Hepatitis A virus.

HAV (see Chapter 168 ) is a member of the Picornaviridae and formerly was known as enterovirus 72. A small, nonenveloped RNA virus with icosahedral symmetry ( Fig. 47.1 ), HAV is transmitted by the fecal-oral route among young and school-aged children receiving care in group settings such as daycare, summer camp, schools, and institutions. The incubation period is 30 days but ranges from 15 to 50 days. HAV infection in young children often is asymptomatic, and outbreaks in children are recognized first when symptoms occur in adult caretakers. Older children are more likely to have the classic symptoms of nausea, malaise, jaundice, and tender hepatomegaly. Rarely HAV causes fulminant hepatitis. Acute HAV infection is diagnosed serologically by detecting HAV IgM antibody in serum. No licensed, specific antiviral treatment is available. However, prevention may be accomplished by passive immunization with immune globulin or active immunization with licensed inactivated HAV vaccines. Two monovalent HAV vaccines are approved and recommended for all children 12 months of age or older in a two-dose series in the United States.

A 27-nm hepatitis A virus (HAV) isolated from the stool filtrate of a patient with acute HAV infection. The HAV particles are aggregated by convalescent serum containing anti-HAV antibodies. The line represents 100 nm.

(Courtesy Dr. Jules Dienstag, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD.)

Hepatitis B virus.

HBV (see Chapter 157 ), previously known as the Dane particle and hepadnavirus type 1, is a member of the Hepadnaviridae and is a DNA virus that is a 42-nm, nonenveloped spherical particle ( Fig. 47.2 ). There are eight known genotypes, of which A through D are the most predominant in the United States. It is highly transmissible through parenteral exposure to blood or blood products, organ transplantation, or intravenous drug use; it is also transmissible sexually and perinatally. The incubation period is prolonged, usually 90 days, with a range of 45 to 180 days reported. Neonates may acquire HBV vertically from HBV-infected mothers, especially those who are positive for hepatitis Be antigen (HBeAg) and/or those with very high HBV DNA levels (>10 ⁷ ). Whereas neonates and toddlers rarely are symptomatic, older children and adults may have mild to moderate symptoms of acute hepatitis or progress to fulminant or fatal disease. HBV also is a common cause of chronic hepatitis in children, with 10% of older children and adults infected with HBV being affected. The figure rises to approximately 30% in infancy or early childhood and reaches a striking 90% to 95% in infants born to HBeAg-positive mothers.

Electron micrograph of hepatitis B virus particles. Most particles are 20 to 25 nm in diameter and consist of both spheres and tubules. A larger, 42-nm Dane particle also is present (arrowhead) . Hepatitis B surface antigen determinants are present on the surface of all three forms.

Acute hepatitis B is diagnosed serologically by the presence of HBsAg and hepatitis B core antibody (HBcAb), which can identify infected patients in the window period. HBV DNA also may be detected and quantified in serum by PCR during acute hepatitis. Individuals with HBeAg in their serum are highly infectious. Diagnosis of chronic HBV requires a combination of persistent clinical symptoms and laboratory abnormalities and persistence of HBsAg and/or HBV DNA for at least 6 months. Primary hepatocellular carcinoma also is a long-term complication of HBV infection. Successful resolution of infection with HBV is marked serologically by the presence of antibody to HBsAg, known as hepatitis B surface antibody (HBsAb). For children with chronic HBV, the decision to treat is largely based on ALT level, HBV viral load, and liver histology. Treatment of children is still controversial and should be considered for children with persistently elevated ALT levels for at least 6 months (12 months if HBeAg negative) in order to avoid treating patients who are undergoing spontaneous HBeAg seroconversion. First-line therapy remains interferon-α in children with immune active chronic HBV. In cases where interferon-α is not recommended, or in compensated or decompensated cirrhosis, treatment with nucleos(t)ide analogues such as entecavir for children older than 2 years of age or tenofovir for children older than 12 years of age is recommended. Liver transplantation has been attempted in patients with end-stage HBV-associated cirrhosis, with variable results. Prevention is achieved by passive immunization with hepatitis B immune globulin (HBIG) in the delivery room and active immunization with licensed recombinant vaccines. Pregnant women with chronic hepatitis B should have their HBV viral load and HBeAg status determined to assess their risk for vertical transmission. All infants born to infected women should receive hepatitis B immunoglobulin (HBIG) at delivery and a vaccination within 12 hours of birth. The standard of care for prophylaxis of HBV vertical transmission is evolving, with tenofovir or telbivudine administration to mothers having HBV DNA with more than 10 ⁵ copies continuing during pregnancy through the postpartum period to suppress HBV viremia.

