Hepatitis: Resti M

Indolfi G, Resti M. · Department of Paediatrics, University of Florence, Anna Meyer Children's Hospital, Florence, Italy. · J Med Virol. · Pubmed #19319981 No free full text.

Abstract: In industrialized countries, hepatitis C virus (HCV) is the most common cause of chronic liver disease in children. Perinatal transmission is the leading cause of infection. Perinatal transmission is confined almost always to women with detectable HCV ribonucleic acid (RNA) in the peripheral blood by the polymerase chain reaction but all children born to women with anti-HCV antibodies should be tested for HCV. Some but not all studies found that a high concentration of serum HCV RNA is associated with a higher risk of transmission. Maternal peripheral blood mononuclear cell infection by HCV, membrane rupture of longer than 6 hr before delivery, and procedures exposing the infant to maternal blood infected with HCV during vaginal delivery are associated with an increased risk of transmission. Maternal coinfection with HCV and human immunodeficiency virus, maternal history of intravenous drug use and of HCV infection of the sexual partner of the mother predict the risk of perinatal transmission and are dependent on the peripheral blood mononuclear cell infection by HCV. Delivery by Cesarean section is not recommended in pregnant women infected with HCV. Infected mothers can breast feed safely their infants if the nipples are not damaged. A previous delivery of a child infected perinatally with HCV does not increase the risk of transmission in subsequent pregnancies. Immunogenetic factors and HCV genotypes are not related to HCV perinatal transmission. Despite an increased understanding of the risk factors involved in perinatal transmission of HCV, to date little is known about the transmission mechanisms and timing.

Resti M, Bortolotti F, Vajro P, Maggiore G, Anonymous00429. · Department of Pediatrics, University of Florence, Florence, Italy. · Dig Liver Dis. · Pubmed #12870728 No free full text.

Abstract: Hepatitis C virus infection in infancy largely depends on vertical transmission. The transfer of hepatitis C virus from mother to child is almost invariably restricted to children whose mother is viremic, and the rate of transmission seems to be influenced by maternal virus load, although, in the single patient, the levels of viremia cannot be used as predictors of pediatric infection. In fact, the flow-chart for screening children at risk for vertically transmitted hepatitis C virus infection takes into account maternal viremia. In children born to anti-hepatitis C virus antibody positive, hepatitis C virus-RNA negative mothers, alanine aminotransferase and anti-hepatitis C virus should be investigated at 18-24 months of life. If alanine aminotransferase values are normal and anti-hepatitis C virus is undetectable, follow-up should be interrupted. In children born to hepatitis C virus-RNA positive mothers, alanine aminotransferase and hepatitis C virus RNA should be investigated at 3 months of age: (1) hepatitis C virus-RNA positive children should be considered infected if viremia is confirmed by a second assay performed within the 12th month; (2) hepatitis C virus-RNA negative children with abnormal alanine aminotransferase should be tested again for viremia at 6-12 months, and for anti-hepatitis C virus at 18 months; (3) hepatitis C virus-RNA negative children with normal alanine aminotransferase should be tested for anti-hepatitis C virus and alanine aminotransferase at 18-24 months, and should be considered non-infected if alanine aminotransferase is normal and anti-hepatitis C virus undetectable; (4) anti-hepatitis C virus seropositivity beyond the 18th month in a never-viremic child with normal alanine aminotransferase is likely consistent with past hepatitis C virus infection.

Resti M, Azzari C, Bortolotti F. · Department of Pediatrics, University of Florence, Florence, Italy. · Paediatr Drugs. · Pubmed #12175272 No free full text.

