Chronic hepatitis C in children is usually considered a clinically mild and slowly progressive disease. Few pediatric studies focused on histopathology of children with hepatitis C are available. Those available show, overall, a wide spectrum of findings ranging from normal liver to cirrhosis and hepatocellular carcinoma. The present systematic review provides a comprehensive overview of the studies that explored histopathology in children with hepatitis C. Factors affecting the presence and the degree of necroinflammation, fibrosis and steatosis and the risk of progression to advanced liver disease were extensively evaluated. Insights on the possible role of histopathology findings in the decision-making process of whether or not to treat children with hepatitis C are provided.

Clinical and histologic progression of liver disease in untreated children with chronic hepatitis C virus (HCV) infection is poorly documented. The aim of this retrospective study was to characterize changes in liver histology over time in a cohort of HCV-infected children who had more than one liver biopsy separated by over 1 year. Forty-four untreated children without concurrent liver diseases, who had repeat liver biopsies at eight U.S.-based medical centers, were included. Biopsies were scored by a single pathologist for inflammation, fibrosis, and steatosis and were correlated with demographic data including age at biopsy, time from infection to biopsies, and laboratory values such as serum alanine aminotransferase (ALT). Mode of transmission was vertical in 25 (57%) and from transfusions in 17 children (39%). Genotype 1 was present in 30/35 (84%) children. The mean age at first and final biopsy was 8.6 and 14.5 years, respectively, and the mean interval between biopsies was 5.8 ± 3.5 years. Duration of infection to biopsy was 7.7 and 13.5 years, respectively. Laboratory values did not change significantly between the biopsies. Inflammation was minimal in about 50% at both timepoints. Fibrosis was absent in 16% in both biopsies, limited to portal/periportal in 73% in the first biopsy, and 64% in the final biopsy. Between the two biopsies, the proportion of patients with bridging fibrosis/cirrhosis increased from 11% to 20% (P = 0.005).

Although in aggregate this cohort did not show significant histologic progression of liver disease over 5 years, 29.5% (n = 13) of children showed an increase in severity of fibrosis. These findings may have long-term implications for the timing of follow-up biopsies and treatment decisions.

The outcome of patients with hepatitis C virus (HCV) infection acquired during childhood in the absence of antiviral therapy is not clear.

The purpose of this study was to review the outcome of untreated HCV acquired in childhood. Only population-based studies were included, as referred cases would be predicted to have more severe disease.

A systematic review of the literature was completed up to October 2010 to identify studies where a population was screened for HCV infection that was presumably acquired during childhood. Demographical and clinical data were collected on infected patients who had not been treated with an antiviral. Primary outcome was development of a severe adverse outcome (cirrhosis, hepatoma, need for a liver transplant or liver-related death).

There were 25 studies reporting a total of 733 infected patients. Liver biopsy results were provided for 180 patients (25%), revealing cirrhosis in eight (1.0% of the total and 4.0% of those who had a biopsy). None of the other patients developed a severe adverse outcome. As a result of the small number of patients with a severe adverse outcome, risk factors for HCV progression could not be identified.

Although HCV can lead to liver transplantation and death during childhood, the vast majority of patients with disease acquired during childhood have slowly progressive disease. There is no clear indication for antiviral therapy in the majority of children with HCV infection.

The slow progression of hepatitis C virus (HCV) infection could ultimately negatively impact pediatric patients during their lifespan. This study describes the symptomatic and pathophysiologic presentation of HCV infection in a cohort of pediatric outpatients.

HCV-positive patients were identified by diagnosis codes from outpatient visits. Demographic and pathophysiologic indicators (comorbidities, reported symptoms, alanine transaminase, aspartate transaminase, gamma glutamyl transpeptidase, HCV viral load, genotype, and liver biopsy results) were collected and analyzed.

We reviewed 62 patients with HCV infection who were from 3 months and 19 years of age (M +/- SD, 12.5 +/- 5.8 years). Sixty percent presented with clinical symptoms of fatigue, joint-abdominal pain, bruising/bleeding, or other non-specific symptoms. On liver biopsy (n = 35) 80% had evidence of inflammation, 57% had fibrosis, and 9% had steatosis. All patients with steatosis or cirrhosis reported symptoms. Males were significantly more likely than women to be symptomatic (58.3% vs. 41.7%, P = 0.04). Patients with symptoms were significantly older (M = 13.5 +/- 5.2 vs. 8.9 +/- 5.5 years, P = 0.003). There was a significant inverse relationship between viral load and symptoms (chi = 4.75, P = 0.03). Patients with low viral load (<2 million copies) were 5 times more likely to have symptoms than those with high viral loads (P = 0.03). Significance was also noted between HCV genotype and ALT levels (chi = 3.72, P = 0.05). There were no significant relationships between symptom status and race, comorbidities, alanine transaminase, aspartate transaminase, gamma glutamyl transpeptidase, HCV genotype, or liver histology.

