Acute Hepatitis A Virus Infection Research Articles

Hepatitis A seroprevalence in Slovene travellers.

Hepatitis A virus (HAV) infection rates used to be very high in the past [1]. In the economically developed countries, HAV infection rates and the proportion of people with immunity to HAV decreased as a result of improved sanitation [2, 3]. There is a scarcity of information on the prevalence rates of anti-HAV in the Central European countries [4, 5]. Travellers to non-industrialized areas are exposed to infections that do not exist, or occur very rarely in their home country, such as HAV infection [6]. Nonimmune persons are effectively protected against HAV infection by timely vaccination. Immunization is not required in HAV seropositive travellers. The purpose of the study was to ascertain the seroprevalence of antibodies to HAV in adult Slovene travellers, and to determine whether prevaccination screening can reduce unnecessary vaccination. From the beginning of July 1999 to the end of October 1999, screening for antibodies to HAV was offered to all travellers aged 18–57 years who presented for immunization or malaria chemoprophylaxis at the travel clinic of the Institute of Public Health. The study included travellers born in Slovenia who had had no previous vaccination against HAV and denied having had known HAV infection. They were notified of test results. The travellers were categorized by the year of birth into the following eight groups: 1942–1946, 1947–1951, 1952–1956, 1957–1961, 1962–1966, 1967–1971, 1972–1976, 1977– 1981. On the basis of the ascertained seroprevalence we determined at what age prevaccination screening for HAV antibodies is cost-effective. Costs of the primary vaccination and booster immunization at months 6–12 were estimated. The total cost, i.e. the price of HAV vaccine plus the cost of vaccination, amounted to 97.8 EUR. The cost of antibody test was estimated to be 28.2 EUR. Over a period of 4 months, we tested 328 travellers (178 men and 150 women) with no history of acute HAV infection or previous vaccination against HAV. Altogether 103 (31.4%) subjects tested positive for HAV antibodies. Seropositivity rates are presented in Table 1. Seropositivity increased with age (p-value 0.001, v-test). Among the travellers born before 1962, 55.6% tested positive for anti-HAV. In contrast, a vast majority of persons (93.7%) born in 1971 and later who gave no history of infectious jaundice showed no immunity to HAV. Our observations are comparable to the results of a similar American study of travellers with no history of hepatitis A before vaccination [7]. It showed that solely 16.6% of persons born in industrialized countries were seropositive for HAV. The HAV seroprevalence rate was higher (32.1%) in individuals travelling frequently to economically less developed countries, and extremely high (82.7%) in people born in nonindustrialized countries. Prevaccination screening is considered cost-effective when the cost of vaccinating the entire population is higher than the cost of testing plus the cost of vaccinating non-immune individuals [8]. Considering the cost of vaccination of 97.8 EUR and 28.2 EUR for testing, the screening is economically valid for a population with a seropositivity rate of 29 per cent. The calculation based on the price of vaccine and cost of testing showed that vaccination without previous testing is cost-effective in subjects born after 1961. As previously mentioned, hepatitis A has become rare in the central part of Europe, too [4, 5]. The number of notified hepatitis A cases in Slovenia has been on a constant decline, particularly since 1990 (Figure 1) [9]. The decline is not attributable solely to the changed notification system, because the reporting

A virological perspective on the need for vaccination

Superinfecton of chronic carriers of hepatitis B virus (HBV) or hepatitis C virus (HCV) with hepatitis A virus (HAV) is often associated with more severe liver disease than infection with HAV alone. Superinfection commonly causes markers of HBV and HCV replication to fall to significantly lower levels. The pathogenesis of acute liver damage characteristic of viral hepatitis is thought to be mediated by host cytotoxic T-lymphocytes (CTLs) directed against virus-infected hepatocytes. It has been proposed that the more aggressive liver disease observed in individuals infected with HAV in addition to chronic HBV/HCV is a result of the induction of interferon (IFN)-alpha during acute HAV infection. This accounts for the antiviral effect on the active markers of HBV/HCV replication, and the enhanced CTL response against HBV/HCV-infected hepatocytes. Alternatively, HAV may indirectly stimulate the T helper 1 (Th1)-type cytokine responses, such as interleukin (IL)-2, IFN-gamma and tumour necrosis factor (TNF)-alpha, which directly promote the antiviral CTL response. Clearance of HBV infection, and possible HAV and HCV, is associated with a specific CTL response, while viral persistence in chronic HBV and HCV infection has been attributed to an imbalance in the Th1-Th2 arms of the immune response. Vaccination against hepatitis A should be considered for patients with chronic HBV/HCV infection, to minimize the risk of exacerbating underlying liver disease.

