Serum levels of hepatitis C virus RNA in infants and children with chronic hepatitis C.

BACKGROUND: The role of serum hepatitis C virus (HCV) load in infectivity, disease activity, and response to interferon treatment has been investigated in adults, and controversial results have been obtained. Little is known about HCV load in infants and children with HCV infection. PURPOSE: To investigate the relation between HCV load in serum and features of associated liver disease in infants and children with HCV infection. METHODS: Hepatitis C viral load was investigated in serial samples in 43 children with chronic HCV infection, including 32 patients aged 4 to 16 years infected by different routes and 11 vertically infected infants observed prospectively since birth. RESULTS: Overall viremia ranged between 2.7 and 6.9 log copies/ml (median, 5.56 log/ml) and fluctuated slightly during the follow-up. Median HCV RNA levels did not significantly differ among infants, children, and adolescents. Viral load was also independent of sex, route of infection, clinical manifestation, alanine aminotransferase levels, and liver histology. All 11 perinatally infected children became chronic HCV carriers, whatever their initial viral load; retrospective testing of sera taken in the first day of life in three infants showed high viremia levels. CONCLUSIONS: Viremia levels observed in children were similar to those reported in adults, were independent of age, biochemical activity of liver disease, and chronicity of infection. They were also relatively stable, suggesting that serial measurement of viral load is useless in untreated infants and children. The detection of viremia at birth in children in whom chronic hepatitis developed later suggests the possibility of in utero infection.     

Increased risk of chronic hepatitis in children with cancer

BACKGROUND: There is a risk of viral hepatitis for children with cancer. Both hepatitis B virus (HBV) and hepatitis C virus (HCV) infections in countries with high prevalence cause major problems in the management of cancer patients. In this study, we evaluated the incidence and chronicity of HBV and HCV infections in children with malignant diseases receiving chemotherapy. PROCEDURE: One hundred ninety-eight children with cancer (mean age = 7.5 +/- 2.5 years) and 100 healthy children as a control group were screened for HBV and HCV. Liver function tests, the number of transfusions, HBV and HCV serology were regularly monitored. In seropositive children, HBV-DNA and HCV-RNA were measured. Chronic hepatitis was defined as having an alanine aminotransferase (ALT) level three times of upper normal limit, positive HBV and HCV antigenemia for longer than 6 months. Liver biopsies were performed in all children with chronic hepatitis. The relationship between the chronic hepatitis and study parameters was statistically analyzed. RESULTS: HBsAg positivity, anti-HCV, and mixed (HBV and HCV) infection were found in 11.6, 5.5, 2% of children, respectively. Most HBV infected children developed chronic hepatitis (48%) while 26 and 21.7% became carriers and immune, respectively. One died of acute fulminant HBV hepatitis. Of HCV infected children, 63.6% also had positive HCV-RNA. Four children with mixed infection (100%) all progressed to chronic hepatitis. In this setting, chronic hepatitis was observed in 22 of 38 infected children (57.8%). The majority had leukemia and lymphoma. Children with HBsAg antigenemia developed chronic hepatitis in shorter time than HCV positive children (median 13 months vs. 51 months, P < 0.001). CONCLUSION: We observed an increased incidence of chronic hepatitis and even mortality due to HBV infection. This suggests that HBV and HCV infections are serious causes of morbidity and mortality in children with cancer.     

Growth in the first 5 years of life is unaffected in children with perinatally-acquired hepatitis C infection

OBJECTIVES: To identify the effect of vertical hepatitis C virus (HCV) infection or exposure on growth in childhood. STUDY DESIGN: Children (n=1203) born to HCV-infected mothers were followed up from birth prospectively in centers of the European Paediatric Hepatitis C virus Network. Z-scores compared height- and weight-for-age in HCV-infected and -uninfected children, adjusting for other factors using linear regression. We also quantified the effect of maternal chronic infection with HCV on childhood growth. RESULTS: There was no significant effect of vertical HCV infection on growth (height P=.223, weight P=.095) nor a significant effect of maternal chronic infection with HCV (height P=.733, weight P=.274). Prematurity and maternal injecting drug use were associated with a significant reduction in height (P < .001) and weight (P < .001) in all HCV-exposed children. CONCLUSIONS: This population of HCV exposed infants has higher rates of maternal injecting drug use and prematurity than standard populations and so there are implications for growth of these children, but this is not a direct result of HCV infection or exposure to chronic maternal HCV infection.     

