A Clinical guide to pediatric infectious disease

5

Hepatitis

Basic Considerations

The term hepatitis refers to any inflammation of the liver.

Although there are many causes of hepatitis in childhood, including toxins and metabolic processes, the most common cause is viral infection. The purpose of this chapter is to review the common viruses that cause hepatitis in childhood and discuss appropriate methods of diagnosis.

Hepatitis A

Epidemiology and Etiology

Hepatitis A is the most common viral etiology of pediatric hepatitis. The mode of transmission is person to person, resulting from fecal contamination of food. Sexual contact and nosocomial transmission have also been documented.

Presentation

Hepatitis A is an RNA virus that usually causes a self-limited illness associated with fever, jaundice, and anorexia. In children younger than 5 years of age, cases are often anicteric and frequently misdiagnosed as gastroenteritis. Rarely, hepatitis A leads to a fulminant disease, which can be fatal. Chronic infection does not occur, although prolonged disease causing relapsing jaundice has been described.

Diagnosis

The diagnosis of hepatitis A is made by serology. Serum immunoglobulin M (IgM) to hepatitis A is usually present at the onset of illness. The presence of hepatitis A IgG without IgM indicates past infection and immunity.

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Management

Currently, there is no specific therapy for hepatitis infection. Treatment is supportive.

Hepatitis A: Major Issues

·         Oral–fecal transmission

·         Often anicteric in young children

·         Diagnosis by hepatitis A IgM

·         No chronic carrier state

Hepatitis B

Epidemiology and Etiology

Hepatitis B is transmitted through blood or body fluids. Transmission by the shared use of nonsterile needles or sexual contact is common in adults.

In the practice of pediatrics, hepatitis B is often transmitted from mothers with chronic infection to their infants at the time of delivery.

Presentation

A wide spectrum of clinical presentations is possible, ranging from nonspecific symptoms of gastroenteritis to fulminant fatal hepatitis.

Diagnosis

There is often considerable confusion regarding the interpretation of hepatitis B serology. The hepatitis B virus (HBV), termed the Dane particle, is divided into two basic components: the surface and the core. The core itself has two parts: the core antigen and the e antigen. The presence of high levels of hepatitis B e antigen is correlated with increased levels of circulating levels of HBV DNA and is thought to be a marker for disease activity. Patients who develop antibodies to the hepatitis B e antigen often have a reduction in circulating levels of HBV DNA and improvements in their serum aminotransferase levels. During hepatitis B infection, all persons make antibodies to the core antigen. Subsequent production of antibodies to the surface antigen confers immunity. Failure to produce surface antibodies results in the patient being chronically hepatitis B surface antigen positive; the patient is then diagnosed as a chronic carrier of hepatitis B. The diagnosis of acute or recent hepatitis B infection

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therefore rests on the presence of IgM antibody to the core antigen because this is the antibody response that all patients will make regardless of their ultimate carrier status.

Failure to make hepatitis B surface antibody and development of chronic hepatitis B status are related to the age at the time of infection. Perinatally infected children have a 90% chance of developing chronic infection; children who acquire their infection at 1 through 5 years of age have a 20% to 50% chance of developing chronic infection.

Chronic Infection

Chronic hepatitis B infection progresses to cirrhosis in 15% to 20% of cases. Chronic hepatitis B is also associated with a higher incidence of hepatocellular carcinoma. Protocols in adults suggest that chronic carriers of hepatitis B should be screened yearly for hepatocellular carcinoma using ultrasound examinations and serum α-fetoprotein assays.

Prognosis of chronic hepatitis B infection is based on a variety of factors, including alcohol consumption, prolonged replicative phase, persistent e antigen, and the clearance of hepatitis B surface antigen. Various genotypes of hepatitis B may have an increased likelihood of progressing to chronic disease. Ongoing viral replication and inflammation are thought ultimately to increase the incidence of cirrhosis and hepatocellular carcinoma in patients with chronic hepatitis B infection. The goal of therapy is thus suppression of ongoing viral replication and prevention of these end-stage conditions.

