Overview of hepatitis A virus infection in children

INTRODUCTION — Although the reported cases of hepatitis A virus (HAV) infection have decreased with the advent of routine childhood immunization, HAV infection is still a frequently reported disease in the United States (figure 1 and figure 2) [1].

The clinical manifestations, prevention, diagnosis, and management of HAV infection in children will be discussed below. HAV infection in adults and in newborn infants is discussed in separate topic reviews. (See "Hepatitis A virus infection in adults: Epidemiology, clinical manifestations, and diagnosis" and "Hepatitis A virus infection: Treatment and prevention" and "Hepatitis viruses and the newborn: Clinical manifestations and treatment".)

VIROLOGY — 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 [2]. 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

●Incidence – HAV infection occurs worldwide (figure 3). In the United States, HAV remains one of the most commonly reported vaccine-preventable diseases [1,3], but the incidence 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) [4]. The incidence of acute HAV infection in the United States declined from 12 cases per 100,000 in 1995 to approximately 0.4 cases per 100,000 in 2011 [5,6]. Declines were greatest in states in which routine vaccination of children for HAV was initiated in 1999.

However, after 2016, there was a marked increase in HAV cases in the United States, rising to 5.7 cases per 100,000 by 2019. The increase is believed to be related to unprecedented person-to-person outbreaks reported in 31 states, primarily involving people experiencing homelessness and with little effect on the pediatric population (figure 1) [7,8]. (See "Hepatitis A virus infection in adults: Epidemiology, clinical manifestations, and diagnosis", section on 'Epidemiology'.)

A decline in the incidence of HAV infection was seen in Israel following a universal immunization program for toddlers initiated in 1999 [9-11]. The incidence declined from 50.4 cases per 100,000 in 1993-1998 to 2.2 to 2.5 cases per 100,000 in 2002-2004, and outbreaks in school and daycare settings were essentially eliminated.

The extent to which 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 [12]. Nonetheless, the above reports highlight the potential for "herd protection" through the immunization of toddlers or children [4,9,11].

●Transmission – 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 [3,13]. The potential for broad exposure is compounded in childcare centers that include children who have not yet been toilet-trained [14]. (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, many of which occurred in non-travelling contacts of adoptees [15]. (See "International adoption: Infectious disease aspects", section on 'Hepatitis A virus' and "International adoption: Immunization considerations", section on 'Hepatitis A vaccine'.)

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 [16].

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 histologic and biochemical evidence of hepatitis [19], and it can be detected for at least 33 days after the onset of disease (figure 4) [20]. In neonates and younger children, HAV RNA can be detected in stools for several months [18].

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 [21]. In the first phase, a noncytopathic stage, viral replication occurs exclusively within the cytoplasm of the hepatocyte. During this first phase, HAV is released into the bile in the absence of elevation of the liver enzymes. Therefore, fecal shedding of HAV starts before the elevation of alanine aminotransferase (ALT) (figure 4). This phase is followed by a second phase, a cytopathic stage, with florid portal zone infiltration, necrosis, and erosion of the limiting plate and elevated ALT (figure 4). Hepatocellular damage and destruction is not the result of a direct cytopathic effect by HAV but a process mediated by human leukocyte antigen (HLA)-restricted, HAV-specific CD8 lymphocytes and natural killer cells [22-24]. (See "Hepatitis A virus infection in adults: Epidemiology, clinical manifestations, and diagnosis".)

Interferon gamma appears to have a central role in promoting clearance of infected hepatocytes [22]. 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 [25].

CLINICAL MANIFESTATIONS — 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.

Symptoms typically develop between 15 and 50 days after exposure (average 28 days) [26]. 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 [27].

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 [28].

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 [5,21,27]. Symptoms lasting for up to six months have been described [29].

Acute liver failure is rare, occurring in less than 1 percent of cases. 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 and 0.1 percent in adolescents and young adults (15 to 39 years) [30]. Acute liver failure secondary to HAV infection is more common in those with underlying liver disease such as hepatitis C [31]. HAV is responsible for less than 1 percent of acute liver failure in children in the United States [32] and up to 80 percent of liver failure in Latin America or other countries in which HAV infection is endemic. (See "Acute liver failure in children: Etiology and evaluation".)

The most common extrahepatic manifestations of HAV infection include an evanescent maculopapular rash (11 percent) and arthralgias (14 percent) [33]. Much less common extrahepatic manifestations include vasculitis, arthritis, optic neuritis, transverse myelitis, encephalitis, and bone marrow suppression [34].

HAV rarely is associated with a relapsing pattern. It may also trigger autoimmune hepatitis in genetically predisposed hosts [35-37]. (See "Hepatitis A virus infection in adults: Epidemiology, clinical manifestations, and diagnosis", section on 'Extrahepatic manifestations'.)

DIAGNOSIS — HAV infection should be suspected in a patient presenting with nonspecific symptoms (fever, malaise, anorexia, vomiting, nausea, abdominal pain or discomfort, and diarrhea), sometimes followed by development of jaundice and mild hepatomegaly approximately one week later, with marked elevations in serum aminotransferases and bilirubin. Many individuals, especially young children, have few or no symptoms. (See 'Clinical manifestations' above.)

