Virology and Pathophysiology

Yellow fever is a single-stranded RNA flavivirus. Strain differences are of little clinical relevance, although they may be of use in epidemiologic studies. The pathophysiologic mechanisms operating in viral hemorrhagic fevers are not well defined. In general, viral replication occurs at the site of inoculation. After the virus spreads to lymph nodes and monocyte-rich organs, further reproduction results in massive viremia.

The liver is the principal target organ. Pathologic studies show coagulative necrosis of hepatocytes and appearance of various markers of cell involvement (Councilman and Torres bodies). However, the degree of physiologic derangement is usually much more severe than expected for the extent of hepatic damage seen on pathologic examination. Perivascular edema and occasional focal bleeding occur in the kidneys, heart, and brain, but these changes are less severe than expected for the degree of clinical disease.

Ecology and Epidemiology

In the Americas, primates in the forest canopy serve as hosts for the yellow fever virus. Mosquitoes of the genus Haemagogus transmit infection. Because this vector does not travel far from the forest, jungle yellow fever occurs when humans enter jungle areas or the forest border zones. Urban yellow fever involves a different vector, A. aegypti. This mosquito is highly anthropophilic, lives in and around human habitations, and prefers domestic water storage containers for breeding. The presence of a large population of A. aegypti breeding sites in an urban area is a significant risk for epidemic spread of yellow fever once the virus is introduced from a nearby forest area. In Africa the presence of larger numbers of mosquito species that can serve as vectors has hindered complete understanding of the ecology of the disease.

Currently, both the Americas and Africa have a constant low level of jungle yellow fever because of inability to control either the monkey reservoir or the mosquito vector. Overall there are about 200,000 cases per year, resulting in approximately 30,000 deaths, occurring primarily in sub-Saharan Africa.⁷⁹ Some suggest that these rates are underestimated by at least 10-fold. Persons at risk include workers or travelers in or near the tropical rainforest canopy. Urban yellow fever had been reduced in the western hemisphere through massive campaigns to control breeding and spread of the Aedes vector. However, the benefits of these campaigns have declined, and there is currently an increased threat of further outbreaks of disease. Introduction of Aedes albopictus, an aggressive anthropophilic dengue vector from Southeast Asia, and reemergence of A. aegypti into the Americas raise the specter of increased yellow fever transmission in the western hemisphere.⁶⁵ Less-intense vector control measures and a more complex ecology have made elimination of urban yellow fever in Africa even more difficult.

Clinical Presentation

Although yellow fever may appear as an undifferentiated viral syndrome, classic disease is characterized by a triphasic pattern. The infection phase begins with sudden onset of headache, fever, and malaise, often accompanied by bradycardia and conjunctival suffusion. After approximately 3 to 4 days, victims often experience brief remission. Within 24 hours, however, the intoxication phase develops, characterized by jaundice, recrudescent fever, prostration, and, in severe cases, hypotension, shock, oliguria, and obtundation. Hemorrhage is usually manifest as hematemesis; however, bleeding from multiple sites may occur. Signs of a poor prognosis include early onset of the intoxication phase, hypotension, severe hemorrhage with disseminated intravascular coagulation (DIC), renal failure, shock, and coma. Death occurs in one-quarter to one-half of all cases. Diagnosis in the infection phase is difficult. With development of the classic syndrome, the differential diagnosis narrows somewhat, but still includes malaria, leptospirosis, typhoid fever, typhus, Q fever, viral hepatitis, and other viral hemorrhagic fevers. The standard means of diagnosis is evaluation for neutralizing antibodies in acute and convalescent sera (available through the Centers for Disease Control and Prevention [CDC] and state health departments in the United States). Several new systems for early detection of immunoglobulin M (IgM) or viral antigen are now being evaluated for more rapid diagnosis. A specimen of whole blood (at −70° C [−94° F] on dry ice) should be sent to the state health laboratory for isolation. Growth of the virus is possible in a number of systems, including Vero cells and infant mice. The virus is most easily isolated during the first 4 days of fever.

