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INTRODUCTION — Yellow fever is a mosquito-borne viral hemorrhagic fever with a high case-fatality rate. Clinical manifestations include hepatic dysfunction, renal failure, coagulopathy, and shock. Travelers to tropical regions of South America and sub-Saharan Africa where the disease is endemic are at risk for acquisition of infection and require immunization.
Issues related to virology, pathogenesis, epidemiology, clinical manifestations, diagnosis, treatment, and prevention of yellow fever will be reviewed here.
VIROLOGY, PATHOGENESIS, AND HISTOPATHOLOGY — Yellow fever is the prototype member of the family Flaviviridae, a group of small (40 to 60 nm), enveloped, positive-sense, single-stranded RNA viruses that replicate in the cytoplasm of infected cells. Yellow fever virus is a single serotype and is antigenically conserved, so the vaccine protects against all strains of the virus. At the nucleotide sequence level, it is possible to distinguish seven major genotypes representing West Africa (two genotypes), Central-East Africa and Angola (three genotypes), and South America (two genotypes) [1,2]. Humans are highly susceptible to infection and disease. Most nonhuman primate species are susceptible to infection, and some species of nonhuman primates develop clinical manifestations.
An infected female mosquito inoculates approximately 1000 to 100,000 virus particles intradermally during blood feeding. Virus replication begins at the site of inoculation, probably in dendritic cells in the epidermis, and spreads through lymphatic channels to regional lymph nodes. Lymphoid cells, particularly monocyte-macrophages and large histiocytes, appear to be the preferred cell types for primary replication. The virus reaches other organs via the lymph and then the bloodstream, seeding other tissues. Large amounts of virus are produced in the liver, lymph nodes, and spleen and are released into the blood. During the viremic phase (days three to six), infection may be transmitted to blood-feeding mosquitoes.
Yellow fever is characterized by hepatic dysfunction, renal failure, coagulopathy, and shock [3-6]. The midzone of the liver lobule is principally affected, with sparing of cells bordering the central vein and portal tracts . Viral antigen localizes to the midzone, indicating that it is the site of direct viral injury. Very high virus loads have been found in the liver and spleen of fatal cases .
Injury to hepatocytes is characterized by eosinophilic degeneration with condensed nuclear chromatin (Councilman bodies) rather than by the ballooning and rarefaction necrosis seen in viral hepatitis. Liver cell death is due to apoptosis. Hepatocytes in the midzone of the liver lobule express Fas ligand, and lymphocytes infiltrating the liver mediate apoptosis. Inflammatory cells, mainly CD4+ cells, are present in low numbers; smaller numbers of NK and CD8+ cells are present [9,10]. There is no disruption of the reticular architecture of the liver. In nonfatal cases, healing is complete without postnecrotic fibrosis. In fatal cases, approximately 80 percent of hepatocytes undergo coagulative necrosis.
Renal damage is characterized by eosinophilic degeneration and fatty change of renal tubular epithelium without inflammation. These findings are believed to be a result of both direct viral injury and nonspecific changes due to hypotension and the hepatorenal syndrome .
Focal injury to the myocardium, characterized by cell degeneration and fatty change, is the result of viral replication.
The hemorrhagic diathesis in yellow fever is due to decreased synthesis of vitamin K-dependent coagulation factors by the liver, disseminated intravascular coagulation, and platelet dysfunction.
The late phase of the disease is characterized by circulatory shock. The underlying mechanism may be cytokine dysregulation, as in the sepsis syndrome. In a series of patients with fatal yellow fever, levels of proinflammatory cytokines (interleukin [IL]-6, IL-1 receptor antagonist, tumor necrosis factor [TNF]-alpha, and interferon-inducible protein-10) were elevated compared with patients with nonfatal yellow fever . Patients dying of yellow fever have cerebral edema at autopsy, probably the result of microvascular dysfunction. Large amounts of complement-fixing antigen (presumably NS1) have been found in blood of severely ill yellow fever patients .
Some nonhuman primate species develop fatal infection with features similar to the disease in humans . A model of yellow fever infection in hamsters has been described [13,14]. Clinical, immunologic, and pathologic features resemble human infection, suggesting that this model might serve to increase the understanding of the pathogenesis of infection and to explore possible treatments. Interferon-alpha/beta receptor-deficient mice are also susceptible to viscerotropic infection .
EPIDEMIOLOGY — Yellow fever occurs in tropical regions of sub-Saharan Africa and South America; it is an epidemic disease problem of considerable magnitude [16,17]. The incidence of endemic disease is not well established, but approximately 1 percent of individuals with severe hepatitis in endemic areas of Africa may be caused by yellow fever . An estimate from serologic and epidemiologic data concluded that there were 130,000 cases with viscerotropic disease and 78,000 deaths in Africa in 2013 .
The incidence of yellow fever in Africa varies widely, and the disease occurs in epidemics . A large Aedes aegypti–borne epidemic occurred in Angola and neighboring Democratic Republic of the Congo in south/central Africa between December 2015 and July 2016 with over 2930 confirmed or suspected cases and 253 deaths and resulting in the emergency distribution of 30 million doses of vaccine [20-22]. Mosquito-borne epidemics in Africa occur where large human populations reside in high density and immunization coverage is low. The highest number of outbreaks has occurred in West Africa, but this situation is changing due to a concerted effort to undertake mass immunization campaigns in that region. Human-to-human transmission in the absence of the mosquito has not been reported.
