Acute and chronic hepatitis: Working Group Report of the First World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition.

Abstract

HEPATITIS A VACCINE Background Hepatitis A virus (HAV) has traditionally been responsible for mini-epidemics, particularly in areas of poor hygiene and high population density. To decrease the rate of infection, we need to understand the routes of transmission so that targeted, effective vaccination programs can be implemented. Children serve as a source of HAV for adults; specifically, child care center exposure seems to play a role in sporadic as well as in “minor epidemics” of HAV. Because a highly effective vaccine was introduced in 1997, an important research priority is to delineate the impact of this vaccine on the incidence, morbidity, and mortality of HAV infection in children in the postvaccine era and to determine the cost-effectiveness of implementation strategies, such as universal early childhood vaccination. In addition, the vaccine has been recommended for children with liver disease of any type; however, the efficacy of the vaccine in this population has not been investigated. Finally, because HAV may be particularly severe in children with immunodeficiency disorders and may serve as a trigger of autoimmune liver disease in predisposed individuals, an important area for research is to investigate basic mechanisms of viral pathogenesis and the role of host defense. I. Summary of the Problem Rates of Hepatitis A Infection Remain High Both in Developed As Well As in Developing Countries: Standard preventive measures, such as good personal hygiene and immune globulin (IG) administration to exposed persons, have had limited impact on the overall disease burden of hepatitis A. Induction of active immunity against HAV is a possible solution; vaccination offers the long-term benefit of a reduction in the ultimate costs of medical care for chronically infected individuals with liver disease and their contacts. Similarities between the epidemiology of hepatitis A and poliovirus suggest that widespread vaccination of appropriate susceptible population can substantially lower disease incidence, eliminate virus transmission, and ultimately eradicate HAV. Rationale for Prevention of HAV through Active Immunization: Reduction in the incidence of HAV infection will be achieved by producing high levels of immunity in persons in age-groups that have the highest rates of HAV infection and that serve as a reservoir of infection. Producing a highly immune population decreases the incidence of hepatitis A and presumably decreases virus circulation by preventing fecal shredding of HAV. Hepatitis A immunization is likely to substantially lower disease incidence because HAV does not produce a chronic infection, and humans are the only natural reservoir of the virus. Potential (Recommended) Use of Hepatitis A Vaccine: Decisions on how to use hepatitis A vaccine have been based on the epidemiology of the disease; yet many persons with hepatitis A do not identify a risk factor. Major pediatric indications for vaccine are travellers to areas with intermediate to high rates of endemic hepatitis A, children living in defined and circumscribed communities with high endemic rates of periodic outbreaks of HAV infection, and patients with chronic liver disease. Because of their critical role in HAV transmission, children should be a primary focus of immunization strategies to lower disease incidence. The most effective means of achieving control of HAV infection would be to include routing hepatitis A vaccination in the childhood vaccination schedule. The problem, of course, is that there are no data regarding efficacy and cost-effectiveness. II. Major Issues in Need of Investigation • What Is the Epidemiology of HAV (Worldwide) in the Post-vaccine Era? • What Is the Long-term Protection of Hepatitis A Vaccine? Estimates of antibody persistence derived from kinetic models indicate that protective levels of anti-HAV could be present for years. Whether other mechanisms (e.g., cellular memory) also contribute to long-term protection is unknown. “The long-term protective efficacy needs to be determined before recommendations can be made concerning the possible need for booster doses.” • What About Immunization of Infants (e.g., in a universal program)? IG is still recommended for protection from hepatitis A in children younger than 2 years, because residual anti-HAV passively acquired from the mother may interfere with vaccine immunogenicity. Limited data indicate that in seronegative infants, an inactivated HAV vaccine achieves very high seroconversion rates and elicits high antibody concentrations. • What About Routine Childhood Vaccination Against Hepatitis A? AAP and ACIP endorsed vaccination of children living in geographically/ethnically well-defined areas with high rates of HAV infection as well as children in communities where there is an outbreak. Even if this strategy of vaccination is successful, the overall effect will be minimal, because high-risk groups constitute a minority of all those infected. Use of HAV vaccine during community-wide or common-source outbreaks is constrained by logistic difficulties that inevitably lead to delays in implementation. The efficacy of HAV vaccine as postexposure prophylaxis is also under study • What Is the Efficacy of the HAV Vaccine in Children with Liver Disease, Particularly Chronic HCV Infection? III. Proposed Plan to Achieve Goals Determine the Cost-effectiveness and Efficacy of Routine Hepatitis A Immunization “Routine vaccination of children against hepatitis A infection in the 15 states with the highest numbers of infected people could eliminate 75% of all hepatitis A in the U.S.”