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.     

Interferon for chronic hepatitis C in patients cured of malignancy

Six patients with chronic hepatitis C who were cured of malignancy were treated with recombinant interferon-alpha at the dose of 4 MU/m² for 12 months; the post-treatment follow up period was 12 months. Therapy was stopped within 6 months in three patients because of persistently abnormal alanine aminotransferase levels. In the remaining three patients, a complete normalization of alanine amnotransferase levels was obtained during treatment but it was not maintained after the end of interferon therapy. In addition, no patient cleared hepatitis C virus ribonucleic acid in serum. These results suggest that recombinant interferon is not effective in patients with chronic hepatitis C who were cured of a previous malignancy.     

Hepatitis C virus antibodies in a long-term follow-up of beta-thalassaemic children with acute and chronic non-A non-B hepatitis

The presence of antibodies toward hepatitis C virus (HCV) was examined in 78 polytransfused betathalassaemic children. The anti-HCV status was correlated with acute and chronic non-A non-B (NANB) hepatitis that developed during a follow up of about 13 years. Anti-HCV was present in 83.3% of children with acute NANB hepatitis and in 82.9% of those with chronic NANB hepatitis. The percentage of chronic evolution was 56.7% for acute anti-HCV positive NANB hepatitis and 50.0% for anti-HCV negative NANB hepatitis. The long-term persistence of anti-HCV antibodies did not correlate with chronic evolution of liver infection in thalassaemic patients. Histological features of chronic hepatitis showed little or no difference between HCV associated or non-associated liver disease. The multifactorial liver injury in beta-thalassaemic children explains the high prevalence of cirrhosis (about 30%) observed in these patients with NANB hepatitis. On the other hand, independent of liver disease, some patients never seroconverted during the follow up in spite of the high number of transfusions suggesting the existence of non-responders.     

Management of chronic hepatitis B and C virus infections

Hepatitis B and C virus (HBV and HCV) infections present an important health problem causing significant morbidity and mortality on a worldwide scale. The younger the subjects infected, the higher the risk predisposing to progression towards chronic infection. Treatment of chronic HBV and HCV infections is aimed at reducing hepatic inflammation and thus improving the symptoms, decreasing the likelihood of long-term sequelae such as hepatocellular carcinoma, and increasing the survival rate. Interferon accelerates the spontaneous course of chronic HBV infection in children with greater disease activity and lower levels of replication. There is limited information on the use of lamivudine and its long-term benefit in children with chronic HBV infection. The response of combination therapy with IFN and ribavirin in children with chronic HCV infection is still under investigation. The long-term clinical and virological effects of various drugs used in chronic HBV and HCV infections on children remain to be evaluated.     

Virus genotype 1b and long-term response to interferon alpha monotherapy in children with chronic hepatitis C

Interferon alpha (IFN-) remains the basic modality in the treatment of chronic hepatitis C in children, but the effects of therapy are still unsatisfactory. The aim of this study was to evaluate parameters linked to IFN- response within a 2-year period. Human C virus (HCV) infected children (n=34) were subdivided into IFN-treated (n=20) and IFN-untreated (n=14 control) groups. The IFN-treated group received a dosage 3 MU of IFN- three times a week for 24 weeks. Liver biopsy was performed in all IFN-treated children and the HCV genotype was determined before the start of the study. Patients were sequentially screened for alanine transaminase (ALT) activity and tested for the presence of HCV-RNA in serum. All patients had either mild persistent or moderate active hepatitis, which was diagnosed from the liver biopsy. In the IFN-treated group ALT normalisation was observed by the end of treatment in 9/20 patients, but after 6 months 10 patients (50%) had sustained ALT normalisation and in 4 of them the virus was eliminated. They continued to show these features up to the end of the observation period (2 years). Eighteen out of 24 children tested had 1b genotype of virus. Out of 10 responders, all patients who were clear of HCV had the 1b genotype. The median age of responders (6.0, range 3.8–16) was significantly lower than non-responders (14.0, range 4–15) In the control group none of the children were clear of HCV-RNA. Conclusion: The negative predictive effect of HCV genotype 1b in the course of IFN- treatment may be not valid in children and other features have to be taken into account in the assessment of the efficacy of therapy.Abbreviations HCV human C virus - RNA ribonucleic acid - PCR polymerase chain reaction - ALT alanine aminotransferase - RBC red blood cells - HBsAg hepatitis B surface antigen - ELISA enzyme linked immunosorbent assay - CMV cytomegaly virus - IFN interferon - MU mega units - ETR end of treatment response - SR ALT sustained biochemical (ALT) response - HAI histological activity index - R responders - NR non-responders - U/l units per litter - CPH chronic persistent hepatitis - CAH chronic active hepatitis - APC antigen presenting cells - MHC major histocompatibility complex - ALL acute lymphoblastic leukaemia - CML chronic myelogenous leukaemia     