Haemolysis in hepatitis A virus infections coinciding with the occurrence of autoantibodies against triosephosphate isomerase and the reactivation of latent persistent Epstein-Barr virus infection.

Haemolysis has been observed frequently as a complication of acute hepatitis A virus (HAV) infection. However, the pathogenic mechanism has not been elucidated completely. In individual cases the detection of anti-erythrocyte antibodies of unknown specificity was described. The raised serum IgM fraction was shown to consist partially of autoantibodies. Previously, we detected autoantibodies of immunoglobulin class M directed against triosephosphate isomerase (IgM anti-TPI) in patients with infectious mononucleosis. These autoantibodies are able to induce haemolysis. In this study the occurrence of IgM anti-TPI in acute HAV infections and other viral diseases has been investigated. In 33 of 134 patients suffering from HAV infection (IgM anti-TPI was detected. Haematological and chemical data were available from seven of these 33 patients. Mild-to-moderate signs of haemolysis correlating with the IgM anti-TPI titre in the follow-up examinations were demonstrated. The presence of IgM anti-TPI in HAV infections is connected with a reactivation of a latent persistent EBV infection. In other viral infections both the detection of IgM anti-TPI and evidence of a reactivated EBV infection is rare. Thus, we anticipate that IgM anti-TPI antibodies occurring with the reactivation of a latent persistent EBV infection take part in provoking haemolysis in acute HAV infections.

Haemolysis in hepatitis A virus infections coinciding with the occurrence of autoantibodies against triosephosphate isomerase and the reactivation of latent persistent Epstein‐Barr virus infection

Haemolysis has been observed frequently as a complication of acute hepatitis A virus (HAV) infection. However, the pathogenic mechanism has not been elucidated completely. In individual cases the detection of anti-erythrocyte antibodies of unknown specificity was described. The raised serum IgM fraction was shown to consist partially of autoantibodies. Previously, we detected autoantibodies of immunoglobulin class M directed against triosephosphate isomerase (IgM anti-TPI) in patients with infectious mononucleosis. These autoantibodies are able to induce haemolysis. In this study the occurrence of IgM anti-TPI in acute HAV infections and other viral diseases has been investigated. In 33 of 134 patients suffering from HAV infection (IgM anti-TPI was detected. Haematological and chemical data were available from seven of these 33 patients. Mild-to-moderate signs of haemolysis correlating with the IgM anti-TPI titre in the follow-up examinations were demonstrated. The presence of IgM anti-TPI in HAV infections is connected with a reactivation of a latent persistent EBV infection. In other viral infections both the detection of IgM anti-TPI and evidence of a reactivated EBV infection is rare. Thus, we anticipate that IgM anti-TPI antibodies occurring with the reactivation of a latent persistent EBV infection take part in provoking haemolysis in acute HAV infections. © 1996 Wiley-Liss, Inc.

Immune response to hepatitis A virus capsid proteins after infection.

This study was undertaken to determine the immune response of humans to viral capsid polypeptides of hepatitis A virus (HAV) after natural infection, which is very important for vaccine development. Antiviral capsids in 73 serum samples from patients with acute and chronic HAV infections were analyzed by immunoblotting against individual HAV capsid polypeptides (VP1, VP2, VP3, and VP4) by using a cell culture-based HAV antigen. For reference, total anti-HAV immunoglobulin G (IgG) and anti-HAV IgM were also determined by radioimmunoassay. As a result, a dominant immune response against VP1 (98% IgG, 94% IgM) was found in the acute phase. However, many other sera also reacted with VP0 (88% IgG; 35% IgM) and VP3 (81% IgG and 29% IgM). In contrast to the acute phase, anti-VP1, anti-VP0, and anti-VP3, IgG antibodies against all three viral proteins (29, 29, and 73% respectively), especially those against VP3, were found years after onset of HAV disease and over long periods in the sera of hepatitis patients. These results suggest that antibodies for capsid polypeptides are present over an extended period in the sera of HAV-infected patients. They are likely of importance in maintaining long-term immunity.