Fewer cases occur in South America than in Africa because transmission occurs from enzootic sources (principally from monkey to human via mosquito vectors), the vector density is relatively low, and vaccination coverage is relatively high (80 to 90 percent in endemic areas of South America). In typical years, there are several hundred cases officially notified, but in epidemic years up to 5000 cases are reported. An outbreak in the Brazilian state of Minas Gerais began in January 2017 in an area with relatively low vaccination coverage .
In Africa and South America, only a small proportion of cases is officially recorded because the disease often occurs in remote areas, recognition of outbreaks is delayed, and diagnostic facilities are limited. In Africa, reports of outbreaks in the 1980s noted the incidence of yellow fever infection to be 20 to 40 percent, the incidence of severe disease to be 3 to 5 percent, and the case-fatality rate to be 20 to 30 percent. In contrast, case-fatality rates in South America are consistently 50 to 60 percent. It is uncertain whether these disparities reflect reporting artifact, a real difference in virus strain virulence, and/or differing genetic susceptibility of the human populations. A racial difference in susceptibility is likely, supported by an analysis of epidemiologic data from an 1878 epidemic in Tennessee, in which yellow fever attack rates were similar in the Caucasian and non-Caucasian populations of the city, but the case-fatality rate was 6.8-fold higher in Caucasians .
Yellow fever epidemics have never been reported in Asia, and introduction to that region could have devastating effects since there is no background of specific immunity, and the urban vector (Aedes aegypti) is prevalent. In the context of the 2016 yellow fever outbreak in Angola, at least 11 Chinese workers have developed yellow fever upon travel home to China, illustrating the danger of introduction and potential secondary spread .
Prior to the reports among travelers from Angola, yellow fever in expatriates and travelers to and from Africa and South America has been rare since the introduction of vaccination after World War II. Since that time, 10 cases had been recorded up to the time of the 2016 Angolan outbreak [8,26-30]. The situation in Angola appears to be linked to a large number of Chinese construction workers and other expatriates who entered the country without vaccination. Changes in human demography, particularly expansion of urban populations throughout the tropics, expansion of air travel, and rapid spread of other viruses (dengue, Zika, chikungunya) transmitted between humans by urban Ae. aegypti throughout the southern hemisphere illustrate the global dangers associated with exportation and spread of yellow fever.
Transmission cycles — The primary transmission cycle involves monkeys and daytime biting mosquitoes (Aedes species in Africa, Haemagogus species in South America).
In Africa, a wide array of Aedes vectors is responsible for transmission. During the rainy season, the virus circulates via mosquitoes in the savanna vegetational zone in proximity to human settlements. Both humans and nonhuman primates can be hosts in the transmission cycle, and the rate of virus transmission may accelerate to reach epidemic levels. Aedes aegypti, a common domestic mosquito that can breed in containers used to store potable water in heavily settled areas, is capable of serving as an epidemic vector with humans as the intermediate viremic hosts (so-called "urban yellow fever").
In South America, the larval development of mosquitoes occurs in areas such as tree holes containing rainwater. Persons entering forested areas are at risk of infection (so-called "jungle yellow fever"); this accounts for the predominance of cases among young males engaged in forest clearing and agriculture. In the 1970s, the Aedes aegypti mosquito reinvaded areas of South America where it previously had been eradicated, increasing the risk that urban yellow fever may reemerge. The first well-documented instance of an urban-cycle epidemic since 1942 occurred in Paraguay in 2008 .
CLINICAL MANIFESTATIONS — The clinical spectrum of yellow fever includes :
●Abortive, nonspecific febrile illness without jaundice
●Life-threatening disease with fever, jaundice, renal failure, and hemorrhage
Yellow fever affects all ages, but disease severity and lethality is highest in older adults. The onset of illness appears abruptly three to six days (median 4.3 days) after the bite of an infected mosquito . The classical illness is characterized by three stages:
●Period of infection
●Period of remission
●Period of intoxication
Period of infection — The period of infection consists of viremia, which lasts for three to four days. The patient is febrile and complains of generalized malaise, headache, photophobia, lumbosacral pain, pain in the lower extremities, myalgia, anorexia, nausea, vomiting, restlessness, irritability, and dizziness . Symptoms and signs are relatively nonspecific; at this phase, it is virtually impossible to distinguish yellow fever from other acute infections.
On physical examination, the patient appears acutely ill with flushed skin, reddening of the conjunctivae and gums, and epigastric tenderness. Enlargement of the liver with tenderness may be present. The tongue is characteristically red at the tip and sides with a white coating in the center. The pulse rate is slow relative to the height of the fever (Faget's sign). The temperature is typically 39ºC but may rise as high as 41ºC.
Laboratory abnormalities include leukopenia (1500 to 2500 per microL) with relative neutropenia; leukopenia occurs rapidly after the onset of illness. Serum transaminase levels start to rise 48 and 72 hours after onset of illness, prior to the appearance of jaundice. The degree of liver enzyme abnormalities at this stage may predict the severity of hepatic dysfunction later in the illness .
