Jia-Feng Wu

Mother-to-infant transmission of hepatitis B virus infection: Significance of maternal viral load and strategies for intervention

BACKGROUND & AIMS Immunoprophylaxis reduces but does not completely eradicate hepatitis B virus (HBV) transmission. This prospective study aims at assessing the rate and risk factors of maternally transmitted HBV infection. METHODS We enrolled 303 mother-infant pairs with positive maternal hepatitis B surface antigen (HBsAg) under current immunization program. Maternal viral load was determined by a real-time PCR-based assay. The children were tested for HBsAg at 4-8 months and/or 1-3 years of age. Rates of HBV infection were estimated using a multivariate logistic regression model. RESULTS HBeAg-positive mothers (81/303, 26.7%) had higher viral loads than HBeAg-negative mothers (7.4 ± 1.9 vs. 2.7 ± 1.4 log10 copies/ml, p<0.0001). Ten children, born to HBeAg-positive mothers with high viral load (median, 8.4; range, 6.5-9.5 log₁₀ copies/ml), were chronically infected. After adjustment for maternal age, birth type, factors related to maternal-fetal hemorrhage, gestational age, infant gender, birth weight, timeliness of vaccination, and feeding practice, maternal viral load was significantly associated with risk of infection (adjusted odds ratio for each log₁₀ copy/ml increase, 3.49; 95% confidence interval (CI), 1.63-7.48; p=0.001). The predictive rates of infection at maternal viral load levels of 7, 8, and 9 log₁₀ copies/ml were 6.6% (95% CI, 0.5-12.6%; p=0.033), 14.6% (95% CI, 5.6-23.6%; p=0.001), and 27.7% (95% CI, 13.1-42.4%; p<0.001), respectively. CONCLUSIONS Additional strategies to further reduce transmission should be considered in mothers with a viral load above 7-8 log₁₀ copies/ml.

Serum Levels of Interleukin-10 and Interleukin-12 Predict Early, Spontaneous Hepatitis B Virus e Antigen Seroconversion

BACKGROUND & AIMS This prospective cohort study aimed to determine the effect of cytokines on spontaneous hepatitis B e antigen (HBeAg) seroconversion in patients with chronic hepatitis B virus (HBV) infection. METHODS Polymorphisms in interleukin (IL)-2, IL-4, IL-10, IL-12beta, and interferon-gamma were evaluated in 288 HBeAg-positive chronic HBV patients (median initial age, 8.6 years; median follow-up duration, 19.3 years). Serum cytokine levels were determined in 154 subjects (53.5%) before and after HBeAg seroconversion by enzyme-linked immunosorbent assay analysis. Peripheral blood mononuclear cells (PBMC) were isolated from patients with chronic HBV infection and stimulated with HBV core antigen (HBcAg); data on cytokine genotypes and phenotypes were compared. RESULTS The IL-10-1082 G/G and IL-12beta -10993C/G genotypes predicted early, spontaneous HBeAg seroconversion (hazard ratio [HRs] = 3.43 and 1.54; P < .001, and P < .004, respectively), based on multivariate survival analysis. The IL-10 -1082 G/G genotype was associated with higher serum levels of IL-10 and IL-12; the IL-12beta -10993 C/G genotype predicted higher levels of IL-12 secretion by PBMC after in vitro HBcAg stimulation (P = .04). Higher levels of serum IL-12 (>45 pg/mL) and IL-10 (>70 pg/mL) were associated with early, spontaneous HBeAg seroconversion (HR = 1.52 and 1.48; P = .04 and .02, respectively). CONCLUSIONS The IL-10-1082 G/G is associated with higher serum IL-10 and IL-12 levels and IL-12beta -10993 C/G is associated with increased secretion of IL-12 in response to HBcAg stimulation of PBMC. Both genotypes are associated with early, spontaneous HBeAg seroconversion. Higher serum levels of IL-10 and IL-12 in HBeAg-positive patients are correlated with early, spontaneous HBeAg seroconversion.

Effects of the infant stool color card screening program on 5-year outcome of biliary atresia in Taiwan.