Management

Appropriate management of viral hemorrhagic fevers requires awareness of the geographic distribution of the disease and travel history of the victim. In the first several days of infection, differentiation of a viral hemorrhagic fever from other infectious diseases is nearly impossible. However, occurrence of an undifferentiated febrile syndrome in a traveler from a yellow fever–endemic area warrants a careful physical examination, thick and thin blood smears to rule out malaria, and blood cultures for bacterial pathogens (e.g., Salmonella typhi). In recently returned travelers, dengue serologic tests should be considered. Progression to the intoxication phase or any sign of volume disturbance, renal failure, or hemorrhage mandates immediate admission to an intensive care unit. There is no effective antiviral therapy for yellow fever. Intensive supportive care and management of end-organ failure is paramount. Although efficacy of intensive care treatment has not been studied for victims of yellow fever, clinical experience with DSS suggests that similar benefits might be obtained.

Prevention

Avoidance of this potentially fatal infection is possible through use of yellow fever vaccine. The vaccine strain 17D is an attenuated live virus grown in chicken embryos. Greater than 95% of persons vaccinated achieve significant antibody 1evels. Repeat vaccinations are recommended every 10 years, although persistent antibody titers have been detected as long as 30 to 40 years after vaccination. Yellow fever vaccine is generally well tolerated, with headache or malaise occurring in less than 10% of those vaccinated. Rare allergic side effects occur primarily in persons with hypersensitivity to eggs. Other serious adverse events, including death, have been reported, with the greater risk being associated with age older than 60 years.^5,49,66,81 Vaccination is not recommended in the first 6 months of life or in other situations where live virus vaccines are contraindicated. Although pregnant women have received the vaccine without adverse effect to themselves or their infants, it is not recommended for use in this group because of possible teratogenic effects. Other means of reducing the risk for yellow fever (and any mosquito-borne infectious disease) include liberal use of mosquito repellent and netting in endemic areas. Outbreak control in endemic countries is primarily through focused vaccination campaigns.

Treatment of severe yellow fever is difficult and often unsuccessful, with a mortality rate of approximately 50%. Avoidance through mosquito protection measures and administration of the highly effective vaccine before entry into endemic areas are of utmost importance.

Virology and Pathophysiology

The etiologic agent is a single-stranded RNA flavivirus, which may be one of four serotypes, denoted DEN-1 through DEN-4. As with yellow fever, local viral replication is followed by dissemination to lymphocyte- and macrophage-rich areas, where most of the reproductive activity occurs. Infection with one virus serotype provides long-lasting immune protection against that type only. After infection with one serotype, a subsequent infection with a heterologous serotype may result in a more severe clinical course. Non-neutralizing antibodies produced in response to infection to the primary infection are thought to facilitate entrance of the heterologous virus into host macrophages. Although cases of DHF and DSS may result from this “immune enhancement,” severe DHF and DSS also occur with other serotypes in the absence of previous infection with a heterologous dengue virus serotype.^60,61 Pathologic studies of DHF and DSS show hemorrhage, congestion, and perivascular edema of multiple organs. The liver may show areas of focal necrosis. As with yellow fever, the extent of pathologic findings does not correspond to severity of the clinical course.

Ecology and Epidemiology

A. aegypti is the principal vector for dengue viruses worldwide. In the Americas and Asia, viral transmission is maintained through a mosquito–human cycle without a major animal reservoir. Monkey carriers have been identified in Africa and Asia, but their importance in transmission is unclear. A. albopictus, an anthropophilic dengue vector from Southeast Asia, has also been recognized recently in the western hemisphere. Both of these mosquitoes are capable of large-scale transmission to humans in endemic areas. Currently, dengue is endemic in tropical and subtropical Asia, Africa, South America, and the Caribbean basin. In the early 1920s, large epidemics occurred in Texas, where dengue infections were reported in 500,000 inhabitants. In the last 30 years, endemic transmission on the mainland United States has been documented only in Texas. Travelers to Southeast Asia have highest risk for dengue, especially when travel takes place during periods of high transmission and epidemic dengue.⁹⁸