Period of remission — A period of remission lasting up to 48 hours may follow the period of infection, characterized by the abatement of fever and symptoms. Patients with abortive infections recover at this stage. Approximately 15 percent of individuals infected with yellow fever virus enter the third stage of the disease.
Period of intoxication — The period of intoxication begins on the third to sixth day after the onset of infection with return of fever, prostration, nausea, vomiting, epigastric pain, jaundice, oliguria, and hemorrhagic diathesis. The viremia terminates at this stage and antibodies appear in the blood. This phase is characterized by variable dysfunction of multiple organs including the liver, kidneys, and cardiovascular system. Multiorgan failure in yellow fever is associated with high levels of proinflammatory cytokines similar to that seen in bacterial sepsis and systemic immune response syndrome (SIRS) .
Hepatic dysfunction — Hepatic dysfunction due to yellow fever differs from other viral hepatitides in that serum aspartate aminotransferase (AST) levels exceed those of alanine aminotransferase (ALT). This may be due to concomitant viral injury to the myocardium and skeletal muscle. The levels are proportional to disease severity. In one study, the mean AST and ALT levels in fatal cases were 2766 and 660 U, respectively, while in surviving patients with jaundice, the mean levels were 929 and 351 U . Alkaline phosphatase levels are normal or only slightly elevated. Direct bilirubin levels are typically between 5 and 10 mg/dL, with higher levels in fatal than in nonfatal cases .
Renal dysfunction — Renal damage is characterized by oliguria, azotemia, and very high levels of protein in the urine. Serum creatinine levels are three to eight times normal. In some patients who survive the hepatitic phase, renal failure predominates. Death is preceded by virtually complete anuria.
Hemorrhage — Hemorrhage is a prominent component of the third phase of illness, including coffee-grounds hematemesis, melena, hematuria, metrorrhagia, petechiae, ecchymoses, epistaxis, oozing of blood from the gums, and bleeding from needle puncture sites. Gastrointestinal hemorrhage may contribute to circulatory collapse. Laboratory abnormalities include thrombocytopenia, prolonged prothrombin time, and global reductions in clotting factors synthesized by the liver (factors II, V, VII, IX, and X). Some patients have findings suggesting disseminated intravascular coagulation, including diminished fibrinogen and factor VIII and the presence of fibrin split products.
Myocardial injury — The clinical significance of myocardial injury is poorly understood and probably has been underestimated in clinical studies. In some cases, acute cardiac enlargement has been documented during the course of infection . The electrocardiogram may show sinus bradycardia without conduction defects, ST-T abnormalities, particularly elevated T waves, and extrasystoles. Bradycardia and myocarditis may contribute to hypotension, reduced perfusion, and metabolic acidosis in severe cases. Arrhythmia has been suggested to explain the rare reports of late death during convalescence.
Central nervous system dysfunction — Patients exhibit variable signs of central nervous system (CNS) dysfunction including delirium, agitation, convulsions, stupor, and coma. In severe cases, the cerebrospinal fluid is under increased pressure and may contain elevated protein but no cells. Pathologic changes include microscopic perivascular hemorrhages and edema. Given the absence of inflammatory changes suggesting viral neuroinvasion and encephalitis, CNS alterations are probably due to metabolic encephalopathy. True yellow fever viral encephalitis is exceedingly rare.
Outcome — The outcome is determined during the second week after onset, at which point the patient either dies or rapidly recovers. Approximately 20 to 50 percent of patients who enter the period of intoxication succumb to the disease. Poor prognostic signs include anuria, shock, hypothermia, agitation, delirium, intractable hiccups, seizures, hypoglycemia, hyperkalemia, metabolic acidosis, Cheyne-Stokes respirations, stupor, and coma.
Convalescence may be associated with fatigue lasting for several weeks. In some cases, jaundice and serum transaminase elevations may persist for months, although such patients may have yellow fever superimposed on other hematologic or hepatic diseases. The outcome of yellow fever appears to be comparable in patients with or without hepatitis B surface antigenemia.
Complications of yellow fever include bacterial superinfections, such as pneumonia, parotitis, and sepsis. Late deaths during convalescence occur rarely and have been attributed to myocarditis, arrhythmia, or heart failure.
DIAGNOSIS — Diagnosis is made by serology, detection of viral genome by polymerase chain reaction (PCR), by viral isolation or histopathology, and immunohistochemistry on postmortem tissues.
Serology — Serologic diagnosis is best accomplished using an enzyme-linked immunosorbent assay (ELISA) for IgM. The presence of IgM antibodies in a single sample provides a presumptive diagnosis; confirmation is made by a rise in titer between paired acute and convalescent samples or a fall between early and late convalescent samples.
Persistence of antibodies from earlier receipt of the live-attenuated vaccine can complicate interpretation of IgM results . In addition, cross-reactions with other flaviviruses complicate the diagnosis of yellow fever by serologic methods, particularly in Africa where multiple flaviviruses circulate. The neutralization test is more specific but requires a specialized laboratory.
Rapid diagnostic tests — Rapid diagnostic tests include PCR to detect viral genome in the blood or tissue and ELISA for determination of IgM antibody . Next-generation sequencing of RNA directly amplified from blood has been used to confirm the diagnosis and compare the patient’s strain to known geographic clades of the virus. These tools are increasingly available in national and regional laboratories in the endemic areas. A reverse-transcription loop-mediated isothermal amplification (RT-LAMP) yellow fever diagnostic test, which does not require thermocycling equipment and can be read visually, has shown promise as a sensitive and rapid test for use in field conditions .