Pediatric patients with HCV can have significant symptoms and physiologic liver changes related to HCV.

Interferon (IFN)-alpha2b plus ribavirin is approved for treatment of hepatitis C in children; however, little is known about efficacy and tolerability of pegylated IFN (PEG-IFN)-alpha2b in this population. The objective of this study was to test the efficacy and safety of PEG-IFN-alpha2b plus ribavirin in children with chronic hepatitis C.

Thirty children 3-16 years of age who had detectable hepatitis C virus (HCV) RNA for >or=3 years after exposure and elevated alanine aminotransferase values received PEG-IFN-alpha2b 1.0 microg/kg/wk plus ribavirin 15 mg/kg/d for 24 weeks (genotype 2/3) or 48 weeks (genotype 1/4). The primary endpoint was sustained virologic response (SVR), defined as undetectable HCV RNA (<50 IU/mL) at week 24 of follow-up.

SVR was achieved in 50% of patients (3/3 genotype 3; 12/27 genotype 1/4). At week 12, 52% of patients were HCV RNA negative and 72% had a >2 log10 decrease in viral load, compared with baseline; 87% and 71% of these patients, respectively, attained an SVR. Therapy was discontinued in 3 patients as a result of adverse events. No patient required ribavirin dose reduction; PEG-IFN-alpha2b dose was reduced in 23% of patients to manage neutropenia.

Combination therapy with PEG-IFN-alpha2b and ribavirin treatment was effective in children with chronic hepatitis C. Virologic status at week 12 identified future responders and nonresponders. PEG-IFN-alpha2b and ribavirin were reasonably well tolerated, with no unexpected or permanent adverse effects. Further studies are needed to identify the optimum treatment regimen for this patient population.

Hepatitis C virus (HCV) infection occurs less frequently in children than in adult patients, and the natural history, prognosis, and clinical significance of HCV infection in children are poorly defined. We report here a descriptive follow-up of the clinical course, biochemical data, and viral markers observed in 37 children with anti-HCV. Ten patients included in the study tested persistently negative for serum HCV-RNA (group 1) and 27 patients tested persistently positive (group 2). In group 1, serum alanine aminotransferase (ALT) was normal in all patients, while two patients had non-organ-specific autoantibodies. In group 2, serum ALT was elevated in 13 of 27 patients, and five patients had non-organ-specific autoantibodies. HCV genotype 1a and 1b were the most prevalent among HCV-RNA-positive patients. Twenty liver biopsies were carried out on 17 patients in our series (mean evolution time, 11.2 years; range, 3-21 years). The liver specimens showed mild necroinflammatory changes in most patients, and fibrosis was absent or low grade. Two HCV-RNA-positive patients became persistently HCV-RNA negative. Of the 26 children investigated, 7 (one in group 1, six in group 2) had a co-infection with hepatitis G virus. Conclusion Most children chronically infected with HCV were asymptomatic and presented only mild biochemical evidence of hepatic injury. Autoimmunity in the form of non-organ-specific autoantibodies was common. HCV in children induced mild changes in the liver with a low level of fibrosis and at a low rate of progression.

To conduct a single-centre "look-back" study of the prevalence of hepatitis C in teenagers who had received blood products as newborns, prior to hepatitis C virus (HCV) blood donor screening.

Using blood bank records, we identified 732 surviving teenagers aged 14-18 years who had received blood products as neonates during 1986-1990. Letters recommending HCV antibody testing were sent to 732 surviving teenagers; 581 recipients were contacted and invited to undergo testing, and, of these, 429 consented (59% of the survivors). HCV antibody testing was performed on all and HCV-RNA was tested on those who were antibody positive.

Three teenagers (0.7%, 95% CI 0.54-0.86) tested positive for HCV antibodies and all three were HCV-RNA positive. There were no cases in which antibodies were detected and polymerase chain reaction (PCR) was negative. Two of the three had mildly elevated liver enzymes and all three had mild inflammatory activity and low fibrosis scores on liver biopsy.

The look-back process, even in a single centre with a stable urban population, is relatively inefficient in screening at-risk populations. Although the prevalence of hepatitis C in this sample was relatively low, paediatricians should offer screening to teenagers and young adults who received blood products in the neonatal period.