Clinical Presentation

Most dengue infections appear after an incubation period of 2 to 14 days, either as an undifferentiated viral syndrome with fever and mild respiratory or gastrointestinal symptoms or as dengue (“break-bone”) fever with bone pain, generalized myalgia, severe headache, and retroorbital pain. Febrile illnesses that appear more than 2 weeks after putative exposure to dengue virus are unlikely to be due to this virus. After 1 to 3 days, a quiescent period may ensue. There may be a subsequent second episode of fever accompanied by a patchy maculopapular or morbilliform rash that spreads outward from the chest and that ultimately desquamates. Lymphadenopathy and leukopenia occur during this phase of the illness. The distinct severe forms of dengue disease referred to as either DHF or DSS may occur around the usual time of recovery. These are due to the development of capillary leak syndrome with associated hemorrhagic manifestations (Figure 85-1). The advanced forms have the unique feature that the platelet count decreases to less than 100,000 per mm³ and hematocrit increases by more than 20%. The severity is classified as grade I to IV, according to World Health Organization guidelines. In cases of grade I DHF, the only hemorrhagic manifestation is a positive tourniquet test, in which inflation of a tourniquet to midway between systolic and diastolic blood pressure for 5 minutes leads to development of 20 or more petechiae per square inch distal to the tourniquet. A complete blood cell count classically shows decreased platelet and leukocyte counts and increase in hematocrit value. Grade II DHF is defined as the above with hemorrhage from any site (e.g., gingiva, nares, conjunctivae). Grade III DSS includes clammy skin, hypotension, or a narrow pulse pressure (<20 mm Hg) in a patient with DHF. An undetectable blood pressure defines grade IV DHF and DSS. Most studies have noted DHF and DSS primarily in infants and young children, usually with a history or serologic evidence of previous heterologous dengue infection, but there is an increasing trend of cases in adults.

FIGURE 85-1 Hemorrhagic manifestations of dengue hemorrhagic fever or dengue shock syndrome.

(From Ryan ET, Wilson ME, Kain KC: Illness after international travel, N Engl J Med 347:505, 2002.)

Prevention and Management

There is currently no vaccine to protect against dengue infection or disease, although several encouraging candidates are in development with one in clinical trials.^24,92

Awareness of the local epidemiology of DHF and DSS, especially the occurrence of other cases, is important in establishing the diagnosis. The diagnosis may be confirmed by a fourfold change in antibody titer between acute and convalescent sera or by presence of antidengue IgM antibodies. In the United States, isolation of the virus from serum can be arranged through state health departments. Management is symptomatic and directed in severe cases to fluid management. In the dengue fever syndrome, acetaminophen may be given for fever and myalgia. Salicylates should not be used. Hydration should be vigorously maintained.

Select victims of grade I or II DHF may be managed as outpatients. However, outpatient care requires careful monitoring of hematocrit value, platelets, and electrolytes. If significant bleeding develops, hospitalization is appropriate for rapid and continuous assessment. Progression to DSS (grade III or IV) is a medical emergency and requires immediate hospitalization. There is no specific antiviral chemotherapy. Supportive measures with careful monitoring are appropriate.

Epidemiology

The principal animal host for this virus is a rat, Mastomys natalensis, which prefers living in and around human dwellings. The rodents become chronically infected, secreting viral particles for long periods. Natural infection in humans occurs after rodent contamination of food and drink, inhalation of aerosolized rodent secretions, or contact with rodent material through skin abrasions. Lassa fever has been reported in several areas of sub-Saharan West Africa, and large outbreaks have been noted in Nigeria, Sierra Leone, Guinea, and Liberia.^21,62 It affects up to 500,000 people with 5000 deaths annually.⁵⁴ Complete seroprevalence data are lacking, making definition of an endemic area impossible at this time. Secondary human infection has been reported and may occur after contact with infected secretions.

Virology and Pathophysiology

Lassa virus is a single-stranded RNA arenavirus. Proliferation and dissemination presumably occur after initial replication at the inoculation site. As with the flaviviral diseases, the extent of end-organ involvement noted at autopsy does not account for the rapid death of infected patients. Recent work in an animal model provides evidence for platelet dysfunction and an endothelial cell defect in shock caused by Lassa fever virus.³¹ DIC, believed to be a major cause of bleeding and death in patients with other viral hemorrhagic fevers, appears to play a relatively minor role in arenavirus infections. The liver is most consistently the organ in which pathologic changes are observed at autopsy.

