Control of a community-wide outbreak of hepatitis A by mass vaccination with inactivated hepatitis A vaccine.

The epidemiology and control of hepatitis A virus was investigated during an outbreak of hepatitis A in a village in Israel. Postexposure administration of immune globulin to contacts was ineffective in controlling the outbreak. However, within 2 weeks of starting a mass immunization campaign with hepatitis A vaccine, the incidence of hepatitis A declined dramatically; the last case occurred 6 weeks after the immunization program began. The study demonstrated that while postexposure administration of immune globulin may diminish but not entirely arrest transmission of hepatitis A virus, active hepatitis A vaccination is a safe and effective intervention that can be used safely in hepatitis A virus antibody-positive children.

Evaluation of screening for hepatitis B surface antigen during pregnancy in a population with a high prevalence of hepatitis B surface antigen-positive/hepatitis B e antigen-negative carriers.

BACKGROUND: Universal hepatitis B vaccination in infancy was implemented in Israel in 1992. The program consists of active vaccination at birth and at 1 and 6 months of age, without hepatitis B surface antigen (HBsAg) screening during pregnancy. Infants of HBsAg carrier mothers do not receive specific hepatitis B immunoglobulin in addition to vaccine at birth. The recently arrived Jewish immigrants from Ethiopia are the group with the highest rate of HBsAg carriage (approximately 10%) in Israel. AIM: The objective of this study was to evaluate whether the present policy is effective against perinatal HBV transmission from mothers of Ethiopian origin to their infants. METHODS: The study group included 411 Israeli born children, offspring of mothers of Ethiopian origin. All infants were fully vaccinated starting at birth. Sera were collected from the children at the age of 9 to 36 months and from their mothers. Tests for HBsAg, antibodies to HBsAg (anti-HBs) and antibodies to hepatitis B core antigen (anti-HBc) were performed. RESULTS: Eighty-nine percent of the children had detectable anti-HBs, including 82.2% with protective anti-HBs concentrations (> or =10 mIU/ ml). Although 24 mothers (6.2%) were HBsAg carriers, none of the children was HBsAg-positive. Seven of 394 infants (1.7%) tested positive for anti-HBc. This test became negative in 5 of 6 who were followed for 12 months. The percentage of infants with protective anti-HBs concentrations decreased significantly from 91.4% at 9 to 12 months to 70.1% at 31 to 36 months of age. The mother's infection status was not associated with the infant's response to vaccine. Calculation based on the above data suggests that screening for HBsAg in pregnancy in that group is not cost-effective. CONCLUSIONS: Our results suggest that the Israeli vaccination program against HBV infection is effective, even in a high risk population, and additional measures are not cost-effective.

[An epidemic of respiratory syncytial virus bronchiolitis among infants in northern Israel].

In the wake of a community outbreak of bronchiolitis in northern Israel from December 1993 to March 1994, we conducted a retrospective study of 108 infants aged 2 weeks to 14 months with proven respiratory syncytial virus (RSV) infection (diagnosed by a rapid RSV antigen test in nasopharyngeal secretions). 47% of the infants were less than 8 weeks old. Mean hospital stay was 6.6 days (range 1-60). The characteristic clinical findings were: cough in all patients, dyspnea in 96%, rhinitis in 95% and fever in 55%. In those younger than 8 weeks, or in those with underlying diseases, hospitalization was longer, the disease was more serious and complications more frequent (p < 0.002). 4 children (3%) died, 3 of whom had severe congenital heart defects. All children were treated with oxygen and beta-agonist inhalations. The 33% who also received corticosteroids were older and most had a history of pulmonary diseases, such as asthma or bronchopulmonary dysplasia. There was no difference between those who did or did not receive corticosteroids with regard to severity of disease or rate of complications. Ribavirin was used to treat 19 (17.5%), most of whom had underlying lung disease. The others were otherwise healthy infants younger than 8 weeks. 13 were cared for in the intensive care unit, 11 of whom required mechanical ventilation. A rapid test for detection of RSV infection enabled prompt isolation of infected patients so that the risk of nosocomial infection was reduced and Ribavirin therapy could be started early, if required.

