Carlo Crivellaro

Chronic hepatitis B in children after e antigen seroclearance: Final report of a 29‐year longitudinal study

Chronic hepatitis B is usually a benign disease in Caucasian children; however, the long‐term prognosis remains unsettled. This report describes the results of a 29‐year longitudinal study including 99 white children with chronic hepatitis B, mainly acquired horizontally: 91 were hepatitis B e antigen (HBeAg) positive (4 had cirrhosis), and 8 were HBeAg negative at presentation. Of the 91 HBeAg‐positive children, 89 underwent HBeAg seroconversion after a mean period of 5.2 ± 4.0 years and were included in the study. Of the 85 children without cirrhosis, one had HBeAg‐negative hepatitis and the other 84 became inactive carriers. During a mean follow‐up of 14.5 ± 6.1 years after HBeAg seroclearance, 4 carriers experienced reactivation, and 3 of them had HBeAg‐negative hepatitis at the last follow‐up. Of the 8 initially HBeAg‐negative children, 2 had HBeAg‐negative hepatitis, and 6 were inactive carriers. Of the 4 children with cirrhosis, 2 had hepatocellular carcinoma (HCC) and remained alive and 2 lost the histological features of cirrhosis in adulthood. Two patients with HBeAg‐negative hepatitis and 1 with cirrhosis had experienced drug abuse. At the end of follow‐up, 15 of the 89 initially HBeAg‐positive patients and 2 of 8 initially HBeAg‐negative children had cleared hepatitis B surface antigen. In conclusion, the overall prognosis for chronic hepatitis B in horizontally infected Caucasian children is favorable; however, some patients progress to HCC and HBeAg‐negative hepatitis. Long‐term monitoring is important, as is counseling on cofactors of liver damage, such as alcohol and drug abuse. (HEPATOLOGY 2006;43:556–562.)

Chronic hepatitis C virus infection in childhood: clinical patterns and evolution in 224 white children.

The characteristics and evolution of hepatitis C virus (HCV) infection were retrospectively investigated in a study of 224 HCV RNA-seropositive white children who were consecutively recruited at 7 European centers in 1980-1998. At presentation, all patients were positive for antibodies to hepatitis C virus, 87% were asymptomatic, and 48% had alanine aminotransferase (ALT) levels that were < or =2 times the upper limit of the range considered to be normal. Of 200 children followed for 1-17.5 years (mean follow-up +/- standard deviation [SD], 6.2+/-4.7 years), only 12 (6%) achieved sustained viremia clearance and normalization of the ALT level. In 92 revised liver biopsy specimen analyses, the mean fibrosis score (+/-SD) was 1.5+/-1.3 for children <15 years of age and 2.3+/-1.2 for children > or =15 years of age (range, 0-6 years; P<.01). Pediatric HCV infection is usually mild, but few patients, especially those who are perinatally infected, clear viremia in the medium-term follow-up. Conversely, the higher rates of fibrosis observed in older patients suggest the possibility of an insidious progression of HCV-associated liver disease.

Outcome of chronic hepatitis B in Caucasian children during a 20-year observation period