Treatment of Chronic Infection

There has been great interest in identifying patients with chronic infection who will possibly benefit from preemptive therapy. A National Institutes of Health Consensus Workshop on the management of hepatitis B recommended that treatment be considered in patients who are hepatitis B surface antigen positive with an accompanying a viral load of greater than 105/mL. This number is somewhat arbitrary; the precise DNA level associated with progressive disease is not known. Aminotransferase levels have been shown to be the best noninvasive marker for the presence of chronic active hepatitis, although up to 40% of patients with histologically confirmed chronic active hepatitis have normal aminotransferase levels. Many specialists consider liver biopsy the best method to determine the need for therapy.

Response to therapy is usually defined as undetectable HBV DNA, loss of hepatitis B antigen, and improvement in liver disease as determined by normalization of aminotransferase levels or by biopsy.

Currently, there are two drugs used for the treatment of hepatitis B infection. Interferon-α has been shown to suppress HBV replication in 30% of adults as compared with 10% of controls. The dose for children is 6 million units/m2 three times weekly, with a maximum of 10 million units. The recommended duration of treatment is 24 weeks for patients who are hepatitis e antigen positive. Long-term follow-up in adults has suggested that the 5-year cumulative rate of hepatitis B e

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antigen clearance is similar in untreated patients. The main role of interferon-α may be to hasten viral clearance and thus reduce duration of active liver disease. Patients with high pretreatment aminotransferase levels and low baseline HBV DNA levels appear to have the best response to interferon.

Lamivudine is a nucleotide analog that is frequently used in the treatment of human immunodeficiency virus (HIV) infection. There is increasing use of this drug in patients with chronic hepatitis B infection. Treatment with 3 mg/kg per day (up to 100 mg/day) leads to a significantly higher proportion of children losing hepatitis B e antigen as compared with controls. A major concern in treatment of hepatitis B with lamivudine is the development of the YMDD mutation (thyroxine [y], methionine [m], aspartate [D], and aspartate [D]). These mutations replicate less efficiently than wild-type strains; the long-term implications of the development of these resistant strains are not clear.

Hepatitis B: Treatment

1.   Consider treatment in patients with a hepatitis B viral load > 105/mL, persistently abnormal aminotransferase levels, or inflammation on liver biopsy.

2.   Treatment options include lamivudine, 3 mg/kg per day (maximum, 100 mg/day), or interferon-α, 6 million units/m2 three times weekly (maximum, 10 million units).

Guidelines for Adoption

As international adoption becomes more common, there will be an increasing number of hepatitis B surface antigen–positive children residing in the United States. The primary mode of transmission is blood and body secretions; household and day care transmission of hepatitis B is rare. Parents and caretakers should be instructed regarding the following:

  • Use thick disposable towels to attend to any bleeding wounds.
  • Household items, such as toothbrushes and nail clippers, should not be shared.
  • Household contacts should all receive the standard hepatitis B vaccination so that they are protected.

Hepatitis B: Major Issues

·         Blood or body fluid transmission

·         Diagnosis of acute infection: IgM to hepatitis B core antigen

·         Persistence of hepatitis B surface antigen denotes chronic infection.

·         Chronic infection is associated with cirrhosis (15% to 20%) and hepatocellular carcinoma.

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Hepatitis C

Epidemiology and Etiology

Hepatitis C virus is transmitted in similar fashion to hepatitis B, through exposure to blood and blood products.

Sexual transmission and transmission among family contacts are rare.

Between 2% and 4% of women of childbearing age are antibody positive for hepatitis C. The vertical transmission rate has been reported to be about 5%, although this increases if the mother is also HIV positive. Most studies have not shown a role in transmission based on the method of delivery. Mothers who are infected with hepatitis C virus may breast-feed their children because transmission through breast milk has not been proved. Transmission from a single needle-stick accident is about 1%.