Clinical Presentation

Most seroconversions to Lassa virus are not accompanied by obvious symptoms.^63,64,69 Only 5% to 14% of seroconverters experienced a febrile illness. The incubation period is between 3 and 21 days. Patients hospitalized with Lassa fever show a distinct clinical syndrome. Fever, malaise, and purulent pharyngitis often develop after the insidious onset of headache. Retrosternal chest pain, possibly a result of pharyngitis and esophagitis, suggests the diagnosis. The combined presence of retrosternal chest pain, fever, pharyngitis, and proteinuria is the best predictor of Lassa fever.⁶² Hemorrhagic complications (hematemesis, vaginal bleeding, hematuria, lower gastrointestinal bleeding, and epistaxis) were seen in fewer than 25% of patients with Lassa fever. Nonfatal disease usually begins to resolve in 8 to 10 days. The combined presence of fever, sore throat, and vomiting was associated with a poor prognosis (relative risk for death = 5.5). Terminal stages of fatal disease were accompanied by hypotension, encephalopathy, and respiratory distress caused by stridor (presumably secondary to laryngeal edema). The most common complication after recovery from Lassa fever is sensorineural hearing loss, presumably due to host immune response reactions against elements of the inner ear.

Diagnosis

Establishing an accurate diagnosis is extremely difficult during the early phase of the infection. As the classic clinical syndrome develops, differentiation from other viral hemorrhagic fevers depends on serologic confirmation. Serologic diagnosis is made by indirect fluorescent antibody analysis of acute and convalescent sera or detection of Lassa-specific IgM antibody. Clotted whole blood may be sent to the CDC for viral culture if handled appropriately. If the diagnosis is suspected, the CDC should be contacted immediately for assistance in diagnosis, isolation, and management.

Management

Ribavirin has been used with success in patients with Lassa fever. It is most effective if started early in the course of the illness. For adults, a 2-g loading dose, followed by 1 g every 6 hours for 4 days, then 0.5 g every 8 hours for 6 days is recommended. Additional supportive care with maintenance of appropriate fluid and electrolytes, ventilation and blood pressure support, and treatment with broad-spectrum antibiotics for concomitant bacterial superinfections are often necessary.

Lassa fever has been associated with outbreaks of fatal person-to-person spread. Secondary infection occurs through direct contact with infected persons or their secretions. The role of aerosols in person-to-person spread is unclear. Blood and body fluids should be considered infectious. In light of the potentially fatal outcome of Lassa fever and the relative ease of transmission, the CDC has published specific recommendations for management of possible or confirmed cases. If a person has (1) a compatible clinical syndrome (especially pharyngitis, vomiting, conjunctivitis, diarrhea, and hemorrhage or shock); (2) a relevant travel history, including time spent in an endemic area; and (3) prior contact within 3 weeks of presentation with a person or animal from an endemic area suspected of having a viral hemorrhagic fever, he or she should be isolated and local, state, and federal health officials contacted. Ideally, an isolation unit with negative air pressure vented outside the hospital should be used. However, lack of a negative-pressure room alone is not a reason for transfer to another medical care facility.

The probability of transmission of Lassa fever virus to medical and nursing staff can be reduced by routine blood and body fluid precautions as well as strict barrier nursing. Barrier nursing includes wearing gloves, gown, mask, shoe covers, and, if there is risk for splashing fluids, goggles whenever entering the patient’s room. Decontamination of solid articles and rooms may be accomplished with 0.5% sodium hypochlorite solution. Recommendations for the management of patients with viral hemorrhagic fever have been published.^17,11

There is no vaccine available. Prevention is through avoidance of contact with rodents, especially in geographic areas where outbreaks occur.

Pathophysiology and Clinical Presentation

Marburg and Ebola viruses are presumed to act through similar pathophysiologic mechanisms that involve initial infection of monocytes, macrophages, and dendritic cells that are then distributed through the circulation to many organs and cell types. The viruses suppress both innate and adaptive host immune responses, leading to overwhelming infection and wide release of proinflammatory cytokines and chemokines causing fever, vascular instability, hypotension, and shock followed by multiorgan failure and death.^7,22,41,57