BACKGROUND/AIMS Chronic hepatitis B virus infection can lead to cirrhosis and hepatocellular carcinoma, particularly in men over 40 years of age and in areas where childhood-onset infection is common. The sequence of events from paediatric infection to severe disease in adults is only partially known. The aim of this study was to evaluate the evolution of chronic hepatitis B acquired in childhood during 20 years of follow-up. PATIENTS One hundred and eighty-five consecutive, otherwise healthy, Caucasian children were enrolled in Padua (Italy) and in Madrid (Spain) between 1975 and 1985, and followed for an average period of 13 years; 168 were hepatitis B e antigen (HBeAg) positive and five had cirrhosis. RESULTS Thirty patients received steroids or levamisole and 21 interferon, but treatment did not significantly influence HBeAg clearance. Overall, two (1.1%) children, with initial cirrhosis, developed hepatocellular carcinoma and the other three (1.6%) cirrhotic patients became asymptomatic carriers of infection after anti-HBe seroconversion and biochemical remission; 14 (7.5%) children maintained HBeAg positive hepatitis; 155 (83.8%) became asymptomatic carriers of infection after anti-HBe seroconversion and biochemical remission; six (3.2%) experienced reactivation of liver disease and viral replication after remission and five (2.7%) maintained biochemical features of liver damage after HBeAg clearance. Only 6% cleared hepatitis B surface antigen. CONCLUSIONS Even considering the bias of treatment, the large majority of Caucasian children with chronic hepatitis B became asymptomatic carriers of infection with normal alanine amino-transferase during the first 20 years of observation. Cirrhosis is an early, rare complication, and a risk factor for hepatocellular carcinoma. A subgroup of patients who experienced reactivation or maintained liver damage after HBeAg clearance seems to be at greater risk for disease progression during adult life.

Posttransfusion and community-acquired hepatitis C in childhood

Following a longitudinal study of chronic non-A, non-B hepatitis in Italy and Spain, we evaluated the epidemiologic and clinical features of chronic hepatitis C in 77 consecutively observed children (35 male; mean age, 4 years) without underlying systemic diseases. All subjects were positive for antibody to hepatitis C virus in serum by second-generation tests. Forty-six patients had received blood transfusions in the perinatal period; 12 had a mother with antibodies to HCV in serum (five of these mothers were drug users or partners of a drug user); seven had a history of putative percutaneous exposure; and 12 had not been exposed to any risk factors for viral hepatitis. At presentation, only 22% were symptomatic, mean alanine-aminotransferase levels were three times the upper normal value, and liver histology showed active disease in only nine of 28 cases (32%). During a mean observation period of 6 years, only 11 of 57 patients (19%) complained of symptoms and 11 of 40 cases (27%) had histologic features of active hepatitis. Two patients had severe hepatitis with associated cirrhosis. However, only six of 57 cases (10%) achieved sustained biochemical remission. The clinical features and the outcome were similar in both the posttransfusion and the community-acquired cases. These results indicate that transfusions in the perinatal period are the single most important cause of hepatitis C in otherwise healthy children. Community-acquired cases represent an heterogeneous epidemiologic group in which maternal transmission, whether perinatal or postnatal, could be relevant. Histologically severe hepatitis and cirrhosis seem to be an infrequent feature of chronic hepatitis C virus infection in childhood and adolescence, in spite of persistent liver damage.

Fibrosis in chronic hepatitis C acquired in infancy: is it only a matter of time?

Abstract Objective 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. Methods 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. Results Both age of patients at biopsy and duration of infection correlated with stage of fibrosis (p Conclusions 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.

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 1/2 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.

Changing epidemiologic pattern of chronic hepatitis C virus infection in Italian children

OBJECTIVE To evaluate the epidemiologic features of chronic hepatitis C virus (HCV) infection in children. STUDY DESIGN All 106 children with chronic HCV infection consecutively observed in 3 Italian pediatric centers between 1991 and 1997 entered the study. RESULTS Fifteen children had a history of non-A, non-B hepatitis, and 5 complained of nonspecific symptoms. The 86 remaining patients were free of symptoms and were recruited after HCV screening for intercurrent diseases, maternal infection, or other putative exposure; 39% (none of 30 children born after 1990) had received transfusions, whereas 44%, had a mother with HCV infection. Of the 47 infected mothers, 36% were or had been intravenous drug users, 15% had received transfusions, and 45% had no history of exposure. CONCLUSIONS Children with chronic HCV infection are often free of symptoms, and thus HCV screening for putative risk has greatly increased the chances of diagnosis. Vertical transmission seems to now be the most common route of infection. Both current and past maternal intravenous drug abuse are risk factors for pediatric infection; however, in an area with relatively high prevalence of anti-HCV in the general population such as Italy, a consistent proportion of infectious mothers have no risk factors of HCV exposure.