Coinfection with hepatitis viruses and human immunodeficiency virus in multiply transfused patients.

The prevalence, clinical manifestations and serological markers of hepatitis C virus (HCV), hepatitis B virus (HBV) and human immunodeficiency virus (HIV) infections were studied in 112 multiply transfused patients (49 hemophiliacs receiving either nonheat-treated factor concentrates or cryoprecipitate, 33 thalassemic, 20 refractory anemia and 10 leukemia patients). Positive serological markers for HCV, HBV and HIV were found to correlate with number of donors and duration of disease (logistic regression P = 0.0001 and 0.01 respectively). Viral infectivity was significantly correlated with type of blood product. HCV seropositivity was more common in hemophiliacs treated with nonheat-treated factor concentrates (93%) compared to those receiving cryoprecipitate (37%) or nonhemophiliacs receiving red packed cells (20%) (P < 0.001). Likewise, HBV seropositivity in patients receiving the above blood products was 83%, 61% and 26% respectively (P < 0.001), and HIV seropositivity was 35%, 6% and 0% respectively (P < 0.001). Acute or chronic liver disease was documented in 4 of 14 (28%) HCV-positive patients. Increased liver enzymes were recorded in sera of 43% HCV-positive patients and 18% HBV-positive patients compared to 22% of HBV and 20% HCV-seronegative patients (P = 0.076). Of 47 HCV-positive patients 24 were coinfected by HBV and 9 had triple infection (HCV, HBV and HIV). No solitary HIV infection was found. HIV seropositivity was always accompanied by serologic evidence for HBV with or without HCV infection.

Epidemiological and serological studies in HIV-infected Ethiopian immigrants to Israel.

In the last 10 years, Ethiopian Jews have immigrated to Israel in large numbers. Up to 1990 they came directly from their remote villages in northern Ethiopia and no HIV infection was detected in the several thousands that came. In contrast, 1.74% of approximately 14,000 new immigrant Ethiopians who arrived in 1991-92, after spending more than a year in Addis Ababa, were HIV positive. Several infants born in Israel following the latter immigration were found to be infected, whereas more than 2500 children born in Ethiopia were negative. Sexual transmission during their stay in Addis Ababa is thought to be the only route of infection, and therefore this is a newly infected population. Immunological studies revealed very low CD4 count in HIV-infected people. HIV-negative Ethiopian immigrants to Israel also have a lower CD4 count than the general Israeli population. Further studies are currently under way to look at the natural history of this particular HIV-infected group.

Evaluation of a monoclonal antibody-based enzyme immunoassay for early detection of herpes simplex virus genital infection.

A monoclonal antibody-based enzyme immunoassay test for detection of herpes simplex virus (HSV) type-common antigen was evaluated in 40 women with vulvar lesion suspicious for genital HSV infection. The assay gave interpretable readings in 90% of the cases, with sensitivity and specificity of 100% and 92% respectively, a negative predictive value of 100%, and a positive predictive value of 75%. With a few limitations, the assay may be used for early diagnosis of genital HSV infection.

Anamnestic response to hepatitis B vaccine in nonalcoholic liver cirrhosis patients with and without HBV-DNA.