Abstract: Mothers with hepatitis C virus (HCV) and HIV coinfection are the major source of HCV/HIV coinfection in infancy and childhood. There is no known intervention capable of interrupting HCV spread from mother to child, while the majority of infant HIV infections occurring in the developed world can be prevented by antiretroviral prophylaxis in the mother and child, elective caesarean section, and formula-feeding. In the era preceding treatment of HIV infection with highly active antiretroviral therapy, HCV coinfection was of little concern because the short-term survival of patients with HIV infection prevented the slowly developing consequences of chronic hepatitis C. As the life expectancy of patients with HIV infection increased with therapy, HCV has emerged as a significant pathogen. Several lines of evidence in adult patients suggest that liver disease may be more severe in patients coinfected with HIV and that progression of HIV disease may be accelerated by HCV coinfection. Whether coinfected children may share these clinical patterns remains a matter of speculation. Chronic hepatitis C in otherwise healthy children is usually a mild disease; liver damage may be sustained and fibrosis may increase over the years, suggesting slow progression of the disease. Interferon-alpha has been the only drug used in the past decade to treat hepatitis C in children and adolescents, with average response rates of 20%. Preliminary results of treatment with interferon-alpha and ribavirin suggest that the efficacy would be greater with combined therapy. These treatment protocols have not yet been applied to children coinfected with HIV, but the increasing number of long-term survivors will probably prompt further investigation in the near future. At present, treating HIV disease and monitoring HCV infection and hepatotoxicity induced by antiretroviral drugs seem to be the more reasonable approach to HCV/HIV coinfection in childhood.

Resti M. · III Paediatric Clinic, Department of Paediatrics, University of Florence, Meyer Hospital, Italy. · Ital J Gastroenterol Hepatol. · Pubmed #10575568 No free full text.

Abstract: Since the programme of the hepatitis B virus vaccination started, hepatitis C virus has become the most significant cause of chronic liver disease of infectious aetiology in paediatric age. After the introduction of hepatitis C virus screening of blood units, vertical transmission seems to now be the most common route of hepatitis C virus infection in children. According to studies on infants born to anti-hepatitis C virus positive women, the rate of mother-to-infant transmission is about 5% when the mother is anti-hepatitis C virus positive and anti-HIV negative, but the risk is three-five times higher when the mother is coinfected with HIV. Both viral and host-related factors are of importance as risk factors in vertical hepatitis C virus transmission. Among the first, only viral load has been demonstrated by some authors as a relevant risk factor while genotype seems not to be influent. The importance of quasispecies has been hypothesized but not yet clarified. Among host-related factors, beyond maternal HIV coinfection, maternal drug abuse has certainly an important role. Other factors such as breast feeding and vaginal delivery do not seem to influence the rate of vertical transmission. Progression to chronicity occurs in the majority of perinatally infected children, although hepatitis C virus associated liver disease is usually mild throughout infancy and childhood.

Indolfi G, Bartolini E, Azzari C, Becciolini L, Moriondo M, de Martino M, Resti M. · Department of Paediatrics, University of Florence, Anna Meyer Children's Hospital, Florence, Italy. · J Med Virol. · Pubmed #18814243 No free full text.

Abstract: The aims of the present study were to evaluate in a cohort of mothers infected with hepatitis C virus (HCV) the prevalence of HCV infection of their sexual partners, the influence of infection of the partners on perinatal transmission, and whether this influence is mediated by other well known risk factors for perinatal transmission. Forty-nine consecutive mothers infected with HCV who transmitted infection to their offspring and, as a control group, 557 consecutive mothers infected with HCV who did not transmit infection, together with their children and the fathers of the children who were also the sexual partners of the mothers were evaluated. History of intravenous drug use was significantly more frequent in women with partners infected with HCV than in women with partners not infected [115/180 (63.9%) vs. 87/401 (21.7%); relative risk (RR): 6.38, 95% confidence intervals (CI): 4.34-9.39, P < 10(-3)]. HCV infection was more frequent in the partners of mothers who transmitted perinatally HCV [23/49 (46.9%) vs. 174/557 (31.2%); RR: 1.95, 95%CI: 1.08-3.51, P = 0.03]. Multivariate analysis demonstrated that paternal HCV infection is not a risk factor per se for perinatal HCV transmission, but its role is dependent on maternal intravenous drug use [adjusted RR: 1.23 (95%CI: 0.44-3.39, P = 0.6)]. In conclusion, the present study shows that partners of mothers infected with HCV with a history of intravenous drug use were at a higher risk of HCV infection. HCV infection of the father seems to be associated with perinatal transmission but this relationship is dependent on maternal history of intravenous drug use.

Azzari C, Indolfi G, Betti L, Moriondo M, Massai C, Becciolini L, Bertelli L, Poggi GM, De Martino M, Resti M. · Department of Paediatrics, University of Florence, Anna Meyer Children's Hospital, Florence, Italy. · Int J Immunopathol Pharmacol. · Pubmed #18179755 No free full text.

