F. Blaine Hollinger

Long-Term Mortality after Transfusion-Associated Non-A, Non-B Hepatitis

Abstract Background. Acute non-A, non-B hepatitis after blood transfusion often progresses to chronic hepatitis and sometimes culminates in cirrhosis or even hepatocellular carcinoma. However, the frequency of these sequelae and their effects on mortality are not known. Methods. We traced patients with transfusion-related non-A, non-B hepatitis who had been identified in five major prospective studies conducted in the United States between 1967 and 1980. We matched each patient with two control subjects (identified as the first and second controls) who received transfusions but who did not have hepatitis. The mortality rates in the three groups were determined with use of data from the National Death Index and Social Security Death Tapes. Cause-specific mortality was determined by reviewing death certificates. Results. Vital status was established for over 94 percent of the 568 patients who had had non-A, non-B hepatitis and the two control groups (526 first controls and 458 second controls). After an ave...

Emerging infectious disease agents and their potential threat to transfusion safety

BACKGROUND: Emerging infections have been identified as a continuing threat to human health. Many such infections are known to be transmissible by blood transfusion, while others have properties indicating this potential. There has been no comprehensive review of such infectious agents and their threat to transfusion recipient safety to date.

Hepatitis B Virus Antibody in Blood Donors and the Occurrence of Non-A, Non-B Hepatitis in Transfusion Recipients: An Analysis of the Transfusion-Transmitted Viruses Study

Patients who received transfusions and nontransfused control patients were followed to assess the incidence and cause of post-transfusion hepatitis and to identify donor factors that might relate to risk of hepatitis. We evaluated as risk factors in donors the presence of antibody to hepatitis B virus compared with elevated alanine aminotransferase (ALT) level. Units of blood that were positive for antibody to hepatitis B core antigen (anti-HBc) were associated with a twofold to threefold greater risk of non-A, non-B hepatitis in the recipients than were units without anti-HBc. In the absence of specific serologic tests for non-A, non-B agents, screening of donors for anti-HBc might be considered. Our data suggest that the incidence of non-A, non-B hepatitis might have been reduced by about one third by such screening. However, elevated ALT levels in donors had a similar association with non-A, non-B hepatitis in recipients but would have resulted in fewer units of blood being discarded than would screening for anti-HBc.

Perinatal Transmission of Hepatitis C Virus from Human Immunodeficiency Virus Type 1-Infected Mothers

Antepartum plasma hepatitis C virus (HCV) RNA was quantified in 155 mothers coinfected with HCV and human immunodeficiency virus type 1 (HIV-1), and HCV RNA was serially assessed in their infants. Of 155 singleton infants born to HCV antibody-positive mothers, 13 (8.4%) were HCV infected. The risk of HCV infection was 3.2-fold greater in HIV-1-infected infants compared with HIV-1-uninfected infants (17.1% of 41 vs. 5.4% of 112, P = .04). The median concentration of plasma HCV RNA was higher among the 13 mothers with HCV-infected infants (2.0 x 10(6) copies/mL) than among the 142 mothers with HCV-negative infants (3.5 x 10(5) copies/mL; P < .001), and there were no instances of HCV transmission from 40 mothers with HCV RNA concentrations of < 10(5) copies/mL. Women dually infected with HIV-1 and HCV but with little or no detectable HCV RNA should be reassured that the risk of perinatal transmission of HCV is exceedingly low.

