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INTRODUCTION — Although the reported cases of hepatitis A virus (HAV) infection have decreased over the past decade, HAV infection is still a frequently reported disease in the United States . HAV is a 27 nm single-stranded, icosahedral, nonenveloped RNA virus that belongs to the Heparnavirus genus of the Picornaviridae. Four well-defined genotypes of HAV have been described in humans, yet they belong to a single serotype . The virus is stable at low pH and moderate temperature, but it is inactivated by high temperature, chlorine, and formalin. These characteristics are relevant for preventive measures.
EPIDEMIOLOGY — Hepatitis A virus (HAV) infection occurs worldwide (figure 1). Although it remains one of the most commonly reported vaccine-preventable diseases in the United States and among American travelers [1,3], the incidence in the United States has declined substantially since vaccination was recommended for persons at increased risk (in 1996), for children living in states with the highest incidence of HAV (in 1999), and for all children (in 2006) . The incidence of acute HAV infection in the United States has declined from 12 cases per 100,000 in 1995 to about 0.4 case per 100,000 in 2011 [5,6]. Declines were greatest in states in which routine vaccination of children for HAV was initiated in 1999. In 2013, a total of 1781 cases of hepatitis A were reported in the United States to CDC (0.6 cases per 100,000), a 14 percent increase from 2012, indicating that hepatitis A infection is still an important issue in the United States. This increase is believed to be due to a large hepatitis A outbreak from imported pomegranate arils consumed by people in several southwestern states and Hawaii [1,7]. (See "Hepatitis A virus infection in adults: An overview", section on 'Epidemiology'.)
A similar decline in the incidence of HAV infection was seen in Israel following a universal immunization program for toddlers that was initiated in 1999 [8-10]. The incidence declined from 50.4 cases per 100,000 in 1993 to 1998 to 2.2 to 2.5 cases per 100,000 in 2002 to 2004, and outbreaks in school and day care settings were essentially eliminated.
To what extent the observed reductions in the incidence of HAV infection in these reports can be attributed to improved environmental and hygienic conditions or variation in the epidemic cycle is difficult to evaluate . Nonetheless, the above reports highlight the potential for "herd protection" through the immunization of toddlers or children [4,8,10].
HAV is spread via the fecal-oral route. The majority of patients who acquire the illness have had personal contact with an infected person. In the childcare setting, spread of HAV usually takes place before the index case has been recognized. Outbreaks are usually recognized only after childcare staff members develop symptoms, such as jaundice, since most of the children are asymptomatic or have nonspecific symptoms [3,12]. The potential for broad exposure is compounded in childcare centers that include children who have not yet been toilet-trained . (See 'Clinical manifestations' below.)
Community, restaurant, and school outbreaks due to contaminated water or food have been described. In the United States, clusters of cases have been seen around international adoptions, more than half of which occurred in non-travelling contacts of adoptees . In a report of 288 international adoptees, 1 percent had acute HAV infection .
Nosocomial spread of HAV is rare [16-18]. Among these reports include outbreaks in neonatal intensive care units where newborns were infected through blood-product transfusions and later transmitted the virus to other neonates and the units' staff members .
The incubation period for HAV is 15 to 50 days. HAV RNA can be detected in stools at least one week before the onset of histological and biochemical evidence of hepatitis , and it can be detected for at least 33 days after the onset of disease (figure 2) . In neonates and younger children, HAV RNA can be detected in stools for several months .
PATHOGENESIS — The degree of hepatic injury during HAV infection depends upon the host's immune response. HAV infection traditionally has been considered a biphasic process . In the first phase, a non-cytopathic stage, viral replication occurs exclusively within the cytoplasm of the hepatocyte. This phase is followed by a second phase, a cytopathic stage, with florid portal zone infiltration, necrosis, and erosion of the limiting plate. Hepatocellular damage and destruction is not the result of a direct cytopathic effect by HAV but a process mediated by HLA-restricted, HAV-specific, CD8 lymphocytes, and natural killer cells [22-24].
Interferon gamma appears to have a central role in promoting clearance of infected hepatocytes . An excessive host response, reflected by a marked reduction in HAV RNA during acute infection, is associated with severe hepatitis and a possible fulminant course .
CLINICAL MANIFESTATIONS — Hepatitis A virus (HAV) infection in children is typically an acute, self-limited illness associated with general, nonspecific symptoms, such as fever, malaise, anorexia, vomiting, nausea, abdominal pain or discomfort, and diarrhea. During the prodromal period, aminotransferases are typically elevated. Jaundice (conjugated hyperbilirubinemia) usually occurs one week after onset of symptoms, along with choluria (bilirubin in the urine) and mild hepatomegaly .
Symptomatic hepatitis occurs in approximately 30 percent of infected children younger than six years, some of whom become jaundiced. When it does occur, jaundice usually lasts for less than two weeks. Conjugated bilirubin and aminotransferases return to normal within two to three months .
