Hepatitis: Yuen KY

Cheng VC, Yuen KY, Chan WM, Wong SS, Ma ES, Chan RM. · Department of Microbiology, Queen Mary Hospital, Hong Kong, People's Republic of China. · Clin Infect Dis. · Pubmed #10880300 No free full text.

Abstract: Immunorestitution disease (IRD) is defined as an acute symptomatic or paradoxical deterioration of a (presumably) preexisting infection that is temporally related to the recovery of the immune system. We report the temporal sequence of events that led to IRD caused by Pneumocystis carinii and Aspergillus terreus in 2 human immunodeficiency virus (HIV)-negative patients soon after the recovery of adaptive and innate immunity, respectively, and we review episodes noted in the English-language literature that fit the definition of IRD (109 episodes in 107 patients). The median time from the recovery of neutrophil counts or termination of steroid therapy to the development of IRD was 8 days in cases of pulmonary aspergillosis (23 episodes) and hepatosplenic candidiasis (8) and 21 days for viral diseases such as hepatitis B (24) and viral pneumonitis (6). For IRD due to mycobacteriosis (27 episodes) and cryptococcosis (4) in HIV-positive patients, the median interval between the initiation of highly active antiretroviral therapy (HAART) and the onset of IRD was 11 days; for viral infections, including those due to cytomegalovirus (14), hepatitis B virus (1), and hepatitis C virus (2), the median interval was 42 days. As an emerging clinical entity, IRD merits further study to optimize treatment of immunosuppressed patients.

Chu CM, Cheng VC, Hung IF, Wong MM, Chan KH, Chan KS, Kao RY, Poon LL, Wong CL, Guan Y, Peiris JS, Yuen KY, Anonymous00302. · Department of Microbiology and Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong. · Thorax. · Pubmed #14985565 links to  free full text

Abstract: BACKGROUND: The clinical response of patients with severe acute respiratory syndrome (SARS) to a combination of lopinavir/ritonavir and ribavirin was examined after establishing the in vitro antiviral susceptibility of the SARS associated coronavirus to a panel of antiviral agents. METHODS: The in vitro susceptibility of the prototype of SARS associated coronavirus to a panel of nucleoside analogues and protease inhibitors currently licensed for clinical use was studied. Forty one patients with SARS followed for 3 weeks were treated with a combination of lopinavir/ritonavir and ribavirin. The clinical progress and virological outcomes were monitored and compared with 111 patients treated with ribavirin only who served as historical controls. RESULTS: In vitro antiviral activity against SARS associated coronavirus was demonstrated for lopinavir and ribavirin at concentrations of 4 micro g/ml and 50 micro g/ml, respectively, only at 48 hours. The adverse clinical outcome (ARDS or death) was significantly lower in the treatment group than in the historical controls (2.4% v 28.8%, p<0.001) at day 21 after the onset of symptoms. The adverse outcome remained significantly lower in the treatment group than in the controls-both those diagnosed early (p<0.001) and those diagnosed later in the course of the epidemic (p = 0.002)-but there was no significant difference in adverse outcome rates between the two time periods (p = 0.548). No time related difference in outcome was observed in the control groups. A reduction in steroid usage and nosocomial infections was seen in patients initially treated with lopinavir/ritonavir, and these patients had a decreasing viral load and rising peripheral lymphocyte count. Multivariate analysis showed that age, hepatitis B carrier status, and lack of treatment with this antiviral combination were independent predictors of an adverse outcome. Lopinavir/ritonavir treatment was associated with a better outcome even when adjusted for baseline lactate dehydrogenase level. CONCLUSIONS: The apparent favourable clinical response with lopinavir/ritonavir and ribavirin supports further randomised placebo controlled trials in patients with SARS.

Zhou J, Huang JD, Poon VK, Chen DQ, Chan CC, Ng F, Guan XY, Watt RM, Lu L, Yuen KY, Zheng BJ. · Department of Microbiology, Research Centre of Infection and Immunology, The University of Hong Kong, Pokfulam, Hong Kong. · J Hepatol. · Pubmed #19501422 No free full text.

Abstract: BACKGROUND/AIMS: We previously demonstrated that two linked single nucleotide polymorphisms (SNPs) at -408 and -3 of type I interferon receptor 1 (IFNAR1) promoter are associated with susceptibility to chronic HBV infection. We aimed to elucidate the mechanism by which -3 and/or -408 C/T SNPs had such profound effects. METHODS: A functional SNP in IFNAR1 promoter was defined by reporter gene assay, mutational analysis, flow cytometry analysis and gel shift assay. The nuclear protein binding to the essential polymorphic site was identified and its effect on transcriptional regulation of IFNAR1 was further demonstrated in a series of ex vivo and in vivo experiments. RESULTS: We found C>T change at the -3 locus reduced the transcriptional activity of IFNAR1 promoter. High mobility group B protein 1 (HMGB1) and PARP-1 were co-recruited to the IFNAR1 promoter to regulate its transcription. We demonstrated HMGB1-binding affinity to IFNAR1 promoter was reduced in the -3T variant. Additionally, PARP-1, a cofactor for IFNAR1 transcription activation, was significantly suppressed by HBV. CONCLUSION: Upon HBV infection, decreased binding affinity of HMGB1 to the IFNAR1 promoter -3T variant is aggravated by the suppressed PARP-1 expression caused by HBV, resulting in a further attenuated IFNAR1 expression. This compromises the antiviral and immuno-regulatory effects of IFN-alpha/beta, which may in turn affect the clinical outcome of HBV infection.