Nucleic Acid Testing to Detect HBV Infection in Blood Donors

BACKGROUND The detection of hepatitis B virus (HBV) in blood donors is achieved by screening for hepatitis B surface antigen (HBsAg) and for antibodies against hepatitis B core antigen (anti-HBc). However, donors who are positive for HBV DNA are currently not identified during the window period before seroconversion. The current use of nucleic acid testing for detection of the human immunodeficiency virus (HIV) and hepatitis C virus (HCV) RNA and HBV DNA in a single triplex assay may provide additional safety. METHODS We performed nucleic acid testing on 3.7 million blood donations and further evaluated those that were HBV DNA-positive but negative for HBsAg and anti-HBc. We determined the serologic, biochemical, and molecular features of samples that were found to contain only HBV DNA and performed similar analyses of follow-up samples and samples from sexual partners of infected donors. Seronegative HIV and HCV-positive donors were also studied. RESULTS We identified 9 donors who were positive for HBV DNA (1 in 410,540 donations), including 6 samples from donors who had received the HBV vaccine, in whom subclinical infection had developed and resolved. Of the HBV DNA-positive donors, 4 probably acquired HBV infection from a chronically infected sexual partner. Clinically significant liver injury developed in 2 unvaccinated donors. In 5 of the 6 vaccinated donors, a non-A genotype was identified as the dominant strain, whereas subgenotype A2 (represented in the HBV vaccine) was the dominant strain in unvaccinated donors. Of 75 reactive nucleic acid test results identified in seronegative blood donations, 26 (9 HBV, 15 HCV, and 2 HIV) were confirmed as positive. CONCLUSIONS Triplex nucleic acid testing detected potentially infectious HBV, along with HIV and HCV, during the window period before seroconversion. HBV vaccination appeared to be protective, with a breakthrough subclinical infection occurring with non-A2 HBV subgenotypes and causing clinically inconsequential outcomes. (Funded by the American Red Cross and others.).

The Relationship of Acute Transfusion-Associated Hepatitis to the Development of Cirrhosis in the Presence of Alcohol Abuse