In contrast, older children and adults with HAV infection are usually symptomatic for several weeks. Approximately 70 percent are jaundiced, 80 percent have hepatomegaly, and 40 percent are hospitalized [5,21,26]. Symptoms lasting for up to six months have been described .
Acute liver failure is rare, occurring in fewer than 1 percent of cases. However, the case-fatality for HAV infection varies with age. In 2001, the case fatality rate was 0.3 percent in children younger than 14 years, 0.1 percent in adolescents and young adults (15 to 39 years), 0.4 percent in older adults (40 to 59 years), and 1.7 percent in people older than 60 years . This case fatality rate has remained fairly stable. In 2013 case-fatality estimates ranged from 0.3 to 0.6 percent for most age groups, and up to 1.8 percent among adults aged >50 years . From 2009 to 2013, the overall mortality rate also remained approximately steady at 0.02 deaths per 100,000 population each year . Acute liver failure secondary to HAV infection is more common in those with underlying liver disease such as hepatitis C . HAV is responsible for no more than one percent of acute liver failure in children in the United States , and up to 60 percent of liver failure in Latin America [33,34] or other countries in which HAV infection is endemic . (See "Acute liver failure in adults: Etiology, clinical manifestations, and diagnosis".)
The most common extrahepatic manifestations of HAV infection include an evanescent rash (11 percent) and arthralgias (14 percent) . Much less common extrahepatic manifestations include vasculitis, arthritis, optic neuritis, transverse myelitis, encephalitis, and bone marrow suppression .
HAV rarely is associated with a relapsing pattern. It may also trigger autoimmune hepatitis in genetically predisposed hosts [38-40]. (See "Hepatitis A virus infection in adults: An overview", section on 'Extrahepatic manifestations'.)
DIAGNOSIS — The diagnosis of acute HAV infection is made by the detection of anti-HAV IgM in a patient with the typical clinical presentation. Serum IgM anti-HAV is the gold standard for the detection of acute illness. This antibody is positive at the onset of symptoms, peaks during the acute or early convalescent phase of the disease, and remains positive for approximately four to six months (figure 2).
The serologic detection of antibodies is simpler, easier, and less expensive than other techniques, such as HAV detection in stool and body fluids by electron microscopy and HAV RNA detection in stool, body fluids, serum, and liver tissue. IgG anti-HAV appears early in the convalescent phase of the disease, and remains detectable for decades.
There may be special considerations when assessing anti-HAV antibodies. In adults, antibodies become detectable two weeks after HAV vaccination, but titers are 10- to 100-fold lower than levels induced by wild-type infection [41,42]. Similar data are not available in children. Anti-HAV IgM may persist at a low titer for 12 to 14 months in patients with a relapsing or protracted course . (See "Hepatitis A virus infection in adults: An overview", section on 'Diagnosis'.)
PREVENTION AND PROPHYLAXIS
General measures — Since hepatitis A virus (HAV) is transmitted predominantly by the fecal-oral route, prevention can be aided by improved sanitary conditions, adherence to sanitary practices (eg, handwashing), heating foods appropriately, and avoidance of water and foods from endemic areas. Handwashing is highly effective in preventing the transmission of the virus, since HAV may survive for up to four hours on the fingertips. Chlorination and certain disinfecting solutions (household bleach 1:100 dilution) are sufficient to inactivate the virus. (See "Hepatitis A virus infection: Prevention", section on 'Hygienic practices'.)
Vaccination — In January, 2006, Hepatitis A vaccine was added to the recommended childhood and adolescent immunization schedule in the United States . Hepatitis A vaccine is administered in a two-dose schedule and is recommended for all children at one year of age (ie, 12 to 23 months) . It also is recommended for specific high-risk groups, such as international travelers, close contacts of newly arriving international adoptees, persons with clotting factor disorders, patients with chronic liver disease, men who have sex with men, injecting/noninjecting drug users, and people living in communities with HAV outbreaks [3,44]. By 2009, 74 percent of adolescents in states that have been practicing universal hepatitis A vaccination since 1999 had received at least one dose of the vaccine; in states practicing hepatitis A vaccination since 2006, coverage for adolescents was only 28 percent . (See "Hepatitis A virus infection: Prevention".)
A compelling argument for universal vaccination of children is the observation that the disease tends to be more severe when acquired at older ages. In a report from the Centers of Disease Control and Prevention, for example, hospitalization was required in 13 percent of children younger than five years compared to 31 percent of older children and adults . Because humans are the only known reservoir for HAV, universal immunization strategies could hypothetically eradicate HAV.
Immune globulin — Polyclonal serum immune globulin (IgG) pre- and post-HAV exposure has been available since the 1940s and can decrease the incidence of HAV infection by more than 90 percent. Passive immunity lasts for up to six months depending upon the IgG dose used but is only effective if administered within two weeks post-exposure. (See "Hepatitis A virus infection: Prevention".)