Clinical manifestations and diagnosis of hepatitis A virus infection

Hepatitis A is an acute, necroinflammatory disease of the liver which results from infection by the hepatitis A virus (HAV). The mean incubation period is approximately 30 days. Although the disease is usually self-limited, the severity of illness is age-dependent. In children, hepatitis A is usually asymptomatic, while in adults, symptomatic infection is characteristic and jaundice is common. Fulminant hepatitis A is rare and is also age-dependent. The onset of hepatitis A is often abrupt and characteristic prodromal symptoms are followed, within a few days to a week, by dark urine and jaundice. Mild to moderate tenderness over an enlarged liver is usually detected. Serum alanine and aspartate aminotransferase levels usually both rise rapidly during the prodromal period, reach peak levels and then decrease by ≈ 75% per week. Serum bilirubin concentrations reach peak levels later and decline less rapidly than serum aminotransferases. Nonetheless, the period of jaundice persists for < 2 weeks in ≈ 85% of cases. Nearly all adult patients with clinically apparent disease experience complete clinical recovery with restoration of normal serum bilirubin and aminotransferase values by 6 months. Relapses and prolonged cholestasis are unusual manifestations of hepatitis A, and even in these circumstances, recovery is the rule and chronic hepatitis is not seen. The diagnosis of hepatitis A requires the detection of immunoglobulin M antibody to HAV in a patient who presents with, or has recently had, clinical features of hepatitis (icteric or anicteric disease) or in an individual with inapparent, asymptomatic infection in whom serum aminotransferase elevations may be detected. In occasional individuals monitored because of exposure to the disease, serological confirmation of acute HAV infection may occur in the absence of detectable aminotransferase elevations.

An Outbreak of Hepatitis A among Cancer Patients Treated with Interleukin-2 and Lymphokine-Activated Killer Cells

An outbreak of hepatitis A virus (HAV) infection occurred among cancer patients treated with interleukin-2 (IL-2) and lymphokine-activated killer (LAK) cells between July and September 1986 at six different clinical centers. Among 85 patients tested serologically for recent HAV infection, 22 (39%) of 56 susceptible patients developed acute HAV infection. Only exposure to LAK cells cultured in medium containing human serum from two specific manufactured pools was associated with HAV infection. Attack rates were 85% among patients exposed to pool X, 62% in patients exposed to pool Y, and 50% in those exposed to both pools, compared with none among the 24 susceptible persons exposed to other serum pools (P less than .001). The serum used in production of LAK cell medium was obtained from multiple paid donors. Twenty persons donated plasma to both serum pools X and Y. Although none of 12 donors tested had evidence of recent HAV infection, it is likely that an asymptomatic plasma donor viremic for HAV contaminated both serum pools and the LAK cell medium made from it.

Liver-Derived Cytotoxic T Cells in Hepatitis A Virus Infection

An autologous in vitro model was developed to analyze the immunologic cause of liver tissue injury during hepatitis A virus (HAV) infection. Human T lymphocytes infiltrating the livers of two patients with acute HAV infection were isolated from liver biopsy cores, cloned, and expanded in vitro. Procedures using a cell culture system with HAV-infected autologous skin fibroblasts demonstrated that 42% and 53% of the liver-infiltrating CD8+ clones were HAV-specific and that they kill HAV-infected skin fibroblasts in a human leukocyte antigen-restricted manner. Data show virus-specific killing by liver-infiltrating T lymphocytes in man and support the hypothesis that liver cell injury in acute HAV infection is mediated by HAV-specific CD8+ T lymphocytes and is not caused by a cytopathic effect of the virus itself.

Detection of hepatitis a virus rna in serum from patients with acute hepatitis

Hepatitis A virus (HAV) RNA was extracted from the sera of patients with acute hepatitis and then detected by molecular hybridization using cloned HAV complementary DNA (cDNA). HAV RNA was detected in 20 of 85 patients with acute HAV infection, mainly during the prodromal stage, or early during the icteric phase of the disease; it was detected as long as 21 days after its initial detection. Patients with HAV RNA in the serum had a significantly higher titer of anti-HAV IgM.

Human gamma interferon production by cytotoxic T lymphocytes sensitized during hepatitis A virus infection

The production of interferon (IFN) during a chromium-51 release assay with hepatitis A virus (HAV)-infected fibroblasts and autologous peripheral blood lymphocytes from patients with acute HAV infection was studied to determine whether IFN plays a role in immunopathogenesis of hepatitis A infection in humans. Skin fibroblasts of eight patients after acute HAV infection and from two control persons without history of current or past HAV infection were infected with HAV. Peripheral blood lymphocytes were collected at different times after the onset of icterus and tested in a chromium-51 release assay against autologous HAV-infected skin fibroblasts for their cytolytic and IFN-producing activity. The IFN produced during the assay was characterized and found to have the properties of human gamma IFN. Cytotoxicity and gamma IFN release were virus specific. The cell types responsible for both functions were characterized and found to be in the HLA-dependent T8+ lymphocyte subset. Considering that gamma IFN has an antiviral effect on persistent HAV infection in vitro and that it probably accounts for stimulation of HLA class I antigen expression on hepatocytes, our experimental results presented here demonstrate that human gamma IFN produced by HAV-specific T cells may participate in pathogenesis of hepatitis A infection in humans.