Chronic viral hepatitis

Among hepatitis A to E viruses, hepatitis B, C, and D viruses can cause chronic hepatitis, in both children and adults. Hepatitis B virus (HBV) infection is the most prevalent and important one. Perinatal transmission accounts for about 40–45% of chronic HBV infection in hyperendemic areas. Horizontal transmission through intramuscular injection using non-sterile needles and intrafamilial spread accounts for the other half of carriers. During the natural course of HBV infection, the host gradually clears HBV and hepatitis B e antigen (HBeAg), liver damage and elevation of aminotransferases occur during the process of HBV clearance. The most effective way to eliminate HBV infection is immunoprophylaxis starting since birth. It can prevent both HBV and hepatitis D virus (HDV) infections. Hepatitis C virus (HCV) infection in children occurs mainly in high risk children, such as those who received blood product or injection using non-sterile needles, or infants of HCV viremic mothers, etc. Screening of blood product reduced markedly the prevalence of post-transfusion HCV infection, but the prevention of sporadic cases requires HCV vaccination which is still under investigation.     

Hepatitis B and C viruses in infants and young children

Advances during the past 20 years have led to a better understanding of the prevention, diagnosis, and treatment of acute and chronic hepatitis B (HBV) and hepatitis C (HCV) infections in the pediatric population. Universal vaccination and prenatal testing for HBV have decreased the incidence rate of acute HBV infections from more than 3/100,000 to 0.34/100,000 in all children. Diagnosis of chronic HBV is confirmed with positive serologic testing on two occasions at least 6 months apart. Current approved therapies with interferon alpha and lamivudine for children with chronic HBV infection have shown some efficacy, but results have been variable. In contrast, the lack of an effective HCV vaccine and the risk of mother-to-child transmission may increase the number of children with vertically acquired HCV that ultimately go on to develop liver fibrosis or cirrhosis. Diagnosis of HCV in the neonate should be postponed until after the child reaches 1 year of age because infants may have transient viremia. Treatment for HCV infected children has not been studied extensively. Peginterferon alpha-2a and Ribavirin are not currently approved for pediatric use; however, recent studies in children have shown potential benefit. More effective and less toxic therapies for young patients with HBV and HCV are needed, as are methods to interrupt perinatal transmission of HBV and HCV.     

Treatment of chronic hepatitis C in children

Since the discovery of hepatitis C virus (HCV) in 1989, significant advances have been made in our understanding of this important viral pathogen. Children at risk for HCV infection include recipients of potentially contaminated blood products and organ transplants, and infants born to HCV-infected mothers. Chronic HCV infection is usually asymptomatic in children but active hepatitis, cirrhosis and hepatocellular carcinoma can occur. The development of treatment strategies for chronic hepatitis C in children has directly evolved from clinical trials in adults. Sustained virologic response, defined by undetectable HCV RNA in serum 24 wk after completion of treatment, occurs in approximately 36% of children treated with conventional interferon alone and in about 50% of those given conventional interferon in combination with ribavirin. Pegylated interferon-based treatment regimens are better than those based on conventional interferon in adults but little is known about pegylated interferon in children. Factors associated with a favorable response to antiviral therapy in children are similar to those in adults and include infection with HCV genotype 2 or 3 and low pretreatment serum HCV RNA levels. Treatment related adverse events in children include 'flu-like' syndrome, fatigue, anorexia, weight loss, depression, anemia, leukopenia and thrombocytopenia.     

