Viruses in Human Disease

Viruses of medical importance to humans comprise seven families of deoxyribonucleic acid (DNA) viruses and fourteen families of ribonucleic acid (RNA) viruses. This chapter examines the specific families of viruses, including the diseases and the symptoms associated with the viral infection. Tables 66-1 and 66-2 present a quick reference to the viral families and syndromes caused by these viruses. Table 66-1 divides the virus families according to the makeup of the viral genome, either RNA or DNA. Table 66-2 lists some of the common human viral infections.

Adenoviruses

Adenoviruses (Table 66-3) are medium-sized (70 to 90 nm), icosahedral, nonenveloped, double-stranded, linear DNA viruses. This virus was first isolated from cultures of human adenoids and tonsils in the early 1950s, hence the name adenovirus. The adenoviruses belong to the family Adenoviridae and are widely distributed in nature. However, only members of the genus Mastadenovirus cause human infection. Currently, 52 serotypes of human adenoviruses have been described. Most human disease is associated with one third of the viral types. These types are then divided into seven species, A through G, with species B subdivided into two subspecies; virus serotypes are then numbered within the species classification. The viruses can cause a broad range of disease in humans. Respiratory and gastrointestinal diseases are the most common clinical manifestation associated with adenovirus infection.

Adenoviruses cause less than 5% of all acute respiratory disease in the general population, however, they account for up to 18% of respiratory infections in children. By the age of 10, most children have been exposed to and infected with at least one of the adenovirus species. In addition, adenovirus serotypes 40 and 41 cause gastroenteritis in infants and young children, and other serotypes are associated with conjunctivitis and keratitis. Although respiratory and gastrointestinal diseases are most common, disseminated disease in multiple organ systems may develop in compromised hosts.

Transmission of the virus may occur as an aerosolized droplet or maybe airborne. Respiratory disease caused by adenovirus is usually acquired through contact with contaminated respiratory secretions, stool, and fomites. The virus is very stable and can remain viable for weeks at variable temperatures on surfaces and in solution. The incubation period for respiratory disease is 2 to 14 days. Common upper respiratory tract infections caused by adenovirus include colds, tonsillitis, pharyngitis, pharyngoconjunctival fever, and sometimes croup (viral infection of the larynx). Infections of the eye and conjunctivitis often accompany respiratory infection, and in children, otitis media (ear infection) is often a complication of the respiratory disease. Lower respiratory tract infections can be quite severe in children, and adenovirus pneumonia is often fatal in infants and young children.

A unique feature of the adenoviruses is the ability to cause severe, acute respiratory disease epidemics in military recruits, often resulting in considerable morbidity and mortality. A highly effective vaccine to control the outbreaks was developed for serotypes 4 and 7 and administered to recruits from 1971 to 1996. Once the vaccination program was discontinued, the outbreaks resumed. The current adenovirus contains live serotypes 4 and 7 and is approved for military personnel between the ages of 17 and 50. In addition to the reemergence of epidemics, the emergence of a new, unusually severe lower respiratory tract infection caused by adenovirus type 14 has been identified in healthy individuals of all ages in several areas of the United States.

Adenoviruses can be detected from respiratory secretions or stool in cell culture using various epithelial cell lines, such as A-549, HEp-2, and He-La cells. Growth is usually apparent in 2 to 5 days. Adenovirus produces a characteristic grapelike cluster cytopathic effect (CPE). Viral confirmation follow-up is performed using an indirect fluorescent antibody (IFA) technique or enzyme immunoassay (EIA). Nucleic acid testing for adenovirus is becoming more popular because of the s’ detection time and the increased sensitivity over traditional cell culture. Rapid cell culture (i.e., shell vials) using centrifugation reduces detection time but is less sensitive than tube culture.

Arenaviruses

Arenaviruses, of the family Arenaviridae, include 29 spherical, enveloped RNA viruses that have T-shaped glycoprotein spikes 7 to 10 nm long surrounding the surface membrane of the virion (Table 66-4). The viruses can readily infect a variety of mammalian species, especially rodents and bats, often resulting in a deleterious effect on the reservoir rodent host. Human transmission usually occurs through inhalation of aerosols of infected rodent excrement (urine, saliva, feces, nasal secretions) or by direct contact with infected rodents. Disease in humans clinically displays a broad range of symptoms, from asymptomatic (no symptoms) to fever, prostration, headache and vomiting, to the more severe cases of meningitis and hemorrhagic fever.