Post-exposure prophylaxis — Indications for and detailed recommendations about postexposure prophylaxis are discussed separately. (See "Hepatitis A virus infection: Prevention".)
General principles — Treatment is supportive. Hepatitis A virus (HAV) infection in children is usually a minor and self-limited infection; as mentioned above, HAV is often asymptomatic or associated only with symptoms indistinguishable from nonspecific viral gastrointestinal infections. The usual supportive measures for fever and diarrhea may be undertaken. (See "Acute viral gastroenteritis in children in resource-rich countries: Management and prevention" and "Fever in infants and children: Pathophysiology and management", section on 'Management of fever'.)
No particular diet has had a major impact on outcomes of patients with acute hepatitis A. As a result, no specific diet is recommended unless patient has severely compromised hepatic function (ie, fulminant hepatic failure).
Patients rarely require hospitalization except for those who develop fulminant hepatic failure. The following criteria were proposed by the Pediatric Acute Liver Failure Study Group (PALF SG) to identify such patients [32,46]:
●Absence of known chronic liver disease
●Evidence of hepatic injury
●PT>15 and/or INR>1.5 with encephalopathy
●PT>20 and/or INR>2.0 with or without encephalopathy
These criteria should be fulfilled within eight weeks from the onset of illness, and the above-described coagulopathy (prolonged prothrombin time and/or INR) should be unresponsive to vitamin K therapy.
These patients require aggressive supportive therapy, and should be transferred to a center capable of performing liver transplantation. (See "Acute liver failure in adults: Etiology, clinical manifestations, and diagnosis".)
Return to school or daycare — Children should not return to school or daycare until one week after onset of the illness, the prophylaxis program for contacts is completed, or directed by the responsible health department . In addition, adherence to universal precautions is crucial, since HAV may be present in stool for several months after the initial onset of disease [18,20]. Post-exposure prophylaxis and universal precautions are discussed separately. (See "Hepatitis A virus infection: Prevention" and "Infection prevention: Precautions for preventing transmission of infection".)
SUMMARY AND RECOMMENDATIONS
●Hepatitis A virus (HAV) infection occurs worldwide (figure 1). HAV is spread via the fecal-oral route. The majority of patients who acquire the illness have had personal contact with an infected person. (See 'Epidemiology' above.)
●The incubation period for HAV is 15 to 50 days. HAV RNA can be detected in stools at least one week before the onset of histological and biochemical evidence of hepatitis, and it can be detected for at least 33 days after the onset of disease. In neonates and younger children, HAV RNA can be detected in stools for several months. In the childcare setting, spread of HAV usually takes place before the index case has been recognized. (See 'Epidemiology' above.)
●HAV infection in children is typically an acute, self-limited illness associated with nonspecific symptoms, such as fever, malaise, anorexia, vomiting, nausea, abdominal pain or discomfort, and diarrhea. During the prodromal period, aminotransferases are typically elevated. Jaundice (conjugated hyperbilirubinemia) usually occurs one week after onset of symptoms, along with choluria (bilirubin in the urine) and mild hepatomegaly. (See 'Clinical manifestations' above.)
●HAV disease tends to be more severe when acquired at older ages. Among younger children (under six years of age) with HAV infection, only one third develop symptomatic hepatitis, and this often lasts less than two weeks. In contrast, most older children and adults with HAV infection are jaundiced and have hepatomegaly, and they are usually symptomatic for several weeks. Acute liver failure is rare, occurring in less than 1 percent of cases. (See 'Clinical manifestations' above.)
●The diagnosis of acute HAV infection is made by the detection of anti-HAV IgM in a patient with the typical clinical presentation. Serum IgM anti-HAV is the gold standard for the detection of acute illness. This antibody is positive at the onset of symptoms, peaks during the acute or early convalescent phase of the disease, and remains positive for approximately four to six months (figure 2). (See 'Diagnosis' above.)
●Hepatitis A vaccine is part of the recommended childhood and adolescent immunization schedule in the United States. It is recommended for all children at one year of age (ie, 12 to 23 months), and also for specific high-risk groups, including international travelers and patients with chronic liver disease. (See 'Vaccination' above.)
●Post-exposure prophylaxis for individuals with recent exposure to HAV may be accomplished with the HAV vaccine or immune globulin. Indications for and detailed recommendations about postexposure prophylaxis are discussed separately. (See "Hepatitis A virus infection: Prevention".)
●HAV infection in children is usually a minor and self-limited infection requiring no specific therapy. The usual supportive measures for fever and diarrhea may be undertaken. Patients rarely require hospitalization except for those who develop fulminant hepatic failure. Children with HAV-related hepatic failure are candidates for liver transplantation. (See 'Treatment' above.)
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