Chronic hepatitis C virus infection in children]

Peripartum transmission is today the main cause of hepatitis C virus (HCV) infection in children. HCV infection rarely causes a clinical illness during childhood and adolescence, except when it is associated with additional risk factors such as hepatitis B or HIV infection, chemotherapy or immunodeficiency. Present data suggest that between 20 to 50 percent of contaminated infants will become spontaneously non viremic within 15 to 20 years. Studies on treatment with interferon-alpha are limited and show a mean recovery rate of 40%.     

Hepatitis C virus infection and related liver disease in children of mothers with antibodies to the virus

Objective: To evaluate the clinical, biochemical, and virologic features associated with hepatitis C virus (HCV) infection acquired early in life from mothers with antibodies to HCV (anti-HCV).Study design: Multicenter prospective-retrospective study in Italian children.Patients: Two groups of children were investigated. Group 1 included 14 infants, born to mothers with anti-HCV but without human immunodeficiency virus infection, who became seropositive for HCV RNA during the first year of life and were thus considered infected. Group 2 included 16 children with chronic hepatitis C, aged 1 ½ to 14 years, whose mothers were the unique potential source of infection. Both groups were followed for 12 to 48 months.Methods: Alanine transaminase (ALT), anti-HCV, and HCV RNA were investigated by the polymerase chain reaction on entry to the study and during follow-up.Results: All children in group 1 had anti-HCV throughout follow-up, and all had ALT abnormalities, ranging from 1.5 to 10.5 times the normal value during the first 12 months. During further follow-up, 5 of 10 children had HCV RNA with abnormal ALT values, 3 had a return to normal of the ALT values but continued to have viremia, and 2 eventually had normal ALT values and clearance of HCV RNA. Of the 16 children in group 2, all were free of symptoms and 62% had only slight ALT elevations; 7 who underwent liver biopsy had histologic features of minimal or moderate hepatitis.Conclusions: HCV infection acquired early in life from mothers with anti-HCV is usually associated with biochemical features of liver damage during the first 12 months of life. Progression to chronicity seems to occur in the majority of cases, although HCV-associated liver disease is likely to be mild throughout infancy and childhood. (J Pediatr 1997;130:990-3)     

Prevalence of hepatitis C virus antibody in newborn infants in southern California in 2003

The prevalence of hepatitis C virus (HCV) antibody in newborn infants in 3 counties in southern California in 2003 was found to be 2.5 per 1000 live births using dried blood spot testing. With advances in HCV antiviral therapy providing decreasing morbidity from chronic HCV infection, prenatal HCV screening to identify both mothers and at-risk infants should be reconsidered.     

High rate of maternal-infant transmission of hepatitis G virus in HIV-1 and hepatitis C virus-infected women

The prevalence of hepatitis G virus (HGV) infection was investigated in 56 mothers with both human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) infection. Thirty-three (58.8%) women had markers of HGV infection, including 7/15 (46.6%) with no history of parenteral exposure to blood. Sixteen (48%) had HGV RNA in serum by a polymerase chain reaction assay, and 17 (52%) had antibody to E2 viral protein. No woman was positive for both markers. Of 20 infants born to the 16 mothers with HGV viremia, 9 (45%, 95% CI 34-56%) acquired the infection. No infected child seroconverted to HGV during the first year of life. At the latest visit (mean: 37.1 mo, range: 9-89 mo) 7 children were still seronegative HGV RNA carriers, 1 was both RNA- and antibody-negative, while 1 RNA-negative child had developed the E2 antibody. Of the 20 HGV-exposed infants, 2 contracted HCV and 1 HIV-1 (all 3 with HGV coinfection). No abnormalities in clinical findings and ALT levels were observed throughout the follow-up period in the six children with HGV infection alone. Our findings show that HGV infection is widespread among HIV-1- and HCV-infected women. Maternal-infant transmission of HGV is common and occurs independently from that of HIV-1 and HCV in women with triple infection. Most perinatally HGV-infected children develop persistent infection with no clinical or biological signs of liver damage, at least in the first years of life.     