—Dr. Harold Margolis Several countries and at least 11 states require hepatitis A vaccine for day care or school entry. Universal early-childhood immunization should be implemented immediately, along with catch-up vaccination for school-age children; this would lead to a dramatic reduction in the incidence of HAV infection within a decade. “Failure to begin such a program represents a missed opportunity” (Koff RS: NEJM 340:644–645, 1999). • Develop a Strategy for Developing Countries in Which Hepatitis A Is Hyperendemic Mass immunization of very young children; incorporate hepatitis A vaccine into expanded program of immunization globally. Improvements in water supplies and sanitary standards are the keys to future control of infection Major obstacles include vaccine cost, absence of health-care infrastructure for vaccine delivery, and competing health-care problems • Determine the Cost-effectiveness and Efficacy of Hepatitis A Immunization in Children with Chronic Liver Diseases (such as Chronic HCV, chronic cholestasis, and metabolic liver disease) • Investigate the Unique Basic Mechanisms of Hepatitis A Viral Pathogenesis: The Role of Host Defense in Children This is of particular interest because HAV may be severe in children with immunodeficiency disorders and may serve as a trigger of autoimmune liver disease in predisposed individuals. HEPATITIS B Background Hepatitis B virus (HBV) infection, a public health problem worldwide, is associated with a risk of cirrhosis and hepatocellular carcinoma (HCC). With the implementation of widespread HBV vaccination in many countries, the prevalence of HBV infection and the rate of HCC have been reduced. For example, in Taiwan, where a nationwide hepatitis B vaccination program was implemented in July 1984, the average annual incidence of HCC in children has been reduced from 0.70 per 100,000 children in 1981 to 0.36 in 1994. The main approaches to immunization against hepatitis B are vaccination of high-risk babies, universal infant immunization, and universal adolescent immunization. However, there are barriers to implementation of vaccination strategies. Because the traditional major route of infection is through maternal–infant transmission, antenatal screening theoretically would permit identification of carrier mothers and immunization of their children; however, implementation is not universal, for various reasons. Although universal vaccination of all infants is the best option, implementation has been hampered by several factors. Development of low-cost combination (e.g., hepatitis B-diphtheria-pertussis-tetanus) vaccines would be beneficial. Vaccination of adolescents would provide protection close to the time when risk of exposure increases, and could be delivered as part of a wider package on health education. For those children already infected, the major problem is a lack of reliable antiviral strategies; this is due to a combination of a poor understanding of the mechanism of persistence of HBV infection in children infected at birth and an absence of controlled trials of established and novel antiviral drugs. It is presumed that the pathogenesis of HBV in the child with normal immunity is via antigen presentation and subsequent T-cell–mediated hepatocytolysis. Little is known about the pathogenesis of HBV in the child with immune defenses altered by HIV, congenital immune deficiency, or administration of immunosuppressive agents in children after organ transplantation. A major priority for HBV research is the development of safe and effective antiviral therapies. Alpha-interferon (IFN) is the only effective therapy for children with chronic hepatitis B. In most controlled studies, performed in white children, IFN therapy achieves clearance of HBV-DNA and hepatitis B e antigen (HbeAg) in 30% to 50% of treated patients. Although this treatment is fairly well tolerated, better therapies are needed for higher rates of viral eradication. Furthermore, the long-term impact of this therapy in those children who exhibited an initial response needs to be clarified. Clearly more effective therapies for chronic HBV in children need to be defined by well-designed, large scale, placebo-controlled multi-center trials, and for each therapy tested there is a