The arenaviruses capable of causing disease in humans include lymphocytic choriomeningitis (LCM) virus and Lassa fever virus (first detected in Lassa, Nigeria). LCM has been identified in cases of aseptic meningitis in Europe and the Americas. Lassa has been associated with hemorrhagic fever, shock, and death in 5% to 15% of symptomatic patients (80% of cases are asymptomatic). Lassa fever virus is a significant cause of morbidity and mortality in West Africa, where economic resources are limited. Capillary leak and widespread organ involvement, accompanied by shock, respiratory distress, and/or hemorrhage, are responsible for most deaths from Lassa fever. Other, less commonly reported arenaviruses may also cause hemorrhagic fever.

Arenavirus infection is diagnosed using serologic tests or reverse transcriptase polymerase chain reaction (RT-PCR) to detect viral nucleic acid. Viral isolation using cell culture is not routinely recommended. Cell culture for viral isolation has proven to be unreliable because of inconsistent sensitivity. In addition, handling cultures and specimens puts laboratory personnel at high risk. Samples and cultures containing LCM virus require Biosafety Level (BSL) 3 facilities, and Lassa fever virus requires a BSL 4 laboratory. Serologic diagnosis is also difficult because the immunologic antibody response is delayed for several days and often weeks following symptomatic illness. An RT-PCR assay has been developed to detect arenaviruses, but it is not widely available in the acute care setting.

Bunyaviruses

Bunyaviruses, first detected in Bunyamwera, Uganda, belong to the family Bunyaviridae (Table 66-5). The virus is an RNA virus consisting of three, single-stranded RNA segments enclosed in a helical nucleocapsid that is surrounded by a lipid envelope. A unique feature of this family of viruses is their tripartite genome. The genomic structure provides a mechanism for genetic reassortment in nature, much like the orthomyxovirus family of viruses. Bunyaviruses comprise a large, diverse group of viruses (approximately 300 total members with 12 human pathogens), most of which are transmitted by mosquitoes (arboviruses).

The most important human pathogens in the United States consist of the California serogroup (CAL), which includes the California encephalitis and Lacrosse viruses (LAC). Although the name California encephalitis implies that these cases are related to the state of California, they are identified primarily in Minnesota, Wisconsin, Iowa, Illinois, Indiana, and Ohio. Disease is typically mild and self-limiting; however, severe, even fatal, encephalitis ensues in approximately 2% of patients infected. Other human disease–causing members of the family Bunyaviridae include the Cache Valley (CV), Jamestown Canyon (JC), Snowshoe hare (SSH), Tahyna, Rift Valley fever, and Inkoo viruses.

Bunyaviruses that belong to the Hantavirus genus are not arboviruses. The viruses are rodent borne and transmitted through exposure (inhalation) to aerosolized rodent excreta. Rodents develop a chronic infection that results in shedding of the virus in saliva, feces, and urine. Disruption of these animal excreta by vacuuming, sweeping, or shaking rugs aerosolizes infected particles, which are then inhaled. Evidence indicates that the chance of inhaling these particles is greater in indoor, poorly ventilated spaces than through outdoor exposure.

The disease that ensues is called hantavirus pulmonary syndrome (HPS). It was originally discovered in 1993 in the four corners area of the southwestern United States (Arizona, New Mexico, Colorado, and Utah). The discovery of this virus resulted from the outbreak of an unexplained pulmonary illness among several young, healthy people who died from acute respiratory failure. Diagnostic testing failed to identify a known cause of death. Through exhaustive analysis by the virologists at the Centers for Disease Control and Prevention (CDC) using molecular testing, the scientists were able to link the pulmonary syndrome with a previously unknown type of hantavirus. The new virus originally was called Muerto Canyon virus, but later the name was changed to sin nombre (no name) virus (SNV).

HPS begins with generalized symptoms that include headache, fever, and body aches, typically after an incubation period of 11 to 32 days. Subsequently, the symptoms become much more severe, leading to hemorrhagic fever, kidney disease, and acute respiratory failure. The deer mouse (Peromyscus maniculatus) is the primary host for the sin nombre virus. Transmission of the virus from rodent to human has been the only documented mode of human infection. No person-to-person transmission of HPS has ever been documented in the United States.