小儿庚型肝炎的探讨

为了探讨一种新型肝炎病毒，即庚型肝炎病毒（ｈｅｐａｔｉｔｉｓＧｖｉｒｕｓ，ＨＧＶ）在小儿中的感染特点，检测了３６例肝炎患儿及１６例健康体检儿童血清中ＨＧＶ－ＲＮＡ（套式逆转录ＰＣＲ法）。结果表明，３６例肝炎中有１１例ＨＧＶ感染者，其中６例合并慢性ＨＣＶ感染（３例接受过干扰素治疗），２例合并慢性ＨＢＶ感染，２例为慢性非Ａ－Ｅ肝炎，１例合并ＨＢＶ＋ＨＡＶ感染。１６例健康儿童均阴性。ＨＧＶ感染率在血制品输入者１０例中７例阳性，在未输入者２２例中３例阳性（两者比较，Ｐ＜０．０１），在血制品使用情况不明者２０例中１例阳性。提示输入血制品是小儿ＨＧＶ感染的主要途径，但不排除还有其他途径，感染者主要为慢性肝炎患儿，干扰素的疗效有待进一步研究     

Transmission of hepatitis C virus from infected mother to offspring during subsequent pregnancies

BACKGROUND: Several studies have demonstrated that hepatitis C virus (HCV) may be transmitted from mother to offspring. To date, however, little is known about the risk of vertical transmission during subsequent pregnancies. The purpose of this study was to evaluate the risk of vertical HCV transmission in offspring in subsequent pregnancies of HCV infected women. METHODS: In a multicenter study, two groups of index cases were selected. Group 1 included 75 children investigated for HCV infection during prospective studies of vertical transmission. Group 2 included children born to HCV-infected mothers and found to be HCV infected, independent of studies on vertical transmission. All children in the index cases had one or more siblings. Anti-HCV, HCV-RNA (determined by polymerase chain reaction), and HCV genotype were evaluated in all the infected children, their mothers, and siblings. RESULTS: The results indicate that a mother who has already delivered an HCV-infected baby is not at greater risk of infecting her second child. Duration of maternal infection does not seem to be a risk factor in offspring infection, because HCV infection is equally distributed among first-born infants and infants of subsequent births. Because clustering of HCV infection among siblings appeared to be rare in this study, data also indirectly confirm that the risk of horizontal transmission of HCV among siblings is low. CONCLUSION: For practical purposes, the current observations indicate that mothers who have already delivered an HCV-infected child can be advised that this event does not increase the probability of infecting the second child.     

NASPGHAN practice guidelines: Diagnosis and management of hepatitis C infection in infants, children, and adolescents

Hepatitis C virus (HCV) is an RNA virus that affects >180 million individuals worldwide with a high propensity for chronic infection. Children with HCV infection differ from adults in several ways including some modes of transmission, rates of clearance, progression of fibrosis, and the duration of potential chronic infection when acquired at birth. Since the discovery of HCV in 1989, there have been significant advances in the understanding of the virology and natural history of chronic HCV infection in children. In addition, there are now several treatment options for children with chronic hepatitis C infection and many new therapies on the horizon. As a consequence, the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition brought together experts in pediatric hepatology to review the available data in children and provide clinicians with approaches to the diagnosis, management, and prevention of HCV infection in children and adolescents. The guideline details the epidemiology and natural history of HCV infection in children, the diagnostic workup, monitoring and treatment of disease, and provides an update on future treatment options and areas of research.     

Breastfeeding and hepatitis C virus (HCV): the need for a careful appraisal]

We review the available data on the possible role of breast-feeding in hepatitis C virus (HCV) transmission to infants of HCV-RNA-positive mothers. Current knowledge about HCV excretion through breast milk, HCV infection of breast-fed infants by mothers contaminated after delivery, and vertical transmission risk to infants breast-fed by chronic HCV viremic mothers are presented. Vertical transmission risk by breast-feeding HCV-RNA-positive mothers is unclear: no study has been performed with the aim and the required methodology to evaluate HCV transmission risk related to breast-feeding duration. Recommendations to HCV-RNA-positive mothers who wish to breast-feed their infant are discussed in light of present knowledge about HCV secretion in breast milk, mother-to-infant HCV transmission, and historical records on vertical transmission of other viruses to infants breast-fed by their viremic mothers.     