need to identify factors predicting response. Candidate drugs include lamivudine, famcyclovir, pegylated interferon, lobucavir, and adepovir. Novel strategies, such as immunization of chronically infected children with adjuvant vaccines, should be also be tested. I. Summary of the Problem There are major obstacles to the implementation of HBV vaccination programs; therefore, rates of HBV infection remain high in certain world populations. This is a particularly true for Asia, Romania, and Russia. There are high rates of undiagnosed infection in international adoptees from those countries and in inner city adolescent populations, particularly in users of intravenous drugs. Universal vaccination has accelerated an accumulation of HBsAg determinant mutants with amino acid changes critical for immune escape in vaccinated subjects who became infected. A significantly higher frequency of HBV mutants has been found in HCC tissue than in the corresponding nontumorous tissue of the same patients. The accumulation of these envelope mutants in the HCC tissue suggests that such envelope protein mutations may play a role in the process of oncogenesis and that specific vaccines may need to be developed to prevent the occurrence of mutant HBV-associated HCC. A safe and effective therapy for children with chronic hepatitis B is lacking. Antiviral treatments, most notably interferon alpha, probably modify the natural history of hepatitis B, decreasing the risk of HCC and increasing survival. However, studies with longer period of observation are needed in children. As far as nucleoside analogues are concerned, the efficacy of this treatment should be weighed against the increasing risk over time of mutation development in the YMDD region of the DNA polymerase reverse transcriptase. II. Major Issues in Need of Investigation Investigation of optimum means of advocating for universal immunization Investigation of new vaccines against hepatitis B virus (HBV) infection. Vaccines containing the small(s), middle (Pre S2) and large (Pre S1) surface proteins of HBV may achieve better response rates and prevent infection with HBV mutants in vaccinees. Development of safe and effective antiviral therapies for children with HBV infection. Determine the optimum means of monitoring the side effect of interferon and of nucleoside analogs such as lamivudine. Define the determinants of HCC in children with HBV. Develop optimum strategies for management of HBV infection after liver transplantation and for HCC. III. Proposed Plan to Achieve Goals Develop new strategies to improve vaccine efficacy and delivery. Use of new vaccines to improve immunogenicity (from 95% to 100%) to protect against mutants. Organize an HBV working group—to work with international health organizations to promote universal immunization and promote standards for international adoptees, which include mandatory accurate testing for HBV by adoption agencies and provision of information regarding HBV for all families seeking to adopt international children. Organize an International Pediatric Hepatitis B Antiviral Study Group: to have the structure to test emerging antiviral therapics in properly designed randomized controlled trials to create a database for collection of data regarding HBV and liver transplantation, fulminant hepatitis, and HCC—could be done by website, and funding from pharmaceutical company interested in HBV therapies could be sought. HEPATITIS C Background Hepatitis C virus (HCV), an RNA virus, was identified in 1989 as the major cause of posttransfusion non-A, non-B hepatitis. Since that time, there has been an explosion of knowledge about the magnitude of this infection in adults. It has been estimated that approximately 170 million people worldwide are infected, and approximately 4 million in the United States are anti-HCV positive. Much less is known about HCV infection in children; reports regarding the epidemiology of this infection in children, indicate that approximately 7% of infected mothers transmit the infection to their newborns and that, to a lesser extent, contaminated blood products have been a mode of HCV transmission in children in the past. The role of intravenous drug use as a significant risk factor for acquisition of HCV during childhood should be clarified. Better estimates of worldwide infection rates during childhood and adolescence are needed. Effective antiviral therapies are urgently needed. There are anecdotal reports of treatment with interferon (IFN) in children; long-term response rates vary from 0 to 45%, although the best virologic sustained response rates have been reported in non-U.S. populations, where the IFN-resistant HCV genotype 1 is less prevalent. Because treatment with the combination of IFN and ribavirin have yielded improved sustained response rates in adults, large-scale multicenter pediatric trials are indicated. A long-acting form of IFN (pegylated) has been shown to be as effective in adults as combination therapy. Use of