Yellow Fever

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Chapter 262 Yellow Fever

Scott B. Halstead

Yellow fever is an acute infection characterized in its most severe form by fever, jaundice, proteinuria, and hemorrhage. The virus is mosquito-borne and occurs in epidemic or endemic form in South America and Africa. Seasonal epidemics occurred in cities located in temperate areas of Europe and the Americas until 1900, and epidemics continue in West, Central, and East Africa.

Etiology

Yellow fever is the prototype of the Flavivirus genus of the family Flaviviridae, which are enveloped single-stranded RNA viruses 35-50 nm in diameter.

Yellow fever circulates zoonotically as 3 genotypes: type I in Central Africa, type IIA in West Africa, and type IIB in South America. Type IIA virus is capable of urban transmission between human beings by Aedes aegypti. Sometime in the 1600s this virus was brought to the American tropics through the African slave trade. Subsequently, yellow fever caused enormous coastal and riverine epidemics until the 20th century, when the virus and its urban and sylvan mosquito cycles were identified, mosquito control methods were perfected, and a vaccine was developed. The Central African genotype of yellow fever has not fully entered the urban cycle and has never spread to the East Coast of Africa or to the countries of Asia.

Epidemiology

Human and nonhuman primate hosts acquire the yellow fever infection by the bite of infected mosquitoes. After an incubation period of 3-6 days, virus appears in the blood and may serve as a source of infection for other mosquitoes. The virus must replicate in the gut of the mosquito and pass to the salivary gland before the mosquito can transmit the virus. Yellow fever virus is transmitted in an urban cycle—human to A. aegypti to human—and a jungle cycle—monkey to jungle mosquitoes to monkey. Classic yellow fever epidemics in the USA, South America, the Caribbean, and parts of Europe were of the urban variety. Since 2000, West Africa has experienced 5 urban epidemics, including in the capital cities of Abidjan (Cote d’Ivoire), Conakry (Guinea), and Dakar (Senegal). Most of the approximately 200 cases reported each year in South America are jungle yellow fever. In colonial times, attack rates in white adults were very high, suggesting that subclinical infections are uncommon in this age group. Yellow fever may be less severe in children, with subclinical infection:clinical case ratios ≥2 : 1. In areas where outbreaks of urban yellow fever are common, most cases involve children because many adults are immune. Transmission in West Africa is highest during the rainy season, from July to November. The migration of nonimmune laborers into endemic regions is a significant factor in some outbreaks.

In tropical forests, yellow fever virus is maintained in a transmission cycle involving monkeys and tree hole-breeding mosquitoes (Haemagogus in Central and South America, Aedes africanus in Africa). In the Americas, most cases involve men who work in forested areas and are exposed to infected mosquitoes. In Africa, the virus is prevalent in moist savanna and savanna transition areas where other tree hole–breeding Aedes vectors transmit the virus between monkeys and humans and between humans.

Pathogenesis

Pathologic changes seen in the liver include (1) coagulative necrosis of hepatocytes in the midzone of the liver lobule, with sparing of cells around the portal areas and central veins; (2) eosinophilic degeneration of hepatocytes (Councilman bodies); (3) microvacuolar fatty change; and (4) minimal inflammation. The kidneys show acute tubular necrosis. In the heart, myocardial fiber degeneration and fatty infiltration are seen. The brain may show edema and petechial hemorrhages. Direct viral injury to the liver results in impaired ability to perform functions of biosynthesis and detoxification; this is the central pathogenic event of yellow fever. Hemorrhage is postulated to result from decreased synthesis of vitamin K–dependent clotting factors and, in some cases, disseminated intravascular clotting. However, because the pathogenesis of shock in patients with yellow fever appears similar to that described for dengue shock syndrome and the other viral hemorrhagic fevers, viral damage to platelets and endothelial cells resulting in release of prohemorrhagic factors may be the central mechanism of hemorrhage in yellow fever.

Renal dysfunction has been attributed to hemodynamic factors (prerenal failure progressing to acute tubular necrosis).

Clinical Manifestations

In Africa, inapparent, abortive, or clinically mild infections are frequent; some studies suggest that children experience a milder disease than adults do. Abortive infections, characterized by fever and headache, may be unrecognized except during epidemics.

In its classic form, yellow fever begins with sudden onset of fever, headache, myalgia, lumbosacral pain, anorexia, nausea, and vomiting. Physical findings during the early phase of illness, when virus is present in the blood, include prostration, conjunctival injection, flushing of face and neck, reddening of the tongue at the tip and edges, and relative bradycardia. After 2-3 days, there may be a brief period of remission, followed in 6-24 hr by reappearance of fever with vomiting, epigastric pain, jaundice, dehydration, gastrointestinal and other hemorrhages, albuminuria, hypotension, renal failure, delirium, convulsions, and coma. Death may occur after 7-10 days, with the fatality rate in severe cases approaching 50%. Some patients who survive the acute phase of illness later succumb to renal failure or myocardial damage. Laboratory abnormalities include leukopenia; prolonged clotting, prothrombin, and partial thromboplastin times; thrombocytopenia; hyperbilirubinemia; elevated serum transaminase values; albuminuria; and azotemia. Hypoglycemia may be present in severe cases. Electrocardiogram abnormalities such as bradycardia and ST-T changes are described.

