Viral Characteristics

The virion of HAV is a small spherical particle of 27–32 nm; it does not have an envelope, contains single-stranded RNA, and belongs to the hepatovirus group of picornaviruses. It is highly infectious and relatively stable to drying, ether, heat, cold storage, and denaturation by acidic conditions, making it resistant to disinfection. Inactivation of the virus can be achieved by heating food to >185°F (85°C) and treating contaminated surfaces with a 1:100 dilution of sodium hydrochloride (household bleach) in tap water. In the absence of these measures, HAV remains stable in the environment for long periods and may result in outbreaks.

There is only one serotype of HAV but there are seven genotypes based on 15–20% nucleotide diversity over a 168 base segment at the VP1/2A junction [1]. Genotype 1 A predominates in the USA and western Europe [2, 3]. The genome for HAV is enclosed in the nucleocapsid, which has been designated HAV antigen. It contains a linear, single-stranded molecule of RNA. The virus has been cultured in several cell lines, and the HAV genome has been cloned [4–6]. Humans are the principal hosts for HAV. Several non-human primates may also become infected with HAV. There is no known carrier state for HAV; consequently, infection is maintained by serial transmission from acutely infected individuals to those who are susceptible [4–7]. In the USA, there were approximately 4,000 new HAV infections in 2016. However, the official number of reported cases is much lower since many people who are infected do not have symptoms and are not reported to public health officials. Until 2004, HAV was the most frequently reported type of hepatitis in the USA. A vaccine was introduced in 1995 and health professionals now routinely vaccinate all children, travelers to certain countries, and people at risk for the disease. Vaccination has dramatically affected rates of the disease in the USA.

Infectivity occurs primarily through fecal–oral transmission after ingestion and absorption. The ingested virus replicates in the small bowel and is transported to the liver via the portal vein. The virus enters the hepatocyte by specific receptors located on the hepatocyte plasma membrane. The viral RNA is uncoated after uptake and binds to ribosomes, causing synthesis of viral proteins. Replication of the viral genome occurs by RNA polymerase. The virus is subsequently secreted into the biliary tree and excreted in feces, where high concentrations of the virus may be detected. An immunologic response occurs in the liver, resulting in portal and periportal lymphocytic infiltration and liver injury.

Transmission is highest during the anicteric prodromal phase 14–21 days after exposure, when fecal and serum viral concentrations are high. The incubation period is typically two to six weeks, averaging 28 days. Fecal viral excretion may last up to three weeks. Children may excrete virus longer than adults. Although HAV is present in serum, its concentration is several orders of magnitude less than in feces.

Epidemiology

Worldwide, HAV infection is a common illness with prevalence rates highest in areas with limited hygiene and sanitation practices. High prevalence rates are seen in Mexico, India, the Middle East, and Africa. In developing countries, where infection is endemic, most individuals are infected by five years of age. In developed countries, there is a large population susceptible to periodic outbreaks because of fewer exposures and infections in childhood. Better quality sanitary standards have reduced the likelihood of fecal contamination and subsequent environmental exposure in developed countries. With the introduction of universal childhood immunization against HAV in 2006, the incidence of acute hepatitis A has declined from 6 to 0.4 cases per 100,000 between 1999 and 2014 in the USA. However, decreased rates of natural immunity have facilitated the ability of HAV to cause outbreaks owing to an expanding susceptible population and have shifted the burden of HAV to older populations, who are more likely to experience morbidity and mortality.

Since July 2016, there have been five large outbreaks with more than 1,600 cases, with two outbreaks traced back to food and three outbreaks involving person to person transmission [8].

Hepatitis A virus is highly contagious. Factors associated with increased transmission rates include crowding, poor personal hygiene, improper sanitation, and contamination of food and water. Prominent risk factors include close contact with patients infected with HAV, travel to endemic regions, people with clotting factor disorders, people working with non-human primates, users of injection and non-injection drugs, and men who have sex with men. Transmission by blood transfusion or from mother to newborn (perinatal vertical transmission) is rare.

Spread of the virus usually occurs by the virus being taken in by mouth from contact with objects, food, or drinks contaminated by the feces of an infected person. Person-to-person contact can also spread the virus when infected people do not wash their hands properly after going to the bathroom and then touch other objects or food, when parents or caregivers do not properly wash their hands after changing diapers or cleaning up the feces of an infected person, or when someone engages in oral–anal contact with an infected person.

