Altered T cell receptor beta repertoire patterns in pediatric ulcerative colitis.

The antigenic specificity of T cells occurs via generation and rearrangement of different gene segments producing a functional T cell receptor (TCR). High-throughput sequencing (HTS) allows in-depth assessment of TCR repertoire patterns. There are limited data concerning whether TCR repertoires are altered in inflammatory bowel disease. We hypothesized that pediatric ulcerative colitis (UC) patients possess unique TCR repertoires, resulting from clonotypical expansions in the gut. Paired blood and rectal samples were collected from nine newly diagnosed treatment-naive pediatric UC patients and four healthy controls. DNA was isolated to determine the TCR-ß repertoire by HTS. Significant clonal expansion was demonstrated in UC patients, with inverse correlation between clinical disease severity and repertoire diversity in the gut. Using different repertoire variables in rectal biopsies, a clear segregation was observed between patients with severe UC, those with mild-moderate disease and healthy controls. Moreover, the overlap between autologous blood-rectal samples in UC patients was significantly higher compared with overlap among controls. Finally, we identified several clonotypes that were shared in either all or the majority of UC patients in the colon. Clonal expansion of TCR-ß-expressing T cells among UC patients correlates with disease severity and highlights their involvement in mediating intestinal inflammation.

The state of hepatitis B and C in the Mediterranean and Balkan countries: report from a summit conference.

The burden of disease due to chronic viral hepatitis constitutes a global threat. In many Balkan and Mediterranean countries, the disease burden due to viral hepatitis remains largely unrecognized, including in high-risk groups and migrants, because of a lack of reliable epidemiological data, suggesting the need for better and targeted surveillance for public health gains. In many countries, the burden of chronic liver disease due to hepatitis B and C is increasing due to ageing of unvaccinated populations and migration, and a probable increase in drug injecting. Targeted vaccination strategies for hepatitis B virus (HBV) among risk groups and harm reduction interventions at adequate scale and coverage for injecting drug users are needed. Transmission of HBV and hepatitis C virus (HCV) in healthcare settings and a higher prevalence of HBV and HCV among recipients of blood and blood products in the Balkan and North African countries highlight the need to implement and monitor universal precautions in these settings and use voluntary, nonremunerated, repeat donors. Progress in drug discovery has improved outcomes of treatment for both HBV and HCV, although access is limited by the high costs of these drugs and resources available for health care. Egypt, with the highest burden of hepatitis C in the world, provides treatment through its National Control Strategy. Addressing the burden of viral hepatitis in the Balkan and Mediterranean regions will require national commitments in the form of strategic plans, financial and human resources, normative guidance and technical support from regional agencies and research.

Has the time come to control hepatitis A globally? Matching prevention to the changing epidemiology.

For the first time a global meeting on hepatitis A virus (HAV) infection as vaccine preventable disease was organized at the end of 2007. More than 200 experts from 46 countries gathered to investigate the changing global HAV epidemiology reflecting the increasing numbers of persons at risk for severe clinical disease and mortality from HAV infection. The benefits of childhood and adult hepatitis A (HepA) vaccination strategies and the data needed by individual countries and international health organizations to assess current HepA prevention strategies were discussed. New approaches in preventing HAV infection including universal HepA vaccination were considered. This introductory paper summarizes the major findings of the meeting and describes the changing epidemiology of HAV infections and the impact of HepA vaccination strategies in various countries. Implementation of HepA vaccination strategies should take into account the level of endemicity, the level of the socio-economic development and sanitation, and the risk of outbreaks. A stepwise strategy for introduction of HepA universal immunisation of children was recommended. This strategy should be based on accurate surveillance of cases and qualitative documentation of outbreaks and their control, secure political support on the basis of high-quality results, and comprehensive cost-effectiveness studies. The recognition of the need for increased global attention towards HepA prevention is an important outcome of this meeting.

Iloprost treatment for refractory Raynaud's phenomenon in two infants.

Raynaud's phenomenon (RP) is rare in young children. We describe two infants with severe RP, manifesting as fingertip necrosis, who were resistant to conventional vasodilators and were treated successfully with iloprost, a prostacyclin analogue. The application of iloprost is safe and should be considered in children with threatening ischemic digits.