Two methods were used to unveil a possible previous hepatitis B virus (HBV) infection in patients with postnecrotic liver cirrhosis. The anamnestic response to a booster injection of HB vaccine was assessed, and the polymerase chain reaction (PCR) technique for the detection of HBV-DNA in serum and liver tissue, using primers to span the precore and core regions, was employed. Seventeen patients with postnecrotic liver cirrhosis were selected from a population with a high prevalence of HBV infection and were compared with 11 liver cirrhosis patients who were positive for antibodies to surface antigen (anti-HBs) IgG antibodies. All patients were given one dose of HB vaccine into the deltoid muscle, and anti-HBs titers were measured 1 and 4 wk after injection. Three of 17 patients, initially negative for anti-HBs, showed a primary response, with titers of anti-HBs rising from 0 to a maximum of 85 mIU/ml after 4 wk; the rest had no response. Of the 11 patients positive for anti-HBs, of whom nine were also IgG anti-HBs positive, only four had an intense anamnestic response, with anti-HBs titers rising to more than 10 times the initial values (up to 10,800 mIU/ml). Serum HBV-DNA was detected in eight patients in the antibody-negative group and in only one patient in the antibody-positive group (p less than 0.02). None of the four patients with positive anamnestic response had HBV-DNA in the serum. The prevalence of HBV-DNA in the liver was similar in both groups. Absence of HBV-DNA in serum of most patients positive for anti-HBs supports the hypothesis that HBV particles released from the liver may be captured by antibodies in the serum. We conclude that assessment of the anamnestic response to HB vaccine has no diagnostic advantage, compared with direct measurement of conventional HBV serological markers in patients with liver cirrhosis. Moreover, we suggest that this type of immunologic response may not occur when virion-associated HBV-DNA is present in the serum.

The prevalence and interaction of human immunodeficiency virus and hepatitis B virus infections in Israeli hemophiliacs.

The prevalence, clinical manifestations and serological markers of hepatitis B virus (HBV) and human immunodeficiency (HIV) infections were studied in 117 Israeli hemophiliacs. Positive serological markers for HBV infection (HB surface antigen, antibody to HB surface antigen or antibody to HB core antigen) were more common in patients treated with non heat-treated F-VIII concentrates (NHTC) than with cryoprecipitate (48/49 vs. 23/29, P less than 0.05), and in patients treated with greater than 10,000 factor units/year (90% vs. 62%, P less than 0.05). Of the 117 patients, 55% were HIV negative, 29% had asymptomatic HIV seropositivity and 16% had symptomatic HIV infection (lymphadenopathy syndrome, AIDS-related complex or AIDS). HIVB seropositivity was more common in patients treated with NHTC than in those treated with cryoprecipitate (83% vs. 11%, P less than 0.001), and in patients treated with greater than 100,000 compared to less than 10,000 F-VIII units/year (70% vs. 15%, P less than 0.001). Hypergammaglobulinemia correlated with HIV seropositivity, alanine aminotransferase levels and type and amount of concentrate therapy. Of 50 HIV-seropositive patients, 40 (98%) had serological markers of HBV infection compared with only 40 of 52 HIV-negative patients (77%) (P less than 0.01). Symptomatic HIV infection was more common in patients with a positive history of jaundice, 7 of 18 (38%) compared with 12 of 99 (12%) (P less than 0.005). These findings suggest that HBV and HIV infections are less prevalent in cryoprecipitate-treated patients, and that HBV seropositivity is a predictor of HIV seropositivity in hemophiliacs.

Hepatitis B virus infection in patients with idiopathic liver disease.

We studied 67 HBsAg-negative Israeli patients (36 negative for all HBV serological markers as group 1 and 31 positive for antibodies to HBs and HBc as group 2) with chronic liver disease and cirrhosis of unknown origin using a rapid, sensitive and specific assay for the detection of low levels of hepatitis B virus in serum. This technique uses a high-affinity monoclonal antibody to HBs against an a domain epitope of HBsAg to capture the virion, followed by hepatitis B virus DNA amplification with the polymerase chain reaction. In addition, 55 subjects without liver disease served as controls: Group 3 (n = 32) was negative for all hepatitis B virus markers; group 4 (n = 23) was positive for antibodies to HBs and HBc. We found 11 individuals in group 1 (31%) and 10 in group 2 (29%) harboring low levels of hepatitis B virus DNA in serum. In contrast, no one in group 3 or group 4 was positive by this technique (p less than 0.0001). Using polymerase chain reaction primers spanning other regions of the hepatitis B virus genome and a method of restriction-fragment analysis of polymerase chain reaction-amplified sequences, we detected significant DNA sequence heterogeneity, suggesting infection with distinct hepatitis B virus strains. DNA extracted from paraffin-embedded liver biopsy specimens of 42 patients from groups 1 and 2 was shown to contain hepatitis B virus DNA by polymerase chain reaction in 11 of 12 patients with circulating virion DNA. More important, 18 additional patients whose sera were negative by HBs-antibody capture/polymerase chain reaction amplification had hepatitis B virus DNA sequences in their livers.(ABSTRACT TRUNCATED AT 250 WORDS)