this therapy in children would have the benefits of once-weekly therapy with resultant sustained IFN levels in blood. Eradication of HCV in a child, thereby preventing the development of cirrhosis and liver cancer, can have major public health benefits. I. Summary of the Problem Although the natural history of HCV infection in adults has been well characterized, only a few studies have attempted to address this question in children. It has been suggested that HCV infection may have a better prognosis in children than in adults; however, there are a number of reports of rapidly progressive end-stage liver disease secondary to HCV in young children. Determinants of hepatic fibrosis, cirrhosis, and HCC in children with chronic HCV have not been characterized. Although the number of children with HCV affected worldwide is unknown, prevalence rates in the United States range from 0.2% of children ages 6 to 11 years and 0.4% of children 12 to 14 years of age. Rates may be higher in certain populations such as the homeless (approximately 5% to 6%) and select medical populations, such as the majority of hemophiliac children who received clotting factor concentrates before 1990. Social customs such as tattooing or scarification would be predicted to increase rates, as would parenteral therapy with unclean needles, as occurred in Egypt during efforts to treat schistosomiasis with mass inoculations. Prevention of HCV infection has been hampered by the lack of an effective vaccine and of a reliable means of preventing maternal–fetal transmission. Because the incidence of posttransfusion HCV has fallen precipitously after the advent of screening of blood products for HCV, maternal–fetal transmission is the most important means of spreading HCV infection in the pediatric population. The observations that premature rupture of membranes and invasive fetal monitoring might be lined to transmission of HCV to the fetus provide the rationale for testing the efficacy of Caesarean section and avoidance of in utero monitoring in prevention of maternal–fetal transmission of HCV. Another major area in need of study is that of management of the child with HCV. Development of safe, highly effective antiviral agents for HCV is a priority. There is no FDA-approved agent for treatment of children younger than 18 years of age. There have been a number of reports of the use of alpha-IFN monotherapy in children. Although it has been suggested that children may respond better to this drug than do adults, large-scale prospective randomized trials are lacking. Currently, trials are underway in children to test the combination of IFN and the nucleoside analog ribavirin as well as a new form of long-acting IFN (“pegylated”), which is given weekly as opposed to thrice weekly for conventional interferon. Children may well respond better to these agents than do adults; however, it is likely that the drugs will not be 100% effective and that more effective antiviral agents will be needed before eradication of the infection is an achievable goal for all HCV-infected children. There is little knowledge regarding management of the HCV-infected child undergoing liver transplantation. The role of HCV in HCC in children is not understood; without these data, it is impossible to know what strategy if any should be used for early detection in HCV-infected children. There is a need to develop public policies that will protect the child with HCV from social stigmatization; the child with HCV should not be excluded from daycare or school. The issue of whether a child with HCV should participate in contact sports is unsettled. Children should be educated about prevention of HCV via sexual transmission, and the child with HCV needs to be educated about the deleterious effects of alcohol. The child with HCV should be given hepatitis A vaccine. Public policies need to be developed to screen adoptees (both local and international) for HCV and to require adoption agencies to inform potential adoptive parents about the risks and consequences of adopting a child with HCV. There are no precise estimates of the costs of HCV for a child and family. In the United States alone, it is likely that several thousand children per year need treatment and that treatment would cost several thousand dollars/child. Thus, global costs of treating infected children would be millions of dollars annually. However, treatment of a child that results in sustained viral clearance is likely to be highly cost-effective because of the high costs of the long-term consequences of HCV: chronic liver disease, cirrhosis, or HCC. Even the small number of liver transplantations for children with HCV performed each year worldwide are likely to cost several million dollars. The emotional costs of having an HCV-infected child are more difficult to calculate but are nonetheless real; the anxiety over the possible development of chronic liver disease, the possibility of needing a liver transplant some day, or of developing