In Taiwan, a screening system using an infant stool color card to promote the early diagnosis of biliary atresia (BA) was established in 2002. This study aimed to investigate the 5‐year outcome of BA before and after using the screening program. BA patients were divided into three cohorts according to their birth dates. The patients in cohort A (n = 89) were born before the stool card screening program (1990‐2000); those in cohort B (n = 28) were screened by the stool card regional screening program (2002‐2003); and those in cohort C (n = 74) were screened by the stool card universal screening program (2004‐2005). The relative odds ratios were computed using logistic regression to compare the different factors affecting survival time. The rate of age at Kasai operation <60 days was 49.4% and 65.7% in cohorts A and B+C, respectively (P = 0.02). The jaundice‐free (total serum bilirubin <2.0 mg/dL) rate 3 months after surgery was 34.8% and 60.8% in cohorts A and B+C, respectively (P < 0.001). The 3‐year jaundice‐free survival rate with native liver was 31.5% in cohort A and 56.9% in cohort B+C (P < 0.001), whereas the 3‐year overall survival rates were 64.0% and 89.2%, respectively (P < 0.001). The 5‐year jaundice‐free survival rate with native liver was 27.3% in cohort A and 64.3% in cohort B (P < 0.001), and the 5‐year overall survival rates were 55.7% and 89.3%, respectively (P < 0.001). Conclusion: The stool color card screening program for BA allows for earlier Kasai operation, which increases the jaundice‐free rate at 3 months postsurgery. With higher surgical success rates, the 3‐ and 5‐year outcome of BA patients in Taiwan improves remarkably. (HEPATOLOGY 2011.)

No Increase in Prevalence of Hepatitis B Surface Antigen Mutant in a Population of Children and Adolescents Who Were Fully Covered by Universal Infant Immunization

BACKGROUND Mutants of the a determinant of hepatitis B surface antigen (HBsAg) can escape neutralization by vaccine-induced antibodies and prevail in an immunized population. METHODS We evaluated the a mutants in a pediatric population surveyed in 2004 and compared these findings with the data of previous surveys. RESULTS There were 38 children and 74 adolescents who were HBsAg positive, and serum hepatitis B virus (HBV) DNA was obtained and tested from 31 and 34 of them, respectively. The a mutants were found in 7 (22.6%) of 31 HBV DNA-positive children and in 7 (0.10%) of 7234 children, the entire population that was surveyed in 2004. After the beginning of universal immunization, the very low prevalence of mutants has remained unchanged for 20 years. More a mutants were found in immunized than in nonimmunized HBV DNA-positive children aged 1-4 years old (31% vs 4%, P = .016) but not in those children aged 5-12 years old. Approximately 68% of immunized, mutant-infected children had carrier mothers. More a mutants emerged in children immunized with plasma-derived vaccines than in those immunized with recombinant vaccines (14 of 5166 vs 3 of 4970, respectively; P = .04). HBV DNA levels were significantly lower in hepatitis B e antigen-positive sera containing the G145R mutant than were levels in sera containing wild-type virus. HBsAg-negative sera containing a mutants had very low HBV DNA levels. CONCLUSIONS Less infectivity of G145R, recombinant vaccine use, and mutant loss with older age seem to decrease the a mutant prevalence in an immunized population over time.

Clinical Implication of the C Allele of the ITPKC Gene SNP rs28493229 in Kawasaki Disease: Association With Disease Susceptibility and BCG Scar Reactivation.

Background: A functional single nucleotide polymorphism (SNP) (rs28493229) in the inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) gene has been linked to the susceptibility to Kawasaki disease (KD). The implication remains unclear. Subjects and Methods: Genotyping for the ITPKC polymorphism was conducted on 280 unrelated Taiwanese children with KD and 492 healthy ethnically and gender-matched controls. The clinical manifestations and laboratory data were systemically collected. Results: The GC and CC genotypes of ITPKC gene SNP rs28493229 were overrepresented in KD patients (GG:GC:CC was 236:43:1, C allele frequency: 8.04%) than those in the controls (GG:GC:CC was 454:37:1, C allele frequency: 3.96%; OR: 2.23, P = 0.001). In KD patients, those with GC or CC genotypes of SNP rs28493229 (19/44) were more likely to have reactivation at the Bacille Calmette-Guérin (BCG) inoculation site than those with GG genotypes (66/236; OR: 1.96, P = 0.044). Such association was particularly strong in patients aged <20 months (OR: 3.26, P = 0.017). The other clinical manifestations were not related to this SNP. There were 160 (57.1%) patients with coronary arterial lesions. The development and the severity of coronary arterial lesion were also not associated with this SNP. Comparison between patients with and without BCG reactivation revealed only one difference: patients with reactivation were younger. Conclusion: In a cohort from a population with the worlds third highest incidence of KD, we demonstrated that the C-allele of ITPKC SNP rs28493229 is associated with KD susceptibility and BCG scar reactivation during the acute phase, although its frequency is lower than that in the Japanese cohort (22.6%), suggesting this SNP contributes to KD susceptibility through induced hyperimmune function reflected in the BCG reactivation.