Since the discovery of SNV, several hantaviruses that cause HPS have been discovered throughout the United States. The Bayou virus, carried by the rice rat (Oryzomys palustris), was first discovered in a male from the state of Louisiana. The cotton rat (Sigmodon hispidus) is the carrier of the Black Creek Canal virus, discovered in a resident from Florida. The white-footed mouse (Peromyscus leucopus) has been implicated in a case of a hantavirus infection called the New York-1 virus. Cases of HPS stemming from related hantaviruses have been documented in Argentina, Brazil, Canada, Chile, Paraguay, and Uruguay, making HPS a panhemispheric disease.

Laboratory diagnosis relies on the identification of hantavirus-specific IgM and or IgG antibody. By the time symptoms have appeared, all patients have formed hantavirus-specific IgM antibody, and most have also developed hantavirus-specific IgG antibody. Enzyme-linked immunosorbent assay (ELISA) is usually the method of choice for diagnosis. Other available diagnostic methods include identification of viral antigen in tissue using immunohistochemistry or the presence of amplifiable viral RNA sequences in blood or tissues. Although RT-PCR assays have been developed for some hantaviruses, the variation in the viral genome reduces sensitivity, making routine identification by RT-PCR complicated for the diagnosis of hantavirus infections. Virus isolation from human sources is difficult, and to date no isolates of SNV-like viruses have been recovered from humans.

Caliciviruses

Caliciviruses are small (30 to 38 nm), rounded, nonenveloped, single-stranded, positive RNA viruses that cause acute gastroenteritis in humans. Caliciviruses (Table 66-6) have been previously recognized as major animal pathogens and have a broad host range and disease manifestation. The virus causes respiratory disease in cats, a vesicular disease in swine, and a hemorrhagic disease in rabbits. Not until the 1990s did the taxonomic status of noroviruses (formerly known as Norwalk-like viruses, named after Norwalk, Ohio) and hepatitis E virus result in classification in the family Caliciviridae. Hepatitis E virus has since been removed from the calicivirus family and included in a new family, the Hepeviridae. (Hepatitis E virus is discussed later in this chapter.)

Members of the Norovirus and Sapovirus genera are the primary cause of viral gastroenteritis in humans and are referred to as the human caliciviruses (HuCV). Previously called “Norwalk-like viruses” and “Sapporo-like viruses,” the viruses were named after their prototype strains, the Norwalk virus and the Sapporo virus, respectively. These viruses are now referred to as the “norovirus” and “sapovirus.” The HuCVs are further classified into genogroups, and within the genogroups, into genetic clusters. Human isolates in the norovirus genogroup include genogroups I, II, and IV and in the sapovirus genogroup, I, II, IV, and V.

The clinical symptoms associated with norovirus infection include nausea, abdominal cramps, vomiting, and watery diarrhea. Symptoms usually occur after a 1- to 2- day incubation period and continue for approximately 1 to 3 days. Vomiting occurs more often in children than in adults. Infection with sapovirus is similar to that with norovirus; however, sapoviruses more frequently cause disease in infants and toddlers than in school-age children, whereas norovirus infections are common to all age groups. Maximum viral shedding in the feces occurs early, at the onset of clinical symptoms, but viral shedding can occur for up to 2 to 3 weeks after cessation of the clinical symptoms. As a result, control of viral transmission is problematic, and infection does not confer long-lasting immunity.

Norovirus is the source of more than 80% of nonbacterial acute gastroenteritis cases and more than 50% of food-borne outbreaks for all ages in developed and underdeveloped countries. A major public health concern is its ability to cause large outbreaks in semiclosed environments. In recent years, noroviruses have been implicated in large outbreaks of disease on cruise ships, in nursing homes, in schools, summer camps, hospitals, and restaurants. Several factors contribute to the rapid spread of infection: fecal-oral transmission, the low infectious dose (fewer than 100 virus particles), and the virus’s high environmental stability. Noroviruses are easily transmitted in water, person to person, or in airborne droplets of vomitus. The virus persists in water despite treatment processes.

Norovirus cannot be cultivated using cell culture. The most widely used identification method is RT-PCR. Commercially available ELISA kits that use monoclonal antibodies (MoAbs) or hyperimmune sera are also available to detect norovirus but are inferior in sensitivity and specificity to RT-PCR. RT-PCR may also be used to detect the HuCVs in environmental specimens, such as drinking water or contaminated food or both.