Hepatitis B virus, hepatitis C virus and other blood-borne infections in healthcare workers: guidelines for prevention and management in industrialised countries.

The Viral Hepatitis Prevention Board (VHPB) convened a meeting of international experts from the public and private sectors in order to review and evaluate the epidemiology of blood-borne infections in healthcare workers, to evaluate the transmission of hepatitis B and C viruses as an occupational risk, to discuss primary and secondary prevention measures and to review recommendations for infected healthcare workers and (para)medical students. This VHPB meeting outlined a number of recommendations for the prevention and control of viral hepatitis in the following domains: application of standard precautions, panels for counselling infected healthcare workers and patients, hepatitis B vaccination, restrictions on the practice of exposure-prone procedures by infected healthcare workers, ethical and legal issues, assessment of risk and costs, priority setting by individual countries and the role of the VHPB. Participants also identified a number of terms that need harmonization or standardisation in order to facilitate communication between experts.

Hepatitis A and B vaccination and public health.

The introduction and implementation of hepatitis B vaccination programmes in areas of high endemicity has been very stressful. However, this initial accomplishment has led to the reassessment of priorities in some countries which could undermine these early successes. Work still remains to be done to support and implement interventions that will bring us closer to the WHO goal and to the control of hepatitis B in the community at large. Hepatitis A vaccine strategy for immunizing toddlers is shifting to those countries with intermediate endemicity where increasing morbidity in adults is being observed. Accumulating evidence indicates that such programmes can result in impressive reductions in the incidence of hepatitis A by herd immunity. Monitoring of these populations to determine durability of protection will be important to avoid shifting the infection to the older age population, when symptoms are more likely to occur. National policies need to consider hepatitis A vaccination in the context of other public health priorities.

Prevention of hepatitis C virus infection.

In spite of advances made in our understanding of the biology of the hepatitis C virus (HCV), the epidemiology and natural history of HCV infection, and the treatment of chronic hepatitis C, the development and worldwide implementation of a comprehensive prevention and control strategy remains necessary. A World Health Organization informal consultation with the Viral Hepatitis Prevention Board was convened and met in Geneva, Switzerland, 13-14 May 2002, to review epidemiological and public health aspects of HCV infection, and the various prevention and control strategies that are currently in place. Based on the presentations and discussions, a number of specific recommendations were made, which should be considered in conjunction with previously published recommendations.

Hepatitis A booster vaccination: is there a need?

Hepatitis A is one of the most common vaccine-preventable infectious diseases in the world. Effective vaccines against hepatitis A have been available since 1992, and they provide long-term immunity against the infection. However, there is no worldwide consensus on how long protection will last or whether there will be a need for hepatitis A virus (HAV) booster vaccinations in the future. In most countries, booster-vaccination policy is guided by manufacturers' recommendations, national authorities, or both. In June, 2002, a panel of international experts met to review the long-term immunogenicity and protection conferred by HAV vaccine in different population groups. Data have shown that after a full primary vaccination course, protective antibody amounts persist beyond 10 years in healthy individuals, and underlying immune memory provides protection far beyond the duration of anti-HAV antibodies. The group concluded that there is no evidence to lend support to HAV booster vaccination after a full primary vaccination course in a healthy individual. However, further investigations are needed before deciding if boosters can be omitted in special patient-groups.

Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections in health care workers (HCWs): guidelines for prevention of transmission of HBV and HCV from HCW to patients.

The transmission of viral hepatitis from health care workers (HCW) to patients is of worldwide concern. Since the introduction of serologic testing in the 1970s there have been over 45 reports of hepatitis B virus (HBV) transmission from HCW to patients, which have resulted in more than 400 infected patients. In addition there are six published reports of transmissions of hepatitis C virus (HCV) from HCW to patients resulting in the infection of 14 patients. Additional HCV cases are known of in the US and UK, but unpublished. At present the guidelines for preventing HCW to patient transmission of viral hepatitis vary greatly between countries. It was our aim to reach a Europe-wide consensus on this issue. In order to do this, experts in blood-borne infection, from 16 countries, were questioned on their national protocols. The replies given by participating countries formed the basis of a discussion document. This paper was then discussed at a meeting with each of the participating countries in order to reach a Europe-wide consensus on the identification of infected HCWs, protection of susceptible HCWs, management and treatment options for the infected HCW. The results of that process are discussed and recommendations formed. The guidelines produced aim to reduce the risk of transmission from infected HCWs to patients. The document is designed to complement existing guidelines or form the basis for the development of new guidelines. This guidance is applicable to all HCWs who perform EPP, whether newly appointed or already in post.