Abstract: Mother-child human leukocyte antigen (HLA)diversity is protective for vertical transmission of some viruses. The aim of this study is to evaluate the role of mother-child HLA diversity on hepatitis C virus (HCV) vertical transmission. Forty consecutive HCV infected and 46 consecutive control uninfected children born to HCV-RNA positive mothers were evaluated for HLA class-1 type concordance with their mothers. No significant difference in the degree of HLA concordance was found between HCV infected and uninfected children both when A, B, C (p=0.30) and when only A and B alleles were evaluated (p=0.59). Mother-infant HLA concordance does not affect HCV vertical transmission.

Azzari C, Moriondo M, Indolfi G, Betti L, Gambineri E, de Martino M, Resti M. · Department of Pediatrics, University of Florence, Anna Meyer Children's Hospital, Florence, Italy. · J Med Virol. · Pubmed #18041020 No free full text.

Abstract: Maternal injection drug use and peripheral blood mononuclear cell infection by hepatitis C virus are important risk factors for perinatal transmission of the virus. The aim of present study was to evaluate the independent association of these two factors on perinatal transmission. Forty-eight consecutive mothers who transmitted infection to their offspring and 122 consecutive mothers who did not, together with their children, were examined. Both maternal injection drug use and peripheral blood mononuclear cell infection were significantly more frequent in infected than in uninfected children (respectively P = 0.04; odds ratio 2.33, 95% confidence intervals 1.02-5.42 and P < 10(-6); odds ratio and 95% confidence intervals not calculable due to zero values). Multivariate analysis confirmed the link between maternal peripheral blood mononuclear cell infection and perinatal transmission (P < 10(-6); odds ratio and 95% confidence intervals not calculable due to zero values) but no association was found with maternal injection drug use. The high risk of perinatal transmission found in injection drug use mothers is dependent on maternal peripheral blood mononuclear cell infection by hepatitis C virus. Peripheral blood mononuclear cell infection represents one of the most important risk factors for hepatitis C virus perinatal transmission.

Indolfi G, Stagi S, Bartolini E, Salti R, de Martino M, Azzari C, Resti M. · Department of Paediatrics, University of Florence, Anna Meyer Children's Hospital, Florence, Italy. · Clin Endocrinol (Oxf). · Pubmed #17692107 No free full text.

Abstract: OBJECTIVE: The reported data on thyroid function and anti-thyroid autoantibodies in adults with untreated hepatitis C virus (HCV) infection are controversial. Data are scarce for HCV-infected children, and only in those treated with interferon-alpha (IFN-alpha). We investigated thyroid function and anti-thyroid autoantibodies in a cohort of untreated children with vertically acquired, chronic, HCV infection. DESIGN AND PATIENTS: FT4 and TSH serum levels (measured by immunometric assays) and anti-thyroglobulin (TgA) and anti-thyroperoxidase (TPOA) antibodies (evaluated by fluorescence enzymatic immunoassays) were studied in 36 consecutive HCV-infected children and 150 age- and sex-matched controls. The prevalence of thyroid involvement was also related to family history of autoimmune disease, distribution of HCV genotypes, and duration and activity of HCV infection. RESULTS: Four out of 36 (11.1%) HCV-infected children and 4/150 controls (2.7%) showed subclinical hypothyroidism [P = 0.04; relative risk (RR) 4.56, 95% confidence interval (CI) 1.08-19.21]. None of these had anti-thyroid autoantibodies. Two out of 36 (5.6%) HCV-infected children and 1/150 (0.7%) controls had increased TgA values with normal levels of TSH (P > 0.05). Subclinical hypothyroidism and anti-thyroid autoantibodies were not related to family history of autoimmune disease, duration of infection, HCV viral load, liver function or different HCV genotype distribution, but seemed to be related to the presence of active HCV infection. CONCLUSIONS: Our data suggest a role for HCV infection in the development of nonautoimmune thyroid disease in untreated HCV-infected children, confirming previous studies in adults. Clinicians should be aware of thyroid dysfunction even in untreated children.

Indolfi G, Moriondo M, Galli L, Azzari C, Poggi GM, Resti M, de Martino M. · Department of Paediatrics, University of Florence, Anna Meyer Children's Hospital, Florence, Italy. · J Med Virol. · Pubmed #17457925 No free full text.