Virus isolation — Virus isolation is accomplished by inoculation of mosquito or mammalian cell cultures, intracerebral inoculation of suckling mice, or intrathoracic inoculation of mosquitoes. The virus may also be recovered from postmortem liver tissue. During a yellow fever outbreak in Ivory Coast in 1982 including 90 confirmed cases, 30 percent were diagnosed by virus isolation from the blood; the majority of patients had detectable virus prior to onset of jaundice .
Pathology — Liver biopsy during illness due to yellow fever should never be performed, since fatal hemorrhage may ensue. Postmortem histopathologic examination of the liver often demonstrates the typical features of yellow fever including midzonal necrosis. A definitive postmortem diagnosis may be made by immunocytochemical staining for yellow fever antigen in the liver, heart, spleen, or kidney [42-44]. (See 'Virology, pathogenesis, and histopathology' above.)
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of yellow fever includes:
●Viral hepatitis (hepatitis A, B, C, D, and E) – These entities are characterized by elevated transaminases; hepatitis A and E are acute infections transmitted most frequently by the fecal-oral route, whereas hepatitis B, C, and D can present acutely or chronically and are transmitted by body fluids. In Africa, severe and fatal hepatitis E in pregnancy has frequently been misdiagnosed as yellow fever. (See related topics.)
●Influenza – Influenza is associated with fever, headache, malaise, and myalgias. It is not generally associated with severe hepatic involvement or jaundice. The diagnosis is established by viral detection (table 1). (See "Clinical manifestations of seasonal influenza in adults".)
●Dengue – Dengue and yellow fever are similar in that both are associated with fever, headache and body aches, and hemorrhagic manifestations. Hepatic involvement can occur in the setting of severe dengue infection. The diagnosis of dengue is established by serology. (See "Dengue virus infection: Clinical manifestations and diagnosis".)
●Malaria – Malaria is characterized by fever and anemia; clinical manifestations include jaundice due to hemolysis. The diagnosis of malaria is established by visualization of parasites on peripheral smear. (See "Clinical manifestations of malaria in nonpregnant adults and children".)
●Typhoid – Manifestations of typhoid fever include fever and gastrointestinal symptoms. Abnormal liver function tests are observed but jaundice is not a typical clinical feature. The diagnosis is established by culture. (See "Epidemiology, microbiology, clinical manifestations, and diagnosis of typhoid fever".)
●Leptospirosis – Leptospirosis is a bacterial infection characterized by fever, myalgia, headache, and conjunctival suffusion. Modest elevation of hepatic transaminases may be observed. The diagnosis is established by serology. (See "Epidemiology, microbiology, clinical manifestations, and diagnosis of leptospirosis".)
●Q fever – Q fever occurs as a result of infection with Coxiella burnetii; hepatic involvement includes elevated transaminases, hepatomegaly without jaundice, and granulomas on liver biopsy. The diagnosis is established by serology. (See "Clinical manifestations and diagnosis of Q fever".)
●Hemorrhagic fever – Yellow fever may be distinguished from other viral hemorrhagic fevers (Lassa fever, Marburg virus, Ebola virus, Bolivian and Argentine hemorrhagic fevers) in that these other viral hemorrhagic fevers are not usually associated with jaundice. However, Congo-Crimean hemorrhagic fever may be associated with severe liver damage; Rift Valley fever and dengue hemorrhagic fever may present with this complication as well. (See related topics.)
TREATMENT — The treatment of yellow fever consists of supportive care; there is no specific antiviral therapy available . Management of patients may be improved by modern intensive care, but this is generally not available in remote areas where yellow fever often occurs. Travelers hospitalized after return to the United States or Europe have had fatal outcomes in spite of intensive care, demonstrating the inexorable course of severe yellow fever.
Supportive care should include maintenance of nutrition, prevention of hypoglycemia, nasogastric suction to prevent gastric distention and aspiration, treatment of hypotension by fluid replacement and vasoactive drugs if necessary, administration of oxygen, management of metabolic acidosis, treatment of bleeding with fresh-frozen plasma, dialysis if indicated by renal failure, and treatment of secondary infections .
All antiviral therapies are at a very early stage of development for use in yellow fever [32,45,46]. Ribavirin is active against yellow fever virus but only at very high concentrations that may not be achievable clinically .
The benefit of hyperimmune globulin or monoclonal antibody after the onset of clinical illness is uncertain; further study is required [45,48,49].
PREVENTION — Vaccination is the primary tool for prevention of yellow fever.
Vaccination — A live-attenuated vaccine against yellow fever was developed in 1936 (yellow fever 17D vaccine). In the United States, the vaccine (YF-VAX) is manufactured by Sanofi-Pasteur (Swiftwater, PA). Another vaccine formulation derived from a different passage series of the same vaccine virus strain, 17DD, is manufactured in Brazil . There are six manufacturers of yellow fever vaccine worldwide, which produce about 70 to 90 million doses annually; four are approved by the World Health Organization (WHO) and supply the vast majority of doses. In general supply does not meet demand; expansion of vaccine production is expected.