Coronaviruses

The family Coronaviridae includes the genera Torovirus and Coronavirus (CoV) and contains many species of both human and animal origin (Table 66-7). Once considered a harmless virus capable of causing the human “cold,” the CoVs cause a wide variety of disease in animals and birds. Interest in this virus and its relationship with animals and humans was renewed after the global outbreak of the novel coronavirus severe acute respiratory syndrome (SARS) in 2002 that resulted in severe respiratory distress in the human population. (The SARS outbreak is discussed in detail later in this chapter.) Coronaviruses are pleomorphic, roughly spherical, medium-sized, enveloped RNA viruses. The prefix corona- results from the viral structure and the crownlike surface projections on the external surface of the virus that can be seen with electron microscopy. Human respiratory coronaviruses cause colds and occasionally pneumonia in adults. Together the rhinoviruses and coronaviruses cause more than 55% of the “common colds” in the human populations. Viral transmission is person to person via contaminated respiratory secretions or aerosols. The virus is present in the highest concentration in the nasal passages, where it infects the nasal epithelial cells. Coronaviruses are thought to cause diarrhea in infants based on the presence (as seen with electron microscopy) of coronavirus-like particles in the stool of symptomatic patients. Although antigen detection is available, the technique lacks sensitivity compared with nucleic acid–based testing. No practical diagnostic methods other than electron microscopy and RT-PCR are available. Many CoVs do not grow in routine cell culture. Modified cell cultures have been useful when confirmatory testing with antigen- or nucleic acid–based methods are used.

In November, 2002, SARS was identified as the cause of a worldwide outbreak. It first emerged in the Guangdong province in China. The virus is believed to have mutated and crossed into the human population from palm civets, an exotic mammal present in the live animal markets of China. More than 80% of these animals showed evidence of coronavirus infection. The proximity of humans to animals during exposure in the live animal markets probably facilitated the initial human infection. The outbreak started as a single case in a hotel in China and then snowballed, with a subsequent outbreak in a Hong Kong hospital as the virus evolved and was able to propagate through person-to-person transmission. Within months, more than 8000 patients worldwide were affected, and approximately 700 people died. The disease was characterized by a rapid onset of high fever, followed by a dry cough and dyspnea. The severe respiratory syndrome followed an incubation period of approximately 2 to 7 days after the appearance of the initial symptoms (fever, headache, myalgia, and malaise). Frequently the illness would progress to severe respiratory distress, requiring the patient to be hospitalized for supportive care and mechanical ventilation. During the hospitalizations of several patients, a secondary attack rate of more than 50% was noted among health care workers caring for the SARS patients. This secondary attack rate is a result of SARS being an unusual respiratory virus. The period of maximum infectivity and highest viral loads in the upper airways begins in the second week of illness, during the time the patients often were severely ill. The CDC soon established a case definition, and a worldwide effort in infection control began in order to stop the spread of the virus. The worldwide SARS outbreak was finally considered “contained” in July, 2003. Since the initial outbreak, the virus has not been detected in humans, but the animal reservoir and live animal markets in China are still present. This indicates that future viral strains may emerge if animal-to-human transmission occurs.

Low levels of virus in the respiratory tract during early disease provide a diagnostic challenge. Because of its sensitivity and specificity, molecular testing by RT-PCR remains the recommended method for laboratory diagnosis. The nonspecific symptoms associated with a SARS infection make laboratory testing crucial in the diagnosis and control of the virus. Although nucleic acid testing by RT-PCR is the most useful diagnostic test available, the virus is capable of growth in cell culture using the Vero-E6 cell line. The characteristic viral CPE appears as a rapid cell rounding, refractivity and detachment. BSL 3 or higher is required for propagation and manipulation of cell cultures containing this virus.

Filoviruses

The Filoviridae family of viruses (Table 66-8) is considered the most pathogenic of the hemorrhagic fever viruses. The term filo means threadlike, referring to the virus’s long, filamentous structural morphology seen with electron microscopy. The viruses are pleomorphic, enveloped, nonsegmented, single-stranded, negative sense RNA viruses. The filamentous morphology appears in many forms or configurations under the electron microscope, such as the number “6,” “U,” or circular. Marburg hemorrhagic fever virus displays the characteristic “shepherd’s hook” morphology. The term “viral hemorrhagic fever” is used to describe a severe multisystem syndrome in which multiple organ systems are affected throughout the body. The patient’s vascular system becomes damaged, and the body’s ability to regulate itself is impaired. Infection with the Marburg or Ebola virus, endemic in Africa, results in severe hemorrhages, vomiting, abdominal pain, myalgia, pharyngitis, conjunctivitis, and proteinuria. Human case fatality rates for Ebola virus infection exceed 80%; the toll for Marburg virus infection is somewhat lower, with a case fatality rate of 23% to 25%. These diseases have no cure or established drug treatment.