Abstract: Infants born from mothers with multiple blood-borne viral infections are at risk of multiple transmissions. Whether the risk of transmission of multiple infections increases with the number of viruses infecting the mother is still unknown. The aim of this study was to describe the risk of mother-to-infant transmission of multiple infections from multi-infected mothers. Sixty-four pregnant women infected by at least two viruses among human immunodeficiency virus-type 1 (HIV-1), hepatitis C virus, TT virus, and GB virus type C, together with their 64 infants, were studied. Maternal blood samples were collected in the third trimester of pregnancy and all infants were prospectively followed for evaluation of transmission within 3 months after birth and two times in the subsequent 24 months. Transmission of single and of dual infection from mothers infected by two viruses was, respectively, 10/40 (25%) and 5/40 (12.5%) and from mothers infected by three viruses 9/20 (45%) and 2/20 (10%). One (25%) infant infected by one virus was born from the four mothers infected by four viruses. Transmission of single or dual infection was not significantly associated with the number of viruses infecting the mother (P = 0.9) in the linear regression analysis. Present study suggests the absence of a synergistic effect from viral interactions toward mother-to-infant transmission of multiple infections and supports the hypothesis that transmission from multi-infected mothers is the result of the specific interaction between each virus and the host. These observations may be of clinical relevance in perinatal counseling.

Moriondo M, Resti M, Betti L, Indolfi G, Poggi GM, de Martino M, Vierucci A, Azzari C. · Department of Paediatrics, University of Florence, Italy and Paediatric Hospital Anna Meyer, Florence, Italy. · J Viral Hepat. · Pubmed #17439525 No free full text.

Abstract: SEN is a newly discovered blood-transmissible virus. Among its variants, SENV-D and -H are most often associated with non-A, -E hepatitis. Very little is known about the risk of vertical transmission of the virus. By using polymerase chain reaction with specific primers for SENV-D and -H, we investigated the prevalence of SENV-H and -D infection, the transmission rate of SENV infection and clinical features of SENV-infected children in 89 hepatitis C virus (HCV)-positive human immunodeficiency virus type 1-negative mothers. SENV infection was found in 36 (40%) mothers, and SENV-D was more frequent than SENV-H infection (34/36, 94%vs 5/36, 14%, P < 0.01). No difference in SENV infection rates was found between injection drug user (IDU) mothers (17/51, 33%) and mothers with no risk for bloodborne infection (19/38, 50%, P = ns). SENV-H infection was found only in IDU mothers and mothers with HCV genotype1b. Both SENV-D and -H can be transmitted to the offspring with an overall rate of 47%. Vertical transmission of HCV does not facilitate SENV infection of the offspring. Among 17 SENV-infected children, none was co-infected with HCV. Maternal HCV genotype or viral load does not interfere with mother-to-infant transmission of SENV. Persistence of SENV infection was demonstrated in 100% of infected children after 1-year follow-up, but none had clinical evidence of liver disease.

Bortolotti F, Iorio R, Jorio R, Resti M, Cammà C, Marcellini M, Giacchino R, Marazzi MG, Verucchi G, Zancan L, Barbera C, Maggiore G, Vajro P, Giannattasio A, Bartolacci S, Anonymous00142. · Clinica Medica 5, Medicina Clinica e Sperimentale - University Padua, via Giustiniani 2, 35100 Padua, Italy. · J Hepatol. · Pubmed #17321633 No free full text.

Abstract: BACKGROUND/AIMS: To evaluate the epidemiological profile of Italian children with hepatitis C virus (HCV) infection over a 15-year period. METHODS: Fifteen tertiary care centers, belonging to a national Observatory established in 1998, retrospectively/prospectively recruited 806 consecutive HCV-infected, otherwise healthy, children seen from 1990 to 2004. RESULTS: Seven hundred and sixty four were Italian and 42 from foreign countries. Newly-diagnosed cases declined from 332 in 1995-1999 to 196 in 2000-2004, while the proportion of foreign children rose from 3% to 13%. Transfusion-transmitted infection disappeared after 1992. Maternal infection (with drug abuse in 63% of cases in the North) has become the most important mode of HCV diffusion throughout Italy and the exclusive source for all children infected in 2000-2004. The prevalence of HCV genotypes 3 and 4 increased and that of genotype 1b decreased significantly (p<0.02). Male/female ratio was significantly (p<0.001) lower among vertically infected (0.6) than in transfused children (1.3). CONCLUSIONS: The number of children with newly-diagnosed HCV infection is declining in Italy and most post-transfusion cases are now young adults. Thus foreign children could significantly contribute to the reservoir of pediatric infection in years to come. New infections result from maternal transmission and seem to privilege females and genotypes 3 and 4.