Spread can also occur through eating or drinking food or water contaminated with HAV. This is more likely to occur in countries where HAV is common and in areas where there are poor sanitary conditions or poor personal hygiene. The food and drinks most likely to be contaminated are fruits, vegetables, shellfish, ice, and water. In the USA, chlorination of water kills any HAV that enters the water supply.

In the recent past, food-borne outbreaks of HAV infection, in spite of apparently high hygiene standards, have occurred in the USA. An outbreak of 601 people in western Pennsylvania in 2003 resulted from ingestion of salsa prepared with contaminated green onions imported from Mexico [10, 11]. Three people died of liver failure during this outbreak. No ill food service workers were identified.

Many other foods have been incriminated as the vehicle for HAV delivery. A multistate food-borne outbreak of HAV infection illustrates the impact of the disease on children; 213 cases of HAV infection were reported in students attending 23 schools in Michigan and 29 cases in 13 schools in Maine [12]. This outbreak was associated with consumption of frozen strawberries served in school lunch programs. In 2016, another multistate outbreak was attributed to contaminated frozen strawberries served in smoothies. Although the agriculture standards in the USA are high, the ease of travel and shipment of produce between areas of high and low endemicity allows for ready transmission of the virus. Once contaminated products are distributed in a population without significant herd immunity, the consequences can prove fatal.

A separate large multistate outbreak in 2013 was traced back to a shipment of contaminated pomegranate seeds from a company in Turkey. Seventy-one people were hospitalized and no deaths were reported.

Food-borne infections and travel as sources of HAV are related. In a recent study, HAV infection among Hispanic children was associated with cross-border travel to Mexico and food-borne exposure during travel [13]. Eating foods from a taco stand or street vendor increased the risk of infection more than 17-fold, whereas eating lettuce increased the risk more than five-fold. Further, there was increased risk with higher socioeconomic status. Families that could not afford to travel were less likely to be exposed to HAV.

Day care centers have long been associated with HAV spread throughout local communities [14–17]. The high rate of spread is related to the crowded conditions, poor hygiene, and mild illness among the infected children seen in day care centers. In addition to the toddlers and staff, HAV infection can also be seen in family members. The clinical symptoms in affected children are often minimal as the majority are anicteric. The illness may be mistaken for flu or gastroenteritis. Many parents may send their children to day care centers with such clinical symptoms. Attention to hand washing and good hygiene are necessary to diminish these infections.

In 2017, an outbreak of hepatitis A in San Diego resulted in 20 deaths and sickened 592 people. Most of the infections occurred among homeless people and people using illicit drugs. Factors contributing to the outbreak in San Diego are similar to those that could aggravate the problem in other cities with large homeless populations, including a shortage of affordable housing, problems with placing people in shelters, and limited accessible, free bathrooms and showers.

Florida declared a public health emergency in response to a state-wide hepatitis A outbreak in August 2019, with documentation of 2,582 cases between January 1, 2018 and July 27, 2019.

In the past, prior to universal childhood vaccination in the USA, the incidence of HAV infection was highest in the western states among people between five and 39 years of age [9]. Overall, one-third of the US population has serologic evidence of previous HAV infection [8]. The prevalence among children 6 to 11 years of age was 9% and among people older than 70 years it was 75%. Cyclic community-wide outbreaks of HAV infection occurring every five to ten years were noted for decades. With the introduction and broad use of the HAV vaccine, a decreasing incidence has been most marked among the western states, which now have rates of HAV infection similar to other parts of the USA. At-risk groups, such as Native Americans, now have incidence rates below the average US rate because of implementation of an HAV vaccine strategy.

While overall the incidence has declined, there have been some groups with increased incidence. The increase in HAV infection is occurring in high-risk groups who are not receiving immunizations. These groups include people using illicit drugs and men who have sex with men. This increase is reflected in an increased proportion of cases among men and an increased mean age of infection. In fact, hepatitis A cases rose almost 300% from 2016–2018 compared with 2013–2015 due to outbreaks in homeless populations and people using illicit drugs [18]. The changing epidemiology of HAV infection is concerning because of the higher morbidity and mortality rate noted in adults.