Toll-like Receptor and Hepatitis B Virus Clearance in Chronic Infected Patients: A Long-Term Prospective Cohort Study in Taiwan

BACKGROUND We sought to elucidate the impacts of the Toll-like receptors (TLRs) on spontaneous hepatitis B virus (HBV) e antigen (HBeAg) and hepatitis B s antigen (HBsAg) seroconversion in chronic HBV-infected patients. METHODS Human TLR2, TLR4, TLR5, and TLR9 gene polymorphisms were assessed in 278 HBeAg-positive, chronic HBV-infected patients. Additionally, HBV core antigen (HBcAg) in vitro stimulation using peripheral blood mononuclear cells (PBMCs) from 113 patients was done to assess interferon γ (IFN- γ) production. RESULTS Of the study subjects, 204 (73.4%) developed spontaneous HBeAg seroconversion, 21 (7.6%) developed spontaneous HBsAg clearance, and 10 (3.6%) had spontaneous HBsAg seroconversion during the 19.1 ± 9.9 years of follow-up. The T allele at TLR5 rs5744174 (p.Phe616Leu) and the C allele at TLR9 rs5743836 promoter predicted earlier HBeAg seroconversion (hazard ratios [HRs], 2.45 and 3.65; P = .04, and .006, respectively). The TLR5 rs5744174 T allele carriers have higher PBMCs IFN-γ secretion to HBcAg stimulation (P= .0002). The G allele carriers at TLR4 rs4986790 (p.Asp299Gly) predicted spontaneous HBsAg seroclearance (HR, 18.73; P < .001) and seroconversion (HR, 43.45; P < .001). CONCLUSIONS Toll-like receptor 5 rs5744174 (p.Phe616Leu) and TLR9 rs5743836 promoter area polymorphism were associated with earlier spontaneous HBeAg seroconversion. Toll-like receptor 4 rs4986790 (p.Asp299Gly) was associated with HBsAg seroclearance/seroconversion in chronic HBV patients. Toll-like receptor 5 rs5744174 (p.Phe616Leu) was associated with higher IFN-γ production in chronic HBV-infected patients.

Effect of Puberty Onset on Spontaneous Hepatitis B Virus e Antigen Seroconversion in Men

BACKGROUND Male predominance is a remarkable phenomenon in hepatitis B virus (HBV)-related liver disease. This study elucidated the effects of puberty on spontaneous hepatitis B virus e antigen (HBeAg) seroconversion in boys. METHODS One-hundred HBeAg-positive chronic HBV-infected males recruited at younger than 10 years of age who had been followed for >10 years were selected randomly from our long-term followed cohort into this study. Serum testosterone levels, androgen receptor exon-1 CAG repeat number and steroid 5alpha reductase type II (SRD5A2, valine vs leucine alleles) polymorphism were determined. Serial clinical data, HBV genotype, and spontaneous HBeAg seroconversion age were also analyzed. RESULTS Seventy-two subjects had spontaneous HBeAg seroconversion during the follow-up period. Subjects with serum testosterone levels > or =2.5 ng/mL at 15 years old (earlier-onset puberty, n = 87) had earlier HBeAg seroconversion (median age, 13.2 vs 22.5 years; hazard ratio = 2.95; P = .005), higher peak alanine aminotransferase levels when HBeAg positive (305.7 +/- 372.7 vs 154.8 +/- 126.0 IU/L; P = .006), and a greater HBV viral load reduction from 10 to 20 years of age (1.6 +/- 2.4 vs 0.2 +/- 1.4 log10 copies/mL; P = .009) than those with serum testosterone levels <2.5 ng/mL (later-onset puberty, n = 13). Valine allele carrier at the SRD5A2 V89L polymorphism was also associated with earlier spontaneous HBeAg seroconversion (median age, 11.7 vs 18.7 years; hazard ratio = 1.88; P = .028). CONCLUSION Earlier-onset puberty and increased SRD5A2 enzyme activity are associated with earlier HBeAg seroconversion, higher serum alanine aminotransferase levels, and a greater HBV viral load decrement in chronic HBV infected males.

