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Hepatic infections. Part II. The effect of acute and chronic hepatitis B antigenaemia on the reaction to antibodies to sheep red cells (microbial antigens) and human T-activated cells (exposed autologous tissue antigens).

Using the agglutination of sheep red cells by human antibodies as an indicator of microbial antibody activity, a highly significant association was found between the response to the e antigen of the hepatitis B virus and the formation of strong antibody levels to microbial substances (chi 2(1) = 33). This kind of association was not found among chronic carriers of the hepatitis B virus who do not produce antibodies to the e antigen (chi 2(1) = 3,7). In the presence of e antigen activity, patients with acute virus B hepatitis almost always show significantly reduced levels of antibodies to microbial substances (chi 2(1) = 20). The findings indirectly reveal that e activity is associated with the inability of the liver to trap bacterial antigens. Circumstantial evidence further suggests that the e factor may bear antigens on its immunoglobulin-like structure very similar to microbial cell wall components. Accepting that human antibodies to the T (Thomsen-Friedenreich) antigen represent reactions to cryptantigenic membrane structure of autologous tissues, it was significant to record that increased anti-t activity is always demonstrated when virus B infections progress from the acute to the chronic carrier stage (chi 2(1) = 73). The most intense anti-T activity is commonly found in subjects who produce antibodies to the hepatitis B surface antigen (chi 2(1) = 138). In the presence of e antigen the amount of anti-T in circulation is always significantly depressed. Since this type of depression is not seen in patients with acute virus B hepatitis who lack the e antigen, we suspect that the reduced anti-T levels in e antigen-positive patients are linked with the in vivo exposure of T receptors by microbial neuraminidase.

Acute Disease↗

[Risk of hepatitis infection of the recipients of blood from donors with HBs-antigenemia].

Observations were made on 100 recipients of blood from 40 donors with HBs-antigenemia and 106 recipients of the control group, who had received 570 ampules of blood from 491 donors, and 499 ampules from 400 donors, respectively. The incidence of post-transfusion serum hepatitis in the icteric forms was 12.7% and 1.9%, respectively (P less than 0.002), varying between 8.9% and 22.2% in the experimental subgroups, and decreasing with the increase of the total number of blood transfusions received by the subjects. The source of infection proved to be 0.5% of the donors in the control group, and 2.65% in the experimental group (P less than 0.01), or 17.9-33.3%, of donors with HBs-antigenemia. With the sufficient number of recipients traced to each donor, all donors with HBs-antigenemia were found to be the sources of infection. It means that HBs-antigenemia may be regarded as the indication of the presence of the complete (infective) hepatitis virus B in the body.

Blood Donors↗

Discovery of (1R,5S)-N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]- 3-[2(S)-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide (SCH 503034), a selective, potent, orally bioavailable hepatitis C virus NS3 protease inhibitor: a potential therapeutic agent for the treatment of hepatitis C infection.

Hepatitis C virus (HCV) infection is the major cause of chronic liver disease, leading to cirrhosis and hepatocellular carcinoma, which affects more than 170 million people worldwide. Currently the only therapeutic regimens are subcutaneous interferon-alpha or polyethylene glycol (PEG)-interferon-alpha alone or in combination with oral ribavirin. Although combination therapy is reasonably successful with the majority of genotypes, its efficacy against the predominant genotype (genotype 1) is moderate at best, with only about 40% of the patients showing sustained virological response. Herein, the SAR leading to the discovery of 70 (SCH 503034), a novel, potent, selective, orally bioavailable NS3 protease inhibitor that has been advanced to clinical trials in human beings for the treatment of hepatitis C viral infections is described. X-ray structure of inhibitor 70 complexed with the NS3 protease and biological data are also discussed.

Administration, Oral↗

Impact of liver disease and hepatitis infections on allogeneic bone marrow transplantation in Europe: a survey from the European Bone Marrow Transplantation (EBMT) Group--Infectious Diseases Working Party.