To identify the prevalence, risk factors and manifestations of asymptomatic hepatitis C virus (HCV) infection in Egyptian children.

Children at the age of 1-9 years were screened for HCV antibodies and alanine aminotransferase (ALT) levels. Every child with elevated ALT and/or detectable HCV antibodies was tested for HCV RNA by RT-PCR and compared with two negative controls for risk factors and signs and symptoms of liver disease.

We screened 1042 children, six of them had elevated ALT, negative HCV antibody and positive RNA, likely representing acute hepatitis C cases. Fifteen children were HCV seropositive, 5 of them were HCV RNA positive. Asymptomatic HCV infection was present in 2.02% (positive results for either HCV antibodies or HCV-RNA or both). Symptoms such as diarrhea, abdominal pain, history of fatigue and school absence because of illness and risk factors such as dental care were significantly more common among HCV positive cases than among controls. None of the HCV positive children was diagnosed as having signs of advanced liver disease upon clinical or ultrasonographic examination.

Asymptomatic HCV infection is detectable in 2.02% Egyptian children.

To define the natural history and outcomes of children infected with hepatitis C virus (HCV) at birth or in early childhood.

This retrospective, prospective study identified 60 HCV-infected children through a transfusion look-back program (group 1) and by referrals (group 2). Perinatal/transfusion history, clinical course, and laboratory studies were correlated with findings from 42 liver biopsy specimens.

Mean age at infection was 7.1 months, and duration of infection 13.4 years. The sources of infection were blood transfusion (68%), perinatal transmission (13%), and both (7%). Most patients were asymptomatic; three referral patients had advanced liver disease at presentation. Mean alanine aminotransferase level was normal in 25%, 1 to 3 times normal in 62%, and greater than 3 times normal in 13%. Liver biopsy specimens showed minimal to mild inflammation in 71%, absent or minimal fibrosis in 88%, and bridging fibrosis in 12%. Age at infection and serum gamma-glutamyltranspeptidase correlated with fibrosis; serum alanine aminotransferase correlated with inflammation unless complicated by comorbidity. Repeat biopsies within 1 to 4 years in four patients showed no significant progression in three and cirrhosis in one. Two patients died after liver transplantation.

Children with chronic HCV infection are generally asymptomatic. By 13 years after infection, 12% of patients had significant fibrosis. Patients enrolled by referral had more severe liver disease than those identified through the look-back program, demonstrating the importance of selection bias in assessing the long-term outcome of HCV infection.

Because several children were found infected with hepatitis C virus (HCV) at a pediatric oncohematological department in Vilnius, 474 children were tested for anti-HCV. Fifty-eight percent of 96 children treated with blood and plasma products manufactured before the introduction of anti-HCV screening of blood in Lithuania in 1994 were positive for anti-HCV versus 3.4% of those treated after 1994. The possible route of transmission for 45 of these was investigated by phylogenetic analyses within the NS5B region. Children treated before 1995 were infected with a multiplicity of strains of different subtypes, predominantly 1b found in 21 cases, 3a in 5 cases, 2 in 3 cases, 1a in 1 case, and not subtypeable genotype 1 strains in 2 cases. Children who had received blood products after 1994 were infected with only two subtypes, 1b in six and 3a in seven. Genetic analysis showed multiple introductions of HCV before 1995 and that horizontal spread between patients had occurred only to a minor extent at the department. However, two transmission chains involved children treated before 1995. Another chain involved five children treated after 1994. Since the most important risk factor for acquiring hepatitis C was blood products manufactured before the introduction of donor screening for anti-HCV, the spread between children would not have been revealed without molecular tools. These and the background strains provide the first reported sequence data on Lithuanian HCV strains. In general, these were shown to form autochthonous clades, except the 3a strains that were related to strains from the former USSR.

The aim of this study was to compare the efficacy of interferon alpha (IFN) or IFN and ribavirin (IFN+RIB) combination therapy in children with chronic hepatitis C (CHC). Most children were infected during treatment for pediatric malignancies.

We reviewed the charts of 20 patients (11 boys and 9 girls) aged 10.6 +/- 3.7 years with CHC who were treated between 1995 and 2001. Seven patients diagnosed with CHC before 1998 were treated with 3 million units of IFN three times weekly for 6 to 12 months. Thirteen children diagnosed after 1998 were treated with 3 million units of IFN three times weekly plus 15 mg/kg of ribavirin daily for 6 months (IFN+RIB).