Clinical Aspects and Pathogenesis

Acute HAV infection is defined as an acute illness with viral-like symptoms and jaundice or elevated serum aminotransferases (Figure 17.1). Initial clinical manifestations may present similar to a viral prodrome, with non-specific symptoms of nausea, vomiting, anorexia, fatigue, low-grade fevers, myalgia, arthralgia, and headaches. Common signs of infection include leukopenia, hepatomegaly, and splenomegaly. Clinical features cannot reliably distinguish HAV infection from other forms of viral hepatitis and other liver diseases. The illness is usually self-limited, and the severity is age dependent. In infants and preschool-aged children, acute HAV infection may be clinically unapparent as they remain anicteric. Individuals may remain in an anicteric phase for an average of seven days [20]. If there is progression to the icteric phase, there is dark urine secondary to excretion of bilirubin conjugates and pale-colored stools. Jaundice is present in only 10% of children younger than six years of age, 40% of children aged 6 to 14 years, and 70% of children older than 14 years of age, compared with 70–85% of adults [20]. Risk of transmission decreases one week after onset of jaundice. Additional symptoms may include abdominal pain, pruritus, fever, and rash.

Figure 17.1 Typical course of acute hepatitis A. ALT, serum alanine aminotransferase level, Anti-HAV, antibody to hepatitis A virus, HAV, hepatitis A virus, IgG , immunoglobulin G, IgM, immunoglobulin M.

Diagnosis

The diagnosis of acute HAV is dependent upon the detection of IgM anti-HAV antibodies, and can be detected in serum five to 20 days following exposure. Past infection or previous immunization is associated with serum IgG anti-HAV antibodies. Other methods to detect HAV are available but are not clinically valuable. Viral RNA can be detected in serum and stool during acute infection by nucleic acid amplification, but this is not readily available. Elevated serum aminotransferases, alkaline phosphatase, total bilirubin and direct-reacting bilirubin are observed with acute HAV. Additional laboratory studies evaluating hepatic synthetic function (international normalized ratio, albumin levels) are often useful in the course of management.

Treatment

The initial goal of treatment of an HAV-infected patient is to establish supportive care. There is no antiviral medication specific for its treatment. Important in the management is early detection, appropriate support and monitoring during the acute illness, recognition of the development of fulminant liver disease, and prevention of disease spread to susceptible individuals.

Prevention

Keys to prevention of HAV infection include improvements in sanitation, water sources, and food preparation techniques. Personal hygiene, hand washing, and proper disposal of soiled diapers in child care settings all contribute to reducing transmission. Viral transmission can be interrupted by eliminating the virus from the population, utilizing appropriate hygiene, sanitation and isolation procedures, and the use of immunization.

Because transmission of HAV occurs before recognition of clinical infection, hygienic measures alone are often ineffective in preventing infections. The most effective method to halt transmission is immunization.

In hospitalized patients, in addition to standard precautions, contact precautions are recommended for patients who are incontinent or use diapers for at least one week after onset of symptoms. Children and adolescents with acute HAV infection who work as food handlers or attend or work in child care should be excluded from attending for at least one week after onset of symptoms.

Public Health Implications of Hepatitis A Infection

Besides the mortality associated with HAV infection, there is significant morbidity with a significant financial burden worldwide. Cost-effective analyses clearly demonstrate the benefit of vaccination programs [61]. Estimated costs include inpatient and outpatient care, intensive care expenses for fulminant liver failure and costs associated with liver transplantation.

In the USA, HAV is a reportable infectious disease. Case reporting results in costs for public health surveillance, contact investigation, outbreak response, and prophylaxis and prevention programs once an index case is identified.

Current Status

An impressive decline in the incidence of HAV infection in the USA can be attributed to the sequential expansion of HAV immunization to the current institution of universal HAV vaccination in children and improved hygiene and sanitation. However, further improvements in combating this infection should be instituted (Figure 17.2, Figure 17.3). Immunization of high-risk groups continues to be underutilized. The use of the vaccine worldwide also is underemployed. Strategies to correct these situations should allow continued declines in the morbidity, mortality, and healthcare costs associated with this vaccine-preventable disease.

Figure 17.2 Changing incidence of Hepatitis A in the United States.

Figure 17.3 Age-related change in the incidence of hepatitis A in the United States.

Viral Characteristics

The HEV is a small icosahedral, non-enveloped, RNA-containing particle 27–34 nm in dimeter that is enterically transmitted like HAV. The HEV genome is a single-stranded, positive-sense RNA of approximately 7.5 kb with three open reading frames (ORFs) [62]. It has indentations and spikes on its surface making it appear similar to calciviruses [63]. It was classified in the Calciviridae family from 1988–1998 [64, 65] but phylogenetic analysis indicated differences in the non-structural regions that did not support this classification and it is now classified in the genus Hepevirus of the family Hepeviridae [66].