YF-VAX is unavailable in the United States until mid-2018, when a new production facility is expected to open. An alternative but similar formulation, Stamaril (produced in France and used in Europe, Australia, and endemic areas), is available under the US Food and Drug Administration's (FDA's) Expanded Access Investigational New Drug Program at high-volume yellow fever vaccination centers .
The WHO maintains an emergency stockpile of six million doses; this was depleted and replenished three times in the 2016 Angolan outbreak. Because vaccine was in short supply in the 2016 outbreaks, and there was apprehension about spread of yellow fever to other countries, especially Asia, WHO considered and approved the use of fractional (1/5th) doses (0.1 mL given by subcutaneous route) in emergency conditions. (See 'Fractional dosing in outbreaks' below.)
In 2016, the WHO announced a new program, Eliminate Yellow Fever Epidemics (EYE), which will incorporate three pillars: prevention of yellow fever in at-risk populations, prevention of international spread, and containment of outbreaks rapidly . The program will ensure more inclusive 17D vaccinations in the Expanded Programme of Immunization, mass vaccination campaigns, and readiness for emergency control of outbreaks, including improved surveillance and laboratory diagnosis.
Clinical approach — The estimated risks of illness and death due to yellow fever in an unvaccinated traveler to an endemic area are relatively high (1 in 1000 and 1 in 5000 per month, respectively) . In the United States, the risks of YEL-AND and YEL-AVD in travelers are estimated at 0.8 and 0.4 per 100,000 respectively, although the risk is higher in older adults. (See 'Adverse effects' below.)
Whom to vaccinate — In accordance with the United States Centers for Disease Control and Prevention (CDC), the United States Advisory Committee on Immunization Practices (ACIP), and the World Health Organization, we recommend vaccination for travelers to yellow fever-endemic areas of Africa and South America and for residents of those areas (figure 1 and figure 2) [53-56].
In June 2015, the ACIP issued recommendations stating that a single primary dose of yellow fever vaccine is adequate for most travelers . In July 2016, the World Health Assembly removed the 10-year booster dose requirement from the International Health Regulations.
●Women who were pregnant at the time of initial yellow fever vaccination should receive one additional dose of yellow fever vaccine prior to subsequent travel to an area with risk for yellow fever virus infection.
●Individuals who received a hematopoietic stem cell transplant after receiving yellow fever vaccination and who are sufficiently immunocompetent to be safely vaccinated should receive an additional dose of yellow fever vaccine prior to subsequent travel to an area with risk for yellow fever virus infection.
●Individuals who were infected with HIV at the time of prior yellow fever vaccination, with continued risk for yellow fever virus infection, should receive a booster dose of yellow fever vaccine every 10 years.
●Individuals whose last dose of yellow fever vaccine was at least 10 years previously and plan to spend a prolonged period in endemic areas, plan to travel to highly endemic areas (such as rural West Africa) during peak transmission season, or plan to travel to an area with an ongoing outbreak should receive an additional dose of yellow fever vaccine.
●Laboratory workers who routinely handle yellow fever virus should have antibody titers measured at least every 10 years to determine if additional vaccination is warranted.
A biweekly "Blue Sheet" Summary of Health Information for International Travel published by the CDC provides updated information on countries officially reporting yellow fever . In addition, there is a free course available online that provides information and training about yellow fever to healthcare professionals who advise travelers . The WHO is revising the geographic risk areas to create an evidence-based analysis of the probability of exposure to yellow fever .
Due to the risk of serious adverse events (particularly in persons >60 years of age), the benefit of immunization should be established based on careful review of the traveler's itinerary with respect to potential for exposure to yellow fever virus . Individuals traveling in rural areas of countries within yellow fever-endemic zones should be immunized even in the absence of official yellow fever reports, since active transmission may be underrecognized.
For individuals with allergy to egg proteins who clearly require immunization due to possible exposure to yellow fever virus, epidermal scratch and intradermal skin testing may be performed to help ascertain whether the vaccine can be given safely. Otherwise, desensitization may be used . Skin testing and desensitization are best performed by an experienced allergist. (See "Allergic reactions to vaccines".)
Vaccination against yellow fever in endemic areas is performed as part of the Expanded Program of Immunization at nine months of age. In some African countries, catch-up mass vaccination campaigns are undertaken based on assessments of geographic risk, as part of a highly successful initiative spearheaded by the WHO to increase vaccine coverage [61,62]. Mass campaigns are also conducted in response to outbreaks in Africa and South America.
Certificates — In the United States, yellow fever vaccine is distributed only through approved vaccinating centers, including travel clinics and some health departments. These designated centers are listed in a registry at the CDC travel website .
Some countries in yellow fever-endemic zones require a World Health Organization international certificate of vaccination as evidence of yellow fever immunization prior to entry; these are listed in the publications and websites of the CDC and WHO [56,58,63]. In addition, some countries outside of yellow fever zones also require evidence of immunizations prior to entry for individuals with recent travel in endemic countries .
The WHO international certificate of immunization for international travel is valid for life.
Individuals with contraindications or precautions deemed to place the traveler at high risk of adverse events may receive a waiver letter from a physician for travel to areas where vaccination is an international travel requirement.