Diagnosis

Yellow fever should be suspected when fever, headache, vomiting, myalgia, and jaundice appear in residents of endemic areas or in unimmunized visitors who have recently traveled (within 2 wk before onset of symptoms) to endemic areas. Clinically, yellow fever is quite similar to dengue hemorrhagic fever. In contrast to the gradual onset of acute viral hepatitis resulting from hepatitis A, B, C, D, or E virus, jaundice in yellow fever appears after 3-5 days of high temperature and is often accompanied by severe prostration. Mild yellow fever is dengue-like and cannot be distinguished from a wide variety of other infections. Jaundice and fever may occur in any of several other tropical diseases, including malaria, viral hepatitis, louse-borne relapsing fever, leptospirosis, typhoid fever, rickettsial infections, certain systemic bacterial infections, sickle cell crisis, Rift Valley fever, Crimean-Congo hemorrhagic fever, and other viral hemorrhagic fevers. Outbreaks of yellow fever always include cases with severe gastrointestinal hemorrhage.

Specific diagnosis depends on detection of virus or viral antigen in acute-phase blood samples or antibody assays. The immunoglobulin (Ig) M enzyme immunoassay is particularly useful. Sera obtained during the 1st 10 days after onset of symptoms should be kept in an ultra-low-temperature freezer (−70°C) and shipped on dry ice for virus testing. Convalescent-phase samples for antibody tests are managed by conventional means. In handling acute-phase blood specimens, medical personnel must take care to avoid contaminating themselves or others on the evacuation trail (laboratory personnel and others). Postmortem diagnosis is based on virus isolation from liver or blood, identification of Councilman bodies in liver tissue, or detection of antigen or viral genome in liver tissue.

Treatment

It is customary to keep patients with yellow fever in a mosquito-free area, with use of mosquito nets if necessary. Patients are viremic during the febrile phase of the illness. Although there is no specific treatment for yellow fever, medical care is directed at maintaining physiologic status with the following measures: (1) sponging and acetaminophen to reduce high temperature, (2) vigorous fluid replacement of losses resulting from fasting, thirsting, vomiting, or plasma leakage, (3) correcting acid-base imbalance, (4) maintaining nutritional intake to lessen the severity of hypoglycemia, and (5) avoiding drugs that are either metabolized by the liver or toxic to the liver, kidney, or central nervous system.

Complications

Complications of acute yellow fever include severe hemorrhage, liver failure, and acute renal failure. Bleeding should be managed by transfusion of fresh whole blood or fresh plasma with platelet concentrates if necessary. Renal failure may require peritoneal dialysis or hemodialysis.

Prevention

Yellow fever 17D is a live-attenuated vaccine with a long record of safety and efficacy. It is administered as a single 0.5-mL subcutaneous injection at least 10 days before arrival in a yellow fever–endemic area. With the exceptions noted later, individuals traveling to endemic areas in South America and Africa should be considered for vaccination, but length of stay, exact locations to be visited, and environmental or occupational exposure may determine the specific risk and individual need for vaccination. Persons traveling from yellow fever–endemic to yellow fever–receptive countries may be required to obtain a yellow fever vaccine (e.g., from South America or Africa to India). Usually countries that require travelers to obtain a yellow fever immunization do not issue a visa without a valid immunization certificate. Vaccination is valid for 10 yr for international travel certification, although immunity lasts at least 40 yr and probably for life.

Since 1996, there have been a number of reports of yellow fever vaccine–associated viscerotropic disease with higher risk in elderly vaccine recipients and in persons with previous thymectomies. Yellow fever vaccine should not be administered to persons who have symptomatic immunodeficiency diseases, are taking immunosuppressant drugs, or have a history of thymectomy. Although the vaccine is not known to harm fetuses, its administration during pregnancy is not advised. The vaccine virus may be transmitted through breast-feeding. In very young children, there is a small risk for encephalitis and death after yellow fever 17D vaccination. The 17D vaccine should not be administered to infants younger than 4 mo. Residence in or travel to areas of known or anticipated yellow fever activity (e.g., forested areas in the Amazon basin), which puts an individual at high risk, warrants immunization of infants 4-9 mo of age. Immunization of children ≥9 mo of age is routinely recommended before entry into endemic areas. Immunization of persons >60 yr of age should be weighed against their risk for sylvatic yellow fever in the American tropics and for urban or sylvatic yellow fever in Africa. Vaccination should be avoided in persons with a history of egg allergy. Alternatively, a skin test can be performed to determine whether a serious allergy exists that would preclude vaccination.

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