Patients present after an incubation period of 4 to 10 days with fever, headache, and myalgias. Diarrhea and abdominal pain occur commonly. In many victims, rash, conjunctivitis, sore throat, and chest pain appear early in the disease. As in other hemorrhagic fevers, hemorrhage, hypotension, shock, and electrolyte abnormalities mark fatal courses. The high mortality reported in various outbreaks and transmission to health care workers taking care of patients emphasizes the importance of intensive supportive care and precautions that limit contact with body secretions of infected individuals.⁷²

Diagnosis and Treatment

If these diseases are suspected, strict isolation procedures should be instituted and the local health authorities and the CDC notified immediately. Diagnosis may be made on a serologic basis or by polymerase chain reaction (PCR). There appears to be no serologic cross reactivity between the two viruses. Although anecdotal reports suggest the efficacy of immune sera in therapy, this has not been consistently observed in experimental studies. There are currently no specific antiviral therapies for Marburg or Ebola virus infection. Care is supportive. Vaccines are in development with one in Phase I testing.^7,47,60,85

Virology and Epidemiology

The etiologic agent of Crimean-Congo hemorrhagic fever (CCHF) is a bunyavirus. Ixodid ticks serve as both reservoirs and vectors of the virus. Infection in humans results from tick bites or direct contact with infected secretions from crushed ticks, animals, or humans. Most cases occur in individuals with occupations or living conditions that bring them in contact with domestic goats, sheep, or cattle on which ticks feed. The disease has been observed in southeastern Europe, south central Asia, the Middle East, and much of Africa.⁹⁵ Nosocomial transmission through contact with infected body fluids has been well documented.^32,89,90,91

Pathophysiology and Clinical Presentation

Pathophysiologic mechanisms are presumably similar to those of other hemorrhagic fevers.²⁸ One in five infections results in clinical disease with a case fatality rate ranging from 10% to 50%. The incubation period is approximately 1 week with initial symptoms of fever, severe headache, myalgias, vomiting, and diarrhea. Various forms of hemorrhage, including petechiae, large ecchymoses, melena, and hematemesis, are more pronounced in CCHF than in other hemorrhagic viral diseases. Severe cases progress rapidly to DIC, shock, and death.

Diagnosis

The diagnosis can be confirmed with acute and convalescent serologic evaluation for a fourfold rise in IgG antibody titers. The virus can be detected by PCR or cultured from whole blood if it is drawn during the first week of symptoms and kept on dry ice (or at −70° C [−94° F]) during shipment to the CDC.

Management

Initial management is similar to those for Lassa, Marburg, and Ebola virus infections, with strict patient isolation and notification of health authorities. Supportive therapy with attention to fluid balance and electrolytes in addition to oxygenation and hemodynamic support is the primary treatment. Although not confirmed in clinical trials, ribavirin has good activity in vitro against CCHF virus. The CDC recommends that patients believed to have CCHF receive intravenous (IV) ribavirin in the doses suggested for treatment of Lassa fever.²⁷ Persons in contact with CCHF patients should receive prophylactic ribavirin as suggested for Lassa fever contacts. To date, almost all therapy has used the oral form of ribavirin.

Epidemiology

Hantaviruses cause chronic, nondebilitating infections of various rodent species. Human infection is initiated by contact with rodent secretions or inhalation of aerosolized rodent material. The disease occurs most commonly in rural areas, although occasional urban outbreaks occur, presumably with the common house rat as vector. Cases have been described most often from Asia, including China, Korea, Japan, and the Soviet Union, but the disease also occurs in Eastern Europe. A recent epidemiologic study from China found the highest rates of infection in men who engaged in heavy farm work and slept on the ground (rather than on raised wooden beds).⁹⁹ The Sin Nombre virus appears to cause chronic infection of the deer mouse, Peromyscus maniculatus, which is the main reservoir of the virus in the United States. Since the initial outbreak, additional cases have been described across the United States and South America. The risk for infection is likely to be related to rodent exposure, but transmission is infrequent.

Virology and Pathophysiology

Members of the genus Hantavirus (family Bunyaviridae) are single-stranded RNA enveloped viruses that form one of the largest viral families, with over 300 species. The most common virus associated with HFRS in Asia is the Hantaan virus. The most common European hantavirus is Puumala virus, which causes a mild form of HFRS termed nephropathia epidemica. Severe HFRS cases in Europe have been caused by the hantavirus Dobrava-Belgrade virus. Sin Nombre virus is one cause of HPS in the United States. Hantaviruses enter host endothelial cells and spread rapidly.