The first filovirus was detected in Marburg, Germany, when a group of German laboratory workers became ill and developed hemorrhagic fever after handling imported African green monkeys or monkey tissue while preparing polio vaccine. Simultaneous hemorrhagic fever outbreaks occurred in laboratories in Frankfurt, Germany, and Belgrade, Yugoslavia (now Serbia). Thirty-one individuals became symptomatic, and seven individual fatalities were recorded. Symptomatic individuals included the laboratory workers, their family members, and medical personnel. The Marburg virus was isolated from the African green monkeys and determined to be the etiologic agent of infection.

Ebola virus is the only other member of the Filovirus family. It is named after a river in Zaire (now the Democratic Republic of the Congo), where it was first identified. The genus Ebolavirus has five subspecies, based on the first location where the virus was identified: Zaire ebolavirus, Sudan ebolavirus, Cote d’Ivoire ebolavirus (formerly referred to as Ebola–Ivory Coast), Bundibugyo ebolavirus, and Reston ebolavirus. All of the Ebola subspecies cause disease in humans and nonhuman primates (i.e., chimpanzees, gorillas, and monkeys) except for Reston ebolavirus, which causes disease only in nonhuman primates. The Ebola virus was first recognized in 1976, when a total of 602 people became ill in Zaire and Sudan. Infections are acute, with no carrier state, and humans become ill after contact with an infected animal, usually a primate. Transmission of the virus is rapid. Individuals caring for the sick who come in contact with the patient’s secretions quickly develop symptoms. In fact, many of the early Ebola outbreaks were attributed to “nosocomial” infections. Personal protective equipment (e.g., gowns, masks, and gloves) often were not used by those caring for sick patients. Also, objects such as needles and syringes often were not sterilized before reuse, and many people were exposed to the virus through contaminated syringes and needles. In the initial Ebola outbreak, 431 people died, a fatality rate greater than 70%.

The natural animal reservoir for the Ebola and Marburg viruses has never been determined, although the animal source is believed to be native to Africa. Disease outbreaks in monkeys have occurred in the United States in research facilities. Several monkeys housed in separate cages became ill simultaneously. Laboratory workers working in these facilities were also infected and developed antibodies but never developed symptoms of the disease. Reston ebolavirus is known to have caused infections through aerosolization of secretions.

RT-PCR is used to identify the Ebola and Marburg viruses. Electron microscopy is also available in some research facilities. Cell culture is available in laboratories with BSL 4 facilities. Antibody production occurs after an Ebola virus infection, and an antigen-capture ELISA is available to detect IgM and IgG antibodies to Ebola virus.

Flaviviruses

The flaviviruses (family Flaviviridae; Table 66-9) include viruses that cause arbovirus diseases, such as yellow fever, dengue, West Nile viral encephalitis, and Japanese and St. Louis encephalitis. Hepatitis C virus (HCV) is a flavivirus but not an arbovirus. Flaviviruses are small, single-stranded, positive sense RNA, enveloped, icosahedral viruses. The name is derived from the Latin word flavus, which means yellow. The first disease identified in this group was yellow fever, which causes yellow jaundice in humans. Diseases in this viral group are transmitted to humans through the bite of an infected arthropod, usually the mosquito.

Yellow fever has been one of the great plagues throughout history. In 1900, thousands of individuals died during the construction of the Panama Canal. An army physician, Dr. Walter Reed, uncovered the source of the infection. In the jungle habitat, monkeys serve as the reservoir and the vector is a mosquito. This was the first virus clearly associated with transmission by a mosquito. The yellow fever virus also is the first flavivirus for which an effective vaccine has been developed. In urban outbreaks, humans can serve as the reservoir, as long as the mosquito vector is present.

