Positive test results for acute hepatitis A virus infection among persons with no recent history of acute hepatitis--United States, 2002-2004

Hepatitis A is a nationally reportable condition, and the surveillance case definition includes both clinical criteria and serologic confirmation. State health departments and CDC have investigated persons with positive serologic tests for acute hepatitis A virus (HAV) infection (i.e., IgM anti-HAV) whose illness was not consistent with the clinical criteria of the hepatitis A case definition. Test results indicating acute HAV infection among persons who do not have clinical or epidemiologic features consistent with hepatitis A are a concern for state and local health departments because of the need to assess whether contacts need postexposure immunoprophylaxis. This report summarizes results of three such investigations, which suggested that most of the positive tests did not represent recent acute HAV infections. To improve the predictive value of a positive IgM anti-HAV test, clinicians should limit laboratory testing for acute HAV infection to persons with clinical findings typical of hepatitis A or to persons who have been exposed to settings where HAV transmission is suspected.     

Molecular characterization of an acute hepatitis A outbreak among healthcare workers at a Korean hospital

The seroprevalence of hepatitis A virus (HAV) antibodies is low in young adults in Korea. From May to July 2005, 17 cases of HAV were reported from healthcare workers (HCWs) in a hospital intensive care unit (ICU). We looked for the presence of anti-HAV IgM from all patients in the medical-surgical ICU with elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and screened AST and ALT levels in all HCWs who came into contact with two suspected index cases. Once the outbreak was confirmed, the molecular subtypes of HAV from the blood of HCWs were determined. Index cases and a transmission route were identified, and intervention strategies applied to control the outbreak. The 17 HCW cases included 13 nurses and four doctors aged 22-32 years, who each suffered acute HAV infection during the study period. The possible transmission of HAV was via the faecal-oral route from bedridden patients with diarrhoea. All HCWs were positive for anti-HAV IgM and eight were positive for HAV RNA. Analysis of the VP1-2A region of each isolate showed genotype IA in five strains and co-circulation of genotypes IA and IB in the others. This HAV outbreak highlights the importance of standard infection control precautions within a hospital. Molecular study of patients' blood would be useful for clarifying the epidemiology of a suspicious HAV outbreak in a hospital.     

Inapparent infection of hepatitis A virus

To detect inapparent infection with hepatitis A virus, serial sera were collected from patients with hepatitis A and their contacts in two waterborne epidemics in China. Epidemic 1 occurred in a rural village near Hangzhou during August 1978-January 1979, and epidemic 2 took place in a rural primary school in Pinghu County in Zhejiang in April-May 1985. These sera were tested for antibodies against hepatitis A virus (anti-HAV), serum glutamic pyruvic transaminase (SGPT) activity, and icteric index. Feces also were collected in epidemic 1 to test for hepatitis A virus antigen. Both anti-HAV immunoglobulin M (IgM) and total anti-HAV were assayed in sera from "healthy persons" (symptomless persons without icterus and with normal SGPT level) who were in close contact with hepatitis A patients. In epidemic 1, among 18 "healthy persons", 12 were anti-HAV IgM positive, two were immune, and four susceptibles escaped infection. In epidemic 2, among 32 "healthy children", three were anti-HAV IgM positive, five had been infected by hepatitis A virus in the past, and 24 were not infected. These results demonstrate that inapparent infections occur along with overt and subclinical infections during epidemics of hepatitis A. The proportions of inapparent, subclinical, and overt infections were, respectively, 34.3%, 45.7%, and 20% in epidemic 1, and 25%, 50%, and 25% in epidemic 2. In addition, hepatitis A virus particles were demonstrated in the feces of all infected subjects who were examined and who included all levels of clinical response. These particles were identified with immuno-electron microscopy and enzyme-linked immunoassay.     

Clinical course and consequences of hepatitis A infection

Hepatitis A virus (HAV) is a small, non-enveloped RNA virus belonging to the Picornaviridae, for which only one serotype has been identified. Transmission is usually through the faecal-oral route by person-to-person contact. The most common risk factors are household or sexual contact with a sufferer, attendance or working at a day-care centre, international travel, and association with food or waterborne outbreaks; 55% of cases have no identifiable risk factors. HAV infection may be symptomatic or asymptomatic, and shows three phases. Virus is shed during the incubation phase, anti-HAV IgM appears during the symptomatic phase and can be used for diagnosis, and anti-HAV IgG appears at the same time but persists lifelong. Unusual clinical manifestations of hepatitis A include cholestatic, relapsing and fulminant hepatitis. Hepatitis A accounts for 93% of cases of acute hepatitis in Argentina, including 7% of atypical clinical cases. Hepatitis A is the major cause of fulminant hepatitis, and has been reported to account for 10% of liver transplants in children in France and 20% in Argentina. One-year survival after liver transplantation is 64%. Prevention must be considered as the main means of averting this severe illness.     