Hepatic dysfunction in children with acute lymphoblastic leukemia in remission: relation to hepatitis infection

BACKGROUND: Viral hepatitis is a cause of hepatic dysfunction in children with ALL in remission during maintenance therapy is debated. The aims of the current study were (1) to explore the incidence of hepatic dysfunction in a group of children (Egyptian and Saudi) with ALL under maintenance therapy, (2) to study the prevalence of hepatitis B (HBV) and/or C (HCV) infection and their contributions to chronic liver disease that might be induced by maintenance therapy. PROCEDURE: The current study included 105 children with ALL (54 Egyptian and 51 Saudi). All eligible patients had been on maintenance therapy for at least 12 months and all had serial assessments of liver function. These included determination of total bilirubin, AST, ALT, and alkaline phosphatase. Markers for HBV and HCV including HBsAg, anti-HBC, and anti-HCV and for some patients HCV RNA by PCR were studied. Percutaneous liver biopsy was performed for a group of children. RESULTS: The prevalence of hepatitis infection (HBV and/or HCV) among Egyptian children was found to be high (43/54-80%). Only five Saudi children had evidence of exposure to HBV (5/51-9.8%), P<0.0001. During the period of study, 22 Egyptian patients vs. four Saudi patients (41 vs. 7.8%, P<0.0001) experienced at least one episode of elevation of liver enzymes, three times the upper limit of normal or more. Twenty-six of the 48 patients (54%) with HBV and/or HCV infection had episodes of elevated liver enzymes, while there was no occurrence among the patients negative for HBV and HCV. In patients with HBV infection, the presence of HBsAg was strongly associated (100%) with elevated liver enzymes. Histopathologic examination of liver biopsies obtained from 35 patients revealed that all five patients negative for HBV and HCV had normal liver biopsies in spite of being under maintenance therapy. CONCLUSION: In children undergoing treatment for ALL, elevations in liver enzymes may be primarily due to hepatitis viruses. However, maintenance therapy using known hepatotoxic drugs, may have additive deleterious effects. Liver enzymes are normalized in affected patients when maintenance therapy is temporarily suspended.     

Hepatitis C virus (HCV). Low infection rate in premature and full-term neonates following multiple transfusions]

BACKGROUND: Nearly all cases of non-A, non-B post-transfusion hepatitis are caused by hepatitis C virus (HCV). Data for HCV infection in childhood are limited. METHODS: 262 Children who received poly-transfusion between 1979 and 1983 were re-examined at a mean age of 3.5 years for HCV infection using an first-generation enzyme immunoassay to detect anti-HCV antibodies. RESULTS: 14 of 262 children had positive anti-HCV titers (5.3%), 7 of them showed border line results. In further two patients HCV infection was suspected by clinical means, but initial serology was not available. 6.5 years later, 15 of these 16 children were re-examined at a mean age of 9.8 years. All had normal liver enzymes and positive anti-HCV serology was shown in 3 patients (1%). CONCLUSIONS: This study demonstrates a low incidence of HCV infection after poly-transfusion during neonatal age. The rate of HCV infection may be even higher, if other more specific tests for HCV serology or PCR will be routinely available in the near future.     

Hepatitis A, B und C im Kindesalter

Hepatitis A, B, and C in children can raise diagnostic and therapeutic problems. Hepatitis A is a self limited infection with a fecal-oral transmission route. In children the clinical course is often asymptomatic or unspecific. The rate of icteric hepatitis A is growing with increasing age of the patient at time of infection. The prognosis is excellent in children. Active immunization against hepatitis A prevents infection. Hepatitis B is a more complex disease as chronic liver disease, aggressive hepatitis, and lack of therapeutic options are common problems in managing these patients. In children vertical transmission of the virus leads to a high rate of chronic disease. As therapeutic options are not very promising prevention of infection is a major tool. Active immunization is a safe and successful way to decrease the infection rate amongst populations. The prevalence of HCV infection in children is often underestimated. Children who have been treated with blood or blood products before 1991 are at major risk for Hepatitis C infection. As HCV in children is often mostly present without any symptoms or with minor symptoms, the disease often remains undiagnosed for a long period of time, especially these patients are at risk to distribute the disease. HCV infection in children seems to be more benign compared to adults, the rate of spontaneous elimination of the virus seems to be higher in children. Treatment of HCV infection in children should currently performed within clinical trials only.     