This survey investigated allogeneic bone marrow transplantation (BMT) policy in European BMT units by questionnaire, in relation to pre-transplant liver disease. It also assessed diagnostic standards for viral hepatitis infections and their prevalence in BMT candidates. Sixty-three EBMT centers from 22 countries participated in the survey. Median pre-transplant prevalences of HBsAg and anti-HCV positivity were 3.5% (range 0-15%) and 5% (range 0-45%), respectively. Forty-six (73%) centers adopt the policy of cancelling or postponing BMT in patients with ALT abnormalities but in four of these centers, BMT is not delayed when progressive disease or acute leukemia is present. In 17 institutions (27%) BMT was reported to be carried out irrespective of transaminase values. Data on fatal post-BMT liver disease were provided by 45 centers. The overall mortality rate for liver failure was 4.5% (258 of 5788) with no differences between centers performing or not performing BMT in cases of ALT elevation. These results indicate that there is strong concern in most European BMT units about performing BMT in the presence of ALT elevation and prospective studies on its real impact on fatal post-BMT liver disease should be conducted.

Alanine Transaminase↗

Prevalence rates of viral hepatitis infections in refugee Kurds from Iraq and Turkey.

BACKGROUND: Since little is known about the burden of viral hepatitis in Kurds, the prevalence of infection with hepatitis A virus (HAV), hepatitis E virus (HEV), hepatitis B virus (HBV) and hepatitis C virus (HCV) was investigated in a sample of refugee Kurds from Iraq and Turkey. PATIENTS AND METHODS: A cross-sectional study was carried out. Serological markers to hepatitis viruses were determined for 1,005 subjects from all age-groups of which 36.6% were from Turkey and 63.4% from Iraq. RESULTS: Overall seroprevalence for anti-HAV was 94.4% and 14.8% for anti-HEV. A significantly higher prevalence for anti-HEV was found among Iraqis (17.5%) compared to Turkish immigrants (10.0%). The prevalence of hepatitis B surface antigen (HBsAg) and total anti-HBc (core) was 6.8% and 35.6% in Turkish Kurds and 2.2% and 12.7% in Iraqis, respectively. Only 10% of children aged up to 10 years and 2.8% of subjects aged 11-20 years had been vaccinated against HBV, the majority of them coming from Iraq. One subject was confirmed as positive for anti-HCV (0.1%) and HCV-RNA and analysis showed a 4c/4d genotype. CONCLUSION: This survey shows a high prevalence of enterically transmitted viral hepatitis in Kurds. HBV infection is moderately endemic, while the prevalence of HCV infection is low. There is a need for a universal immunization strategy for HBV in the Kurd population.

Adult↗

[Intraabdominal and hepatic infections in pediatric cancer patients].

Common complications involved in treating pediatric patients with cancer are bacterial, viral and fungal infections of the gastrointestinal tract including esophagitis, gastritis, duodenitis, colitis and hepatobiliar infections. In many cases there are multiple factors that predispose these patients to gastrointestinal infections, such as granulocytopenia, T-cell dysfunction, and mucosal damage. In addition, newer therapies have changed the spectrum of infection that is seen in these patients. The profound T-cell suppression associated with therapies such as stem cell transplantation has led to the emergence of previously rare infections including cytomegalovirus and adenovirus. This article provides the recommendations of the Infectious Diseases Working Party of the German Society for Pediatric Infectious Diseases (DGPI) and the German Society for Pediatric Hematology/Oncology (GPOH) for diagnosis, prevention, and management of local as well as invasive infections of the gastrointestinal tract.

Anti-Infective Agents↗

The development of hepatic granulomas following interferon-alpha2b therapy for chronic hepatitis C infection.

Hepatic granulomas have been detected in cases of chronic hepatitis C virus (CHCV) infection. Here we report upon three selected cases of CHCV infection who were treated with IFN alpha, in whom hepatic granulomas were absent on initial liver biopsies, but in whom granulomas developed following IFN alpha therapy. In one case, complete regression of these granulomas was noted 17 months following discontinuation of treatment, more strongly implicating IFN alpha in the aetiopathogenesis of such granulomas in this case. These findings suggest that IFN alpha may have a biological role in the pathogenesis of granulomatous liver disease in these patients. All three cases were poor/non-responders to IFN alpha, suggesting that the development of hepatic granulomas during IFN alpha therapy may be associated with a poor response to treatment.

Adult↗

Hepatic infection by thymidine kinase-positive and thymidine kinase-negative herpes simplex virus after partial hepatectomy.