Indolfi G, Azzari C, Moriondo M, Lippi F, de Martino M, Resti M. · Department of Pediatrics, University of Florence, Anna Meyer Children's Hospital, Florence, Italy. · J Med Virol. · Pubmed #16721858 No free full text.

Abstract: Vertical transmission is the most common route of hepatitis C virus (HCV) infection in children. Transmission risk factors have been described, but most risk factors can only be evaluated using expensive laboratory exams. The aim of the present study was to evaluate whether maternal alanine transaminase (ALT) levels before pregnancy correlate with HCV vertical transmission. Seventy-four transmitting and 403 nontransmitting mothers were evaluated. All mothers enrolled had two ALT determinations in the last year before pregnancy, at least 6 months apart. Mothers were divided into two groups: mothers with persistently normal serum ALT levels and mothers with abnormal ALT levels. In the second group both mothers with constantly raised or with fluctuating ALT levels (one normal and one raised determination) were included. ALT was defined as raised if higher than twice the upper limit of normal. Abnormal ALT levels were found in 39/74 (52.7%) HCV transmitting mothers and in 146/403 (32.6%) nontransmitting mothers (P = 0.008; relative risk 1.96; 95% confidence limits 1.19-3.23). The risk of transmission from mothers with constantly raised ALT levels was more evident than that from mothers with fluctuating ALT levels. Increased ALT levels may reflect a more severe liver disease and a higher viral load, factors known to be associated with vertical transmission. ALT determination, a simple, widely available and inexpensive test, may help in identifying mothers with an increased risk of HCV vertical transmission.

Gerotto M, Resti M, Dal Pero F, Migliorato I, Alberti A, Bortolotti F. · Venetian Institute of Molecular Medicine (VIMM), Via Orus 2, 35129 Padova, Italy. · Infection. · Pubmed #16703294 No free full text.

Abstract: BACKGROUND: Hepatitis C virus (HCV) circulates as a mixture of different but closely related genomes: this quasispecies nature could be essential for virus persistence and could induce resistance to interferon therapy. Since little is known on the behavior of HCV quasispecies in children and adolescents with chronic hepatitis C, we analyzed the virus population in six untreated children during a 5-year follow-up. METHODS: Six children aged 1-8 years, infected early in life with HCV, were included in the study. From each of them, 2 or 3 sequential serum samples obtained over a 5-year follow-up period were examined. The HCV quasispecies heterogeneity and diversity in the E2 hypervariable region-1 (HVR-1) were analyzed among samples by the heteroduplex mobility assay, and the distance between variants was estimated by the heteroduplex mobility ratio (HMR). RESULTS: The HCV population was initially highly homogeneous in all six children. During follow-up, diversification of HVR-1 leading to a more complex viral population occurred in all cases, and was particularly evident in the three older children (HMR: 0.82-0.54). Changes in the HVR-1 sequence occurred without relation to the profile of ALT and HCV-RNA levels. CONCLUSIONS: HCV quasispecies diversification is a common event during chronic hepatitis C in childhood. Host and environmental pressure could be major determinants. The increasing viral heterogeneity could impair the response to antiviral therapy, thus indicating a rationale for early antiviral treatment in children with chronic hepatitis C.

Bortolotti F, Resti M, Marcellini M, Giacchino R, Verucchi G, Nebbia G, Zancan L, Marazzi MG, Barbera C, Maccabruni A, Zuin G, Maggiore G, Balli F, Vajro P, Lepore L, Molesini M, Guido M, Bartolacci S, Noventa F. · Clinica Medica 5, Via Giustiniani 2, 35100 Padova, Italy. · Gut. · Pubmed #15888796 links to  free full text