Zhou J, Chen DQ, Poon VK, Zeng Y, Ng F, Lu L, Huang JD, Yuen KY, Zheng BJ. · Department of Microbiology, The University of Hong Kong, Pokfulam, Hong Kong, Hong Kong SAR, China. · Immunogenetics. · Pubmed #19488747 No free full text.

Abstract: The antiviral cascade triggered by interferon-gamma (IFN-gamma) represents a vital event for eradicating hepatitis B virus (HBV) in experimental animals. IFN-gamma signaling is mediated through the ligand binding to IFN-gamma receptor 1 (IFNGR1). Control of IFNGR1 expression level is one of the mechanisms by which cells modulate the potency of IFN-gamma signaling. In this study, we comprehensively investigated the single nucleotide polymorphisms (SNPs) in IFNGR1 gene and correlated their occurrence to susceptibility to HBV infection in a Chinese population. A total of 983 participants, including 361 chronic hepatitis B patients, 256 individuals who had spontaneously recovered from HBV infection, and 366 healthy control subjects, were enrolled in the study. Polymerase chain reaction-restriction fragment length polymorphism was used to identify seven SNPs (-611A/G, -56C/T, 40G/A, 95C/T, 130A/G, 20685A/G, 21227T/C) in IFNGR1 gene. We found that -56C and -56T allele were associated with viral clearance and viral persistence, respectively (P = 0.014). In a reporter-driven assay, we validated that the promoter variant with -56C exhibited a higher transcription level than that with -56T in HepG2 cells in a cell-type-specific pattern. We conclude that a functional -56C/T SNP in IFNGR1 promoter is associated with the clinical outcome of HBV infection in this Chinese population.

Li Z, He ML, Yao H, Dong QM, Chen YC, Chan CY, Zheng BJ, Yuen KY, Peng Y, Sun Q, Yang X, Lin MC, Sung JJ, Kung HF. · Department of Microbiology, The Chinese University of Hong Kong, Hong Kong, China. · BMB Rep. · Pubmed #19192395 links to  free full text

Abstract: Hepatitis B virus (HBV) infection is highly prevalent worldwide. The major challenge for current antiviral treatment is the elevated drug resistance that occurs via rapid viral mutagenesis. In this study, we developed AAV vectors to simultaneously deliver two or three shRNAs targeting different HBV-related genes. These vectors showed markedly better antiviral effects than ones that delivered a single shRNA in vitro. A dual shRNA expression vector (AAV-157i/1694i), which simultaneously expressed two shRNAs targeted the S and X genes of HBV, reduced HBsAg, HBeAg and HBV DNA levels by 87+/-4, 80.3+/-2.6 and 86.2+/- 7% respectively, eight days post-transduction. In a mouse model of prophylactic treatment, HBsAg and HBeAg were reduced to undetectable levels and the serum HBV DNA level was reduced by at least 100 fold. These results indicate that AAV-157i/1694i generates potent anti-HBV effects and that the strategy of constructing multi-shRNA expression vectors may lead to enhanced anti-HBV efficacy and overcome the evading mechanism of the virus and thus the development of drug resistance. [BMB reports 2009; 42(1): 59-64].

Zhou J, Smith DK, Lu L, Poon VK, Ng F, Chen DQ, Huang JD, Yuen KY, Cao KY, Zheng BJ. · Department of Microbiology, The University of Hong Kong, Hong Kong, China. · J Viral Hepat. · Pubmed #18761606 No free full text.

Abstract: The type I interferon (IFN-alpha/beta) receptor 1 (IFNAR1) mediates the potent antiviral and immuno-regulatory effects of IFN-alpha/beta that are believed to be pivotal to eradicate hepatitis B virus (HBV) infection. IFNAR1 promoter polymorphisms (at -568/-77) have been shown to be associated with susceptibility to chronic HBV infection; however, whether these markers are genetic determinants of HBV infection remains unknown. The functional significance of promoter -568/-77 polymorphisms was assessed by mutagenesis and luciferase assays. Sequencing and restriction fragment length polymorphisms in 328 chronic HBV patients, 130 spontaneous resolvers and 148 healthy blood donors identified other polymorphism at IFNAR1 open reading frame. IFNAR1 expression levels in peripheral blood cells were detected by flow cytometry. We found that the -568/-77 promoter variants were unlikely to affect transcription levels. A C/G single nucleotide polymorphism, in strong linkage disequilibrium with the promoter polymorphisms, was found in the coding sequence of IFNAR1 (nt19158). This resulted in a nonsynonymous substitution in the extracellular region of IFNAR1 protein and correlated with susceptibility to chronic HBV infection. Bioinformatic analysis suggested decreased stability of the IFNAR1 protein. Chronic HBV patients with the 19158C/C genotype (Leu141) exhibited higher IFNAR1 protein expression levels in peripheral blood monocytes than those with the 19158G/G genotype (Val141). In conclusion, IFNAR1 19158C/G polymorphism is primarily associated with susceptibility to chronic HBV infection.