The yellow fever virus primarily infects liver cells, resulting in fever, jaundice, and hemorrhage. Transmission through the mosquito bite is followed by a 3- to 6-day incubation period. The onset of symptoms is sudden and includes fever, rigors, headache, and backache. The patient’s clinical condition progresses rapidly, and the patient becomes intensely ill with nausea, vomiting, facial edema, dusky pallor, swollen, bleeding gums, and hemorrhagic tendencies with black vomit, melena (black, tarry feces), and ecchymoses (bruising). Mortality rates range from 5% to 50%; when death occurs, it is usually within 6 to 7 days following the onset of symptoms but rarely after 10 days. The characteristic yellow jaundice typically is seen in convalescing patients. Prevention in urban areas depends on elimination of the yellow fever vector, the mosquito, Aedes aegypti. The current vaccine is very effective at preventing infection.

Diagnosis of yellow fever infection is often a result of correlation of the patient’s clinical symptoms with the patient’s location and travel history. Laboratory testing on serum or cerebrospinal fluid (CSF) is available for detection of virus-specific antibodies or neutralizing antibodies. Serologic testing is also available using IgM-capture ELISA, microsphere-based immunoassays (MIAs), and IgG ELISA. In fatal cases of yellow fever, patient tissues may be sent to reference laboratories for nucleic acid amplification, histopathology, and cell culture.

The dengue virus is the most prevalent arbovirus in the world; more than 100 million people are infected annually. It is the leading cause of illness and death in the tropics and subtropics. The virus is endemic in Latin America, Puerto Rico, and Mexico. Most cases reported in the United States (more than 90%) are travel related. Humans are the main reservoir for this virus, and person-to-person transmission occurs through a mosquito vector. Dengue virus has four serotypes that cause a variety of clinical manifestations, including nonlethal fever, arthritis, and rash. Infection with one serotype confers immunity only to the infecting serotype. Subsequent infection with one of the three remaining serotypes results in immune-enhanced disease in the form of severe hemorrhagic fever or dengue shock syndrome. Of the more than 100 million cases of dengue fever, 250,000 cases result in dengue hemorrhagic fever, resulting in approximately 25,000 deaths annually. Dengue normally affects adults and older children. The infection begins with a sudden onset of fever, severe headache, chills, and general myalgia. Often a macropapular rash may be visible on the trunk of the body, which then spreads to the face and extremities. No vaccine is available for dengue. Laboratory diagnosis is based on the presence of virus-specific IgM antibody, a fourfold rise in specific IgG antibody, or a positive RT-PCR amplification for dengue genomic sequences.

Scores of other arthropod-borne flaviviruses, most transmitted by mosquitoes or ticks, cause encephalitis, hemorrhagic fever, or milder disease characterized by fever, arthralgia, and rash. West Nile virus (first isolated in the West Nile district of Uganda), a flavivirus closely related to the Japanese and St. Louis encephalitis viruses, is endemic in Africa, Israel, and Europe. West Nile virus has been endemic in the United States since 1999. Since the virus was identified in New York City in 1999, it has spread westward across the entire United States and into Canada, Mexico, Central America, South America, and some Caribbean islands. The virus accounts for the largest number of cases of viral encephalitis in the United States.

West Nile virus is maintained in a bird-mosquito cycle. Birds are the natural reservoir for the virus. Currently, 59 species of mosquitos and more than 300 species of birds are infected with the West Nile virus. Amplification of virus during warm months results in the death of bird hosts, most commonly crows, ravens, and jays. Bridge mosquitos (those that bite both humans and birds) are responsible for transmission to humans; as the viral populations in birds increases, more humans become infected. Interestingly, West Nile virus also has been transmitted person to person through blood transfusions, tissue transplantation, and in human breast milk. Infection is often accompanied by fever, leukopenia, and malaise and may progress to encephalitis.

Laboratory diagnosis typically involves detection of IgM antibody to West Nile virus in the patient’s serum or CSF. Several commercial kits are available for detection of West Nile IgM and IgG specific antibodies using ELISA or IFA methods. Nucleic acid amplification testing has been very successful in detecting the arbovirus from the tissues of fatal cases and has also been used to detect the virus from the tissues of birds. Additionally, molecular testing has used to detect West Nile virus in mosquito pools. West Nile mosquito surveillance has become increasingly important in the attempt to control this disease.