Hepatitis C and G Virus infections in polytransfused children

The prevalence of hepatitis C virus (HCV) and a newly identified hepatitis G virus (HGV) and their clinical significance were studied in 42 polytransfused Taiwanese children. Serological assays for antibodies against HCV (anti-HCV) and polymerase chain reaction for serum HCV ribonucleic acid (RNA) and HGV RNA were performed. The prevalence of anti-HCV and HGV RNA was 17% and 14%, respectively in 42 polytransfused children. Anti-HCV seropositives had a significantly higher mean age, peak serum transaminase level, and longer transfusion duration than seronegatives, while children with HGV infection usually had no or only mild hepatitis activities. The prevalence of anti-HCV dropped sharply after implementation of anti-HCV screening, however the prevalence of HGV viraemia remained unchanged. Conclusion HGV infection is not uncommon in polytransfused Taiwanese children and the virus does not cause significant hepatitis compared to HCV infection. Current blood donor screening for anti-HCV can effectively protect polytransfused children from HCV infection but the impact of additional screening for HGV markers awaits further studies. Received: 10 October 1996 and in revised form: 26 November 1996 / Accepted 26 November 1996     

Chronic non-A, non-B hepatitis: role of hepatitis C virus.

Thirty three consecutive children with chronic non-A, non-B hepatitis (NANBH) were studied during a four year period to evaluate clinical and histological features and the role of hepatitis C virus (HCV). All patients were asymptomatic. Thirteen (39%) of them were anti-HCV positive. A history of parenteral exposure was significantly more frequent among anti-HCV positive (69%) than anti-HCV negative patients (15%). Aminotransferase serum values were not statistically different between anti-HCV positive and anti-HCV negative patients. Unlike adults, cirrhosis was never found in the children studied. Our results suggest that chronic NANBH is, during childhood, an asymptomatic disease and that the prevalence of HCV infection is lower than in adults. As the majority of the children with chronic NANBH showed no evidence of HCV infection, it seems unwarranted to identify NANBH with HCV infection in children. The lack of cirrhosis in paediatric patients is probably related to a shorter duration of liver disease.     

Efficacy of interferons in treating children with chronic hepatitis C

Twenty-two children with chronic hepatitis serologically positive for hepatitis C virus (HCV) were treated with interferon-α (IFN-α). Liver biopsy showed chronic active hepatitis in 13 and chronic persistent hepatitis in 9 patients. A sustained clearance of HCV was observed in 8/22 children 12 months after the administration of IFN-α for 26 weeks, associated with normalization of HCV core antibody. Of these eight patients six had HCV genotype III and two HCV genotype II or IV. Hepatitis relapsed in seven other patients after completion of IFN-α with an increase in HCV core antibody titre, five with HCV genotype II, and two with HCV genotype III or IV. A second course of IFN-α suppressed the reactivation of HCV in all seven patients. Three of seven responders who relapsed after the first course remained negative for HCV RNA 12 months after their second course of IFN-α. However, the remaining four patients with HCV genotype II again relapsed after completing their second course of IFN-α. Seven children with the HCV genotype II resistant to IFN, including 8 weeks of IFN-β administration, and showed no significant reduction in HCV core antibody titre. Conclusion The genotype of HCV (III) and a reduction in the core antibody titre appear to be useful parameters for predicting the response to IFN-α therapy. Received: 12 September 1996 and in revised form: 28 January 1997 / Accepted: 11 February 1997