Clinical Presentation

Hantaviruses cause a vascular leak syndrome. As with most viral hemorrhagic fevers, infection may be asymptomatic or accompanied by mild nonspecific illness. In the classic severe form, an initial febrile phase is associated with petechiae, proteinuria, and abdominal pain. After 3 to 5 days, a hypotensive phase occurs, with decreased platelet count and more severe hemorrhagic phenomena. An oliguric phase follows with concomitant electrolyte abnormalities. A diuretic phase usually commences 10 days after the onset of illness. Death occurs from hemorrhage, hypotension, and pulmonary edema, presumably secondary to fluid overload and renal failure. With modern management, the case fatality rate of classic HFRS is about 5%. The more benign nephropathia epidemica syndrome has a case fatality rate of less than 1%. In this disease, hypotension, shock, and hemorrhagic manifestations are rare. With HPS, there is usually a prodromal illness with fever and mild respiratory or gastrointestinal symptoms, followed by shock and pulmonary edema. The tempo of the disease at this stage may be rapid and require respiratory and circulatory support in an intensive care unit. HPS has a case mortality rate of 50%.

Diagnosis

The diagnosis of HFRS, nephropathia epidemica, and HPS is confirmed by indirect fluorescent or enzyme-linked immunosorbent assay (ELISA) for antibodies in acute and convalescent sera. IgM antibody determination may also be helpful. Virus isolation is difficult, but PCR and immunohistochemical staining may be useful in affected tissues.

Management

Care of patients with HFRS is supportive. With HFRS, renal dysfunction occurs early and may require institution of dialysis soon after diagnosis to prevent fluid overload and to correct electrolyte disturbances. Patients’ secretions should be handled with care, and enteric precautions (but not strict isolation) are prudent. It is not clear whether person-to-person transmission of the virus through direct inoculation occurs. For the hantaviruses, viremia recedes and antibody levels rise as the clinical phase appears. Accordingly, nosocomial transmission or hematogenous transmission with hantavirus infections has not been frequently documented, although presumed nosocomial transmission has been reported.⁹⁹ No vaccine is available.

Epidemiology

JE is the most common cause of encephalitis in Asia. Of the estimated 35,000 to 50,000 cases annually, 20% to 30% of infected individuals die and of those that recover, 30% to 50% have neurologic sequelae.^30,46 Transmission correlates with monsoon rains in the tropics and in the summer and fall seasons in temperate regions. Rice field–breeding and other culicine mosquitoes serve as the vectors. In addition to humans, birds and pigs can be infected. Pigs play an important role as amplifying hosts because they develop high-grade viremia from which large numbers of mosquitoes may be infected. Most infections in endemic areas occur in children, whereas all age-groups of previously unexposed populations are at risk. Transmission of JE currently occurs in India, Southeast Asia, China, Korea, Indonesia, and the Western Pacific region.³⁰ Routine use of JE vaccine in Japan has been eliminated because of low risk in this country. Recent outbreaks and case reports of JE in islands of the Torres Strait, which runs between Northern Australia and Papua New Guinea, indicate that the virus spread southward from Asia, presumably by migratory ardeid birds.³⁹

Virology and Pathophysiology

JE is caused by a neurotropic flavivirus that is phylogenetically related to West Nile and dengue viruses. It is transmitted by mosquitoes. After initial replication near the mosquito bite, viremia occurs, which if prolonged may seed infection to the brain. The cytopathologic effect of the flavivirus is believed to cause nerve cell destruction and necrosis.

Clinical Presentation

Incubation period is typically 2 to 15 days. Most infections do not cause clinical illness. Many patients recall a mild undifferentiated febrile illness, which probably coincides with the viremic phase of infection. Patients with encephalitis often report a similar prodrome. The encephalitis syndrome is not easily distinguished from other arboviral encephalitides. The patient usually complains of headache, lethargy, fever, and confusion and may display tremors or seizures. One clinical series suggested that the presence on admission of (1) unresponsiveness to pain, (2) low levels of anti–Japanese B encephalitis virus IgG or IgM antibodies (in serum or cerebrospinal fluid [CSF]), or (3) virus in CSF culture was associated with death. Of the 16 patients with fatal disease, all died within 7 days of hospitalization.¹⁵

Diagnosis

Acute and convalescent sera for antibody determination (virus neutralization or hemagglutination inhibition assays) provide the only reliable method of diagnosis. Paired sera should be sent for these assays through state health departments. Sensitive assays for determinations of IgG and IgM antibodies in serum and CSF have been developed but are not yet widely available. Because most patients seek treatment long after the viremic phase, blood cultures are rarely positive for the virus and CSF cultures are often positive only in patients with a poor prognosis.

