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

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

Increased risk of chronic hepatitis in children with cancer

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

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

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

Active surveillance of hepatitis C infection in the UK and Ireland.

AIM: To investigate the prevalence, distribution, and clinical details of paediatric hepatitis C virus (HCV) infection in the UK and Ireland. METHODS: Active monthly surveillance questionnaire study coordinated through the British Paediatric Surveillance Unit, to all consultant paediatricians in 1997 and 1998. RESULTS: A total of 182 HCV infected children were reported from 54 centres and by paediatricians from eight different specialties. In 40 children HCV was acquired through mother to child transmission (MTC children); 142 were infected by contaminated blood products (n = 134), organ transplantation (n = 2), needles (n = 4), or unknown risk factor (n = 2). Intravenous drug use was the risk factor for 35 mothers of MTC children. Twelve children were coinfected with HIV and four with HBV. Recent serum aspartate aminotransferase or alanine aminotransferase values were at least twofold greater than the upper limit of normal in 24 of 152 children; this occurred in five of 11 HIV coinfected children. Liver histology, available in 53 children, showed normal (7%), mild (74%), moderate (17%), or severe (2%) hepatitis. Twenty eight children had received therapy with interferon alfa. CONCLUSION: Most current paediatric HCV infection in UK and Ireland has been acquired from contaminated blood products, and most children are asymptomatic. There is a need for multicentre trials to inform clinical practice and development of good practice guidelines in this area. Long term follow up of this cohort of HCV infected children is planned to help determine the natural history over the long term of HCV acquired during infancy and childhood.     

Post-transfusion chronic hepatitis C in children

Two hundred and twenty-six patients who received blood products for open-heart surgery in childhood were screened by a second-generation enzyme-linked immunosorbent assay and with surrogate markers for hepatitis C virus (HCV) infection, such as alanine aminotransferase (ALT). Twenty-two (14%) of the 161 recipients who received blood products before 1989 and none of the subjects who had received blood products after 1990 (the year that the blood bank began to screen for HCV antibody) were HCV seropositive. Virologic and histologic studies showed that 10 (45%) of 24 seropositive patients had persistent hepatitis C virus infection, many with ongoing hepatitis. The remaining 12 seropositive patients with absent HCV RNA had normal ALT levels, indicating resolved hepatitis C infection. Enrolment in screening is important to detect chronic hepatitis C in children who received blood products prior to screening of blood donors for HCV antibody.     

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

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

Clinical implications of mother-to-child transmission of HCV

Testing for vertical transmission of hepatitis C virus (HCV) infection in infants and children will enable early identification of the majority of uninfected HCV-exposed infants and children, and will provide significant emotional relief for the parents.

Conclusion: The small percentage of infected children should be offered enrolment in well-designed clinical trials of optimal medical management for prevention of the predicted long-term outcomes of chronic HCV infection: chronic hepatitis, cirrhosis and hepatocellular carcinoma.     

An epidemiological survey of hepatitis C virus infection in Italian children in the decade 1990-1999.

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.     

Hepatitis C and G Virus infections in polytransfused children

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

Liver histology and alanine aminotransferase levels in children and adults with chronic hepatitis C infection

BACKGROUND: Chronic hepatitis C is often a mild disease in children, but whether this is related to younger age or shorter duration of infection is unclear. Histologic severity has been shown to correlate with duration of infection regardless of age. OBJECTIVES: We compared histologic findings in children and adults with chronic hepatitis C while controlling for sex, duration of infection, hepatitis C virus (HCV)-RNA level, and genotype. METHODS: Twenty-one children and 52 adults whose infection was less than 20 years in duration and who had undergone a liver biopsy were included. Two blinded liver pathologists reviewed the liver biopsies and scored inflammatory activity and fibrosis using the modified Knodell scoring system. RESULTS: The groups were the same with respect to HCV-RNA level (P=0.8), and genotype (P=0.6) but differed in duration of disease (P=0.01) and sex composition (P=0.005). Covariate analysis showed no influence of genotype, duration of infection, or HCV-RNA level on outcome. In controlling for sex, children had significantly milder liver disease and alanine aminotransferase (ALT) elevations. CONCLUSIONS: With equal duration of infection, HCV-RNA level, and genotype, children have lower serum ALT levels and less severe liver disease than adults infected with HCV.     