Treatment of chronic hepatitis C in children

Since the discovery of hepatitis C virus (HCV) in 1989, significant advances have been made in our understanding of this important viral pathogen. Children at risk for HCV infection include recipients of potentially contaminated blood products and organ transplants, and infants born to HCV-infected mothers. Chronic HCV infection is usually asymptomatic in children but active hepatitis, cirrhosis and hepatocellular carcinoma can occur. The development of treatment strategies for chronic hepatitis C in children has directly evolved from clinical trials in adults. Sustained virologic response, defined by undetectable HCV RNA in serum 24 wk after completion of treatment, occurs in approximately 36% of children treated with conventional interferon alone and in about 50% of those given conventional interferon in combination with ribavirin. Pegylated interferon-based treatment regimens are better than those based on conventional interferon in adults but little is known about pegylated interferon in children. Factors associated with a favorable response to antiviral therapy in children are similar to those in adults and include infection with HCV genotype 2 or 3 and low pretreatment serum HCV RNA levels. Treatment related adverse events in children include 'flu-like' syndrome, fatigue, anorexia, weight loss, depression, anemia, leukopenia and thrombocytopenia.     

The management of infants,children, and youth at risk for hepatitis C virus infection

Hepatitis C virus (HCV) infection affects 0.5% to 1.0% of the Canadian population. Most paediatric HCV infections are a consequence of vertical transmission or, among youth and young adults, the result of engaging in high-risk behaviours, such as injection drug use and unprotected sexual activity. It is now recommended that all infants, children, and youth with one or more risk factors be screened for HCV infection. Treating chronic HCV infection with direct-acting antivirals has been shown to achieve sustained virologic suppression in 97% to 100% of children as young as 3 years old. Paediatricians and family physicians have an important role in educating youth regarding HCV infection risks and prevention, and in advocating to government and public health authorities for comprehensive harm reduction interventions targeting at-risk youth, accessible treatments, and routine prenatal screening for HCV.     

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.     

Chronic viral hepatitis B in childhood

The results of clinical, biochemical and histological studies in 26 children with chronic hepatitis B are reported.Most cases were detected when diagnostic procedures were arranged because of non specific abdominal complaints, by routine tests after acute hepatitis or multiple transfusions, and by examination of family members.Hepatomegaly was found in half of the cases, splenomegaly in a quarter. Other clinical signs were rarely seen.Among the biochemical findings, elevated serum transaminase activities were the most reliable indicators of chronic hepatitis. There was a significant difference of the mean transaminase activities between patients with CPH and CAH.In 15 children CPH was diagnosed histologically. 9 children had CAH, 2 children showed signs of MinH.Abbreviations used HBV hepatitis B virus - HBsAg hepatitis B surface antigen - anti-HBs antibody to HBsAg - CH chronic hepatitis - CPH chronic persistent hepatitis - CAH chronic aggressive hepatitis - MinH minimal hepatitis - GOT glutamate oxaloacetate transaminase - GPT glutamate pyruvate transaminase - GT gamma-glutamyltranspeptidase - ChE cholinesterase - GIDH glutamate dehydrogenase     

Spontaneous pneumomediastinum in children: Clinical and natural history

Investigation of the clinical characteristics and natural history of nine children with spontaneous pneumomediastinum (SPM) was conducted at the Tel Aviv University Sheba Medical Centre between 1984 and 1994. Most cases occurred in the setting of a valsalva-type manoeuvre, while symptoms and signs on admission were mainly chest pain, dyspnoea, neck pain, subcutaneous emphysema, and Hamman's sign. Three clinical patterns concerning longterm sequelae were identified: patients without any long-term sequelae, patients with a tendency to airway hyperreactivity and subclinical asthma, and patients in whom SPM was the presenting feature of their asthma.Currently at the Weizmann Institute of Science     