The hepatitis C virus causes hepatitis. Worldwide, an estimated 170 million people are HCV carriers, and about 4 million of those live in the United States. Acute infection with HCV progresses to a chronic infection in 50% to 90% of infected individuals (Figure 66-1). The acute infection with HCV often goes undiagnosed, because it is often asymptomatic. When clinical illness is present, it is generally mild. Chronic infection with HCV is an important cause of liver disease and is associated with the development of end-stage liver disease and hepatocellular carcinoma. The virus is transmitted predominantly by exposure to infected blood, such as during intravenous drug use and administration of contaminated blood products. The screening of blood products for HCV has eliminated the risk of transmission through contaminated blood products. Less efficient modes of transmission include sexual contact with infected partners, acupuncture, tattooing, and sharing of razors.

HCV disease is identified with screening antibody tests, anti-HCV EIA, confirmatory antibody testing, anti-HCV immunoblot, and RT-PCR. In addition, RT-PCR and quantitative bDNA (branched chain DNA) is used to quantitate virus in the blood to monitor viral therapy. Finally, viral genotyping using molecular techniques is available for identifying genotypes that do not respond appropriately to therapy. The full benefits of modern laboratory testing, including the application of molecular methods, has significantly improved the recognition, monitoring, and treatment of HCV disease.

Hepevirus

Hepatitis E virus (HEV) is the type species of the new genus Hepevirus, in the family Hepeviridae (Table 66-10). Previously classified in the family of caliciviruses, HEV is a small, nonenveloped virus with a single-stranded RNA genome. The only other member of this virus family is an avian HEV known to cause enlarged liver and spleen disease in chickens. Several genetic and antigenic variants or strains of HEV exist and are referred to as genotypes. The different viral strains are common to different geographic locations. Genotype 3 is the strain found in the United States. HEV has also been isolated from swine worldwide and from wild deer in Japan. This indicates that the potential for transmission from animal to humans, resulting in a zoonotic human infection.

HEV was discovered in Asia by a Russian virologist who volunteered to drink stool filtrates from a patient with an unidentified form of hepatitis. The virus is waterborne. The primary mode of transmission is the consumption of water contaminated with feces. HEV is not endemic in the United States and other developed areas of the world. HEV infection results in an acute and generally self-limiting viral hepatitis (inflammation of the liver). Most infected patients do not progress to a long-term carrier status. This virus is well established in developing countries as a cause of hepatitis clinically similar to infection with the hepatitis A virus (HAV). It differs from HAV in that the virus can cause an exceptionally high fatality rate among pregnant women. Fulminant hepatitis develops rapidly and is fatal in approximately 30% of women when infected during the third trimester of pregnancy. The reason for this high rate of mortality among pregnant women is not known. Women should take all possible precautions to avoid exposure to HEV while pregnant, including refraining from traveling to areas of the country where HEV is endemic, such as India and Pakistan.

HEV infection typically begins with nonspecific symptoms common to many viral illnesses, such as fever, headache, nausea, and stomach pain. One of the first signs of a potential hepatitis infection is dark urine, pale feces, yellow discoloration of the skin and sclera. However, not all patients develop jaundice. The liver of infected individuals typically is enlarged and tender.

Clinical diagnosis of HEV infection is important not only to control outbreaks, but also to clinical management of the disease. During patient diagnosis, it is imperative to rule out the other types of hepatitis that can cause a more serious form of disease. With HEV infection, liver function tests typically demonstrate increased levels of serum bilirubin, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) at the time of disease onset. The diagnosis is confirmed using serologic testing. High levels of both IgM and IgG antibodies are produced at disease onset. Although the high levels of IgG confer lifetime immunity to those infected with hepatitis A, whether the antibodies produced in HEV infection do the same is not known. A variety of commercial immunoassays are available that vary in sensitivity and specificity, primarily because of the antigenic variability of the virus. Nucleic acid testing is recommended to confirm positive serology results in areas where HEV is not endemic. Studies are underway to develop a vaccine against HEV, prompted by the highly successful immunization program against HAV.

Hepadnaviruses

Hepatitis B virus (HBV) (Table 66-11) is the prototype virus of the Hepadnaviridae family (hepa- from hepatitis and dna from the genome type). The virus has long been recognized as a significant cause of liver damage associated with morbidity and mortality. Other mammalian and avian hepadnaviruses are known to exist. Hepadnavirus is a pleomorphic, enveloped virus containing circular, partially double-stranded DNA that replicates through an RNA intermediate. Replication occurs by means of reverse transcription and then DNA replication.