Management

There is no specific therapy. The main interventions are prophylactic: vaccination and reduced arthropod exposure. Supportive care may require an intensive care unit. Because the virus is present in body fluids, especially CSF, blood and body fluid precautions should be considered. JE is only one of several arthropod-borne viruses that may cause encephalitis in different areas of the world. Others include Murray Valley encephalitis in Australia, tick-borne encephalitis in Europe (for which a vaccine exists), and La Crosse, West Nile, and St Louis encephalitis in the United States.

Epidemiology

Hepatitis A virus is transmitted primarily by the fecal–oral route by either person-to-person contact or ingestion of contaminated food or water. Food items commonly associated with outbreaks are raw or undercooked clams and shellfish. Risk factors include contact with a hepatitis A–infected person, international travel, household or personal contact with a child who attends a child care center, foodborne outbreaks, male homosexual activity, and use of illegal drugs.^3,59 Occasional cases are associated with exposure to nonhuman primates. Transmission by blood transfusion has been reported, but this is an uncommon source of infection. Hepatitis A is endemic worldwide, but underdeveloped nations have a higher prevalence than those in North America. Most persons in these areas show serologic evidence of past infection with hepatitis A virus. Hepatitis A is a common viral infection occurring in travelers, but rates are declining with increased use of hepatitis A vaccine

Virology and Pathophysiology

Hepatitis A virus is a picornavirus with a single-stranded RNA genome. Although the pathophysiologic mechanism has not been delineated, most infections begin with introduction of viral particles into the proximal gastrointestinal tract. Brief viremia precedes seeding of hepatocytes, where viral replication has been documented. With replication, hepatocellular necrosis is accompanied by lymphocytic infiltration. In the vast majority of cases, hepatic regeneration occurs after acute disease and no significant sequelae are observed. Chronic infection does not occur with hepatitis A.

Clinical Manifestations

The incubation period ranges from 2 to 7 weeks. The infection may be asymptomatic or mild, especially in children, but also in a minority of adults. The classic syndrome includes initially anorexia, followed by nausea, vomiting, fever, and abdominal pain. These symptoms may be accompanied by hepatosplenomegaly. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels rise within a few days of the onset of symptoms. In children, AST and ALT return to normal levels in 2 to 3 weeks, whereas in adults, resolution of elevated serum aminotransferase levels may take several months. Bilirubin level rises shortly after AST and ALT elevations. Jaundice usually follows gastrointestinal symptoms by several days to a few weeks. Resolution of jaundice may take another 3 to 4 weeks. The syndrome is occasionally preceded by arthralgias and rash, but these prodromal symptoms are uncommon. Resolution of acute disease is permanent in most instances, but rare cases of relapse have been noted. Pregnant women have a higher risk for severe illness than does the general adult population. Anti–hepatitis A antibody (primarily IgG) is detectable in the blood for many years after infection. The presence of the antibody confers immunity. Accordingly, reinfection with hepatitis A virus is not believed to occur.

Diagnosis

The clinical presentation of hepatitis A is usually milder than other types of viral hepatitis. Consequently, the symptoms are not distinctive enough to allow a firm diagnosis, which requires detection of hepatitis A antigen in the stool or serologic evaluation for hepatitis A–specific IgM or total anti–hepatitis A virus antibody. Stool hepatitis A antigen is maximal before the onset of symptoms but may be detected as long as 2 weeks after the onset of disease. A more practical test is measurement of hepatitis A–specific IgM antibody, which is usually present by the time symptoms are recognized and generally absent 6 months later. Measurement of anti–hepatitis A antibodies may be helpful in evaluating possible causes of past icteric episodes or for seroepidemiologic studies, but their presence does not differentiate recent from past infection.