The 2016 Angola outbreak revealed that multiple expatriates working in the country had entered the country without vaccinations; as a result, there have been reports of yellow fever cases in persons travelling from Angola to the Democratic Republic of the Congo, Kenya, and China. This situation illustrates the potential for global spread of the virus.
Fractional dosing in outbreaks — Fractional dosing is a strategy for extending yellow fever vaccine supply in outbreak situations [65,66]. Individuals vaccinated with 1/10 the standard yellow fever vaccine dose have similar innate and adaptive immune responses to individuals vaccinated with the full standard dose (approximately 20,000 infectious units in 0.5 mL) [67,68].
In June 2016, the WHO Strategic Advisory Group of Experts (SAGE) on Immunization stated that vaccination with one-fifth the standard dose is sufficient to provide protection against yellow fever for at least 12 months, and they advocated short-term use of this approach among individuals >2 years in emergency conditions when vaccine supplies are limited [69,70]. This strategy was employed in the Democratic Republic of the Congo in 2016. The titer of vaccine should be reviewed to ensure that the delivered dose exceeds the minimum international standard (1000 infectious units). Fractional dosing of yellow fever vaccination may not qualify for international certificate of vaccination. (See 'Certificates' above.)
Full-dose vaccine should be given to children under 2 years since there are some concerns about lower efficacy of the vaccine in young children . Moreover, no studies of fractional dose have been done in African populations (which appear to respond less well to yellow fever 17D) , children, HIV-positive individuals, or pregnant women, and the durability of fractional dose vaccination beyond one year is unknown.
Pregnancy and breastfeeding — Pregnancy is a precaution for yellow fever vaccine administration; in contrast, most other live vaccines are contraindicated in pregnancy. If travel is unavoidable and the risks for yellow fever virus exposure are felt to outweigh the vaccination risks, a pregnant woman should be vaccinated. If the risks for vaccination are felt to outweigh the risks for yellow fever virus exposure, pregnant women should be issued a medical waiver to fulfill health regulations .
The safety of yellow fever vaccination during pregnancy has not been clearly established. Congenital infection appears to occur at a low rate (probably 1 to 2 percent) and has never been associated with fetal abnormalities [74,75]. Pregnant woman who inadvertently receive vaccination should be reassured; there is no rationale to interrupt the pregnancy.
Administration of yellow fever vaccine to breastfeeding women should be avoided except in situations where exposure to yellow fever viruses cannot be avoided or postponed. Yellow fever vaccine virus can be transmitted via breastfeeding; in one report, two infants acquired yellow fever vaccine virus via breast milk from mothers who had undergone yellow fever vaccination; the infant developed YEL-AND requiring hospitalization [76,77].
Immunocompromised individuals — Yellow fever 17D vaccine should not be administered to immunocompromised individuals because of theoretical concerns about live-attenuated virus vaccines .
Contraindications include inherited immune deficiency, lymphoma, leukemia, HIV/AIDS with low CD4 counts, immunosuppressive chemotherapy or radiotherapy, thymus disorders, DiGeorge's syndrome, and a history of thymectomy. Autoimmune disease may be a risk factor for YEL-AVD but is not a listed precaution in the vaccine label. Immunogenicity seems satisfactory among patients receiving systemic corticosteroid therapy (median prednisone 7 mg/day for 10 months), although local reactions may occur more frequently in these patients; further study is needed .
Travelers with asymptomatic HIV infection may be immunized if potential exposure warrants; such patients should be advised of the possible risks of vaccination . In studies of HIV-infected patients with CD4+ counts above 200/microL, all responded serologically and none had adverse events [79,80]. Nevertheless, it is prudent to confirm development of neutralizing antibodies, since such individuals may have an impaired ability to respond to yellow fever vaccine. Antibody testing can be arranged through state health department laboratories or a commercial laboratory. Waiver letters can also be obtained for these patients .
Vaccine efficacy — The 17D vaccine produces high levels of protection . Protective immunity occurs in 90 percent of individuals within 10 days after receiving the 0.5 mL subcutaneous dose and in nearly 100 percent of individuals within three to four weeks after vaccination. A meta-analysis of studies of vaccine efficacy showed that 97.5 percent of vaccinated individuals mounted a protective serologic response (95% CI 82.9 to 99.7 percent) . The 17DD vaccine produces similar levels of protection .
Infants, toddlers, pregnant women, and persons with HIV or other causes of immune suppression may not respond as vigorously to the 17D vaccine . In one large study, the primary vaccine failure rate in young children was approximately 9 percent .
Immunity after a single dose is long lasting and may provide lifetime protection . The WHO Strategic Advisory Group of Experts in Immunization concluded in 2013 that a single primary dose of yellow fever vaccine is sufficient to confer sustained immunity and lifelong protection against yellow fever disease, and a booster dose of the vaccine is not needed [84,85]. In May 2014, the World Health Assembly adopted the recommendation to remove the 10-year booster dose requirement from the International Health Regulations by June 2016. In 2015, the United States Advisory Committee on Immunization Practices issued recommendations stating that a single primary dose of yellow fever vaccine is adequate for most travelers . (See 'Whom to vaccinate' above.)