A hepatitis B virus mutant associated with an epidemic of fulminant hepatitis.

BACKGROUND: A nosocomial outbreak of fulminant hepatitis B occurred in five patients in Haifa, Israel. Previous investigations identified the suspected source as a carrier of hepatitis B surface antigen who was positive for antibodies to hepatitis B e antigen and had chronic liver disease. We examined the strain of hepatitis B virus (HBV) that caused this epidemic, in order to identify specific mutations in the precore or core region. METHODS: The presence of HBV was identified by polymerase-chain-reaction amplification of viral DNA in serum from the source patient, the five patients with fulminant hepatitis B, and five controls with acute, self-limited hepatitis B. The amplified viral HBV DNA samples were then cloned and sequenced. RESULTS: Sequence analysis of viral DNA established that the same HBV mutant with two mutations in the precore region was present in the source patient and the five patients with fulminant hepatic failure. This HBV mutant had significant sequence divergence from other known HBV subtypes in the X, precore, and core regions. Cloned HBV DNA derived from a hospitalized patient who had subclinical hepatitis B at the same time as the outbreak and from four other control subjects with acute, self-limited hepatitis B all contained the wild-type sequence in the precore region. CONCLUSIONS: In the outbreak we studied, a mutant hepatitis B viral strain was transmitted from a common source to five patients who subsequently died of fulminant hepatitis B infection. Naturally occurring viral mutations hepatitis B infection. Naturally occurring viral mutations in the HBV genome may predispose the infected host to more severe liver injury.

Hepatitis B virus infection in Ethiopian immigrants to Israel.

Two groups of immigrants from Ethiopia, one of 86 and the other of 165 individuals, aged 0-40, were examined for hepatitis B virus (HBV) infection in 1987-88, 3-7 years after their arrival in Israel. The results were compared with those obtained in the same age-group among Ethiopians who immigrated to Israel in 1980-82. The immigrants were found to be in good physical condition, their liver function tests were normal and no clinical evidence of chronic liver disease was found. Of the 22 children aged 0-4, 16 had anti-HBs as a result of vaccination at birth against HBV and they were excluded from the comparative study. In the age-groups 5-40 there was no significant change in the percentage of individuals positive for HBsAg, anti-HBs or anti-HBc only, compared with the group examined in 1980-82. There were two significant findings in this study: a) In 1987-88 [corrected], 8-9% of HBsAg-positive individuals had HBeAg and 64-81% had anti-HBe, while in 1980-82, 36% of those positive for HBsAg had HBeAg and only 25% had anti-HBe. b) At the time of arrival recent infection by HBV was indicated by the presence of IgM anti-HBc in 57% of those positive for HBsAg and 21% in whom anti-HBc was the sole serological HBV marker. In 1987-88 no IgM anti-HBc was found in HBsAg-positive persons or in those with anti-HBc only. These results indicate that most HBV infections in this population had occurred before their arrival in Israel. There is a profound change in the epidemiology of HBV infection in this Ethiopian population following immigration, which is probably due to environmental changes as well as to vaccination against HBV of all young children aged less than or equal to 3 years.

A common-source outbreak of fulminant hepatitis B in a hospital.