Herpes simplex virus (HSV) infection of mouse liver after partial hepatectomy was studied. Partial hepatectomy resulted in the rapid onset of cellular DNA synthesis and the appearance of many mitotic figures (peak, 3 days after surgery). Similar changes were not seen in control animals. After partial hepatectomy, the mice were infected with thymidine kinase-positive (TK+) and -negative (TK-) HSV to investigate virus titers in liver tissue during liver cell replication. In control unoperated mice, liver titers of TK+ HSV (2 X 10(3) PFU/g) were greater than those of mice inoculated with TK HSV (4 X 10(1) to 5 X 10(2) PFU/g). After partial hepatectomy, TK+ and TK- HSV titers increased, and peak TK+ and TK- HSV titers were similar (6 X 10(5) to 8 X 10(5) PFU/g). Hepatic infection was further investigated by infectious center (IC) assays. The numbers of ICs for TK+ HSV increased 50-fold after partial hepatectomy, whereas the increase was less for TK- HSV. From the results of these studies, we hypothesize that the increase in hepatic TK+ HSV after hepatectomy may have been largely due to the increase in ICs, whereas the increase in hepatic TK- HSV was due, in part, to the increase in ICs, but may also have been due to the enhanced synthesis of TK- HSV in replicating liver cells.

Animals↗

The association of infective hepatitis type A (HAV) and diabetes mellitus.

The cases of three patients who developed diabetes mellitus (DM) within 2-3 weeks of acute hepatitis A virus (HAV) infection associated with diabetic ketoacidosis are reported. The ketoacidosis was considered an index of insulin dependent diabetes mellitus most likely precipitated by the acute virus infection.

Adult↗

Clinical course and consequences of hepatitis B infection.

Hepatitis B virus (HBV) is a small enveloped virus containing partially double-stranded DNA. The DNA and HBV-specific DNA polymerase are surrounded by the HBV core antigen (HBcAg), which in turn is surrounded by a lipoprotein envelope containing the HBV surface antigen (HBsAg). Serum of HBV-infected patients contains complete virus particles, as well as non-infectious spherical or filamentous HBsAg particles. Acute hepatitis is characterized by the appearance of serum HBV markers, including HBsAg and IgM anti-HBc, which then disappear during convalescence. Persistence of HBsAg for more than 6 months indicates a carrier state. Chronic hepatitis develops in 90% of newborns who become infected, compared with 29-40% of children infected and 5-10% of adults infected. The immune status of the infected person also influences the development of chronic hepatitis. Chronic HBV infection can be diagnosed by serology (identification of HBsAg and HBV DNA), biochemistry (elevated aminotransferase levels) and liver biopsy. The last is important to assess the severity of disease, its stage and prognosis, and to exclude other hepatic diseases. The outcome of chronic HBV infection varies between individuals, with estimated 5-year survivals of 97% for chronic persistent hepatitis, 86% for chronic active hepatitis, and 55% for chronic active hepatitis with cirrhosis. Treatment with interferon alpha is effective in up to 40% of cases, but in view of the very large number of infected people worldwide, vaccination to prevent spread of the disease is a more cost-effective option.

Adult↗

Clinical aspects of non-A, non-B hepatitis infection.

Although non-A, non-B hepatitis is usually a mild subclinical illness, 40% of cases of fulminant viral hepatitis are attributed to infection by this agent. The administration of coagulation factor IX concentrates before liver biopsy in 17 patients with chronic liver disease was followed by the development of hepatitis in four, which proved fatal in three cases. The diagnosis was confirmed by transmission in chimpanzees, and further studies demonstrated the existence of two types of non-A, non-B hepatitis with different incubation periods and specific ultrastructural changes in the hepatocytes. The progression of 40% of cases of acute viral hepatitis to chronic liver disease and the development of chronic liver disease in renal and hepatic transplant recipients is very disturbing. It is likely that this type of hepatitis is an aetiological factor in some cases of hepatitis B surface antigen-negative chronic active hepatitis.

Animals↗

Interstitial pneumonitis in a patient treated with alpha-interferon and ribavirin for hepatitis C infection.