The WHO international certificate of immunization for international travel is valid for 10 years; a booster 0.5 mL dose is required every 10 years for the certificate to be reissued. In May 2014, the World Health Assembly adopted the recommendation to remove the 10-year booster dose requirement from the International Health Regulations and this was formally implemented in July 2016. Revaccination is no longer required and a certificate of vaccination is now valid for life.
The live-attenuated vaccine virus activates myeloid and plasmacytoid dendritic cells to produce a variety of proinflammatory cytokines and turn on genes that activate signaling pathways [87-93]. Overall, a marked upregulation of the innate immune system persists for about two weeks after vaccination and drives the adaptive immune response.
Adverse effects — More than 600 million doses of vaccines have been administered since the 17D vaccine strain was developed. Serious adverse reactions to the 17D vaccine are very rare events; they include two syndromes, known as yellow fever vaccine-associated neurotropic disease (YEL-AND) and yellow fever vaccine-associated viscerotropic disease (YEL-AVD). In the United States, the risks of YEL-AND and YEL-AVD in civilian travelers are estimated at 0.8 and 0.4 per 100,000 respectively, although the risk is higher in older individuals.
Mild fever, headache, myalgia and malaise, and soreness at the site of inoculation can occur in the absence of liver function abnormalities [71,94].
The vaccine is contraindicated for persons with known egg allergy; allergic reactions to residual egg proteins or gelatin stabilizer in yellow fever 17D vaccine occur, albeit at very low rates.
The yellow fever vaccine virus may be transmitted by transfusion of blood products. Vaccine recipients should defer blood product donation for at least two weeks . In addition, the vaccine virus may be transmitted from lactating mothers to breast-fed infants .
Neurotropic disease — YEL-AND refers to an encephalitis usually caused by infection of the central nervous system with 17D virus . Onset occurs two to eight days after vaccination; the event is nearly always self-limited but rarely is associated with neurological sequelae. Definitive diagnosis is based on virus isolation, detection of viral genome by polymerase chain reaction (PCR), or detection of IgM antibody in cerebrospinal fluid. Cases of neuromyelitis optica, Guillain-Barré, and acute disseminated encephalomyelitis (ADEM) have also been described and presumably have an autoimmune etiology.
YEL-AND has been observed in infants and adults [64,97,98]. Between 2000 and 2006, the rate of YEL-AND in the United States was 0.8 per 100,000 . The incidence of YEL-AND is higher in older adults; persons ≥70 years have a rate of 2.3 per 100,000 [100,101]. Among four cases described in adults in 2001 to 2002, all had fever and two had aphasia; cerebrospinal fluid was all positive for yellow fever-specific IgM in all patients; cultures and PCR were negative . Cases in infants have diminished since restriction of vaccine administration to children more than nine months of age .
Viscerotropic disease — YEL-AVD refers to a syndrome resembling wild-type yellow fever infection that occurs in the setting of yellow fever 17D vaccination [96,102-104]. Case definitions have been published . Onset of illness generally occurs three to five days after vaccination with fever, malaise, jaundice, oliguria, cardiovascular instability, and hemorrhage. The case-fatality rate of YEL-AVD is 63 percent, and there is no specific treatment [96,106,107].
The estimated incidence of YEL-AVD in the United States is 0.4 per 100,000 but may be sixfold higher among individuals ≥60 years of age . Based on the relatively small series of cases, there appears to be a higher incidence in young adult females. In Peru, an unexplained, high incidence of YEL-AVD was reported during a mass immunization campaign (7.9 per 100,000) . In a large experience of 38 million vaccinations given in West Africa between 2007 and 2010, during which pharmacovigilance was undertaken, few serious adverse events and only five suspected YEL-AVD cases were found , emphasizing the high safety record of the vaccine.
Nevertheless, there have been more reports of deaths due to YEL-AVD than due to wild-type disease in unvaccinated travelers. This emphasizes the importance of careful assessment for vaccination need based on full understanding of disease epidemiology and travel itinerary, to avoid unnecessary risk of vaccine adverse effects but to ensure that patients with risk for exposure are protected .
Identifying risk factors for YEL-AVD is difficult because of the relatively low incidence. YEL-AVD does not appear to be caused by mutational changes in the virus [81,96,108]. Rather, YEL-AVD is probably related to defects in host innate immunity; in affected individuals, the early antiviral response appears to be impaired, allowing unchecked viral replication before activation of the adaptive immune response .
Acquired host factors appear to increase the risk of developing YEL-AVD after vaccination: advanced age and thymus disease and possibly female gender in younger persons [96,100,101,106,110,111]. A study in older adults showed that viremia caused by yellow fever 17D vaccine was prolonged and the antibody response delayed, foreshadowing the role of immune senescence in cases with YEL-AVD . Thymus disease (eg, thymoma, myasthenia gravis) was present in 4 of the 23 reported cases; all underwent thymectomy 2 to 20 years before vaccination . In addition, thymic involution increases with age and the associated immune suppression might contribute to the increase in risk of YEL-AVD in older adults. A fatal case in a patient with a thymoma detected only at autopsy illustrates the difficulty in assessing underlying acquired risk factors . There is some evidence that immune dysregulation associated with autoimmune diseases, such as systemic lupus erythematosus and Addison's disease, may also be a risk factor for YEL-AVD [18,108].