Safety and efficacy of interferon retreatment in children with chronic hepatitis B

More than 50% of children with chronic hepatitis B do not respond to treatment with alpha-interferon. Since these patients continue to display high viral replication and progressive liver disease, retreatment should be considered. To date it has not been well evaluated whether a second course of treatment could increase the response rate. In two alpha-interferon retreatment trials in adult patients the response rate, defined by seroconversion from HBeAg to anti-HBe, ranged between 11% and 44%. One beta-interferon retreatment study in children reported a seroconversion rate of 32%. Regrettably, none of the studies included a control group observing the `spontaneous' seroconversion rate after a first interferon cycle. Thus, a nonrandomized alpha-interferon retreatment study in children including control patients was performed. Alpha-interferon for retreatment was administered 3 times a week for 16–24 weeks in 15 children (5–16 years) at least 6 months after ceasing the first cycle. Four children received 5 MU/m² of a natural alpha-interferon and 11 children 9 MU/m² recombinant alpha-interferon 2b. Follow up was 18–47 months after initial treatment. In parallel, a control group of 19 un-retreated children with comparable clinical and demographic data was followed for 12–39 months. HBeAg seroconversion was observed in 5 (33%) of the retreated children and in 5 (26%) of the control patients during follow up. The difference is not significant. In the initially nonresponding children, those with high ALT levels before the first treatment showed late HBeAg seroconversion more frequently than those with low ALT levels (P = 0.017) irrespective of retreatment. The ALT level before retreatment was not a predictor for response. Conclusions A second cycle of alpha-interferon during the 3 years following the first treatment in nonresponding children with chronic hepatitis B can be safely performed but did not increase HBeAg/anti-HBe seroconversion compared with the spontaneous seroconversion rate of patients without retreatment. Received: 29 July 1997 / Accepted in revised form: 23 October 1997     

Interferon therapy for Japanese hemophiliacs with chronic hepatitis C

Eight Japanese hemophiliacs with chronic hepatitis C (CHC) received interferon (IFN) therapy and four of them (50%) responded completely. Non-responders included 3 double-infected patients: I with hepatitis B virus (HBV) and 2 with human immunodeficiency virus-1 (HIV-1). In one of the patients with HIV-1 double infection, the absolute number of CD4* lymphocytes decreased during IFN therapy. These findings suggest that hemophiliac patients with CHC can respond well to IFN therapy, but in patients who are double-infected with HBV and HIV-1, the indication of IFN therapy should be considered seriously.     

Spontaneous remission of a diffuse brainstem lesion in a neonate

We describe here the spontaneous remission of a diffuse brainstem lesion found in an infant at the age of 7 weeks. Clinical and MRI characteristics strongly suggested a diffuse pontine glioma. Repeated MRI studies showed a continuous decrease in the size of the lesion, which was no longer visible by the age of 27 months. Spontaneous remission of diffuse pontine glioma is extremely rare; to our knowledge there are reports of only three similar cases.     

Incidence and morbidity of infection by hepatitis C virus in children with acute lymphoblastic leukaemia

A group of 90 patients with acute lymphoblastic leukaemia (ALL) in first continuous complete remission (CCR), admitted in our hospital between January 1986 and September 1992, were tested for the presence of antibodies against hepatitis C virus (HCV), antibodies against hepatitis B virus and antibodies against HIV-1 during maintenance therapy or thereafter. They were compared with a group of 71 children with other malignancies in first CCR who had been diagnosed consecutively from January 1986 to September 1992. No patient with ALL or any other malignancy was found to be positive for hepatitis B surface antigen or HIV-1. HCV-specific antibodies were detected in 28 out of 87 children (32.1%) with ALL and in 4 out of 44 patients (9%) with malignancies other than ALL who had received at least one transfusion of blood or platelets (P<0.01). HCV-specific antibodies were also detected in one out of three untransfused children with ALL but in none of the untransfused children with malignancies other than ALL. HCV-specific seropositivity influenced the management of children with ALL during maintenance therapy. In fact, as a result of abnormal liver function tests, maintenance therapy had to be suspended significantly more often in the case of HCV-seropositive patients with ALL than in HCV-seronegative ones. Despite the high morbidity during maintenance therapy, chronic liver disease (CLD) was uncommon in both groups: five children with ALL (17.2% of HCV-seropositive children) and one child with a malignancy other than ALL (25%) had CLD. If a follow up for a longer period confirms these observations the impact of HCV-related CLD on the quality of life and survival of patients with ALL or other malignancies will probably be minimal.     