Hepatitis C: Genotypes

Hepatitis C exists with numerous subtypes, labeled genotypes. There are six major genotypes that vary in worldwide distribution and have significance in regard to patient management.
Genotypes 1A and 1B are the most common variants seen in the United States, accounting for more than 75% of all infections. Genotype 2 is more common in the Far East, whereas genotype 3 is frequently seen on the Indian subcontinent. Hepatitis C genotype does not appear to affect the rate of progression, although it is a predictor of a response to therapy. Patients with genotype 2 or 3 are more likely to respond to therapy; those with genotypes 1 and 4 are less likely to respond.

Presentation

The clinical presentation of hepatitis C infection is similar to that of hepatitis A or B: acute disease is often mild and maybe asymptomatic. Only 20% of patients with acute infection become jaundiced.

Diagnosis

Most acute hepatitis C infections are associated with few or no symptoms, making clinical diagnosis difficult. The two available antibody assays are the enzyme immunoassay (EIA) and recombinant immunoblot assay (RIBA). These assays are

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greater than 95% sensitive and specific, although they can be falsely negative early in disease onset. Viral load or polymerase chain reaction (PCR) assays, similar to those used in detecting HIV, have been developed for hepatitis C. Hepatitis C virus can be detected within 1 to 2 weeks after exposure and weeks before abnormalities in liver enzyme tests are seen.

Hepatitis C antibodies cross the placenta and cannot be used for diagnosis in the neonatal period. The evaluation of the hepatitis C–exposed infant is a hepatitis C PCR at 6 to 8 weeks and again at 6 months of age. Because of the persistence of maternal antibodies in exposed infants, evaluation for hepatitis C antibodies should not be performed until the patient is 1 year of age.

Chronic Infection

Like hepatitis B, hepatitis C infection is associated with a chronic state. The chronic infection is defined by detection of hepatitis C virus by PCR in the blood 6 months after infection. About 60% to 85% of patients infected with hepatitis C develop a chronic infection. The proportion of chronically infected patients who develop the sequelae of hepatitis C is not known. Estimates of 2% to 4% of infected children progressing to cirrhosis and hepatocellular carcinoma have been made. Although viral genotype and baseline viral load do not appear to influence the risk for progression, host factors, including older age at time of infection, alcohol consumption, and coinfection with HIV, may play a role.

Treatment of Chronic Infection

There are evolving treatment options for patients with chronic hepatitis C infection. Because many patients with infection do not have progressive disease, there is great interest in defining patients who will most benefit from therapy. Liver enzymes have shown little value in predicting the degree of fibrosis or cirrhosis in a particular patient. Although hepatitis C RNA (viral load) levels are available by PCR, the situation differs from HIV. In the latter, the viral load is a major factor determining progression of disease and is often involved in the decision to initiate treatment. In the case of hepatitis C, viral load levels do not correlate with either the grade or stage of disease on liver biopsy. There are no currently available noninvasive tests that can reliably predict the level of inflammation or fibrosis of hepatitis C.

The decision to initiate treatment at the present time is usually guided by liver biopsy. Liver biopsy results are evaluated in terms of grade and stage. The grade refers to the level of inflammatory activity and is a measure of ongoing disease. The stage of the liver biopsy refers to the degree of fibrosis and is a measure of disease progression. Patients who have a certain grade of inflammation or fibrosis become candidates for treatment.

Pegylated interferon plus oral ribavirin is currently the standard treatment of hepatitis C. Effective treatment, or sustained viral response (SVR), is defined as the absence

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of detectable hepatitis C RNA 24 weeks after the end of therapy. Early viral response (EVR) is defined as a minimum 2-log decrease in the viral load during the first 12 weeks of treatment. This is considered highly predictive of SVR. Patients who fail to achieve EVR at week 12 have only a small chance of achieving an SVR, and treatment is often not extended beyond 12 weeks in these patients.

Hepatitis C: Major Issues

·         Blood, body fluid transmission

·         Acute infection diagnosed by enzyme-linked immunosorbent assay (ELISA) and PCR

·         Chronic infection in 60%, associated with cirrhosis, hepatocellular carcinoma

Epstein-Barr Virus

Epidemiology and Etiology

It is estimated that more than one half of people in the United States will develop Epstein-Barr virus (EBV) infection before the age of 21 years.