Although a successful vaccine against HBV exists, the number of humans infected with HBV worldwide is nearly 400 million, and approximately 50 million new cases occur annually. Humans are the only source of the virus. Percutaneous exposure to blood or blood products is the primary route of transmission. However, the virus may also be contracted through perinatal or sexual contact. HBV is a relatively heat-stable virus and can retain its infectivity in drying blood and other bodily fluids for several days. HBV infection previously was associated with blood transfusion, but this is now rare because of the screening of blood products and vaccination program.

The incubation period for an acute HBV infection usually is 1 to 3 months but may be considerably longer. The initial symptoms of acute infection often are nonspecific, much like mild, flulike symptoms (Figure 66-2). Many cases are asymptomatic, especially in children. The infection presents as an acute or chronic hepatitis with a pathologic effect on the liver, resulting in self-limited or fatal outcomes. Fatal disease is most likely to occur in people co-infected with the hepatitis D virus (delta agent), a deficient RNA virus capable of replication in cells infected with HBV. Chronic HBV infection remains a significant worldwide cause of liver cirrhosis and hepatocellular carcinoma despite the availability of an effective vaccine.

Because of the generality of HBV symptoms and the similarities it shares with other causative agents of hepatitis, clinicians rely extensively on the laboratory for confirmation of the clinical diagnosis of acute or chronic infection and identification of the virus. Laboratory diagnosis typically uses immunoassays. Immunoassays are available for specific identification of viral antigens or antibodies (viral markers) in a patient’s blood. Several commercial types of assays exist. The most common type uses the EIA format. Most of the commercially available serologic assays demonstrate excellent specificity and sensitivity. HBV is not cultivatable in vitro.

Hepatitis B surface antigen (HBsAg) is the most reliable marker for identifying HBV infection. The antigen becomes evident in the patient’s serum weeks before any biochemical evidence associated with liver damage (biochemical liver assays may show only minimal elevation). HBsAg remains in the serum during the acute and chronic stages of hepatitis B. The presence of HBsAg 6 months after acute infection indicates that the patient is a chronic carrier. IgM (anti-HBcAg) to hepatitis B core antigen (HBcAg) appears early in the course of disease, during the acute infection. Anti-HBsAg (antibody to surface antigen) indicates the patient is in convalescence and has developed immunity. The presence of HBeAg (hepatitis B “e” antigen) indicates high infectivity and a chronic carrier state. The best indication of active viral replication and a high state of infectivity is the presence of HBV DNA in the serum. Viral DNA may be detected by a number of molecular tests, including PCR. A number of user-friendly molecular assays are now widely available. The molecular assays provide a quick turnaround time. Also, detection of HBV DNA in serum is used to resolve questionable serologic results, and quantitation is helpful for predicting the patient’s response to treatment.

Herpes Viruses

The word “herpes” is derived from the Greek word meaning “to creep” and was historically used to describe the spreading, ulcerative skin lesions typically seen in a herpes simplex virus (HSV) infection. Herpes viruses are large (150 to 200 nm), double-stranded DNA, enveloped viruses. The virion consists of four components, the nucleic acid core, the capsid, the tegument, and the envelope. The tegument, an asymmetric structure made of a fibrous-like material, surrounds the capsid and contains 20 different proteins. These proteins enter the host cell upon fusion of the envelope and cell membrane and initiate the viral replication cycle.

Eight human herpes group viruses have been described (Table 66-12). Herpes viruses are widely disseminated among animal species. However, the zoonotic forms of herpes do not infect humans, except for herpes B virus from nonhuman primates (not counted among the eight human herpes viruses). Herpes B virus causes a severe, usually fatal encephalitis in humans. Human herpes viruses include HSV types 1 and 2 (HSV-1 and HSV-2), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), and cytomegalovirus (CMV). More recently detected herpes viruses include human herpes virus (HHV) types 6 (HHV-6), 7 (HHV-7), and 8 (HHV-8). HHV-6 and HHV-7 are lymphotropic viruses acquired early in life. HHV-8, Kaposi’s sarcoma–associated herpes virus (KSHV), causes a tumor of the connective tissue. HHV-6 and HHV-7 are associated with the childhood disease roseola (exanthem subitum). The disease is characterized by a short period of fever and a skin rash.

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