Abstract: BACKGROUND AND AIMS: Little is known of hepatitis C virus (HCV) genotypes in HCV infected children. This retrospective, multicentre study investigated genotype distribution and correlation with clinical features and outcome in a large series of Italian children. METHODS: Between 1990 and 2002, 373 HCV RNA positive children, consecutively recruited in 15 centres, were assayed for genotypes by a commercial line probe assay. RESULTS: The following genotype distribution pattern was recorded: genotype 1b = 41%; 1a = 20%; 2 = 17%; 3 = 14.5%; 4 = 5%; other = 2.5%. The prevalence of genotypes 1b and 2 decreased significantly (p<0.001) among children born from 1990 onwards compared with older children (46% v 70%) while the rate of genotypes 3 and 4 increased significantly (from 8% to 30%). Children infected with genotype 3 had the highest alanine aminotransferase levels and the highest rate of spontaneous viraemia clearance within the first three years of life (32% v 3% in children with genotype 1; p<0.001). Of 96 children enrolled in interferon trials during the survey, 22% definitely lost HCV RNA, including 57% of those with genotypes 2 and 3. CONCLUSION: HCV genotypes 1 and 2 are still prevalent among infected adolescents and young adults in Italy but rates of infection with genotypes 3 and 4 are rapidly increasing among children. These changes could modify the clinical pattern of hepatitis C in forthcoming years as children infected with genotype 3 have the best chance of spontaneous viraemia clearance early in life, and respond to interferon in a high proportion of cases.

Resti M, Jara P, Hierro L, Azzari C, Giacchino R, Zuin G, Zancan L, Pedditzi S, Bortolotti F. · Department of Paediatrics and Paediatric Hospital A. Meyer, Florence, Italy. · J Med Virol. · Pubmed #12766999 No free full text.

Abstract: The purpose of this prospective-retrospective study was to provide information about the clinical features and progression of hepatitis C virus (HCV) infection transmitted perinatally. Seventy children born to HCV infected woman were enrolled consecutively in five European centers between 1990 and 1999, provided they had HCV RNA in the serum during the first year of life and/or were still anti-HCV positive at 18 months. Sixty-two infants were followed up to 24 months of age or more (range, 24 months-11 years; average, 4.8 +/- 2.3 years). A wide range of ALT elevation was observed in 93% of the infants in the first year of life. During the follow-up, a sustained ALT normalization with loss of HCV RNA was seen in 12/62 (19%) of the children within 30 months of life; 66% of the infants had developed an ALT peak greater than 5x normal at onset (vs. 28% of children with persistent viremia; P < 0.05), and 50% had HCV genotype 3 (vs. 17% of viremic children). Conversely the cumulative probability of chronic progression was 81%. Chronic infection was asymptomatic and liver disease was mild in all 11 children who underwent a biopsy. In conclusion the early stage of acquired perinatally HCV infection is characterized by a wide range of ALT abnormalities, suggesting the interaction of multiple host and virus factors. The chronic progression rate of infection is high, but the associated liver disease is usually mild. High ALT levels at onset seem to offer greater opportunity of biochemical remission and loss of viremia during follow-up.

Bortolotti F, Muratori L, Jara P, Hierro L, Verucchi G, Giacchino R, Barbera C, Zancan L, Guido M, Resti M, Pedditzi S, Bianchi F, Gatta A. · Department of Pediatrics, University of Padua, Padua, Italy. · J Pediatr. · Pubmed #12584542 No free full text.

Abstract: OBJECTIVE: To evaluate the clinical pattern and evolution of chronic hepatitis C in children with liver/kidney microsomal antibody type 1 autoantibodies (LKM1). STUDY DESIGN: A multicenter, retrospective study, including the following groups of children with hepatitis C virus infection: (1). 21 consecutive LKM1-positive patients, (2). 42 age- and sex- matched LKM1-negative patients, and (3). 4 interferon-induced LKM1-positive cases. LKM1 reactivity to human microsomes and recombinant cytochrome P450IID6 (CYP2D6) was assayed by immunoblotting. RESULTS: Clinical and biochemical features overlapped in LKM1-positive and LKM1-negative children, but a fibrosis score >3 (range 0-6) was significantly more frequent (P =.04) in the former. Reactivity to microsomal protein and CYP2D6 was significantly (P =.02) associated with LKM1 titers >or=1:320 and was found in 39% of patients, including severe cases and both children (of 4 treated) who achieved a sustained alanine aminotransferase (ALT) normalization after steroid treatment. Five of 7 LKM1-positive children treated with interferon had an ALT exacerbation. CONCLUSIONS: LKM1-positive hepatitis C in children is characterized by a wide spectrum of biochemical, serologic, and histologic features. Whether autoimmunity may contribute to liver damage in a subgroup of patients with more severe liver disease, high LKM1 titers, and reactivity to CYP2D6 is a question deserving further investigation.