Lau SK, Woo PC, Tse H, Fu CT, Au WK, Chen XC, Tsoi HW, Tsang TH, Chan JS, Tsang DN, Li KS, Tse CW, Ng TK, Tsang OT, Zheng BJ, Tam S, Chan KH, Zhou B, Yuen KY. · State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong Special Administration Region, Hong Kong SAR. · J Gen Virol. · Pubmed #18632954 links to  free full text

Abstract: Human parvovirus 4 (PARV4), a recently discovered parvovirus found exclusively in human plasma and liver tissue, was considered phylogenetically distinct from other parvoviruses. Here, we report the discovery of two novel parvoviruses closely related to PARV4, porcine hokovirus (PHoV) and bovine hokovirus (BHoV), from porcine and bovine samples in Hong Kong. Their nearly full-length sequences were also analysed. PARV4-like viruses were detected by PCR among 44.4 % (148/333) of porcine samples (including lymph nodes, liver, serum, nasopharyngeal and faecal samples), 13 % (4/32) of bovine spleen samples and 2 % (7/362) of human serum samples that were sent for human immunodeficiency virus and hepatitis C virus antibody tests. Three distinct parvoviruses were identified, including two novel parvoviruses, PHoV and BHoV, from porcine and bovine samples and PARV4 from humans, respectively. Analysis of genome sequences from seven PHoV strains, from three BHoV strains and from one PARV4 strain showed that the two animal parvoviruses were most similar to PARV4 with 61.5-63 % nt identities and, together with PARV4 (HHoV), formed a distinct cluster within the family Parvoviridae. The three parvoviruses also differed from other parvoviruses by their relatively large predicted VP1 protein and the presence of a small unique conserved putative protein. Based on these results, we propose a separate genus, Hokovirus, to describe these three parvoviruses. The co-detection of porcine reproductive and respiratory syndrome virus, the agent associated with the recent 'high fever' disease outbreaks in pigs in China, from our porcine samples warrants further investigation.

Li Z, Yao H, Ma Y, Dong Q, Chen Y, Peng Y, Zheng BJ, Huang JD, Chan CY, Lin MC, Sung JJ, Yuen KY, Kung HF, He ML. · Department of Microbiology, The University of Hong Kong, Hong Kong, China. · J Gene Med. · Pubmed #18383553 No free full text.

Abstract: BACKGROUND: Interferon-alpha2 (IFNalpha2) is routinely used for anti-hepatitis B virus (HBV) treatment. However, the therapeutic efficiency is unsatisfactory, particularly in East Asia. Such inefficiency might be a result of the short half-life, relatively low local concentration and strong side-effects of interferons. Frequent and repeated injection is also a big burden for patients. In the present study, a single dose of vector-delivered IFNalpha1 was tested for its anti-HBV effects. METHODS: Adeno-associated viral vector (AAV-IFNalpha1) was generated to deliver the IFNalpha1 gene into hepatocytes. IFNalpha1, hepatitis B surface (HBsAg) and e (HBeAg) antigens were measured by enzyme-linked immunosorbent assay and/or western blotting. The level of viral DNA was measured by quantitative real-time polymerase chain reaction. RESULTS: AAV-IFNalpha1 effectively transduced HBV-producing cells (HepAD38) and mouse hepatocytes, where IFNalpha1 was expressed in a stable manner. Both intracellular and extracellular HBsAg and HBeAg were significantly reduced in vitro. In the HBV-producing mice, the concentration of IFNalpha1 in the liver was eight-fold higher than that in plasma. Compared with control groups, HBeAg/HBsAg antigen levels were reduced by more than ten-fold from day 1-5, and dropped to an undetectable level on day 9 in the AAV-IFNalpha1 group. Concurrently, the level of viral DNA decreased over 30-fold for several weeks. CONCLUSIONS: A single dose administration of AAV-IFNalpha1 viral vector displayed prolonged transgene expression and superior antiviral effects both in vitro and in vivo. Therefore, the use of AAV-IFNalpha1 might be a potential alternative strategy for anti-HBV therapy.

Hui CK, Zhang HY, Bowden S, Locarnini S, Luk JM, Leung KW, Yueng YH, Wong A, Rousseau F, Yuen KY, Naoumov NN, Lau GK. · Department of Microbiology, Queen Mary Hospital, The University of Hong Kong, Hong Kong SAR, China. · J Hepatol. · Pubmed #18207280 No free full text.