Using molecular techniques, HEV was found to consist of short non-coding regions at both the 50- and 30-ends, and three ORFs. The first consists of 1,693 codons, is the largest, and encodes for non-structural proteins responsible for replication of the viral genome and processing of the viral polyprotein. The second consists of 660 codons and encodes for viral capsid structural proteins. The third consists of 123 codons and encodes for a small cytoskeleton-associated phosphoprotein of uncertain function [67]. Data suggests that it acts as a viroporin, which may aid in release of infectious virions from infected cells.

The virus has been characterized using molecular techniques. The presumed viral agent was serially transmitted in an animal model (macaque), resulting in typical elevation of serum aminotransferases and the detection of characteristic virus-like particles in feces and bile. Bile obtained from the gallbladder of an infected macaque was also shown to be capable of transmitting infection. The bile contained small (32–34 nm) virus-like particles serologically related to HEV, which were used to construct a library of recombinant complementary DNA (cDNA). Differential hybridization techniques were used to identify putative HEV-cloned sequences. A single-cloned sequence (ET 1.1), absent from uninfected bile, was analyzed by sequence-independent single-primer amplification followed by hybridization probing [68]. This sequence was detected by polymerase chain reaction testing of amplified DNAs isolated from human feces obtained in five geographically disparate areas in which outbreaks of HEV had been documented; these studies suggested that HEV was the primary agent of water-borne hepatitis in these patients.

A specific antigen (HEVAg), expressed in the cytoplasm of hepatocytes in the early acute stage of infection, has been shown to induce anti-HEV in infected primates. Anti-HEV is found in acute and convalescent serum samples of patients documented to have enterically transmitted hepatitis (not caused by HAV) during outbreaks.

Although only one serotype has been recognized, extensive genomic diversity has been noted among HEV isolates [69]. Currently, HEV isolates have been designated into four genotypes [66, 69]. Genotype 1 is most prevalent and accounts for most cases in Asia. In this region, the isolates have 92–99% homology [68]. Genotype 2 is the second most common genotype and occurs in Mexico and shares only 75% homology with genotype 1. Although HEV is found predominantly in areas with poor sanitation, it has been identified throughout the world, including the USA and Europe [70, 71]. Genotypes 1 and 2 infect only humans while genotypes 3 and 4 infect both humans and animals.

Epidemiology

Epidemiologic studies have shown that HEV, like HAV, is predominantly a feces- or water-borne infection noted in developing countries, particularly in areas with inadequate public sanitation or at times of extensive flooding [68, 72–78]. Outbreaks of enterically transmitted hepatitis (not caused by HAV) are often traced to contaminated water supplies. Sporadic cases of HEV infection have also been described [77]. Even in developed countries, HEV may be identified infrequently. For example, 2.6% of a control population of Japanese children were positive for anti-HEV IgG [79]; however, in this study, HEV was not associated with fulminant hepatitis and was identified in only one patient with acute hepatitis.

Hepatitis E virus is the second most common cause of sporadic hepatitis in North Africa and the Middle East [80]. In Hong Kong, HEV was shown to account for one-third of the cases of non-A, non-B, non-C hepatitis. Consequently, HEV should be suspected in travelers returning from areas of endemic disease [81].

From epidemiologic studies, it has been postulated that HEV is a zoonosis, with the swine population as a host [66, 80, 82]. In addition to swine, anti-HEV has been detected in cattle, dogs, rodents, and monkeys [66]. In fact, clusters of HEV in Japan have been traced to the ingestion of under-cooked deer meat and pig liver [80].

The development of sensitive assays (most commonly enzyme-linked immunosorbent assays) for antibody to the HEV (anti-HEV) has confirmed that enterically transmitted HEV is also a major cause of acute sporadic and epidemic hepatitis in children in certain geographic areas [83, 84].

There is considerable variability in anti-HEV seroprevalence in endemic regions. In areas of India, anti-HEV has been detected in as many as 5% of children younger than ten years. However, in Egypt, antibodies to HEV are found in more than 60% of children by ten years of age [80]. In India, the seroprevalence rate reaches 30–40% among adults older than 25 years [63, 80, 85]. In all locations, anti-HEV is less frequent than anti-HAV among young children in developing countries. This may be the result of its minimal person-to-person transmission along with other variables. In addition, HEV may be transmitted through blood transfusion [86]. Mother-to-child transmission has been documented [87]. While the data on vertical transmission of HEV are limited, when it does occur it is associated with significant morbidity and mortality [88, 89].