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

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

Spontaneous remission of chronic hepatitis C in children

The clinical course of 48 children with chronic hepatitis C (33 boys, 15 girls; mean age: 12.2 years) was monitored for more than 3 years to clarify its natural course. All patients were positive for the second-generation antibody to hepatitis C virus (anti-HCV) and for serum hepatitis C virus (HCV) RNA. All but one patient had a history of blood transfusion. Serum levels of alanine aminotransferase (ALT) had been abnormal for more than 1.5 years. Spontaneous remission defined as a biochemical remission lasting more than 1 year in association with the disappearance of serum HCV RNA, occurred in 4 (8.3%), however, in 25%, HCV RNA was still detectable in the liver even after its disappearance from serum. In this patient, the level of antibody to HCV core antigen (anti-HCV core) did not decrease significantly and serum HCV RNA eventually reappeared. The serum titre of HCV RNA in the 4 children with spontaneous remission was lower than in the remaining 44 children. Spontaneous remission may occur in children with chronic hepatitis C in whom the serum titre of HCV RNA is low and serum level of anti-HCV core decreases significantly. Assessment of the intrahepatic HCV RNA is necessary to confirm complete remission. Conclusion A low serum titre of HCV RNA and a significant decrease in the serum titre of anti-HCV core were associated with spontaneous remission in children with chronic hepatitis C. Intrahepatic HCV RNA assessment is necessary to confirm complete remission. Received: 9 April 1996 and in revised form: 8 April 1997 / Accepted: 15 April 1997     

Lymphoblastoid interferon alfa treatment in chronic hepatitis C

Interferon is becoming the standard treatment in adults for chronic hepatitis C. Twenty one children with histologically proved chronic hepatitis C (10 boys, range 2.5-13 years), who were otherwise healthy, were enrolled in a randomised controlled study to test their response to interferon alfa. Eleven children were treated with lymphoblastoid interferon alfa (3 million units/m2) for 12 months; 10 children received no treatment. All had raised transaminases and positive antihepatitis C virus (HCV) antibodies and HCV-RNA. Alanine aminotransferase (ALT) serum levels became normal in five (45%) treated patients after a mean of three weeks (range 1-6 weeks) and no relapse had occurred by the end of follow up (30th month). Only one (10%) untreated patient had normal ALT serum levels from the 11th until the 30th month. Disappearance of serum HCV-RNA, persisting throughout the follow up period, was observed in the six children (five treated) whose ALT became normal. Biopsy specimens in treated patients showed a significant improvement in Knodell's score (median (SD) basal 9.0 (2.2); final 2.0 (0.4)). Interferon treatment was well tolerated in all. This study confirms the efficacy of interferon in children with chronic hepatitis C, not only by restoring normal ALT serum levels, but also viral clearance and histological amelioration of liver inflammation. Contrary to reports in adults no biochemical and virological relapses occurred in responder children.     

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

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

Epidemiologic aspects and preventive strategy of hepatitis B and C viral infections in children with cancer.