HCC, are major burdens for families. II. Major Issues in Need of Investigation What is the epidemiology of HCV in children? The priorities include the determination of worldwide prevalence rates of HCV infection, clarification of the roles of horizontal transmission and, because intravenous drug use is known to be a major risk factor for acquisition of HCV in adults, the role of this mode of transmission of HCV in children and adolescents should be investigated so that appropriate interventions can be done. The prevalence of HCV in various medical pediatric cohorts (hemophiliacs, dialysis patients, and cancer survivors) should be studied. How can we prevent maternal–fetal transmission? Because HCV has been eliminated from blood products, one of the major continuing sources of new HCV infection is transmission of HCV from the infected mother to the fetus. Administration of the currently available antiviral agents, IFN and ribavirin, is not advisable because of risks of abortion and teratogenicity. Thus new strategies to prevent this type of transmission should be sought. The role of Caesarean section to prevent transmission to the newborn should be studied in women with premature rupture of membranes as should the elimination of in utero monitoring. What is the natural history of HCV in children and does it relate to the mode of acquisition? The rate at which liver disease progresses and the risk factors for development of fibrosis, cirrhosis, and HCC should be investigated. Whether liver iron overload, age of acquisition, gender, ethnicity, co-infections, or other factors impact on the severity of liver disease should be studied. What is an effective antiviral strategy? As molecular virology techniques are applied to the genomic structure of the virus, it is hoped that more effective antiviral drugs can be designed to inhibit the key enzymes mediating HCV viral replication. How can we hasten the development of an effective, safe vaccine for HCV? The high mutagenicity of HCV has been vaccine development very problematic, as has the lack of small animal models and tissue culture systems for HCV. Because the development of effective vaccines has played a major role in the prevention of a number of other viral diseases, including HBV, poliomyelitis, and smallpox, it is of great importance to direct resources toward development of HCV vaccines as well. What are the factors in the development of HCC in children? There are no published reports of HCV-associated HCC. However, because the infection is now known to be one of the leading causes of this highly fatal malignancy in adults and because HBV is known to be associated with this tumor in children, it seems likely that reports of HCV-associated HCC in children will occur. Thus, it is of great public health importance that the true prevalence rates of this tumor in children can be established. If the tumor is exceedingly rare in infected children, then yearly liver ultrasound or other screening modalities would not be cost-effective; conversely, if it is more common than it is thought to be at present, aggressive screening strategies should be developed. How can we best establish public policies to protect children with HCV and to prevent transmission of HCV? The best ways to achieve these goals (government mandates, educational strategies) need to be elaborated for each country. III. Proposed Plan to Achieve Goals Develop an effective vaccine by developing tissue culture systems and small animal models of HCV. Investigate means of preventing maternal–fetal transmission and horizontal transmission. Organize a working group to work with international health organizations to promote standards for international adoptees, which include mandatory testing for HCV by adoption agencies and provision of information regarding HCV for all families seeking to adopt international children. Organize an International Pediatric Hepatitis C Study Group: a. to develop methods for establishing HCV prevalence on a worldwide basis as well as in high-risk medical cohorts b. to develop a website; funding could be sought both from governmental agencies as well as pharmaceutical companies with antiviral agents for HCV. c. to develop a database to better determine the natural history of HCV in children d. to determine the prevalence of HCV-associated HCC in children e. to have the structure to test emerging antiviral therapies in properly designed randomized controlled trials. FULMINANT HEPATIC FAILURE IN CHILDREN—ETIOLOGY Fulminant hepatic failure (FHF) is defined as sudden onset of liver failure with altered mental status and coagulopathy in an otherwise normal individual. The mortality rate of FHF in general is very high, with variation by different causes. The obvious needs are to understand the mechanism of liver failure, especially those factors unique to children, to search for the causes of “idiopathic” FHF—the most common form in children—and to develop criteria to predict the progression of FHF in