Enzootic hepatitis A infection in cynomolgus monkeys (Macaca fascicularis)

During a toxicology study in cynomolgus (long-tailed or crab-eating) monkeys (Macaca fascicularis), a randomly distributed incidence of significantly increased hepatic enzyme activity was observed. Premedication hepatic enzyme activity in all monkeys of this study was normal, but increased alanine aminotransferase (ALT) activity was found in 4 of the 24 animals 2 weeks after initiation of the study and in 10 of 24 at 4 weeks. A drug-related effect was considered unlikely initially because the increases were not doserelated, and a 3-year review of 655 cynomolgus monkeys revealed a 15-20% incidence of increased hepatic enzyme activity. Good correlation was subsequently established between increased hepatic enzyme activity, active hepatitis A virus (HAV) infection, and histomorphologic confirmation of hepatitis (chronic periportal inflammation). Follow-up viral serodiagnostic screening of resident macaques revealed an overall incidence of anti-HAV IgG in 80% (155/193) of cynomolgus and in 70% (14/20) of rhesus monkeys. Serial screening demonstrated that several initially negative monkeys became seropositive for anti-HAV IgG, and a few acquired active infection (anti-HAV IgM). Among newly acquired cynomolgus monkeys, 2.5% (2/80) had an acute HAV infection, and 35% (28/80) eventually tested positive for anti-HAV IgG while quarantined in the primate facility. The characterization of an enzootic HAV infection in incoming monkeys posed a significant risk for the primate colony and handlers. Rigorous sanitation, isolation, and quarantine procedures, including personnel training and additional protective clothing for personnel working in the primate colony, reduced tho potential for transmission and arrested the outbreak. Experimenters should be cautious in ascribing toxicity to a test article based solely on increased hepatic enzyme activity associated with chronic periportal inflammation.

Acute non-A, non-B hepatitis in Kuwait.

In a prospective study of acute hepatitis in Kuwait covering the period February 1983 to January 1984, a total of 1781 cases were diagnosed as having an acute viral hepatitis. 1,384 (77.7%) were found to be due to hepatitis A virus (HAV), 206 (11.5%) hepatitis B virus (HBV), 8 (0.4%) coinfection with HBV and delta virus (HDV), 8 (0.4%) superinfection of HDV on chronic HBsAg carriers and 157 (9%) non-A, non-B virus (NANB). 13 cases of CMV and 5 of EBV infections were also diagnosed. NANB viral hepatitis was a disease of young adults (mean age 29 years) with a male-female ratio of 3:1. A high incidence was noted among males from the Indian subcontinent (29.1/100,000 of population, compared to 5.4/100,000 among local Arabs), the majority of whom gave a history of recent visit to the Indian subcontinent. The clinical features and biochemical findings of acute NANB infection were found to be less severe than those of acute HBV infection and similar to acute HAV infection. Three patients (2.3%) with acute NANB virus infection developed chronic hepatitis (all women), and another 3 patients died because of fulminant hepatitis.

A »REVERSE« SOLID‐PHASE RADIO‐IMMUNOASSAY FOR IgM‐ANTIBODIES TO HEPATITIS A VIRUS

A "reverse"solid-phase radio-immuno-assay for IgM antibodies to hepatitis A virus (HAV) was developed. Anti-human IgM immunoglobulins were bound on the wells of polyvinylchloride microtiter plates. Serum specimens were incubated in the anti-human IgM coated wells and bound IgM antibodies were then assayed for antigen specificity by subsequent incubations with HAV antigen and 125I-labelled human anti-HAV IgG. The test showed a high sensitivity and specificity for anti-HAV IgM antibodies. No false-positive reactions were observed either in the sera from patients with hepatobiliary disorders other than HAV infection or in the sera containing both rheumatoid factor and anti-HAV IgG antibodies. In acute HAV infections specific IgM antibodies were present already in the first specimens taken within a few days after the onset of jaundice. The persistence of the IgM antibodies was from 4 to 6 months. IgM antibody titers up to 1,000,000 were observed in the acute phase of HAV infection. In routine diagnostic work the titration of the sea was not necessary, since a reliable qualitative result was obtained by testing the sera in a single dilution of 1:100. A similar "reverse" immuno-assay principle may be adaptable for the diagnostic determination of IgM antibodies to different viral and microbial antigens.