Abstract: BACKGROUND/AIMS: In order to prevent the occurrence of drug-resistant mutants associated with treatment for chronic hepatitis B virus (HBV) infection, combination therapy is being developed. To determine the efficacy of adefovir dipivoxil (ADV) plus emtricitabine (FTC) combination therapy in chronic HBV infection. METHODS: Thirty treatment-nai ve, HBeAg-positive patients were randomized to combination ADV plus FTC (n=14) or ADV plus placebo monotherapy (n=16) for 96 weeks. HBV DNA was measured by polymerase chain reaction. Treatment was stopped in those with HBeAg seroconversion. RESULTS: The median decrease in HBV DNA at week 96 was higher in the combination group (-5.30 vs. -3.98 log(10)copies/ml, p=0.05). More patients in the combination group had normalization of alanine aminotransaminase and HBV DNA<300 copies/ml at week 96 when compared with the monotherapy group [11 of the 14 patients (78.6%) vs. 6 of the 16 patients (37.5%), p=0.03]. However, HBeAg seroconversion at week 96 was similar in the 2 groups [2/14 (14.3%) vs. 4/16 (25.0%), p=NS]. No ADV or FTC resistance was detected at week 96. In those with HBeAg seroconversion, 50.0% had post-treatment relapse. CONCLUSIONS: Combination ADV plus FTC resulted in more potent suppression of HBV DNA over 96 weeks of therapy.

Zhou J, Lu L, Yuen MF, Lam TW, Chung CP, Lam CL, Zhang B, Wang S, Chen Y, Wu SH, Poon VK, Ng F, Chan CC, Jiang S, Yuen KY, Zheng BJ. · Department of Microbiology, The University of Hong Kong, Hong Kong. · J Hepatol. · Pubmed #17125879 No free full text.

Abstract: BACKGROUND/AIMS: Exposure to HBV leads to a distinct clinical course which is partially pertained to host genetic variability. We aimed to study polymorphisms of type I interferon receptor 1 (IFNAR1) promoter and their potential effects on chronic HBV infection. METHODS: Polymorphisms of IFNAR1 promoter were identified in 320 chronic hepatitis B patients, 148 spontaneously recovered individuals, 148 healthy Chinese donors and 114 Caucasians. Their functional capability in driving reporter gene expression was analyzed. RESULTS: Four polymorphic alleles were identified at loci -568, -408, -77 and -3. Association analysis revealed that carriers of alleles -568G, -408C and their related haplotype I were less susceptible to chronic HBV infection whereas those of alleles -568C, -408T and related haplotype III were significantly associated with higher risk to chronic hepatitis B (P<0.01). In a reporter-driven system, the promoter variants with alleles -408C and -3C could drive higher expression of the reporter gene than those with alleles -408T and -3T (P<0.01). Interestingly, an allele with 9 GT repeats at -77 that was rarely found in Chinese but prevalent in Caucasian exhibited the highest transcriptional ability. CONCLUSIONS: Our results showed that polymorphisms of IFNAR1 promoter may affect, at least in part, the outcomes of HBV infection.

Cheung WW, Tse E, Leung AY, Yuen KY, Kwong YL. · Department of Medicine, Queen Mary Hospital, Hong Kong. · Am J Hematol. · Pubmed #17013817 No free full text.

Abstract: Ten patients with refractory lymphomas or autoimmune cytopenias were treated with alemtuzumab, and monitored prospectively for cytomegalovirus (CMV) reactivation by antigenemia and polymerase chain reaction. All patients showed virologic CMV reactivation. Two patients developed pneumonitis and hepatitis respectively, necessitating alemtuzumab withdrawal. Eight patients were asymptomatic, and with pre-emptive anti-CMV treatment, alemtuzumab therapy was uninterrupted. All patients ultimately achieved virologic remission. The frequent CMV reactivation was due to a high background seropositivity rate for CMV, severely immunocompromized patients, a sensitive detection method, and the diligence of surveillance. Frequent monitoring for and early treatment of CMV reactivation is necessary during alemtuzumab therapy.

Woo PC, Lau SK, Huang Y, Tsoi HW, Chan KH, Yuen KY. · Department of Microbiology, Faculty of Medicine, The University of Hong Kong, Hong Kong. · Arch Virol. · Pubmed #15986174 No free full text.

Abstract: Phylogenetic trees constructed using predicted amino acid sequences of putative proteins of coronavirus HKU1 (CoV-HKU1) revealed that CoV-HKU1 formed a distinct branch among group 2 coronaviruses. Of the 14 trees from p65 to nsp10, nine showed that CoV-HKU1 was clustered with murine hepatitis virus. From nsp11, the topologies of the trees changed dramatically. For the eight trees from nsp11 to N, seven showed that the CoV-HKU1 branch was the first branch. The codon usage patterns of CoV-HKU1 differed significantly from those in other group 2 coronaviruses. Split decomposition analysis revealed that recombination events had occurred between CoV-HKU1 and other coronaviruses.