Antibodies to hepatitis B surface antigen prevent viral reactivation in recipients of liver grafts from anti-HBC positive donors.

BACKGROUND AND AIMS: Liver donors with serological evidence of resolved hepatitis B virus (HBV) infection (HBV surface antigen (HBsAg) negative, anti-HBV core (HBc) positive) can transmit HBV infection to recipients. In the context of organ shortage, we investigated the efficacy of hepatitis B immunoglobulin (HBIG) to prevent HBV infection, and assessed the infectious risk by polymerase chain reaction (PCR) testing for HBV DNA on serum and liver tissue of anti-HBc positive donors. PATIENTS: Between 1997 and 2000, 22 of 315 patients were transplanted with liver allografts from anti-HBc positive donors. Long term HBIG therapy was administered to 16 recipients. Four naive and two vaccinated patients received no prophylaxis. RESULTS: Hepatitis B developed in the four HBV naive recipients without prophylaxis and in none of the vaccinated subjects. Among the 16 recipients receiving HBIG, one patient with residual anti-HBs titres below 50 UI/ml became HBsAg positive. The remaining 15 remained HBsAg negative and HBV DNA negative by PCR testing throughout a 20 month (range 4-39) follow up period. HBV DNA was detected by PCR in 1/22 donor serum, and in 11/21 liver grafts with normal histology. A mean of 12 months post-transplantation (range 1-23) HBV DNA was no longer detectable in graft biopsies from patients remaining HBsAg negative. CONCLUSION: Anti-HBs antibodies may control HBV replication in liver grafts from anti-HBc positive donors, without additional antiviral drugs. These grafts are thus suitable either to effectively vaccinated recipients or to those who are given HBIG to prevent HBV recurrence.

Wilson's disease with severe hepatic insufficiency: beneficial effects of early administration of D-penicillamine.

BACKGROUND: Wilson's disease, heralded by severe hepatic insufficiency, is a rare disorder for which emergency liver transplantation is considered to be the only effective therapy. AIMS: To report the features of Wilson's disease with severe hepatic insufficiency in a series of 17 patients and, during the second period of the study, to assess the efficacy of a policy consisting of early administration of D-penicillamine. PATIENTS: Seventeen consecutive patients with Wilson's disease were studied. During the first period of the study (up to 1979), none of the patients received D-penicillamine. During the second period (after 1979), all patients without encephalopathy at admission received D-penicillamine. RESULTS: The four patients observed during the first period who did not have encephalopathy at admission and did not receive D-penicillamine progressed to encephalopathy and died. Among the 13 consecutive patients observed during the second period, two patients with encephalopathy at admission did not receive D-penicillamine and were transplanted. The 11 remaining patients all received D-penicillamine. Ten of these patients survived without the need for transplantation and returned to compensated liver disease without liver insufficiency. In one patient, liver insufficiency progressed and transplantation had to be performed. CONCLUSIONS: In most patients with Wilson's disease heralded by severe hepatic insufficiency and without encephalopathy at admission, early administration of D-penicillamine was associated with survival without transplantation. These results suggest the importance of early diagnosis of this form of Wilson's disease before the onset of encephalopathy, and favour early administration of D-penicillamine which could avoid the need for transplantation in most cases.

Hyper-IL-6 gene therapy reverses fulminant hepatic failure.