Jara P, Resti M, Hierro L, Giacchino R, Barbera C, Zancan L, Crivellaro C, Sokal E, Azzari C, Guido M, Bortolotti F. · Hospital Infantil La Paz, Madrid, Spain. · Clin Infect Dis. · Pubmed #12539067 No free full text.

Abstract: 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.

Resti M, Azzari C, Moriondo M, Betti L, Sforzi I, Novembre E, Vierucci A. · Department of Pediatrics, University of Florence, and Pediatric Hospital A. Meyer, I-50132 Florence, Italy. · Clin Infect Dis. · Pubmed #12115087 No free full text.

Abstract: Infection of peripheral blood mononuclear cells (PBMCs) with hepatitis C virus (HCV) has been demonstrated and has been found to play a role in relapse of HCV disease and vertical transmission of HCV. Injection drug use is thought to impair function of the immune system and induce tolerance to viruses; therefore, HCV infection of PBMCs could be more likely to occur in injection drug users (IDUs) with HCV infection. Of 108 women who tested negative for human immunodeficiency virus type 1 and positive for HCV RNA, 51 had a history of injection drug use and 57 had no known risk factor for HCV infection. HCV infection was found, by nested reverse-transcription polymerase chain reaction analysis, in the PBMCs of 33 IDUs and of 13 non-IDUs (P=.00003). No correlation was found between infection of the PBMCs and HCV genotype or virus load. Route of transmission and viral factors, as well as immunologic dysfunction, may play a role in viral tropism.

Resti M, Azzari C, Galli L, Zuin G, Giacchino R, Bortolotti F, Marcellini M, Moriondo M, de Martino M, Vierucci A, Anonymous00049. · Pediatric Clinic III, University of Florence and Pediatric Hospital A. Meyer, Via Luca Giordano 13, I-50132 Florence, Italy. · J Infect Dis. · Pubmed #11865412 No free full text.

Abstract: 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.

Giacchino R, Zancan L, Vajro P, Verucchi G, Resti M, Barbera C, Maccabruni A, Marcellini M, Balli F, Cascio A, Nebbia G, Crivellaro C, Bortolotti F, Clemente MG, Bragetti P, Valentini P, Mazzoni N, Losurdo G, Cristina E. · Infectious Diseases Unit Giannina Gaslini Children's Hospital, Genova, Italy. · Infection. · Pubmed #11545477 No free full text.

Abstract: BACKGROUND: 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 positive. 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 coming from highly endemic areas. The vaccination of nonimmune native populations must be strongly recommended.

Bortolotti F, Iorio R, Resti M, Verucchi G, Giacchino R, Vegnente A, Vajro P, Marazzi MG, Marcellini M, Barbera C, Zuin G, Zancan L, Maggiore G, Anonymous00261. · Clinica Medica 5, Via Giustiniani 2, 35100 Padua, Italy. · J Pediatr Gastroenterol Nutr. · Pubmed #11429517 No free full text.

Abstract: BACKGROUND: A retrospective-prospective survey of Italian children with hepatitis C virus (HCV) infection was planned in 1998 to explore the epidemiologic features of infection during the past decade. METHODS: Anti-HCV-positive patients (or HCV RNA-positive infants) aged 1 month to 16 years, consecutively observed in 20 pediatric Institutions, were considered. An anonymous epidemiologic questionnaire based on clinical records was used. RESULTS: From 1990 through March 1999, 606 patients were observed (296 boys, average age 5.8 years). Maternal infection (46% of cases) and blood transfusions (34%) were the most frequent risk factors. Of 279 infected mothers, 61% did not recall a putative source of infection (by history, many could possibly have had exposure through routes such as therapeutic injections with nondisposable material), whereas 94 (34%) admitted drug abuse, including 49 (17%) coinfected with human immunodeficiency virus (HIV). Only 157 (26%) children were born after 1991: 90% of their mothers were infected (11% were HIV coinfected vs. 25% mothers of older children, P < 0.01). CONCLUSIONS: Maternal infection is a prominent source of pediatric HCV infection in Italy. The fact that most mothers had a history of covert exposure to HCV, probably through percutaneous routes that are no longer operating, and that the number of those with HIV coinfection has decreased suggests that the frequency of pediatric infection could decrease in the future.