Peiris JS, Chu CM, Cheng VC, Chan KS, Hung IF, Poon LL, Law KI, Tang BS, Hon TY, Chan CS, Chan KH, Ng JS, Zheng BJ, Ng WL, Lai RW, Guan Y, Yuen KY, Anonymous00115. · Department of Microbiology, Queen Mary Hospital, University of Hong Kong, Hong Kong, Special Administrative Region, China. · Lancet. · Pubmed #12781535 No free full text.

Abstract: BACKGROUND: We investigated the temporal progression of the clinical, radiological, and virological changes in a community outbreak of severe acute respiratory syndrome (SARS). METHODS: We followed up 75 patients for 3 weeks managed with a standard treatment protocol of ribavirin and corticosteroids, and assessed the pattern of clinical disease, viral load, risk factors for poor clinical outcome, and the usefulness of virological diagnostic methods. FINDINGS: Fever and pneumonia initially improved but 64 (85%) patients developed recurrent fever after a mean of 8.9 (SD 3.1) days, 55 (73%) had watery diarrhoea after 7.5 (2.3) days, 60 (80%) had radiological worsening after 7.4 (2.2) days, and respiratory symptoms worsened in 34 (45%) after 8.6 (3.0) days. In 34 (45%) patients, improvement of initial pulmonary lesions was associated with appearance of new radiological lesions at other sites. Nine (12%) patients developed spontaneous pneumomediastinum and 15 (20%) developed acute respiratory distress syndrome (ARDS) in week 3. Quantitative reverse-transcriptase (RT) PCR of nasopharyngeal aspirates in 14 patients (four with ARDS) showed peak viral load at day 10, and at day 15 a load lower than at admission. Age and chronic hepatitis B virus infection treated with lamivudine were independent significant risk factors for progression to ARDS (p=0.001). SARS-associated coronavirus in faeces was seen on RT-PCR in 65 (97%) of 67 patients at day 14. The mean time to seroconversion was 20 days. INTERPRETATION: The consistent clinical progression, shifting radiological infiltrates, and an inverted V viral-load profile suggest that worsening in week 2 is unrelated to uncontrolled viral replication but may be related to immunopathological damage.

Zheng BJ, Ng MH, Chan KW, Tam S, Woo PC, Ng SP, Yuen KY. · Department of Microbiology, University of Hong Kong, Hong Kong. · Eur J Immunol. · Pubmed #12555675 No free full text.

Abstract: The efficacy of immunization with Salmonella typhimurium aroA to deliver the plasmid pRc/CMV-HBsAg (i.e. an oral DNA vaccine) was compared with that of intramuscular immunization with the same plasmid DNA, and with recombinant HBsAg protein, in a HBsAg transgenic mouse model. A single dose of oral DNA vaccine evoked vigorous Th1 cell and CTL responses and production of IgG2 subclass of anti-HBs after 2 weeks, and this was accompanied by a transient hepatitic flare with elevated alanine aminotransferase in the first 3 weeks. Concomitantly, the level of HBsAg-mRNA in liver tissues decreased by more than fourfold and viral-antigen expression was curtailed markedly in hepatocytes compared with controls. Hepatitic flare subsided after 3 weeks, but suppression of the transgene expression was continued in the absence of overt liver pathology for the remaining duration of the experiment (i.e. 12 weeks), and possibly beyond. The other vaccines could also break immune tolerance, but this was achieved only after repeated booster doses of the respective vaccines, and they did not affect transgene expression, or induce hepatic flare. We previously showed in non-transgenic mice that immunization by the oral DNA vaccine is achieved by an active intestinal infection with a bacterial carrier that is an adept intracellular parasite, and the immune response to the vaccination is orchestrated by phagocytic APC. Our present findings further implicated that the combined effects of an innate and a specific immune response induced by oral DNA vaccination are crucial in down-regulating HBsAg-transgene expression in hepatocytes.

Saing H, Fan ST, Tam PK, Lo CM, Wei WI, Chan KL, Tsoi NS, Yuen KY, Ng IO, Chau MT, Tso WK, Wong J. · Department of Surgery, University of Hong Kong Medical Centre, Queen Mary Hospital, Hong Kong, China. · J Pediatr Surg. · Pubmed #12483627 No free full text.