The diagnosis of acute HAV infection is confirmed by the detection of anti-HAV immunoglobulin M (IgM), which 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 4). Anti-HAV IgM may persist at a low titer for 12 to 14 months in patients with a relapsing or protracted course [38].

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. Immunoglobulin G (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 [39,40]. Similar data are not available in children. (See "Hepatitis A virus infection in adults: Epidemiology, clinical manifestations, and diagnosis", section on 'Diagnosis'.)

PREVENTION AND PROPHYLAXIS

General measures — Since 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: Treatment and prevention", section on 'Hygienic practices'.)

Routine childhood vaccination — In January 2006, hepatitis A vaccine was added to the recommended childhood and adolescent immunization schedule in the United States [3]. 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) and as a catch-up vaccine for all children and adolescents 2 to 18 years who have not previously received the vaccine [41].

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 with 31 percent of older children and adults [30]. Because humans are the only known reservoir for HAV, universal immunization strategies could hypothetically eradicate HAV.

Guidance from the World Health Organization permits the option of a single-dose (off-label) vaccine schedule for children one year and older; this strategy may be useful during hepatitis A outbreaks. (See "Hepatitis A virus infection: Treatment and prevention", section on 'Limited role for single-dose strategy'.)

Vaccination of high-risk groups — In addition to the routine childhood vaccination described above, vaccination is recommended for all nonimmune members of high-risk groups, including [41]:

●Arriving international adoptees from endemic areas (≥1 year of age) and their close contacts

●International travelers to endemic areas (including infants ≥6 months of age)

●People with HIV (≥1 year of age)

●People with chronic liver disease (≥1 year of age)

If the vaccine is given to infants 6 to <12 months (ie, because of travel), this does not count towards the routine two-dose vaccination series [41]. Vaccination of adults in these and other high-risk groups is discussed separately. (See "Hepatitis A virus infection: Treatment and prevention", section on 'Indications'.)

Pre-exposure prophylaxis — The primary tool for protection against hepatitis A prior to exposure is vaccination, which is superior to immune globulin with respect to achievable antibody concentrations and durability of immune response. Administration of immune globulin is warranted for selected nonimmune individuals at risk for hepatitis A exposure. Indications for each of these interventions are outlined in the table (table 1) and discussed separately. (See "Hepatitis A virus infection: Treatment and prevention", section on 'Passive immunization'.)

Post-exposure prophylaxis — Post-exposure prophylaxis to individuals exposed to HAV consists of hepatitis A vaccine and/or immune globulin, depending on the patient characteristics. Indications for and detailed recommendations about post-exposure prophylaxis are discussed separately. (See "Hepatitis A virus infection: Treatment and prevention", section on 'Protection following exposure'.)

Return to school or daycare — Children should not return to school or daycare until one week after onset of the illness, until the prophylaxis program for contacts is completed, or until directed by the responsible health department [26]. 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: Treatment and prevention" and "Infection prevention: Precautions for preventing transmission of infection".)

TREATMENT

Treatment of acute HAV infection is supportive. 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-abundant 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 the patient has severely compromised hepatic function (ie, acute liver failure).

Patients rarely require hospitalization, except for brief admissions for hydration and evaluation, or for those who develop acute liver failure. The Pediatric Acute Liver Failure Study Group (PALF SG) criteria are used to identify such patients [32,42]:

●Absence of known chronic liver disease

●Evidence of hepatic injury

●Prothrombin time (PT) >15 and/or international normalized ratio (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 PT 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 children: Management, complications, and outcomes".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pediatric liver disease".)

SUMMARY AND RECOMMENDATIONS

●Epidemiology

•Hepatitis A virus (HAV) infection occurs worldwide (figure 3). HAV is spread via the fecal-oral route. The majority of patients who acquire the illness have had personal contact with an infected person. The incidence among children has decreased substantially since the introduction of the HAV vaccine (figure 1). (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 histologic 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, the spread of HAV usually takes place before the index case has been recognized. (See 'Epidemiology' above.)

●Clinical manifestations

•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.)

●Diagnosis – The diagnosis of acute HAV infection is made by the detection of anti-HAV immunoglobulin M (IgM) in a patient with the typical clinical presentation. 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 4). (See 'Diagnosis' above.)

●Prevention

•Hepatitis A vaccine is part of the recommended childhood and adolescent immunization schedule in the United States. It is recommended as a two-dose series for all children beginning at one year of age and also for specific high-risk groups, including international travelers and patients with chronic liver disease. (See 'Routine childhood vaccination' above and "Hepatitis A virus infection: Treatment and prevention", section on 'Vaccination'.)

•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 post-exposure prophylaxis are discussed separately. (See "Hepatitis A virus infection: Treatment and prevention", section on 'Protection following exposure'.)

●Management – 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 acute liver failure. Children with HAV-related hepatic failure are candidates for liver transplantation. (See 'Treatment' above.)