EBV is a ubiquitous virus that is frequently the cause of infectious mononucleosis.

Presentation

Adolescents and young adults with infectious mononucleosis typically have fever, severe pharyngitis, rash, and mild to moderate hepatitis. Patients with underlying immunodeficiencies can present with a wider spectrum of disease, including disseminated disease and lymphoproliferative disorders.

Epstein-Barr Virus: Diagnosis

1.   VCA is first antibody to appear. IgM antibody lasts about 4 weeks.

2.   Early antigen (EA) is the second antibody class to appear. EA is usually detectable several months after acute infection.

3.   Nuclear antigen (EBNA) appears during recovery and indicates old infection.

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Diagnosis

The diagnosis of EBV is also subject to considerable confusion. The monospot test is frequently used to screen for EBV infection. However, children younger than 5 years of age often do not produce the heterophile antibodies measured by this test. EBV-specific serology is often indicated, although interpretation can be difficult.

Acute EBV infection

Recent EBV infection

Past EBV infection

+IgM, VCA

–IgM, VCA

–IgM, VCA

–IgG, VCA

+IgG, VCA

+IgG, VCA

+EA

+EA

–EA

–EBNA

–EBNA

+EBNA

A variety of antigens have been identified in EBV. The presence of IgM and IgG antibodies to specific antigens is used to diagnose acute or past EBV infection. Viral capsid (VCA) antigens are detected in cells undergoing active EBV infection. Anticapsid antibodies appear at the onset of acute infection and persist for life. IgM to viral capsid antigens is the hallmark of acute EBV infection. Early antigens (EA) are a group of proteins that become positive later in acute infection. EBV nuclear antigen (EBNA) antibodies appear during convalescence and persist for life; anti-EBNA titers indicate old EBV infection.

Management

Treatment is generally supportive. Patients with extreme tonsillar hypertrophy who are at risk for airway obstruction can be treated with a brief of course of prednisone, usually 1 mg/kg per day for 5 to 7 days. Because of the potential risk for splenic rupture, contact sports such as martial arts or football should be avoided until the patient has recovered.

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Cytomegalovirus

Epidemiology

Cytomegalovirus (CMV) is a DNA virus that is also ubiquitous and transmitted person to person and through body fluids such as blood, breast milk, and urine.

Presentation

CMV is another herpesvirus infection that causes a variety of clinical syndromes, the most common being an infectious mononucleosis-like syndrome with prolonged fever and hepatitis. The disease is usually self-limited in immunocompetent individuals, although severe illness can be seen in oncology patients, organ transplant recipients, and patients infected with HIV.

Diagnosis

The diagnosis of acute CMV infection can be complex; diagnosis is difficult because of the large number of asymptomatic persons shedding the virus at any given time. IgM antibody is produced with primary infection, yet can also be produced with reactivated infections. PCR technology can be used, although typically this test is used only in patients with underlying immunodeficiencies. In an immunocompetent patient with a mononucleosis-like syndrome and negative studies for EBV, the diagnosis of CMV is often presumed.

Management

In the immunocompetent patient, care is usually supportive. In certain patient populations such as organ transplant recipients and patients with HIV infection, antiviral therapy with ganciclovir is given.

Selected Readings

Conjeevaram HS, Lok AS. Management of chronic hepatitis B. J Hepatol 2003;38[Suppl 1]:S90–103.

Lee WM. Hepatitis B virus infection. N Engl J Med 1997;337(24):1733–1745.

Lai CL, Dienstag J, Schiff E, et al. Prevalence and clinical correlates of YMDD variants during lamivudine therapy for patients with chronic hepatitis B. Clin Infect Dis 2003;36(6):687–696.

Seef CB, Hoofnagle JH. Appendix: National Institute of Health Consensus Development Conference. Management of hepatitis C. Clin Liver Dis 2003;7(1):261–287.