Demographic and clinical characteristics were not different between the two treatment groups. A sustained complete response defined as serum alanine aminotransferase normalization and hepatitis C virus RNA clearance at 6 and 12 months after termination of treatment occurred in three of seven children (43%) treated with IFN monotherapy compared with 7 of 12 children (54%) in the group treated with IFN+RIB combination therapy (not significant). The only difference between responders and nonresponders was the duration of infection before the initiation of therapy, which was significantly shorter in responders (1 +/- 0.3 vs. 5.6 +/- 2.2; P = 0.001).

In this small cohort of children with CHC, early initiation of antiviral treatment was associated with a sustained response rate independent of treatment type. Regular follow-up of children at risk of acquiring hepatitis C virus infection should assist in the early diagnosis. Early initiation of antiviral treatment may improve the rate of sustained response.

We investigated the efficacy of natural interferon (IFN)-alpha treatment in 34 Japanese children with chronic hepatitis C.

Thirty-four children completed 6 months of therapy with natural IFN-alpha and were followed for 12 months or longer. We examined the serum hepatitis C virus (HCV) RNA titer and liver histology before, during, and after IFN treatment.

At 6 months after the cessation of IFN-alpha treatment, 16 patients (47%) had normal serum alanine aminotransferase concentration and no detectable serum HCV RNA. There were no major side-effects, excluding some influenza-like symptoms during the IFN-alpha treatment. Most genotype 2a patients had a complete response (80%). Moreover, patients who had a low HCV RNA titer (<102 copies/mL) after 1 month of IFN-alpha treatment became complete responders at 6 months after the cessation of treatment. Histological improvement was observed in almost all patients after IFN-alpha treatment.

Interferon-alpha treatment is safe and effective for children with chronic hepatitis C and has no serious side-effects. A HCV RNA concentration of <102 copies/mL after 1 month of IFN-alpha treatment and genotype 2a may be useful predictors of long-term IFN efficacy.

The natural history of chronic hepatitis C acquired in infancy is not well understood. The progression of fibrosis was analyzed in untreated children with chronic hepatitis C virus infection and no other hepatotoxic cofactors.

A total of 112 pediatric patients (13 with paired liver biopsies) were considered. Fibrosis was assessed by METAVIR score (i.e., stage F1 to F4). The ratio between the stage of fibrosis (METAVIR units) and the presumed duration of infection represented the "estimated" rate of fibrosis progression per year. In patients with paired biopsies, the "observed" rate of fibrosis progression was defined as the difference between the stage of fibrosis in the two biopsies divided by the time interval between them.

Both age of patients at biopsy and duration of infection correlated with stage of fibrosis (p < 0.002 and p < 0.0005, respectively). Stage of fibrosis differed significantly between patients with infection lasting less or more than 10 yr (p < 0.0006). Sex, hepatitis C virus genotype, and route of infection did not correlate with stage of fibrosis. Among the 13 patients with paired biopsies, stage of fibrosis increased in seven and did not change in six; the median rate of estimated fibrosis progression per year was 0.142. The difference between estimated and observed fibrosis progression rates was significant (coefficient of determination, r(2) = 0.031), which demonstrated that the prediction of the fibrosis progression was unreliable in 97% of patients.

Chronic hepatitis C acquired in childhood is a progressive, slow-moving, fibrotic disease. Fibrosis progression inferred on the basis of linear mathematical models should be critically evaluated in the clinical practice.

Despite preventive measures, patients who have cancer or who undergo bone marrow transplantation remain at higher risk of viral infection since they often receive multiple blood products. This category of patients also includes subjects from countries that are highly endemic for hepatitis B virus and hepatitis C virus infection and who travel to developed countries for specialized treatment. This review discusses the current opinions concerning the diagnostic, clinical, and therapeutic aspects of hepatitis B and C virus infection in different groups of patients: children with chronic infection before chemotherapy, children infected during chemotherapy or bone marrow transplantation, and patients with chronic infection after the end of treatment.

Hospital-related hepatitis C virus (HCV) infections continue to occur even after the introduction of blood donor screening. We report an outbreak of HCV in nine patients of a pediatric oncology ward in 1996/1997. Sequencing of the hypervariable genomic region 1 (HVR1) of the E2/NS1 region showed near identity between HCV isolates from these patients as evidence for infection with the same virus. Despite a detailed and careful investigation, the source of infection and the mode of virus transmission could not be established. Based on a review of the current literature about nosocomial HCV infection and HCV infection in children, hypotheses for possible means of transmission in this outbreak are discussed.