Azzari C, Resti M, Moriondo M, Ferrari R, Lionetti P, Vierucci A. · Department of Pediatrics, University of Florence, and Azienda Ospedaliera Meyer, Florence, Italy. · Blood. · Pubmed #10979945 links to  free full text

Abstract: Infection of peripheral blood mononuclear cells (PBMNCs) has been demonstrated to be a crucial event in the vertical transmission of viruses, and it is known that hepatitis C virus (HCV) can infect PBMNCs. The relationship between vertical transmission of HCV and the presence of positive and negative strands of HCV-RNA in the PBMNCs of HCV-carrier mothers was investigated using reverse transcriptase-polymerase chain reaction (RT-PCR). During the study, 13 consecutive mothers who transmitted infection to their offspring and 53 consecutive mothers who did not were examined. The positive strand of HCV-RNA was identified in the PBMNCs of all mothers who transmitted the infection and in 13 of 53 mothers who did not (P < 10(-6)). The HCV-RNA(-) strand was found in 5 of 13 mothers who transmitted the infection, and the strand was not found in the mothers who did not transmit the infection (P =.0001). Neither maternal PBMNC infection nor HCV transmission to the offspring was significantly related to the viral genotype or to the maternal viral load. These data show that maternal PBMNC infection by HCV and viral replicative activity in PBMNCs are important factors in the transmission of HCV from mother to child. The mechanism through which HCV infection of PBMNC favors vertical transmission of the virus is still incompletely understood.

de Martino M, Moriondo M, Azzari C, Resti M, Galli L, Vierucci A. · Department of Paediatrics, University of Florence, Florence, Italy. · J Med Virol. · Pubmed #10861644 No free full text.

Abstract: Serum TT virus (TTV) DNA was determined in 83 human immunodeficiency virus type 1 (HIV 1) infected mothers [46 intravenous drug user and 37 non-intravenous drug user women] and their infants. Twenty-nine (34.9%) mothers were TTV infected. Infection was more frequent among intravenous drug user than non-intravenous drug user mothers [21/46 (45.6%) vs. 8/37 (21.6%); relative risk (RR): 2.1; 95% confidence limits (95% CL): 1.1-4.2; P = 0.023] and among intravenous drug users who carried on injecting than in those who had given it up [10/14 (71.4%) vs. 11/32 (34.3%); RR: 2.1 (95%CL: 1.2-3.7); P = 0. 021]. Infection was not related to age, CD4-positive T-lymphocyte counts, HIV 1 load, hepatitis B (HBV), G/GB-C (GBV-C/HGV), C (HCV) virus exposure. Eight (27.5%) infants born to TTV infected (but none of those born to TTV uninfected) mothers were TTV infected at a median age of 1.5 (range: 0.6-2.8) months. Infants born by vaginal/emergency caesarean delivery were more frequently infected than those born by elective caesarean delivery [7/16 (43.7%) vs. 1/13 (7.6%); RR: 2.1; 95%CL: 1.2-3.5; P = 0.033]. Infection in infants was not related to maternal CD4-positive T-lymphocyte counts, HIV 1 load, and HIV 1, HBV, GBV-C/HGV, or HCV transmission. No infant became TTV infected thereafter. No TTV infected child [follow-up: 31 (median; range: 6-60) months] showed signs of liver disease; five infants cleared TTV DNA after 22 (median; range: 6-60) months. TTV infection in HIV 1 infected women is prevalently related to intravenous drug user. The findings suggest that infants may acquire TTV at birth. Infection may persist without evident liver disease.

Resti M, Bortolotti F, Azzari C, Giacchino R, Zancan L, Gussetti N, Vierucci A. · Department of Paediatrics, University of Florence and Pediatric Hospital A. Meyer, Italy. · J Pediatr Gastroenterol Nutr. · Pubmed #10817277 No free full text.

Abstract: 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.

Azzari C, Resti M, Bortolotti F, Moriondo M, Crivellaro C, Lionetti P, Vierucci A. · Department of Pediatrics, University of Florence, Italy. · J Pediatr Gastroenterol Nutr. · Pubmed #10467998 No free full text.

Abstract: 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.