Raffaella Giacchino

Long-Term Course of Chronic Hepatitis C in Children: From Viral Clearance to End-Stage Liver Disease

BACKGROUND & AIMS The natural course of chronic hepatitis C (CHC) in children is not well understood. The aim of this study was to assess the long-term course of CHC in a large sample of otherwise healthy children. METHODS From 1990 to 2005, 504 consecutive antihepatitis C virus (HCV)-positive children were enrolled at 12 centers of a national observatory and were followed up retrospectively/prospectively. RESULTS Putative exposure was perinatal in 283 (56.2%) cases, parenteral in 158 (31.3%), and unknown in 63 (12.5%). At baseline, 477 (94.6%) cases were HCV RNA seropositive, 118 (24.7%) of which were treated with standard interferon alpha. Ten years after putative exposure, the outcome in 359 HCV RNA-positive, untreated patients was (1) undetectable viremia in 27 (7.5%) (by Cox regression analysis, spontaneous viral clearance was independently predicted by genotype 3 [hazard ratio 6.44; 95% confidence interval: 2.7-15.5]) and (2) persistent viremia in 332 (92%) cases. Six of these 332 cases (1.8%) progressed to decompensated cirrhosis (mean age, 9.6 years). This latter group included 5 Italian children perinatally infected with genotype 1a (4 of the mothers were drug users). Thirty-three (27.9%) treated patients achieved a sustained virologic response. CONCLUSIONS Over the course of a decade, few children with chronic HCV infection cleared viremia spontaneously, and those who did were more likely to have genotype 3. Persistent viral replication led to end-stage liver disease in a small subgroup characterized by perinatal exposure, maternal drug use, and infection with HCV genotype 1a. Children with such features should be considered for early treatment.

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.

Chronic Hepatitis C in Children: The Pathological and Clinical Spectrum

BACKGROUND & AIMS Apart from the high-risk groups, the pathology of chronic hepatitis C in children is not well known. The aim of this study was to investigate the morphology of chronic hepatitis C in children without any underlying systemic disease and to evaluate its relationship to clinicovirological factors. METHODS Liver biopsy specimens from 80 children positive for antibody to hepatitis C virus were evaluated using a semiquantitative scoring system. RESULTS Chronic hepatitis was mild in most cases but had high-grade activity in 17 children (21.2%). A significant association was found between the grade of focal necrosis and alanine transaminase levels (P < 0.003). Fibrosis was absent in 22 cases (27.5%), mild in 44 (55%), and moderate in 13 (16.2%). Only 1 patient had cirrhosis. A significant relationship was detected between fibrosis scores and (1) duration of disease (P < 0.03); (2) portal inflammation (P < 0. 002); and (3) interface hepatitis (P < 0.003). CONCLUSIONS In otherwise healthy children, chronic hepatitis C is a morphologically mild disease in most cases. Fibrosis increases with the duration of disease, suggesting that end-stage disease may develop in young adulthood. Alanine transaminase levels correlate with intralobular focal necrosis but not with other lesions. In this respect, liver biopsy retains its importance in the management of chronic hepatitis C in children.

Maternal Drug Use Is a Preeminent Risk Factor for Mother-to-Child Hepatitis C Virus Transmission: Results from a Multicenter Study of 1372 Mother-Infant Pairs

This prospective multicenter study evaluated separately the significance of maternal injection drug use (IDU) and human immunodeficiency virus type 1 (HIV-1) coinfection in vertical transmission of hepatitis C virus (HCV). In all, 1372 consecutive, unselected HCV antibody-positive mothers and their infants were studied. Maternal HIV-1 coinfection (crude odds ratios [OR], 1.41; 95% confidence interval [CI], 1.16-1.66; P =.007) and IDU (OR, 1.58; 95% CI, 1.37-1.78; P <.00001) were linked to mother-to-child HCV transmission in unadjusted analysis when all anti-HCV-positive mothers were evaluated. When only HCV RNA-positive mothers were evaluated, maternal IDU, but not maternal HIV-1 coinfection, was significantly associated with mother-to-child HCV transmission. Multivariable analysis confirmed the link between maternal IDU and HCV transmission (adjusted OR [AOR], 1.51; 95% CI, 1.19-1.92; P =.0006), but no association was found with HIV-1 coinfection (AOR, 0.98; 95% CI, 0.73-1.33; P =.93). IDU, but not HIV-1 coinfection, seems to be a preeminent risk factor for vertical HCV transmission.

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.

Epidemiology and clinical features of Mycoplasma pneumoniae infection in children

Mycoplasma pneumoniae (MP) is, considered to affect rarely children less than 5 yrs of age. This study was performed to describe the epidemiology and the clinical features of MP lower respiratory tract infection (LRTI) in children, presenting to a tertiary children hospital. Eleven month-longitudinal study of LRTI due to MP, diagnosed by polymerase chain reaction (PCR) on throat swab specimen, was performed. Out of 866 children with LRTI admitted to the Gaslini Pediatric Institute in Genoa, 102 had a positive PCR for MP. We found 39 preschool-aged children, 42 school-aged children and 21 young adolescent [6.20 (3.81) yrs old]. Interestingly, eight MP+ infants had <8 months of age. The commonest presentations were cough and/or fever (76.5%). Tachypnoea, upper respiratory tract involvement, diarrhoea and vomiting were more common in the <5 yr Gr as compared to the other groups. Chest X-ray was found abnormal in 76 children: consolidations were the commonest finding. Laboratory test showed that the preschool-aged children had a higher number of lymphocytes (p<0.0001) and monocytes (p=0.009). Thrombocytosis was found in 35.7% of children and was more frequent in the preschool-aged children (p=0.013). MP infection is common in preschool-aged children, including young infants, and may have different clinical presentation, as compared to older children.

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.

Mutation analysis in patients of Mediterranean descent with Wilson disease: identification of 19 novel mutations.

In this study, we report further results of mutation analysis of the ATP7B gene in Wilson disease (WD) patients of Mediterranean origin. A total of 136 WD chromosomes, 73 of which were of Italian, 43 of Turkish, 18 of Sardinian, and two of Spanish origin, were analysed and the mutation characterised in 84.5% of them. We found 50 different mutations of which 19 are novel, including three nonsense, one frameshift, and 15 missense mutations. The mutations detected were rare and mostly found in the compound heterozygous state together with other mutations and only rarely in homozygosity. Most of these mutations lie in the transmembrane and ATP binding loop regions. These data expand our knowledge of both the structure-function relationships of the WD protein and the molecular pathology of WD, thus improving our capability of prevention and genetic counselling.

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.