Newer, potentially safer vaccines — Serious adverse events (except acute hypersensitivity reactions) are caused by replicating virus. Therefore, efforts are underway to develop safer, inactivated vaccines. A whole-virion inactivated vaccine adsorbed to aluminum hydroxide adjuvant was protective in animal models and was shown to be well tolerated and immunogenic in a phase I clinical trial .
Immune globulin — There is no specific yellow fever immune globulin product available. Immune globulin produced in the United States (where many military personnel have been vaccinated) may contain yellow fever-neutralizing antibodies. Passive immunization has been used off label to protect persons traveling to high-risk areas who have contraindications to vaccination . If exposure to yellow fever virus occurred at a defined time (eg, in the case of accidental exposure in the laboratory or to blood from an acutely ill patient), postexposure treatment with immune globulin (from United States donors) or interferon-alfa (preferably not longer-acting pegylated interferon) would be warranted. Treatment would be expected to be effective only within the first 24 hours after exposure .
SUMMARY AND RECOMMENDATIONS
●Yellow fever is a mosquito-borne viral hemorrhagic fever with a high case-fatality rate. Travelers to tropical regions of South America and sub-Saharan Africa are at risk for acquisition of infection and require immunization. (See 'Introduction' above.)
●Mosquito-borne epidemics in Africa occur where human populations reside in high density and immunization coverage is low (so-called "urban yellow fever"). Fewer cases occur in South America than in Africa because transmission occurs principally from monkey to human via mosquito vectors, the vector density is relatively low, and vaccination coverage is relatively high (so-called "jungle yellow fever"). (See 'Epidemiology' above.)
●Yellow fever is characterized by three stages: periods of infection, remission, and intoxication. The period of infection consists of viremia with nonspecific symptoms and signs including fever, malaise, headache, joint pain, nausea, and vomiting. This is followed by a period of remission with abatement of fever and symptoms lasting up to 48 hours. The subsequent period of intoxication is characterized by hepatic dysfunction, renal failure, coagulopathy, and shock. (See 'Clinical manifestations' above.)
●Diagnosis may be made by serology, by detection of viral genome by polymerase chain reaction (PCR) in serum, by virus isolation, or by histopathology and immunocytochemistry (postmortem samples only). Serologic diagnosis is best accomplished using an enzyme-linked immunosorbent assay (ELISA) for IgM. The presence of IgM antibodies in a single sample provides a presumptive diagnosis; confirmation is made by a rise in titer between paired acute and convalescent samples or a fall between early and late convalescent samples. More specific neutralization tests may be performed but require a specialized laboratory. (See 'Diagnosis' above.)
●The treatment of yellow fever consists of supportive care; there is no specific antiviral therapy available. (See 'Treatment' above.)
●In accordance with the United States Centers for Disease Control and Prevention (CDC), the United States Advisory Committee on Immunization Practices (ACIP), and the World Health Organization (WHO), we recommend yellow fever vaccine for travelers to yellow fever-endemic areas of Africa and South America and for residents of those areas (Grade 1A). The vaccine may be administered to individuals over the age of nine months. (See 'Prevention' above and 'Whom to vaccinate' above.)
●Serious adverse reactions to the 17D vaccine are very rare; they include two syndromes, yellow fever vaccine-associated neurotropic disease (YEL-AND) and yellow fever vaccine-associated viscerotropic disease (YEL-AVD). In the United States, the risks of YEL-AND and YEL-AVD in civilian travelers are estimated at 0.8 and 0.4 per 100,000, respectively, although the risk is higher in older adults, persons with immune dysregulation, and possibly young females. Serious adverse events have been significantly less frequently observed during immunization campaigns in endemic countries. In an ongoing epidemic in Angola, multiple cases of yellow fever have been exported to various countries, including China. This illustrates the danger of travel to endemic regions without vaccination and the risk of global spread of the virus. (See 'Adverse effects' above.)
●Some countries in yellow fever-endemic zones require an international certificate of vaccination as evidence of yellow fever immunization prior to entry. In addition, some countries outside of yellow fever zones also require evidence of immunizations prior to entry for individuals with recent travel in endemic countries. The international certificate of immunization is valid for 10 years; a booster 0.5 mL dose is required every 10 years for the certificate to be reissued. (See 'Certificates' above.)
●Immunity after a single dose is long lasting. In May 2014, the World Health Assembly adopted the recommendation to remove the 10-year booster dose requirement from the International Health Regulations by June 2016. Until this time, travelers to countries with a yellow fever vaccination entry requirement must have received a dose of yellow fever vaccine within the past 10 years. In June 2015, the United States Advisory Committee on Immunization Practices (ACIP) issued recommendations stating that a single primary dose of yellow fever vaccine is adequate for most travelers; the ACIP does recommend additional doses of yellow fever vaccine at-risk laboratory personnel and certain travelers. (See 'Whom to vaccinate' above.)
●Fractional dosing is a strategy for extending yellow fever vaccine supply in outbreak situations. In 2016, the World Health Organization Strategic Advisory Group of Experts on Immunization stated that vaccination with one-fifth the standard dose is sufficient to provide protection against yellow fever for at least 12 months, and they advocated short-term use of this approach among individuals >2 years in emergency conditions when vaccine supplies are limited. (See 'Fractional dosing in outbreaks' above.)
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