Validation of HAV biomarker 2A for differential diagnostic of hepatitis A infected and vaccinated individuals using multiplex serology

BackgroundWorldwide about 1.5 million clinical cases of hepatitis A virus (HAV) infections occur every year and increasingly countries are introducing HAV vaccination into the childhood immunization schedule with a single dose instead of the originally licenced two dose regimen. Diagnosis of acute HAV infection is determined serologically by anti-HAV-IgM detection using ELISA. Additionally anti-HAV-IgG can become positive during the early phase of symptoms, but remains detectable after infection and also after vaccination against HAV. Currently no serological marker allows the differentiation of HAV vaccinated individuals and those with a past infection with HAV. Such differentiation would greatly improve evaluation of vaccination campaigns and risk assessment of HAV outbreaks. Here we tested the HAV non-structural protein 2A, important for the capsid assembly, as a biomarker for the differentiation of the immune status in previously infected and vaccinated individuals.MethodsHAV antigens were recombinantly expressed as glutathione-S-transferase (GST) fusion proteins. Using glutathione tagged, magnetic fluorescent beads (Luminex®), the proteins were affinity purified and used in a multiplex serological assay. The multiplex HAV assay was validated using 381 reference sera in which the immune status HAV negative, vaccinated or infected was established using the Abbott ARCHITECT® HAVAb-IgM or IgG, the commercial HAV ELISA from Abnova and documentation in vaccination cards.ResultsHAV multiplex serology showed a sensitivity of 99% and specificity of 95% to detect anti-HAV IgG/IgM positive individuals. HAV biomarker 2A allowed the differentiation between previously infected and vaccinated individuals. HAV vaccinated individuals and previously infected individuals could be identified with 92% accuracy.ConclusionHAV biomarker 2A can be used to differentiate between previously HAV-vaccinated and naturally infected individuals. Within a multiplex serological approach this assay can provide valuable novel information in the context of outbreak investigations, longitudinal population based studies and evaluations of immunization campaigns.     

Hepatitis A shifting epidemiology in Poland and Eastern Europe

The clinical morbidity of hepatitis A probably only represents 20% of cases of hepatitis A virus (HAV) infection. When it became possible to determine specific antibodies, a seroepidemiological survey of anti-HAV was undertaken in Poland, which showed that between 1979 and 1997 there was a shift in the peak age of infection from childhood to adulthood, concomitant with a substantial decline in the incidence of HAV infection. Data from the World Health Organization also indicate that there has also been a decline in the incidence of hepatitis A in Eastern European countries in general, over the 3 years from 1994 to 1996. The potential risk of epidemics still exists, however, when appropriate conditions are created. The available data show that fewer young people are becoming infected with HAV, and general preventive measures, including vaccination of children and high-risk groups (e.g. healthcare and childcare personnel and those living in 'closed communities') are needed to deal with HAV infections in Eastern Europe.     

Demonstration of specific antibodies to a coxsackie-like virus in patients of a hepatitis outbreak.

Lynchburg fecal virus (LFV), originally isolated from the stool of an infectious hepatitis patient, was passaged 15 times in WI-38 cells and partially characterized. Its properties are as follows: RNA virus; 27 nm in diameter, picornavirus-like morphology; inactivated at 56 C for 60 minutes; resistant to treatment with hydrochloric acid (pH 3.0), chloroform (33%), and diethyl ether (20%). Neutralization studies indicated that LFV is antigenically related to coxsackievirus A-24 but not to prototype hepatitis A virus (HAV). The simultaneous occurrence of infections with LFV and with HAV was indicated by the results of enzyme immunoassay (EIA) of the sera of patients of the Lynchburg outbreak. Absence of anti-LFV in patient sera was accompanied by an absence of anti-HAV and, conversely, an increased titer in anti-LFV was accompanied by an increased titer in anti-HAV. Each antibody type was shown to be elicited independently indicating simultaneous infections with LFV and HAV. The contribution, if any, of LFV to disease in the outbreak remains unknown.     

Immunoglobulin M-specific serologic testing in an outbreak of foodborne viral hepatitis, type A

Ninety-seven symptomatic and five asymptomatic infections with viral hepatitis, type A (102 cases) were identified in members, guests and employees of a private country club in an outbreak associated with consuming food and ice prepared or handled by an employee of the club's kitchen pantry. Twenty-three symptomatic persons were tested by differential radioimmunoassay for immunoglobulin M (IgM) (acute-phase) hepatitis A antibody (anti-HAV) and all 23 were documented to be infected with hepatitis A virus (HAV). Forty-one member/guest cases had only a single exposure at the county club. Their incubation periods ranged from 21 to 40 days, with a mean of 30 days. The exposure of these single-day patrons occurred over a 14-day period. The index case was not icteric and only moderately symptomatic and was diagnosed retrospectively to have viral hepatitis, type A by serologic determination of IgM anti-HAV in blood samples. Four items implicated in disease transmission were potato salad, hot dogs, molded salmon and ice handled by the index case. Serologic screening of controls did not appear to alter the conclusions of the food item analysis.     