Hepatitis C virus.

HCV (see Chapter 177 ) is a single-stranded positive-sense RNA virus in the genus Hepacivirus, family Flaviviridae. At least six distinct genotypes and 100 subtypes have been identified throughout the world and appear to have a variable effect on the development of clinical disease and response to antiviral therapy. It is transmitted most commonly to children and adolescents who have been exposed to blood products, clotting factor concentrates before 1987, hemodialysis, organ transplantation, intravenous drug use, cocaine snorting, or tattoos and piercing procedures performed at parlors that do not practice sterile technique. Perinatal transmission from an HCV-seropositive mother to her infant also occurs at an estimated risk of 5%, especially if the mother is HCV RNA positive at delivery. Infection with HCV usually does not cause acute hepatitis; however, chronic hepatitis develops in more than 50% of children infected with HCV. In adults, cirrhosis, end-stage liver failure, and hepatocellular carcinoma also may develop. Infection with HCV is diagnosed serologically by detecting the presence of HCV antibody and confirming with HCV RNA quantification by PCR. Peginterferon-α2b (PegIntron) plus ribavirin is still the only US Food and Drug Administration (FDA)-approved therapy for children age 3 to 12 years with HCV. Achieving a sustained virologic response (SVR), defined as being HCV RNA negative 6 months after discontinuation of treatment, is the standard of care. The rates of achieving SVR with treatment in children with genotypes 2 and 3 are much higher (75–80%) than in genotype 1 (35–40%). Treatment response, and even spontaneous clearance without treatment, seems to be strongly influenced by a genetic polymorphism near the IL28B gene. More recently approved directly acting antiviral therapies for adults are being tested in children through currently ongoing clinical trials. In 2017, the FDA approved two all-oral drugs, sofosbuvir alone and combined sofosbuvir/ledipasvir, for treatment of children age 12 to 17 years. With this new therapy, SVR is defined as being HCV RNA negative 12 weeks (3 months) after discontinuation of therapy. Liver transplantation may be performed in patients with end-stage liver disease. Currently no biologic products or vaccines are licensed for prevention of infection with HCV. The hypermutation rate of HCV has hindered the development of such products because a vaccine that is protective across multiple genotypes will be necessary for global protection.

Hepatitis D virus.

HDV (see Chapter 157 ), also known as the delta agent, delta virus, helper virus, and defective virus, is a small, 37-nm RNA virus that requires the presence of HBV, especially HBsAg, to replicate. HDV can coinfect a patient simultaneously or subsequent to infection with HBV. Like HBV, HDV is acquired by exposure to blood products or clotting factors, intravenous drug use, or sexual contact. It also may be transmitted by liver transplantation, and vertical transmission has been reported. Infection with HDV occurs more commonly in Europe, South America, Africa, and the Middle East and appears to be less common in the United States. The incubation period after superinfection occurs is 1 to 2 months, but it is similar to that for HBV (90 days) if coinfection occurs simultaneously. Coinfection with HDV is associated with more severe disease or progression to fulminant hepatitis in HBV-infected patients. Laboratory diagnosis includes detection of HDV antibody (IgG, IgM) and HDV RNA by PCR, although this is not commercially available. Treatment with peginterferon-α2b results in sustained HDV clearance in about one-fourth of patients. Because HDV cannot be transmitted to or infect humans without HBV, prevention of HBV infection by vaccination prevents the acquisition of HDV infection. HDV coinfection of individuals already infected with HBV, however, cannot be prevented by any licensed biologic product or vaccine.

Hepatitis E virus.