Abstract: PURPOSE: The aim of this study was to analyze the early and late results of pediatric liver transplantation, with particular reference to complications that required surgical or radiologic intervention. METHODS: The records and code sheets of children who underwent liver transplantation in the authors' institution between September 1993 and December 2001 were reviewed. RESULTS: Twenty-nine children (16 boys and 13 girls) underwent 31 liver transplantations (23 living donor, 8 cadaveric donor) during the study period. The ages of the children ranged from 4 months to 132 months (median, 16 months). Eighteen children had complications that required surgical or radiologic interventional procedures. Complications included, among others, hepatic vein thrombosis (n = 1, 3%), hepatic vein stenosis (n = 2, 7%), portal vein thrombosis (n = 2, 7%), biliary stricture (n = 3, 10%), bile leakage (n = 2, 7%), hepatic artery pseudoaneurysm (n = 1, 3%), jejuno-jejunostomy leakage (n = 1, 3%), graft hepatitis (n = 1, 3%), and posttransplant lymphoproliferative disorder (n = 2, 7%). In addition, 6 children (21%) suffered from intraabdominal bleeding from a variety of causes. After appropriate interventions, at a median follow-up of 38 months (range, 1 to 96 months), patient and graft survival rates were 79% and 74%, respectively. The retransplantation rate was only 7%. There was no incidence of hepatic artery thrombosis. All living donors remain alive and well. CONCLUSIONS: Complications are inevitable in pediatric liver transplantation. However, with timely recognition and active intervention, a good outcome can be achieved.

Lo CM, Fan ST, Liu CL, Yong BH, Lai CL, Lau GK, Wei WI, Tam PK, Tsoi NS, Ng IO, Young K, Chan JK, Tso WK, Yuen KY, Wong J. · Liver Transplant Centre, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong. · Hong Kong Med J. · Pubmed #12167726 links to  free full text

Abstract: OBJECTIVE: To report the experience with liver transplantation at the Queen Mary Hospital from 1991 to 2000. DESIGN: Retrospective study. SETTING: Liver transplant centre of a University teaching hospital, Hong Kong. PATIENTS: One hundred and forty-eight patients (127 adults and 21 children) who underwent a total of 155 liver transplants using 75 cadaver grafts (full-size, 67; reduced-size, 5; split, 3) and 80 living donor grafts (left lateral segment, 15; left lobe, 6; right lobe, 59) from October 1991 to December 2000 were reviewed. MAIN OUTCOME MEASURES: Graft and patient survival rate. RESULTS: The most common disease indications for liver transplantation were chronic hepatitis B-related liver disease (n=74) in adults and biliary atresia (n=14) in children. Eighteen patients had hepatocellular carcinoma. Forty-eight (31%) liver transplants (three ABO-incompatible) were performed in high-urgency situations for patients requiring intensive care. The proportion of living donor liver transplants was 47.7% in adults and 73.9% in children. The overall 1-year and 5-year patient survival rates were 82% and 77%, respectively. The survival of high-risk recipients, such as those with fulminant hepatic failure (80%), chronic hepatitis B (81%), or hepatocellular carcinoma (94%), was not inferior to that of other patients. CONCLUSION: Over the last decade, the promotion of (cadaver) organ donation through public education coupled with innovative techniques in living donor liver transplantation have enabled a liver transplantation programme to be established in Hong Kong with gratifying results.

Wang TK, Woo PC, Yuen KY. · Department of Microbiology, The University of Hong Kong, University Pathology, Queen Mary Hospital, Hong Kong. · New Microbiol. · Pubmed #12019732 No free full text.

Abstract: We describe the first case of community-acquired Propionibacterium avidum subcutaneous tissue infection in a cirrhotic patient. A 70-year-old Chinese male with a 2-year history of hepatitis B virus-induced chronic liver failure and hemorrhoidectomy 17 months previously presented with a painful left buttock abscess, which was culture positive for P. avidum. Being a normal flora of skin with low pathogenicity, there have been only 3 case reports on P. avidum infection, all associated with surgical intervention within 2 to 6 weeks before the onset of P. avidum infection. We hereby review the literature on P. avidum summarizing

Zheng BJ, Ng MH, He LF, Yao X, Chan KW, Yuen KY, Wen YM. · Department of Microbiology, The University of Hong Kong, Hong Kong, People's Republic of China. · Vaccine. · Pubmed #11457548 No free full text.

Abstract: Therapeutic efficacy of HBsAg-anti-HBs-recombinant DNA harboring hepatitis B virus (HBV) S gene complex was compared with three other therapeutic vaccine candidates (recombinant HBsAg, HBsAg complexed to anti-HBs antibodies and naked plasmid DNA encoding the HBV S gene). After four injections at 3-week intervals, the most pronounced decrease of serum HBsAg, the highest titer of anti-HBs response, the highest level of interferon-gamma produced by splenocytes and potent cytotoxicity T cell response were observed in the HBsAg-anti HBs-sDNA immunized group. Reduced expression of HBsAg in hepatocytes was also shown. The therapeutic mechanism of HBsAg-anti-HBs-DNA was speculated as modulation of HBsAg presentation via both endogenous and exogenous pathways.

Woo PC, Wong LP, Zheng BJ, Yuen KY. · Department of Microbiology, University Pathology Building, Queen Mary Hospital, The University of Hong Kong, Pokfulam Road, Hong Kong. · Vaccine. · Pubmed #11282206 No free full text.