Long-term interferon-α treatment of children with chronic hepatitis delta: A multicentre study

Summary We assessed the efficacy of prolonged interferon‐α (IFN) therapy in children with chronic hepatitis caused by hepatitis delta virus (HDV) by treating 26 paediatric cases with IFN‐α2b(5 MU m‐2, then 3 MU m‐2 three times weekly for 12 (medium‐term group, MTG) or 24 months (long‐term group, LTG). Compliance and tolerability were acceptable. At the end of therapy a complete biochemical response [normalization of alanine aminotransferase (ALT)] occurred in 12 children (5/13 in MTG and 7/13 in LTG). A relapse occurred after stopping IFN in 10 cases (five in MTG and five in LTG). Two patients from the LTG had normal liver function tests during 12 months of follow‐up. Six of the eight hepatitis Be antigen (HBeAg) positive children lost HBeAg, while all six hepatitis B virus (HBV) DNA positive patients lost HBV DNA during treatment. HBeAg reappeared later in two children. HDV RNA, present in 10/10 cases of MTG before treatment, persisted after 12 months IFN therapy in 3/10. One year after stopping therapy, 8/10 patients were again HDV RNA positive. Two children cleared hepatitis delta antigen (HDVAg) from the liver. No significant improvements in liver histology were seen in both groups. Our experience suggests that IFN‐α treatment in children with chronic type D hepatitis has a transient effect, and long‐term treatment does not appear to induce a greater therapeutic benefit in terms of biochemical and virological response.

Antibodies to hepatitis C virus in community-acquired acute non-A, non-B hepatitis

Circulating antibodies to the recently identified hepatitis C virus (anti-HCV) have been investigated by ELISA in a series of 129 adult Italian patients with acute, community-acquired non-A, non-B hepatitis. Anti-HCV was detected in 50 (38%) cases with a prevalence rate which increased from 19%, in sera taken during the first 2 weeks of illness to 52% in samples obtained 5-6 weeks after onset, indicating a rather late appearance of the antibody. Anti-HCV positivity was independent of risk factors in the clinical history, but correlated with the outcome of the disease. Eighteen (26%) of 68 patients who recovered were anti-HCV positive compared to 10 of 14 (71%) who progressed to chronicity (p less than 0.01). In this latter group the antibody persisted for more than 12 months after the onset of the illness. Conversely, in 12 (85%) of 14 serially tested patients who recovered, anti-HCV positivity was transient, lasting from a few weeks to a few months. These findings indicate that HCV is implicated in a consistent proportion of acute community-acquired non-A, non-B hepatitis cases, particularly cases which progress to chronicity. A large proportion of cases remained unclassified, however, and it will be important to define whether they represent cases of HCV infection with poor serologic response, or are due instead to other, as yet unidentified, non-A, non-B agents.

Hepatitis B virus infection in native versus immigrant or adopted children in Italy following the compulsory vaccination.

AbstractBackground: Compulsory vaccination of children against hepatitis B virus (HBV) infection was introduced in Italy in 1991. Patients and Methods: To evaluate the current importance of pediatric HBV infection, we studied 359 HBsAg-positive children admitted to 16 centers in Italy from 1991 to 1998. 185 patients were natives of Italy and 174 (39 immigrants and 135 adopted) came from highly endemic countries (eastern Europe: 60.9%, Asia: 16.7%, Africa: 14.9% and Central and South America: 5.7%). Results: Transaminase levels were moderately altered in both Italian (mean 134 UI/l) and foreign children (mean 168 UI/l). In total, 77% of Italian children and 88% of foreign children tested HBeAg postive. High transaminase levels and HBeAg positivity were more frequent in adopted children. Follow-up of 317 patients showed that the incidence of HBeAg/anti-HBe serum conversion was similar in all cohorts, but in adopted children it occurred at an earlier age and was associated with HBsAg clearance in 5%. Conclusion: HBV is not frequent in Italian children today, but it is common among children comming from highly endemic areas. The vaccination of nonimmune native populations must be strongly recommended.