HEV (see Chapter 170 ) is a small RNA virus that is transmitted by the fecal-oral route. HEV infection in U.S. residents is a rare occurrence, but it may be a common cause of acute, self-limited viral hepatitis in developing countries and has been linked to outbreaks associated with contaminated water supplies and/or breakdowns in public health during times of conflict. The incubation period is an average of 6 to 7 weeks. HEV appears to cause a mild to moderate acute hepatitis, especially in adults, and has a high case-fatality rate in pregnant women. Chronic hepatitis is only seen in immunosuppressed patients. Laboratory diagnosis is established by detection of IgG and IgM antibody to HEV in serum or detection of HEV RNA by PCR in serum or feces performed in reference laboratories or at the Centers for Disease Control and Prevention (CDC). No antiviral agent is licensed for HEV, although ribavirin has been shown to achieve a sustained virologic response. A vaccine against HEV is licensed for use in China and has demonstrated significant protection that is durable and safe in pregnant women.

Herpes simplex virus.

HSV-1 and HSV-2 most often cause mucocutaneous vesicles or ulcers, and dissemination usually occurs during periods of relative immune compromise, such as pregnancy, the neonatal period, malnutrition, congenital or acquired immunodeficiency syndromes, or organ transplantation. Transient, subclinical hepatitis may occur during acute mucocutaneous HSV disease, but fulminant hepatitis with hepatic necrosis rarely has been documented in a normal host. A special exception to this observation is HSV-associated primary hepatic necrosis and disseminated HSV disease in pregnant women. Most cases occur during the late second or early third trimester, and most, but not all, cases are associated with primary infection with HSV-2. Obvious skin lesions may not be present. This disease is associated with high mortality rates in both the mother and infant. Neonates, both term and preterm, are at risk for the development of neonatal HSV hepatitis as part of a disseminated HSV disease that includes viral sepsis–like syndrome, coagulopathy, abdominal distention with hepatomegaly and ascites, pneumonitis with respiratory distress, and meningoencephalitis. Skin lesions often are absent in this form of HSV disease. Neonatal HSV hepatitis develops most often in the child’s first 2 weeks of life, and aminotransferase levels may initially be slightly elevated and then rise to be more than a thousand times higher than normal as disease progresses. Recipients of solid organ, bone marrow, and stem cell transplants may have HSV infection with dissemination within the first 3 weeks after undergoing transplantation, most often as a result of reactivation. Patients with hepatitis secondary to HSV infection may be shedding HSV from a mucocutaneous source or may be viremic, with virus detected in the blood by DNA PCR. Some patients may require analysis of ascites fluid or liver biopsy for confirmation. Acyclovir therapy is recommended for HSV-associated hepatitis, in preventing posttransplant HSV disease, and in preventing HSV infection of neonates born to HSV-infected mothers. Children with HSV fulminant hepatitis have significantly better survival rates than adults before and after liver transplantation.

Varicella-zoster virus.

Varicella-zoster virus also causes mucocutaneous vesicles in both immunocompetent and immunocompromised hosts. Primary infection is known as varicella (also chickenpox) and is associated with primary and secondary viremias that often seed the visceral organs. Approximately one-fourth of healthy children experiencing varicella will have silent hepatitis with aminotransferase levels at least twice normal. Fulminant hepatitis with varicella is rare and generally is seen in immunocompromised hosts. Patients have severe abdominal pain with little nausea or vomiting, skin lesions may or may not be present, and aminotransferase levels may be more than a thousand times higher than normal. Zoster in a normal host is not associated with fulminant hepatitis, but immunocompromised hosts may experience disseminated zoster with hepatitis and hepatic necrosis. The diagnosis often is based on clinical findings, but direct PCR testing of cutaneous lesions or blood may help establish the diagnosis. Treatment with acyclovir is recommended. Varicella may be prevented or attenuated by passive immunization with varicella-zoster immune globulin or intravenous immunoglobulin (IVIG) or by active immunization with a licensed live virus vaccine.

Cytomegalovirus.

CMV infection usually is asymptomatic but can cause gastroenteritis, pneumonitis, or a mononucleosis-like syndrome that consists of fever, lymphadenopathy, and atypical lymphocytosis. Hepatitis occurs as part of these syndromes but often is silent or mild and rarely is accompanied by jaundice. Granulomatous hepatitis also may be associated with CMV. Infants born congenitally infected with CMV frequently have hepatosplenomegaly, elevated aminotransferase levels, and conjugated hyperbilirubinemia. The hepatitis that neonates and infants experience with postnatal infection is self-limited and generally resolves within the first few months of life. If hepatitis with cholestasis persists, other diseases such as extrahepatic biliary atresia should be considered. Solid organ and marrow transplant recipients and patients with acquired immunodeficiency syndrome (AIDS) and other immunodeficiency states may experience persistent fever, malaise, leukopenia, and hepatitis caused by primary or recurrent infection with CMV. Severe liver disease can occur in transplant recipients and may be associated with graft-versus-host disease or graft rejection. CMV-associated hepatitis may be diagnosed clinically and supported by evidence of high-level CMV viremia and/or demonstration of involvement of the end organ by liver biopsy. Treatment with ganciclovir, valganciclovir, foscarnet, or cidofovir appears to be beneficial in immunocompromised hosts, and prophylaxis or preemptive therapy with antiviral agents or CMV hyperimmune globulin may prevent the development of severe CMV disease in transplant recipients.

