Yellow fever

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) . Humans are highly susceptible to infection and disease. Most non-human primate species are susceptible to infection, and some species of non-human 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 and spleen and 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. 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 . 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 pro-inflammatory cytokines (interleukin [IL]-6, IL-1 receptor antagonist, 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.

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 . 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 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 . 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 .

The incidence of yellow fever in Africa varies widely because of the occurrence of epidemics in which humans serve as the viremic host for infection of Aedes mosquito vectors (eg, in Ethiopia in 1960-1962, Nigeria in 1987) . While official records have documented up to 5000 cases in such epidemic years, the true incidence likely approached >100,000 cases. Mosquito-borne epidemics in Africa occur where large human populations reside in high density and immunization coverage is low. Human-to-human transmission in the absence of the mosquito does not occur.

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.

In both Africa and South America only a small proportion of cases are 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 if these disparities reflect reporting artifact, a real difference in virus strain virulence, and/or differing genetic susceptibility of the human populations. These historical epidemiological descriptions of the medical impact of yellow fever may be changing as use of yellow fever vaccine is expanding.

Among expatriates and travelers to Africa and South America, yellow fever has been rare since the introduction of vaccination after World War II. Since that time, 10 cases have been recorded .

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 are 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. 

CLINICAL MANIFESTATIONS  — 

The clinical spectrum of yellow fever includes :

• Subclinical infection
• 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 the elderly. The onset of illness appears abruptly three to six 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 (particularly the knee joints), 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. Multi-organ failure in yellow fever is associated with high levels of pro-inflammatory 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  — 

Diseases that may be confused clinically with yellow fever include dengue hemorrhagic fever, leptospirosis, louse-borne relapsing fever (Borrelia recurrentis), viral hepatitis, Rift Valley fever, Q fever, typhoid, and severe malaria. Mild yellow fever, characterized by fever, headache, malaise, and myalgias, resembles many other arboviral infections and influenza. (See appropriate topic reviews).

Other viral hemorrhagic fevers, including Lassa, Marburg, and Ebola virus diseases, Bolivian and Argentine hemorrhagic fevers, and Congo-Crimean hemorrhagic fever, are not usually associated with jaundice.

Diagnosis is made by serology, detection of viral genome by PCR, by viral isolation or histopathology, and immunohistochemistry on post-mortem 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 . These tools are increasingly available in national and regional laboratories in the endemic areas.

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 .

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 .

Antiviral activity against yellow fever has been demonstrated for a number of nucleosides and plant-derived alkaloids . Ribavirin is active against yellow fever virus, but only at very high concentrations that may not be achievable clinically; further study is warranted. In the monkey and mouse models, alpha-interferon is effective in abrogating infection if administered within 24 hours of infection and may be the treatment of choice in the event of a known exposure, for example, of an unvaccinated person exposed to wild-type yellow fever virus in the laboratory.

The benefit of hyperimmune globulin after the onset of clinical illness is uncertain; further study is required .

PREVENTION  —

 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 .

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. The 17DD vaccine also produces similar high levels of protection .

Immunity after a single dose is long-lasting and may provide lifetime protection. The minimum level of neutralizing antibody needed for protection has been estimated using animal models at approximately 1:40. The World Health Organization (WHO) 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.

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. 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 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 elderly individuals.

Mild fever, headache, myalgia and malaise, and soreness at the site of inoculation can occur in the absence of liver function abnormalities.

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 .

YEL-AND  — 

YEL-AND refers to yellow fever vaccine -associated neurotropic disease, 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 PCR, or detection of IgM antibody in cerebrospinal fluid. Cases of Guillain-Barré and acute disseminated encephalomyelitis (ADEM) have also been described and presumably have an autoimmune etiology.

YEL-AVD  — YEL-AVD refers to yellow fever vaccine -associated viscerotropic disease, a syndrome resembling wild-type yellow fever infection that occurs in the setting of yellow fever 17D vaccination [ 54,61-63 ]. Onset of illness 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 .

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) .

Pregnancy and breast feeding  — 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 . Pregnant woman who inadvertently receive vaccination should be reassured; there is no rationale to interrupt the pregnancy.

Administration of yellow fever vaccine to breast-feeding 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 breast-feeding; 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.

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) frequently contains adequate titers of yellow fever neutralizing antibodies (typically 1:320). 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), post exposure treatment with immune globulin (from United States donors) or interferon-alpha (preferably not longer-acting pegylated interferon) would be warranted. Treatment would be expected to be effective only within the first 24 hours after exposure.