儿童乙型肝炎血清乙型肝炎病毒共价闭合环状DNA与临床和病理分级分期的关系

目的 了解慢性乙型肝炎患儿血清乙型肝炎病毒共价闭合环状DNA(hepatitis B virus covalently closed circle DNA,HBV cccDNA)与病情、肝功能指标及肝组织病理变化的关系.方法 选择HBV-DNA阳性124例乙型肝炎患儿,其中携带者65例,慢性乙型肝炎59例(轻度31例、中度18例、重度10例),检测其血清HBV cccDNA及肝功能,对其中的46例患儿进行了肝脏穿刺,对肝组织进行炎症分级及纤维化分级.结果 中、重度慢性乙型肝炎患儿血清HBV cccDNA阳性率(77.8％、100％)高于携带者和轻度组(32.3％、54.8％)(x2=25.429,P＜0.01),患儿病情越重外周血HBV cccDNA检出率越高.血清HBV cccDNA阳性组的谷丙转氨酶、谷草转氨酶、总胆红素[(95.6±18.2) U/L、(88.8±20.3)U/L、(68.4±24.6)μmol/L]均高于阴性组[(52.5±17.7) U/L、(48.4±21.4) U/L、(28.3±23.9) μmol/L](t=15.572、10.750、17.067,P均＜0.01).血清cccDNA与肝组织炎症活动度和纤维化程度无明显相关性.结论 血清HBV cccDNA是代表病毒复制的一个敏感指标,病情越重,外周血HBVcccDNA检出率越高,但其与肝组织炎症及纤维化并非完全一致,所以其不能完全反映肝脏的损伤程度.     

小儿慢性乙型肝炎干扰素治疗引起的抗纤维化效应

目的观察儿童慢性乙型肝炎(CHB)应用α-干扰素(IFN-α)治疗引起的抗纤维化效应。方法30例小儿CHB应用IFN-α治疗24周以上,且停药后随访36周,其中5例治疗前后均行肝活体组织检查。所有患儿均在治疗前、治疗后24周和36周,应用放射免疫法检测患儿血清肝纤维化标志物:透明质酸(HA)、层连蛋白(LN)、Ⅳ型胶原(Ⅳ-C)。结果应用IFN-α治疗前(0周)、治疗后24周和36周,小儿CHB血清肝纤维化标志物HA值分别为(243.6±70.5)ng/mL、(145.2±51.6)ng/mL、(85.1±40.3)ng/mL;LN值分别为(180.5±61.3)ng/mL、(102.7±40.6)ng/mL、(62.8±32.6)ng/mL;Ⅳ-C值分别为(137.1±48.6)ng/mL、(108.9±40.3)ng/mL、(70.5±30.7)ng/mL,治疗后血清肝纤维化标志物较治疗前显著下降(P<0.05)。肝活体组织病理检查显示,治疗后肝组织纤维化分期比治疗前有明显降低(P<0.01)。结论IFN-α在治疗小儿CHB时,不仅有抗病毒作用,在改善肝纤维化方面,也具有一定疗效。     

Cellular cytotoxicity against autologous hepatocytes in children with different forms of chronic hepatitis B

Cell-mediated immune reactions play the most important role in the pathogenesis of chronic viral and auto-immune hepatitis. Cellular cytotoxicity (CC) of peripheral blood lymphocytes against autologous hepatocytes isolated from liver biopsies was studied in 29 children with different types of hepatitis B surface antigen (HBsAg)-positive hepatitis. Children with chronic hepatitis B showed higher cytotoxicity than control patients. However, a correlation of cytotoxicity to serum amino-transferases, HBeAg-/Anti-HBe-status, and hepatitis B virus DNA in serum could not be found. Children with a higher percentage of hepatitis B core antigen (HBcAg) expression in their liver tissue presented lower CC values, and vice versa. This supports the hypothesis that virus elimination occurs via T-cell attack against HBcAg expressing hepatocytes. Furthermore, children with a longer duration of chronic hepatitis B had considerably higher cytotoxicity values. Possibly, CC plays a role in perpetuating liver damage after infection with hepatitis B virus.     

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