children. I. Summary of the Problem Definition The definition of FHF varies; the most widely used definition, proposed by Trey and Davison, defined FHF as the onset of altered mental status occurs within 8 weeks of initial symptoms in an otherwise healthy individual. Bernau et al. defined fulminant hepatitis as the onset of hepatic encephalopathy that develops within 2 weeks after the onset of jaundice, whereas the term subfulminant was used to indicate onset between 2 to 12 weeks. O'Grady et al. later proposed a term hyperacute liver failure to define encepalopathy occurs within 7 days of the onset of jaundice, acute liver failure 8 to 28 days after the onset of jaundice, and subacute liver failure 5 to 12 weeks after the onset of jaundice. The first problem, therefore, is to agree on a uniform definition of FHF in children, especially infants and toddlers, in whom encephalopathy may be subtle and not conform to established criteria. What is the proper duration from the initial symptoms to the onset of encephalopathy? The timing of encephalopathy differs in different underlying causes. Jaundice is a more reliable symptom than other subjective symptoms. Most mental changes in FHF occur within 2 weeks after the onset of jaundice. What is the most proper definition for “fulminant hepatitis” and for “FHF”? Is fulminant hepatitis a more narrow term limited to the cases with histology of massive/submassive hepatic necrosis, and FHF a more broad term that includes all of the diseases with sudden-onset hepatic encephalopathy and coagulopathy, that is, fulminant hepatitis and Reye or Reye-like syndrome? In addition, is there a difference between definitions used in adults versus those in children? In children with FHF due to metabolic diseases or infections such as Dengue fever, enterovirus infection, or other systemic infections, diffuse fatty change of the liver, but not massive hepatic necrosis, is the main liver histologic finding. Is it appropriate that both types of histologic changes (diffuse fatty changes/massive hepatic necrosis) be included in the term “fulminant hepatitis” or “FHF”? Should Reye syndrome and the entire Reye-like syndrome with coagulopathy and encephalopathy should be included in the term “FHF”? Etiologies Infectious agents, drug and toxin, metabolic diseases, and ischemia are the main causes of FHF in children; however, a large proportion of cases remain “idiopathic.” Infectious Agents: Hepatitis viruses (rarely), Epstein-Barr virus (EBV), cytomegalovirus, herpes virus types 1, 2, and 6, Coxsackievirus, adenovirus, parvovirus, Dengue virus, etc. are etiologic agents in FHF. Among those viruses, in countries in which HBV infection is endemic, hepatitis B virus is the most common agent causing fulminant hepatitis in children. The infection source includes mainly anti-Hbe–positive mothers or hepatitis B surface antigen (HbsAg) carrier blood donors with low viral titer. The role of HBV precore mutant (e minus strain) in fulminant B is controversial. The incidence of fulminant hepatitis A in children is much lower than that in fulminant hepatitis B. Hepatitis C or D virus is not an important causative agent for FHF in children. Hepatitis E virus can cause fulminant hepatitis, mainly in adolescents and young adults in endemic areas. Drugs and Toxins: Direct hepatotoxic agents, such as acetaminophen (paracetamol) or salicylate overdose, or drugs with idiosyncratic reactions, such as valproic acid, halothane, carbamazepine, propyluracil, isoniazid, herbal medicine, etc. have all been reported to be the causative agents for FHF in children. Toxicity due to herbal medicine is difficult to identify; once suspected, the complex ingredients make the identification of the exact etiologic component more difficult. Metabolic: Wilson disease in children older than age 4 years may present as FHF with profound jaundice and hemolysis. Tyrosinemia type I, neonatal iron storage disease, galactosemia, hereditary fructose intolerance, fatty acid oxidation disorders, and other causes of Reye-like syndrome may lead to FHF. Other Causes: Ischemia and autoimmune hepatitis can also cause FHF in children. Unknown: This group accounts for the largest percentage of cases of FHF in children; following a detailed history and physical examination, and multiple tests performed in search for the known causes of FHF mentioned above, many patients remain undiagnosed. This is a major concern because certain causes may be treatable (analogous to NISD or inborn errors in bile acid metabolism), whereas others may be contraindications to liver transplantation. What remains to be defined is the causative role of new viral agents in fulminant hepatitis of children. Up to now, the data available indicated that no evidence could show that HGV or TTV is a causative agent for FHF in children. Because the clinical phenotype resembles an acute viral injury, further efforts to search for agent(s) other than the above-mentioned known causative agent(s) are needed.