AIMS: We present the efficacy of a strategy to control infections with hepatitis B (HBV) and C viruses (HCV) in children with cancer and assessment of risk for their relatives and health care personnel. A total of 1242 people entered the study, including 558 children with cancer, 193 relatives of infected children, 302 health care workers and 189 controls. METHODS: To stop dual HBV and HCV nosocomial infection in the oncology department, a preventive strategy was introduced. It involved immunoprophylaxis against HBV, screening blood donors for HCV infection, intensification of nonspecific prophylaxis, an educational program and estimation of risk for relatives of infected children and health care personnel. RESULTS: Retrospective analysis showed that the prevalence of HBV and HCV infections in children with cancer was 74 of 119 (62.2%) and 50 of 92 (54.3%), respectively, with the highest rate among patients with leukemia. Inferior anticancer therapeutic response were obtained in infected children. Specific anti-HBV immunoprophylaxis introduced simultaneously with anticancer therapy resulted in protection of 160 of 168 (95.2%) children in the first 4 years, when 62.9% of patients receiving therapy developed protective antibodies. Screening of blood donors and intensification of nonspecific prophylaxis reduced HCV prevalence to 2.8% during the most recent 1.5 years. Genotype analysis showed that the risk of HCV infection was 0.5% for relatives of infected children. The risk for health care personnel was 0 in the oncology ward and 1.9% in the other departments, and it reached 0.53% in control group. CONCLUSIONS: The preventive strategy of viral hepatitis in children with cancer, including passive-active HBV immunoprophylaxis from the beginning of chemotherapy and intensive nonspecific prophylactic measures is effective. With this strategy the risk of intrafamily and occupational infection is low.     

Clinical spectrum of HIV infection

OBJECTIVE: To study the modes of transmission of pediatric HIV infection, to categorize clinical manifestations and to compare clinical spectrum of perinatal with transfusion acquired HIV infection. DESIGN: Case series study. SETTING: Hospital based pediatric HIV clinic. METHODS: Children confirmed to have HIV infection were evaluated and relevant details recorded. RESULTS: 55 children were enrolled of whom 41 (74.5%) had perinatal transmission of HIV, 12 (21.8%) were infected through blood transfusions and 2 (3.6%) through other routes. Thirty-seven (90.2%) of the 41 perinatally infected children were symptomatic. Tuberculosis was seen in 25 (67.5%) of these children and failure to thrive in 18 (48.6%). Nonspecific features such as recurrent bacterial infection, oral candidiasis and chronic diarrhea were other manifestations. Eight (26.3%) of the 30 children available for follow up for a median period of 9 months died at the median age of 8.5 months. Amongst the transfusion acquired HIV infection, 11 (91.6%) of the 12 were asymptomatic at presentation. Six (50%) of these children died at the median age of 3 years and the remaining 6 had no major symptoms at a median follow up of 3.5 years. CONCLUSION: Perinatal route is the major route of HIV transmission in children and clinical manifestations are different from those of adults.     

Lymphoblastoid interferon alfa treatment in chronic hepatitis C.

Interferon is becoming the standard treatment in adults for chronic hepatitis C. Twenty one children with histologically proved chronic hepatitis C (10 boys, range 2.5-13 years), who were otherwise healthy, were enrolled in a randomised controlled study to test their response to interferon alfa. Eleven children were treated with lymphoblastoid interferon alfa (3 million units/m2) for 12 months; 10 children received no treatment. All had raised transaminases and positive antihepatitis C virus (HCV) antibodies and HCV-RNA. Alanine aminotransferase (ALT) serum levels became normal in five (45%) treated patients after a mean of three weeks (range 1-6 weeks) and no relapse had occurred by the end of follow up (30th month). Only one (10%) untreated patient had normal ALT serum levels from the 11th until the 30th month. Disappearance of serum HCV-RNA, persisting throughout the follow up period, was observed in the six children (five treated) whose ALT became normal. Biopsy specimens in treated patients showed a significant improvement in Knodell''s score (median (SD) basal 9.0 (2.2); final 2.0 (0.4)). Interferon treatment was well tolerated in all. This study confirms the efficacy of interferon in children with chronic hepatitis C, not only by restoring normal ALT serum levels, but also viral clearance and histological amelioration of liver inflammation. Contrary to reports in adults no biochemical and virological relapses occurred in responder children.     

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

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