Hepatitis C is a common infection with worldwide prevalence. It has a variable course and can lead to chronic hepatitis, cirrhosis and hepatocellular carcinoma. Until recently alpha-interferon (IFN-alpha) was the only effective treatment available. Combination therapy with IFN-alpha and ribavirin has been found to be more efficacious than IFN-alpha alone. Various side effects have been ascribed to interferon, such as arthralgias, myalgias, fatigue, and gastrointestinal and neuropsychiatric symptoms. Interstitial pneumonitis is a rare but known complication of IFN-alpha when given at a high dosage of 6 to 10 million units per day. Ribavirin is associated with dose-dependent hemolytic anemia, cough, dyspnea, rash, depression, and dyspepsia, although a potential role in interferon-induced interstitial pneumonitis has not been described. We describe a patient with an excellent clinical response of chronic hepatitis C to combination therapy with IFN-alpha at a dosage of 3 million units per day and ribavirin. The patient developed interstitial pneumonitis that resolved after discontinuation of IFN-alpha and ribavirin. Given that interstitial pneumonitis has previously been reported with high-dose IFN-alpha, this case suggests that this complication may occur with lower dosages of IFN-alpha, although a potential role for ribavirin in this disorder at present remains speculative.

Antiviral Agents↗

[Natural history of hepatitis B infection].

Hepatitis B virus (HBV) is transmitted by parenteral, sexual and perinatal routes. While fulminant hepatitis may occur in 1% of cases of symptomatic acute hepatitis, the principal problem of HBV infection is that it may become chronic, classically defined by carriage of HB surface antigens (HBsAg) for more than 6 months. This occurs in only 0.5 to 3% of immunocompetent adults but more frequently in children (up to 90%) and in immune-compromised patients (30 to 100%). The course of chronic HBV infection is characterized by variations in viral replication with spontaneous reactivation or discontinuation, and potential exacerbations observed clinically or by laboratory testing. The pathogenesis of HBV infection is mainly immune-mediated, resulting from host-virus interactions but also from the complexity of the virus itself (integration, mutation, occult replication). These factors explain the variety of presentations of chronic HBV infection, which range from immune tolerance to inactive carriage of HBsAg, passing through a stage of immune clearance, where chronic active hepatitis which may lead to cirrhosis (yearly incidence of 1.3 to 5.9%). Cirrhosis may be complicated by portal hypertension, liver failure, or hepatocellular carcinoma, which together explain 80% of the morbidity and mortality associated with HBV. The 5-year survival rate for HBV-related cirrhosis ranges from 52 to 82%. Immunosuppression, hepatitis D virus superinfection, and chronic alcohol consumption are the principal factors that modify this natural history. Chronic HBV infection is a major public health problem, particularly in developing countries, and it requires that efforts to make HBV vaccination universal be intensified.

Acute Disease↗

Viral antigens and antibodies in hepatitis B infection.

Hepatitis B virus antigens and antibodies were detected in the sera of acute and persistently infected patients. Evidence of active virus replication was confined to immediately before or during the initial detection of hepatitis B surface antigen during acute hepatitis B. Hepatitis B core antibody appeared during the period of antigenaemia and preceded recovery. Hepatitis B e antigen was dound in a proportion of sera which contained significant levels of virus particles. In contrast, all sera containing hepatitis B virus particles from persistently infected patients treated by maintenance haemodialysis also contained the e antigen. Among a group of 50 persistent carriers of hepatitis B virus, significant levels of virus production occurred in the presence of antibody to e antigen. In addition, evidence of exposure to hepatitis B virus was found among 3% of blood donors in whose sera the surface antigen was not detected by radioimmunoassay. The significance of these findings is discussed in relation to the aetiology of hepatitis type B.

Antibodies, Viral↗

T and B lymphocytes in uremic patients with type B hepatitis infection.

Peripheral T and B lymphocytes were measured in (1) hepatitis B surface antigen (HBsAg)-positive, (2) HBsAg-negative uremic patients on chronic hemodialysis (CHD) therapy, and (3) patients with type B chronic active viral hepatitis (CAVH). When compared to normals, a decrease in the absolute number of T and B lymphocytes was detected in both CHD groups. CAVH patients had a decrease in the total number of T lymphocytes. When expressed as percentage of T lymphocytes, normals and HBsAg-negative CHD patients had similar values, while a decrease was detected in both HBsAg-positive CHD and CAVH patients. Also, in the latter two groups, hepatitis B virus infection resulted in an increase in the total number and percentage of null cells.

Adult↗