Fulminant hepatic failure is a catastrophic condition caused by massive hepatocellular apoptosis and necrosis. Inhibition of hepatocyte apoptosis and the enhancement of the endogenous potential for liver regeneration could potentially form an effective basis for treatment of this condition. In response to injury in the liver, IL-6 mediates the acute-phase response and induces both cytoprotective and mitogenic functions. Hyper-IL-6 is a superagonistic designer cytokine consisting of human IL-6 linked by a flexible peptide chain to the secreted form of the IL-6 receptor. In a mouse model of acute liver failure induced by d-galactosamine administration, a single low dose of a hyper-IL-6-encoding adenoviral vector, in contrast to an adeno-IL-6 vector, maintained liver function, prevented the progression of liver necrosis, and induced liver regeneration, leading to dramatically enhanced survival. Thus, hyper-IL-6 gene therapy may be useful for the treatment of fulminant hepatic failure, which is often fatal even following treatment by transplantation.

Lack of known hepatitis virus in hepatitis-associated aplastic anemia and outcome after bone marrow transplantation.

Viral infection has been shown to induce aplastic anemia, unidentified types of hepatitis being the most common cause for aplastic anemia-associated viral hepatitis. The survival rate for this group of patients after bone marrow transplantation with stem cells from an HLA-matched sibling is not well known. The aim of this study was to determine the prevalence of hepatitis G virus (HGV) and transfusion transmitted virus (TTV) infection in non-A, non-B, non-C hepatitis associated-aplastic anemia (HAAA) patients, and to define the role of bone marrow transplantation (BMT) as a therapeutic modality for this disease. Sixty-eight patients (43 males and 25 females) with aplastic anemia, underwent allogeneic BMT at the Hadassah University Hospital between 1981 and 1997. Onset of hepatitis was defined as jaundice and elevated alanine aminotransaminase (ALT) levels. Onset of aplastic anemia was defined as the first date on which varying degrees of pancytopenia occurred: hemoglobin level below 10 g/dl, WBC below 2 x 10(9)/l and low platelet count 10 x 10(10)/l. Serial serum samples from HAAA patients were assayed for virological and/or serological markers of hepatitis A, B, C, D, E, G viruses, TTV and parvovirus B19. Seventeen of the 68 patients with aplastic anemia (25%) suffered from hepatitis, 12 males and five females, ages 5 to 36 years. The mean interval between onset of hepatitis and first indication of aplastic anemia was 62 days (range 14-225 days). The development of aplastic anemia was unrelated to age, sex or severity of hepatitis. Ten of the 17 patients (59%) achieved complete ALT recovery prior to the diagnosis of aplastic anemia. Serum samples were available for 15 patients; none had evidence of acute or active hepatitis A, B, C, D, E, G and TTV virus infection at the time of diagnosis. Parvovirus B19 DNA sequences were not detectable in 10 of 12 tested cases; two positive results were detected in serum samples obtained after blood transfusion, making the analysis of these positive results difficult. All 17 patients underwent BMT. The mean post-BMT follow-up period was 38 months (range 1 day-123 months), five patients (30%) died 1 to 160 days post BMT, and 12 (70%) are alive 31 to 123 months after BMT. Relapsing hepatitis was not observed in any of the patients. In conclusion, HAAA is a disease of the young and the etiologic agent associated with HAAA remains unknown. HGV, TTV and parvovirus B19 sequences were not detected in any of the HAAA cases. The survival rate after BMT with stem cells from an HLA-matched sibling is similar to that for patients with non-hepatitis-associated aplastic anemia.

Rapid seroprotection against hepatitis B following the first dose of a Pre-S1/Pre-S2/S vaccine.

BACKGROUND/AIMS: Will immunization with an experimental Pre-S1/Pre-S2/S hepatitis B vaccine (Bio-Hep-B) induce faster seroprotection using fewer doses as compared with a yeast derived S vaccine (Engerix B). METHODS: Healthy volunteers, n = 36, mean age 23 y, randomized to receive 2 or 3 doses of both vaccines given months 0 and 6, or 0, 1 and 6. RESULTS: Following primary immunization, seroprotection occurred in 6, 39, 53 and 60% in the Bio-Hep-B group at weeks 1, 2, 3 and 4, compared with 0, 12, 18 and 12.5% in the Engerix-B vaccinees, respectively. Six months following injection of the first dose, seroprotection was 70 and 25% in Pre-S/S and S vaccinees respectively. Area under the curve in vaccinees of Bio-Hep-B; versus Engerix-B showed mean anti-HBs level of 365 +/- 166 and 85 +/- 48 mIU/ml x day respectively (P = 0.012). At month 7, 100% seroprotection was achieved in both groups while anti-HBs rose from 81 to 28,800 mIU/ml and from 12 to 923 mIU/ml in recipients of Bio-Hep-B and Engerix-B respectively (P < 0.025). CONCLUSIONS: Bio-Hep-B induces rapid seroprotection against hepatitis B in 60-70% of vaccinees, within 4-24 weeks after the first dose. Two instead of the conventional three doses of the Pre-S/S vaccine may be sufficient to induce adequate seroprotection.