A nosocomial outbreak of fulminant hepatitis B infection at a medical center in Haifa, Israel, between 7 and 26 June 1986, involved five patients who had been hospitalized previously in the medical ward in late April and early May (first generation). This outbreak had an unusual clinical course, with fulminant hepatic failure associated with acute renal failure from acute glomerulonephritis, leading to death within a few days. The onset dates of hepatitis were tightly clustered temporally and incubation periods were short. Extensive laboratory and epidemiologic evaluation showed that the probable common-source vehicle of transmission was a multiple-dose vial of heparin and normal saline flush solution that may have been contaminated by blood of a known HBsAg carrier, who was positive for anti-HBe, hospitalized at the same time. A sixth patient died in August 1986 (second generation), after his initial admission in June that coincided with the terminal hospitalizations of three first-generation patients. Those patients had marked coagulopathies, and transmission to the sixth patient most probably occurred through environmental contamination by patients or through cross-contamination between patients through staff. The unusually high mortality rate (5 of 6) in this outbreak has not been definitely explained.

Natural killer cell activity in post-necrotic cirrhotic patients as related to hepatitis-B virus infection and plasma zinc levels.

In view of the suggested physiological role of natural killer (NK) cells in immunosurveillance and defence against viral infections, we have investigated the relationship between hepatitis B virus (HBV) infection and NK activity against K-562 cells in patients with post-necrotic cirrhosis. Overall, the NK activity in cirrhotic patients did not differ from age- and sex-matched controls. However, cirrhotic males with evidence of HBV infection with or without HBs antigenemia tend to have lower NK activity than controls. Cirrhotic males without evidence of HBV infection do not differ from controls. Such a trend was not observed in the female cirrhotic patients examined. In addition significantly reduced NK activity was observed in cirrhotic patients with low plasma zinc levels. This relationship is of interest because of the known association between zinc deficiency and various immunodeficiencies.

Correlation of HBV DNA and monoclonal reactivity to HBsAg in serum of patients with HBV infection.

Hepatitis B virus (HBV) DNA hybridization assay, a monoclonal radioimmunoassay (M-RIA) for hepatitis B surface antigen (HBsAg) and conventional polyclonal immunoassays for HBV associated antigens were used to study sera from patients on dialysis and with acute hepatitis B. HBV DNA was detectable in hepatitis B e antigen (HBeAg) negative patients with acute hepatitis but not in HBsAg+ HBeAg- dialysis patients. In acute hepatitis, HBsAg immunoreactivity by M-RIA could still be detected even though a commercial immunoassay for HBsAg, the AUSRIA II, and the HBV DNA assay were no longer positive. Unlike in acute HBV infection, serum HBV DNA was detectable in dialysis patients who were AUSTRIA II negative but M-RIA positive. Serial determination of HBsAg by M-RIA and HBV DNA revealed episodes of HBV DNA positivity months after both the HBsAg was no longer positive by polyclonal immunoassay. Thus, the M-RIA for HBsAg and the molecular hybridization technique for HBV DNA are sensitive and specific assays for the identification of potentially infectious individuals who would not have been characterized as such based on the results of conventional polyclonal immunoassays.

Hepatitis B virus infection and liver disease in Ethiopian immigrants to Israel.

We assessed infection with hepatitis B virus in 357 Ethiopians who immigrated to Israel. Hepatitis B virus infection, as measured by the presence in the serum of HBsAg, anti-HBs, or anti-HBc, started at an early age (35% at the age of 1 to 4 years) and reached an overall rate of 98% in individuals over 40 years old. A high rate of HBsAg antigenemia in the young age group (19% at the age of 1 to 8 years) was associated with HBeAg and serum hepatitis B virus DNA. However, hepatitis B virus DNA was rarely detected in HBsAg-positive serum of older individuals who were anti-HBe-positive. No hepatitis B virus DNA sequences were detected in the serum of individuals who had anti-HBs. Despite the extremely high rate of hepatitis B virus infection that occurred at an early age, no clinical evidence of chronic liver disease in this population was detected.