaccine. May 9 2005;23(25):3256-63. [Medline].
• Massad E, Coutinho FA, Burattini MN, et al. Yellow fever vaccination: how much is enough?. Vaccine. Jun 10 2005;23(30):3908-14. [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].
• Monath TP. Yellow fever. In: Tropical Infectious Diseases: Principles, Pathogens, & Practice. Philadelphia, Pa:. Churchill Livingstone;1999:1253-64.
• Monath TP. Yellow fever: a medically neglected disease. Report on a seminar. Rev Infect Dis. Jan-Feb 1987;9(1):165-75. [Medline].
• Monath TP. Yellow fever. In: Plotkin SA, Orenstein WA, eds. Vaccines. 4th ed. Philadelphia, Pa:. WB Saunders;2004:1095-176.
• Monath TP. Yellow fever vaccine. Expert Rev Vaccines. Aug 2005;4(4):553-74. [Medline].
• Monath TP, Cetron MS. Prevention of yellow fever in persons traveling to the tropics. Clin Infect Dis. May 15 2002;34(10):1369-78. [Medline].
• Nasidi A, Monath TP, DeCock K, et al. Urban yellow fever epidemic in western Nigeria, 1987. Trans R Soc Trop Med Hyg. May-Jun 1989;83(3):401-6. [Medline].
• Nasidi A, Monath TP, Vandenberg J, et al. Yellow fever vaccination and pregnancy: a four-year prospective study. Trans R Soc Trop Med Hyg. May-Jun 1993;87(3):337-9. [Medline].
• Nishioka Sde A, Nunes-Araujo FR, Pires WP, et al. Yellow fever vaccination during pregnancy and spontaneous abortion: a case-control study. Trop Med Int Health. Jan 1998;3(1):29-33. [Medline].
• Pickering LK, Peter G, Baker CJ, et al, eds. Yellow fever. In: Red Book: Report of the Committee on Infectious Diseases. Elk Grove Village, IL: American Academy of Pediatrics;. 2000.
• Poland JD, Calisher CH, Monath TP, et al. Persistence of neutralizing antibody 30-35 years after immunization with 17D yellow fever vaccine. Bull World Health Organ. 1981;59(6):895-900. [Medline].
• Pugachev KV, Guirakhoo F, Monath TP. New developments in flavivirus vaccines with special attention to yellow fever. Curr Opin Infect Dis. Oct 2005;18(5):387-94. [Medline].
• Robertson SE, Hull BP, Tomori O, et al. Yellow fever: a decade of reemergence. JAMA. Oct 9 1996;276(14):1157-62. [Medline].
• Sibailly TS, Wiktor SZ, Tsai TF, et al. Poor antibody response to yellow fever vaccination in children infected with human immunodeficiency virus type 1. Pediatr Infect Dis J. Dec 1997;16(12):1177-9. [Medline].
• Spira A. Yellow fever vaccine as a vehicle to better travel medicine. J Travel Med. Nov-Dec 2005;12(6):303-5. [Medline].
• Tsai T. Viral hemorrhagic fevers: yellow fever. In: Hunter's Tropical Medicine and Emerging Infectious Diseases. 8th ed. Philadelphia, Pa:. WB Saunders;2000:272-5.
• Tsai TF, Paul R, Lynberg MC, Letson GW. Congenital yellow fever virus infection after immunization in pregnancy. J Infect Dis. Dec 1993;168(6):1520-3. [Medline].
• Vainio J, Cutts F. Yellow fever. World Health Organization. 1998;[Full Text].
• WHO. Adverse events following yellow fever vaccine. WHO Website. [Full Text].
• WHO. WHO Report on Global Surveillance of Epidemic-Prone Infectious Diseases: Yellow Fever. [Full Text].
• WHO. The yellow fever situation in Africa and South America in 2004. Wkly Epidemiol Rec. Jul 22 2005;80(29):250-6. [Medline].

Article Last Updated: Nov 29, 2006