Tumour necrosis factor-α promoter region polymorphisms affect the course of spontaneous HBsAg clearance

Background: This study aimed to investigate the roles of tumour necrosis factor‐α (TNF‐α) gene polymorphisms in the spontaneous clearance of HBsAg after a hepatitis B virus (HBV) infection.

Natural history of chronic hepatitis B virus infection from infancy to adult life -the mechanism of inflammation triggering and long-term impacts

Chronic hepatitis B virus (HBV) infection in endemic areas usually starts since infancy and early childhood and persists lifelong. The clinical course varies among different chronic infected subjects. Majority of chronic HBV infected children present with immune-tolerant status initially, experience the immune clearance phase with various degree of liver injury during or beyond puberty, and then enter the inactive phase after hepatitis B e antigen (HBeAg) seroconversion. Part of them may have HBV DNA titers elevation with hepatitis flare after HBeAg seroconversion, the so call HBeAg-negative hepatitis flare. Liver cirrhosis, and even hepatocellular carcinoma may develop afterward.The complex course of chronic HBV infection is associated with the age/route of viral acquisition, host factors such as immune and endocrine factors, viral factors, and host-viral interactions. The adrenarche and puberty onset modulate the start of immune clearance and the severity of liver inflammation in chronic HBV infected children. The genotype and phenotype of human cytokines, innate immunity, and human leukocyte antigens are also associated with the onset of immune clearance of HBV and severity of inflammation. Immune escape HBV mutant strains, emerged during the immune clearance phase under host immune surveillance, may cause different impacts on viral biosynthesis, host immune responses, and clinical course.Early events in childhood during chronic HBV infection may serve as important predictors for the later outcome in adulthood. Understanding the mechanisms triggering liver inflammation and their long-term impacts may enhance the development of better and earlier therapeutic strategies for patients with chronic HBV infection.

Clinical features and treatment responses of children with eosinophilic gastroenteritis.

BACKGROUND Clinical features and treatment responses in pediatric patients with eosinophilic gastroenteritis are rarely reported. This study aimed to evaluate the clinical manifestations and outcome of eosinophilic gastroenteritis in children of Asian background. METHODS Between 1997 and 2009, 14 Taiwanese patients (nine boys and five girls), with median age of 8.3 years (range, 1.4-14.3 years), were diagnosed with eosinophilic gastroenteritis. The diagnosis was confirmed by the presence of gastrointestinal symptoms, peripheral eosinophilia, and a histology-proved biopsy. The clinical data and responses to medical treatment were analyzed. RESULTS Initial symptoms included abdominal pain (43%), anemia (36%), hypoalbuminemia (14%), recurrent vomiting (7%), bloody stool (7%), and growth failure (7%). Peripheral eosinophilia was present in 10 patients (71.4%) and positive stool occult blood in seven patients (50%). Endoscopic examination revealed ulcer disease in four patients (28.6%). The treatment included steroid alone, montelukast alone, steroid+montelukast, and steroid+montelukast+ketotifen. Among the patients treated with steroid, two (two of nine, 22%) had successfully tapered off steroid without recurring symptoms. Three patients (three of nine, 33%) had relapses after discontinuing steroid, three (three of nine, 33%) still required low-dose steroid, and one lost to follow-up. There was no relapse in the four patients treated with montelukast alone. CONCLUSIONS A high percentage of patients presented with gross or occult gastrointestinal bleeding with or without abdominal pain. Endoscopic biopsy is necessary for diagnosis. Steroid was the mainstay treatment for active diseases; montelukast was also effective for the disease or as a maintenance therapy in this study.