Epstein-Barr virus.

EBV infection can be asymptomatic but is a frequent cause of a mononucleosis-like syndrome with mild hepatitis. However, in rare patients with a genetic X-linked predisposition, a severe, often fatal lymphoproliferative syndrome with prominent liver involvement may develop. Transplant recipients also may be susceptible to posttransplant lymphoproliferative disease (PTLD), in which the liver may be involved. In addition, patients with tumors associated with EBV, such as lymphoma, may have hepatic involvement. The diagnosis of mononucleosis usually is clinical and supported by a positive heterophile or “Monospot” test in a child older than 4 years or by specific EBV serologic tests such as detection of IgM antibody to viral capsid antigen (VCA). PCR testing for EBV should not be used in the diagnosis of acute mononucleosis. The immune response to EBV in immunocompromised hosts may be unusual, and the diagnosis of PTLD generally is suspected by an exponential increase in EBV DNA genome copies in peripheral blood, generalized adenopathy, visualization by positron emission tomography, and the presence of histopathologic features on biopsy. Treatment options for PTLD include reducing immunosuppression, rituximab (anti-CD20 monoclonal antibody), adoptive immunotherapy, interferon-α, and anti–interleukin-6 antibody. Antiviral agents such as acyclovir or foscarnet should be used only as an adjunct therapy because they are less effective in the latent phase of PTLD.

Human herpesviruses 6, 7, and 8.

These viruses may involve the liver, especially in immunocompromised patients. Infection with HHV-6 in recipients of liver transplants is usually a result of reactivation and has been associated with acute rejection, portal lymphocyte infiltration, and graft dysfunction. Even though HHV-6 commonly can be detected in blood and tissue, high viral loads have been associated with decreased graft survival. Normal hosts with primary HHV-6 infection may have a silent hepatitis with mild elevation of aminotransferase levels. Rarely severe disseminated disease with fulminant hepatitis has been linked to HHV-6 and HHV-7. HHV-8 (also known as Kaposi sarcoma virus ) causes a complex neoplasm involving the skin, mucous membranes, and internal organs, most often in severely immunocompromised patients. Although rare, it has been reported in human immunodeficiency virus (HIV)-infected children with advanced AIDS. Recipients of solid organ transplants may be infected with HHV-8. The liver is a common site of visceral disease caused by HHV-8, which most often is associated with tumors rather than hepatitis. Diagnosing infection with HHV-6, HHV-7, or HHV-8 is difficult because of the ubiquity of these viruses and their viral DNA in humans, but the diagnosis is supported by serologic evidence and by detection of viral DNA in blood, in secretions, or, more specifically, in tissue. No specific licensed antiviral therapy is available, but these viruses may be inhibited by ganciclovir, foscarnet, and cidofovir. Response also may be noted after withdrawal or reduction of immunosuppression. Chemotherapy may be indicated in some cases of HHV-8.

Herpes B virus.

Also known as herpesvirus simiae or Cercopithecine herpesvirus 1, herpes B virus is an α-herpesvirus of monkeys that causes severe disease in humans. It can be transmitted from Asian monkeys, such as rhesus and cynomolgus monkeys, to humans through bites or contact with mucous membrane secretions from infected monkeys. The human disease associated with herpes B virus involves skin vesicles at the portal of entry, regional lymphadenitis, and hemorrhagic encephalitis. The virus also may disseminate to the liver and lungs and produce hemorrhagic necrosis, with a high mortality rate. The diagnosis is made by isolation of virus or detection of viral DNA by PCR in specialized reference laboratories, and the virus is inhibited by acyclovir and ganciclovir.