Cost-benefit analysis of a nationwide infant immunization programme against hepatitis A in an area of intermediate endemicity.

BACKGROUND/AIMS: The availability of safe and effective Hepatitis A vaccines prompts an evaluation of a nationwide infant vaccination campaign to supplement strategies aimed at high-risk groups such as travellers and military personnel. METHODS: A spreadsheet model was used to estimate costs and benefits of a nationwide infant immunization programme against Hepatitis A for the period from 1997-2014 in Israel. RESULTS: Immunizing all one year olds in Israel from 1997-2014 would for a cost of $32.0 million to the health services and $42.1 million to society (including $10.1 million lost work and transport costs), reduce the number of cases of Hepatitis A during the next 45 years from 181,000 to 47,000. This would save $57.5 million in health service resources alone, $32.0 million in averted work absences and transport costs in addition to a further $17.0 million in averted premature mortality costs. The health service, resource and societal benefit:cost ratios are 1.80:1, 2.13:1 and 2.54:1, respectively. CONCLUSIONS: The recent adoption of a nationwide infant HAV immunisation policy in Israel is both medically and economically justifiable.

Hepatitis c virus infection in employees of a large university hospital in Israel.

OBJECTIVE: To assess whether hospital work constitutes a risk factor for hepatitis C virus (HCV) infection among employees of a large hospital in Israel. DESIGN: Seroprevalence survey. SETTING: A 1,006-bed, tertiary-care university hospital in Jerusalem. PARTICIPANTS: All 5,444 employees (18-65 years old) were eligible; 4,287 (79%) participated in the survey. METHODS: Sera were tested for antibodies to HCV (anti-HCV) using a third-generation enzyme immunoassay. A third-generation strip immunoblot assay was used for confirmation. Participants were interviewed regarding their occupational history, and they completed a self-administered questionnaire covering history of non-occupational exposure to blood and country of birth. Other demographic information was obtained from the personnel department. Rates and odds ratios (ORs) were calculated, and multivariate logistic-regression analyses were performed to adjust for potential confounding variables. RESULTS: Anti-HCV was found in 0.9% of employees (37/4,287; 95% confidence interval, 0.6-1.1), ranging from 0.1% among those born in Israel to 5.7% among those born in Central Asia. After age, gender, social status, country of birth, and history of blood transfusion were controlled for in a logistic regression, occupational exposure to blood > or = 10 years was significantly associated with the presence of antibodies (OR, 2.6; P=.01). Presence of anti-HCV also was associated with country of birth (range: Israel OR, 1; West OR, 3.8 [P=.1]; Central Asia OR, 48.6 [P<.0001]) and history of blood transfusion (OR, 2.7; P=.01). No significant associations were found between anti-HCV and age, gender, social status, history of tattoo, acupuncture, current occupation, department, exposure to blood in current occupation, adherence to safety precautions, or history of percutaneous injury. The association with length of exposure was stronger (OR, 3.6; P=.01) when the same logistic regression was run excluding the outlier ethnic group of Central Asia. CONCLUSIONS: Hospital work does not seem to constitute a major risk factor for HCV infection in Israel today. A higher prevalence of anti-HCV among employees with longer versus shorter lengths of occupational exposure may be due to a cumulative effect of exposure over the years. Infection control efforts in recent years may have contributed to this association.

Liver transplantation and nursing care in Israel.

The Liver Unit in Hadassah Medical Center has been following patients before and after transplantation in a process combining medical and nurse care. Since 1991, 145 patients have been studied. This article reviews the study methods associated with the liver transplantation process, including etiology of basic liver disease, drug adverse effects, complications, and survival rates. The value of the nursing coordinator in liver transplantation is discussed.