Investigation of an outbreak of hepatitis A simplified by salivary antibody testing

In March 1988 a general practitioner notified two cases of hepatitis A in a private boarding school. Epidemiological investigation, including testing for salivary antibodies revealed a further five cases and established immunity to, and recent infection with, hepatitis A virus (HAV). The pattern of the outbreak was described. A number of practices which would encourage cross-infection were corrected. Normal human immunoglobulin was given to contacts. Repeat salivary testing 10 weeks later revealed that two more boys had become reactive for anti-HAV, though at a low titre. These may have been serological responses to HAV infection modified by the passive immunization.     

Serologic investigation of an outbreak of hepatitis A in a rural day-care center

We studied an outbreak of hepatitis A in a day-care center in a rural community where less than 7 per cent of the population possessed anti-HAV. Serotesting for IgM specific antibody to hepatitis A virus identified 78 cases in center attendees, staff, and families. Thirty-five per cent of the center children were seropositive. In children under age three anicteric infection was at least 17 times more frequent than icteric infection, but in older children and adults icterus was a predominant manifestation of the disease. Clinical suspicion should be high in any day-care child with nausea, emesis, diarrhea, or arthralgia. The low incidence of icterus in infected children suggested that outbreak reports reaching public health departments are likely to be incomplete and poorly indicative of outbreak magnitude. The high frequency of intrafamilial transmission and anicteric infection appeared to justify administration of immune serum globulin to household contacts of center children under age three when a day-care outbreak is detected.     

An epidemic of hepatitis A in an institution for young children

A common-source epidemic of hepatitis A occurred in an Athenian institution boarding 38 children (mean age 4.8 years). All children were examined, and blood was drawn from each at the onset of the study and repeatedly during the next three months. Only one child (2.6%) was initially immune to hepatitis A virus as a result of prior infection. The attack rate (62.2%) and the ratio of icteric to anicteric cases (1:1.3) were high despite the administration of immunoglobulin (IG). Assays for anti-HAV IgM and a rising titer of anti-HAV IgG identified 19 (82.6%) and 22 (95.7%) of the 23 hepatitis A infections, respectively. One case (4.3%) was detected only by the presence of hepatitis A virus antigen and hepatitis A virus RNA in a fecal specimen, but these assays were otherwise marginally useful in this study. Nevertheless, the use of all available tests for the detection of hepatitis A virus is mandatory for the most accurate estimation of an epidemic of hepatitis A. Prompt administration of immunoglobulin had no effect on the number of clinical cases that were in the late incubation period, but it may have diminished the clinical expression of the infection and thus made diagnosis of infection more difficult.     

The epidemiology of hepatitis A infection in Palestine: a universal vaccination programme is not yet needed.

In Palestine, there has been an increase in the reported incidence of acute hepatitis A virus (HAV) infection since 1995. Since overt clinical disease occurs only among adults, questions were raised whether or not a shift in the epidemiology of HAV has occurred. This is generally characterized by a decrease in the overall incidence rate and a shifting in the mean age of infection towards adolescence and early adulthood. The need for a vaccination programme is being discussed. To resolve this issue, we examined the prevalence of anti-HAV in a representative sample of 396 school children in the Gaza Strip. The prevalence of anti-HAV was 93.7% (95% CI: 91.3, 96.1%). Stratifying the prevalence by age showed that 87.8% (95% CI: 78.6, 97%) were HAV antibody positive by the age of 6. By the age of 14, almost 98% (95% CI: 92.7, 100%) were HAV antibody positive. This means that the majority of HAV infection is still taking place in early childhood, when it is usually asymptomatic and of little clinical significance. The results refuted the shifting epidemiology theory and we recommend that a vaccination programme against HAV infection is not yet needed. Alternative explanations for the increase in reported cases are discussed.     