Abstract: A novel vaccine for hepatitis B virus (HBV) was designed by putting a naked DNA vaccine carrying hepatitis B surface antigen (HBsAg) into live-attenuated Salmonella typhimurium. Mucosal immunization by the oral route in mice showed significantly stronger cytotoxic T lymphocyte (CTL) response than recombinant HBsAg vaccination (P < 0.01 at an effector:target ratio of 100:1), while comparable to intramuscular naked DNA immunization at all effector:target ratios. Contrary to previous reports on naked DNA vaccines given intramuscularly, the IgG antibody response induced by the mucosal DNA vaccine is relatively weak when compared to recombinant HBsAg vaccine (P < 0.001 at day 21). These findings are supported by a high interferon-gamma but a low interleukin-4 level detected in the supernatant of splenic cell cultures obtained from mucosally immunized mice. As distinct to recombinant HBsAg vaccine which is effective for protection, oral mucosal DNA vaccine should be considered as a candidate for therapeutic immunization in chronic HBV infection, donor immunization before adoptive transfer of HBV-specific CTL to HBsAg positive bone marrow transplant recipients, and immunization of non-responders to recombinant HBsAg vaccine. This strongly cellular and relatively absent humoral response may make this vaccine a better candidate as a therapeutic vaccine for chronic HBV carriers than naked DNA vaccines, as the humoral response is relatively less important for the clearance of HBV from hepatocytes, but its presence may lead to side effects such as serum sickness and immune complex deposition in chronic HBV carriers.

Woo PC, Tsoi HW, Leung HC, Wong LP, Wong SS, Chan E, Yuen KY. · Department of Microbiology, The University of Hong Kong, University Pathology Building, Queen Mary Hospital, Hong Kong. · Clin Diagn Lab Immunol. · Pubmed #10882658 links to  free full text

Abstract: Live-attenuated Salmonella species are effective carriers of microbial antigens and DNA vaccines. In a mouse model, the immunoglobulin M (IgM) and total antibody levels directed toward the lipopolysaccharide of Salmonella enterica serovar Typhi were significantly enhanced at day 21 after oral immunization with live-attenuated serovar Typhi (strain Ty21a) when ampicillin was concomitantly administered (P < 0.05 and P < 0.005, respectively). The heat-killed Ty21a-stimulated lymphocyte proliferation indices for the ampicillin group at day 21 were significantly higher than those for the normal saline (NS) group (P < 0.005, P < 0.001, and P < 0.01) for all three doses of antigen (10(4), 10(5), and 10(6) heat-killed Ty21a per well, respectively). The 50% lethal doses for mice from the ampicillin and NS groups immunized with Ty21a with pBR322 after wild-type serovar Typhi challenge on day 24 were 3.4 x 10(7) and 5.0 x 10(6) CFU, respectively. The fecal bacterial counts for the ampicillin group at days 1, 3, and 5 were significantly lower than those for the NS group (P < 0.01, P < 0.01, and P < 0.05, respectively), and there was a trend toward recovery of Ty21a in a larger number of mice from the ampicillin group than from the NS group. Furthermore, the IgG2a levels directed toward tetanus toxoid were significantly enhanced at days 7 and 21 after oral immunization with Ty21a that carried the fragment c of tetanus toxoid when ampicillin was concomitantly administered (P < 0.05 and P < 0.005, respectively), and the IgM and total hepatitis B surface antibody levels were significantly enhanced at days 7 (P < 0.005 and P < 0.05, respectively) and 21 (P < 0.01 and P < 0.05, respectively) after oral immunization with Ty21a that carried the DNA vaccine that encodes hepatitis B surface antigen when ampicillin was concomitantly administered. The present observation may improve the efficacy of the protein antigens and DNA vaccines carried in live-attenuated bacteria, and further experiments should be carried out to determine the best antibiotics and dosage regimen to be used, as well as the best carrier system for individual protein antigens and DNA vaccines.

Saing H, Fan ST, Chan KL, Lo CM, Wei WI, Tsoi NS, Yuen KY, Ng IL, Chau MT, Tso WK, Chan JK, Wong J. · Department of Surgery, University of Hong Kong Medical Center, Queen Mary Hospital, Hong Kong. · J Pediatr Surg. · Pubmed #10591579 No free full text.

Abstract: PURPOSE: In view of the earlier reports that children below 1 year of age constitute a high-risk group for liver transplantation, the authors reviewed their experience in performing orthotopic liver transplantation in this age group. METHODS: The records of 9 children aged less than 1 year who underwent 6 living-related liver transplants and 3 reduced-size liver transplants between December 1993 and June 1997 were reviewed. RESULTS: Five reexplorations were required for 3 children who had 1 or more of the following early complications: bleeding from hepatic vein to inferior vena cava anastomosis (n = 1), right hepatic vein stump bleeding (n = 1), intraabdominal hematoma (n = 2), jejuno-jejunostomy leakage (n = 1), and colonic perforation (n = 1). Late complications include stricture at the biliary-enteric anastomosis requiring percutaneous balloon dilatation (n = 3) and hepatitis of undetermined etiology requiring retransplantation (n = 1). There was no hepatic artery thrombosis despite the small arteries available for anastomosis. Follow-up ranged from 19 to 61 months (mean, 40 months). Patient survival rate was 100%, and graft survival with good liver function was 89%. All living donors, 2 fathers and 4 mothers, are well. CONCLUSIONS: Liver transplantation in infants less than 1 year of age is technically demanding but feasible and still can be performed with a good outcome. Age alone (under 1 year) should not be considered as a contraindication for liver transplantation.