Detection of antibodies to HAV 3C proteinase in experimentally infected chimpanzees and in naturally infected children

Commercial assays for the diagnosis of hepatitis A detect antibody to hepatitis A virus (anti-HAV), but they cannot discriminate between antibody resulting from infection and antibody induced by inactivated vaccine. With the licensing and increasing use of inactivated hepatitis A vaccines, there is a need for a test to distinguish between infection and vaccination. Since antibodies to viral non-structural proteins are elicited by infection but not by vaccination with inactivated vaccine, we developed and evaluated a test for such antibodies. The antibody response to the non-structural 3C proteinase (anti-3C) of virus HAV was studied by ELISA in chimpanzees experimentally infected with virulent (wild type) or with attenuated HAV strains and in children who received inactivated HAV vaccine or placebo during a vaccination trial in Nicaragua. Anti-3C was detected in 89% of 18 chimpanzees infected with wild-type HAV strains and 27% of 26 chimpanzees infected with attenuated HAV strains. There was a direct correlation between severity of hepatitis and magnitude of the anti-3C response. In the vaccine trial, anti-3C was detected only in children who were infected with HAV during the study; IgG anti-3C persisted for at least 15 months after infection in one child. Vaccinated and uninfected children remained negative for anti-3C. The anti-3C response can be regarded as an indicator of viral replication. Its detection should be useful for distinguishing between antibody acquired in response to HAV infection and antibody induced by immunization with inactivated vaccine.     

An outbreak of hepatitis A caused by consumption of raw oysters.

An outbreak of hepatitis A occurred among the members of the Japan Overseas Corporation Volunteers (JOCV) stationed in the Philippines. Seven out of 10 youths who ate, but none of five youths who did not eat raw oysters developed hepatitis. All these seven cases were positive for hepatitis A antibody (anti-HAV) and six of them were also positive for anti-HAV IgM (immunoglobulin M) 111 days after the infection.     

Vaccination strategies for control of community outbreaks of hepatitis A: A comparison of two outbreaks in England

In August 2015 two community outbreaks of hepatitis A virus (HAV) occurred in sub-urban communities in Northern England. Each was managed by an independent outbreak control team. In outbreak one, mass vaccination was deployed targeting a residential area and two schools, while in outbreak two, vaccination was reserved for household-type contacts of cases. The highest vaccination uptake was achieved in the school settings (82% and 95%). These case studies illustrate the range of approaches that can be used and the factors that influence decision-making in response to a hepatitis A community outbreak. Both outbreaks likely started from importation(s) of HAV by returning travellers and spread through extended social networks and the local community. Vaccination strategies were selected based on hypotheses about transmission pathways, which were informed by evidence from oral fluid (OF) testing of asymptomatic contacts. More evidence about the effectiveness of mass vaccination in community outbreaks of hepatitis A in low endemicity settings is needed. Hepatitis A guidelines should include recommendations for the use of mass vaccination and OF testing in outbreaks.     

Hepatitis A control in a refugee camp by active immunization

An outbreak of hepatitis A occurred among children of a refugee camp in Croatia. In order to disrupt the outbreak, we decided to vaccinate children from 1 to 15 years of age in the camp, in addition to intensified general preventive measures. Assuming high prevalence of hepatitis A virus antibodies within this population, we conducted anti-HAV testing of the children eligible for vaccination. Of 108 children tested, 74 (68.5%) were anti-HAV positive. We vaccinated 34 children. One month after vaccination 31 previously negative children were tested for anti-HAV and 30 of them were found positive, suggesting a seroconversion rate of 96.8%. One child fell ill 5 days after vaccination, after whom no new cases of hepatitis A occurred. Thus we conclude that active immunization is a successful means of stopping an outbreak of hepatitis A.     

Changing patterns of hepatitis A virus infection in children in Palermo,Italy

In 1988 in Palermo, Italy the prevalence of antibodies to hepatitis A virus (anti-HAV) in a sample of 490 children 6–13 years old was 10.6%; it increased from 6.3% among children 6–10 years old to 14.7% in children 11–13 years old (P < 0.01).Compared with findings from a survey conducted in 1978 in the same area, the results of the present study show a significant (P < 0.01) reduction in the anti-HAV prevalence in both age groups.Anti-HAV prevalence was inversely related to the father's years of education and positively related to the family size. Children of fathers with less than 6 years of schooling had a 3.2-fold risk (C.I. 95% = 1.3–8.1), and children with five or more members in their households had a 2.7-fold risk (C.I. 95% = 1.1–6.4) of previous exposure to hepatitis A virus (HAV) infection.Our findings indicate that exposure of children in Palermo to HAV is decreasing significantly, probably because of improvements in socio-economic conditions during recent years; however socio-demographic factors appear to be important determinants of infection.     

Hepatitis A in Peru. The role of children

A serologic survey in 1983-1984 evaluated the presence of hepatitis A antibody (anti-HAV) and hepatitis A immunoglobulin M antibody (anti-HAV IgM) in 3,251 adults and 811 children in the jungle and coastal areas of Peru. All subjects were asymptomatic. Adults had a 98% positive anti-HAV rate except for naval cadets, who had a 76% rate. Children had an 82% positive anti-HAV rate, increasing from 30% at one year of age to 100% at eight years of age. Anti-HAV IgM was present in 27% of children one to four years of age who had antibody and was not present in those older than 12. The vast majority of Peruvian adults are immune to hepatitis A, and children with asymptomatic infection play a significant role in the transmission of this disease.