Woo PC, Tsoi HW, Wong LP, Leung HC, Yuen KY. · Department of Microbiology, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China. · Clin Diagn Lab Immunol. · Pubmed #10548572 links to  free full text

Abstract: The effects of antibiotics on the antigen-specific humoral immune response are not known. Macrolides, tetracyclines, and beta-lactams are commonly prescribed antibiotics. The first two are known to have immunomodulatory activities. The effects of clarithromycin, doxycycline, and ampicillin on the primary and secondary antibody responses to tetanus toxoid, a pneumococcal polysaccharide vaccine, a hepatitis B virus surface antigen (HBsAg) vaccine, and live attenuated Salmonella typhi (Ty21a) were investigated using a mouse model. For the mice receiving the tetanus toxoid, the immunoglobulin M (IgM) level of the clarithromycin group at day 7 was significantly lower than the corresponding antibody level of the normal saline (NS) group. For the mice receiving the pneumococcal polysaccharide vaccine, the total antibody and IgM levels of the clarithromycin group and the IgM level of the doxycycline group at day 7 were significantly lower than the corresponding antibody levels of the ampicillin and NS groups. For the mice receiving the HBsAg vaccine, the IgM level of the doxycycline group at day 7 was significantly lower than the corresponding antibody levels of the clarithromycin and NS groups, while the IgM level of the clarithromycin group at day 28 was significantly lower than the corresponding antibody levels of the doxycycline, ampicillin, and NS groups. For the mice receiving all three vaccines, there were no statistically significant differences between any of the antibody levels of the ampicillin group and the corresponding antibody levels of the NS group. For the mice receiving Ty21a, the total antibody levels of the ampicillin group at days 7 and 21 were significantly higher than the corresponding antibody levels of the NS group. Moreover, the IgM levels of the clarithromycin, doxycycline, and ampicillin groups at days 7 and 21 were significantly higher than the corresponding antibody levels of the NS group. Furthermore, the total antibody level of the ampicillin group at day 21 was significantly higher than the corresponding antibody level of the doxycycline group. For all four vaccines, there were no statistically significant differences among the serum levels of interleukin-10 and gamma interferon for the mice treated with the various antibiotics. We conclude that clarithromycin and doxycycline, but not ampicillin, suppress the antibody responses of mice to T-cell-dependent and T-cell-independent antigens, whereas all three antibiotics enhance the antibody response to live attenuated mucosal bacterial vaccines.

Hui CK, Cheung WW, Leung KW, Cheng VC, Tang BS, Li IW, Luk JM, Lee NP, Kwong YL, Au WY, Yuen KY, Lau GK, Liang R. · Department of Microbiology, University of Hong Kong, Queen Mary Hospital, Hong Kong, Special Administrative Region, China. · Hepatology. · Pubmed #18452145 No free full text.

Abstract: Whether preemptive anti- hepatitis B virus (HBV) therapy should be considered in all hepatitis B surface antigen (HBsAg)-negative patients with occult HBV infection receiving alemtuzumab containing chemotherapy is uncertain. We determined the outcome and effect on HBV-specific immunity of an alemtuzumab-containing chemotherapy regimen in occult HBV-infected patients. Twenty-one consecutive occult HBV-infected patients treated with an alemtuzumab containing chemotherapy regimen were studied. T cell reactivity to HBV antigens and -peptides were quantified by ELISpot and the T cell subset by flow cytometry. Six of the 21 patients (28.6%) developed HBsAg seroreversion. The median (range) time to development of HBsAg seroreversion after the end of chemotherapy was 1.8 months (0.2-2.3 months). Direct sequencing showed that the occult HBV infection of all six patients (100%) was reactivated. These six patients developed severe HBV-related hepatitis. At the end of follow-up, four of these six patients (66.7%) had become negative for HBsAg again. Recovery of CD4+ T cell count and CD4+T cell reactivity against hepatitis B core antigen (HBcAg) occurred 9 months after the end of chemotherapy. Loss of HBsAg occurred after recovery of the CD4+T cell count and increased CD4+T cell reactivity against HBcAg 9 months after the end of chemotherapy. CONCLUSION: An alemtuzumab-containing chemotherapy regimen is associated with a high risk of reactivation of occult HBV infection. Suppression of HBV immunity by an alemtuzumab-containing chemotherapy regimen would persist until 9 months after the end of chemotherapy. In occult HBV-infected patients receiving an alemtuzumab-containing chemotherapy regimen, preemptive anti-HBV therapy should be continued until 9 months after the end of chemotherapy, when recovery of HBV immunity has occurred.