Seroprevalence data from the Third National Health and Nutrition Examination Survey (1984 to 1999) suggest that 3 million persons in the United States are infected with the hepatitis C virus (HCV) (1). Treatment fails to clear the virus in 80% to 85% of acutely infected persons. Not all persons who remain infected eventually develop progressive liver disease (2), but in those who do, clinical evidence of liver damage may not appear until decades later (3). It is widely believed that progression of liver disease in persons with chronic HCV infection is enhanced by concomitant heavy alcoholism (4-12). We sought to quantify the association of transfusion-associated HCV infection and history of alcohol abuse with development of cirrhosis among patients followed from the time of acute HCV infection. Methods The source of this investigation, described in detail elsewhere (13), is a long-term follow-up study of acute non-A, non-B hepatitis in patients included in earlier prospective studies of transfusion-related HCV infection. All patients provided informed consent, and the study was approved by the relevant institutional review boards. Briefly, non-A, non-B hepatitis was identified by otherwise unexplained elevations in serum alanine aminotransferase (ALT) levels developing 2 to 24 weeks after transfusion, in the absence of serologic evidence of hepatitis A or B (13). The ALT level had to be elevated on two consecutive measurements, and at least one of the values had to exceed twice the upper limit of normal. Stored sera from case-patients and controls from three of the prospective studiesthe second Veterans Administration Cooperative study (14), the Transfusion-Transmitted Viruses study (15), and the National Institutes of Health Blood Bank Study (16)were tested for anti-HCV by enzyme immunoassay (HCV EIA 2.0, Abbott Laboratories, North Chicago, Illinois). Transfusion-associated HCV infection was diagnosed if anti-HCV appeared and persisted, was temporally related to elevated ALT levels, and was confirmed by using the supplementary recombinant immunoblot assay (RIBA version 3.0, Ortho Diagnostics, Raritan, New Jersey). Because repository samples were not optimally stored for minimizing nucleic acid loss, HCV RNA testing was not performed. Controls consisted of transfused patients from the original three prospective studies who had not developed hepatitis (13). Controls were matched to case-patients by initial treatment center, sex, ethnicity, use of hepatitis immune globulin, presence or absence of a history of alcoholism, age, number of units of blood transfused, and date of transfusion. We excluded patients with anti-HCVpositive samples that predated the index transfusion and those with anti-HCV reactivity but no confirmatory test. Anti-HCVpositive/RIBA-negative and anti-HCVnegative patients were classified as having transfusion-associated non-A, non-B, non-C hepatitis. Controls with anti-HCV in repository samples were excluded. We used a multifaceted approach to gather information on each patients history of liver disease from participation in the prospective studies through initiation of the follow-up study (13). Vital status was ascertained through searches of death registries, and copies of death certificates were obtained. Patients or their designated proxies (if the patient was deceased or incompetent) were invited to participate in a personal interview that included questions about previous hospitalizations. Authorization for release of medical records was obtained, and information on all hospitalizations at each facility identified was requested. Medical records, death certificates, and biopsy and autopsy reports were reviewed by trained abstractors for the diagnosis of cirrhosis, which was based on the occurrence of features of portal hypertension and overt clinical manifestations of cirrhosis. Evaluation of a sample of records indicated a high level of agreement between abstractors and one of the investigators. Potential risk factors were derived primarily from personal interview. A composite variable aimed at identifying a history of heavy alcohol abuse was designed to minimize the possibility of misclassifying unexposed patients. The composite variable was based on one or more of the following criteria: loss of friends, family, or a job because of drinking; admitting to ever having a problem with alcoholism; evidence of heavy drinking abstracted from medical records; or quantification of usual intake of more than 80 g of alcohol per day during the years when the patient drank. Univariate methods (the Fisher exact, exact FisherFreemanHalton [17], and Wilcoxon rank-sum tests) were used to compare the distribution of characteristics between patients included in and those excluded from the analysis and to examine associations between potential risk factors and development of cirrhosis. The strength of the association between risk factors and cirrhosis was assessed by using the odds ratio obtained from multiple logistic regression. The likelihood of developing cirrhosis associated with a combination of risk factors was estimated from the logistic model (18). Results Of 1030 patients who were followed up from the original prospective studies that had collected repository samples, 836 (81.2%) were included in this analysis. We excluded 108 patients whose repository samples were exhausted, 79 with ALT levels or HCV assays that did not permit reliable classification of hepatitis status, 1 with cirrhosis that predated the index transfusion, and 6 with data inconsistencies that could not be resolved. As shown in Table 1, included and excluded patients differed only in median number of blood units originally transfused. The number of units received could affect the probability of developing acute transfusion-associated hepatitis or its severity but would probably not influence development of cirrhosis decades later. Table 1. Characteristics of Included and Excluded Patients Preliminary analyses indicated that development of cirrhosis was unrelated to tattooing, ear piercing, occupational exposures, extended travel to areas in which hepatitis is endemic, and use of injection or other illegal drugs. Information on prescription drug use was unavailable for analysis. Development of cirrhosis differed (P<0.05) according to transfusion-associated hepatitis status, study cohort, race/ethnicity, units of blood originally transfused, history of heavy alcohol abuse, and vital status at follow-up (Table 2). The absolute risk for developing cirrhosis was higher among patients with transfusion-associated HCV infection (17.0% [35 of 206 patients]) (P<0.001) than among those with transfusion-associated non-A, non-B, non-C hepatitis infection (3.2% [3 of 95 patients]) or controls (2.8% [15 of 535 patients]) but did not differ between the latter two groups (P>0.2). The median time from index transfusion to initiation of follow-up (15.6 years overall) did not differ by cirrhosis status, transfusion-associated hepatitis status, or race/ethnicity (P 0.10). Table 2. Association of Patient Characteristics with Development of Cirrhosis Logistic regression modeling indicated that patients with transfusion-associated HCV infection were 7.8 times (95% CI, 4.0 to 15.1 times) more likely to develop cirrhosis than controls, after adjustment for history of heavy alcohol abuse and study cohort. Patients with transfusion-associated non-A, non-B, non-C hepatitis were at increased risk for developing cirrhosis, but this finding was not significant (odds ratio, 1.4 [95% CI, 0.4 to 5.0]). Patients with transfusion-associated HCV were 5.6 times (CI, 1.6 to 19.3 times) more likely to develop cirrhosis than those with non-A, non-B, non-C hepatitis. A history of heavy alcohol abuse was associated with an increased risk for developing cirrhosis (odds ratio, 4.0 [CI, 2.1 to 7.7]). The HosmerLemeshow goodness-of-fit test indicated that the model fit the data well (P>0.2). From this model, it was estimated that patients with both transfusion-associated HCV infection and a history of heavy alcohol abuse were 31.1 times (CI, 11.4 to 84.5 times) more likely to develop cirrhosis than controls without a history of alcohol abuse. Patients with transfusion-associated non-A, non-B, non-C hepatitis and a history of heavy alcohol abuse were also more likely than controls without such a history to develop cirrhosis (odds ratio, 5.5 [CI, 1.3 to 24.3]). Although cirrhosis was less common among African-Americans (2.2%) than among persons of other ethnicities (7.2%), addition of race/ethnicity, follow-up duration, units of blood originally transfused, vital status, and receipt of additional transfusions to the model changed the risks associated with hepatitis status and history of heavy alcohol abuse only slightly. None of these factors made a significant independent contribution to the model (data not shown). Discussion Patients who contracted transfusion-associated HCV infection were at increased risk for developing cirrhosis (odds ratio, 7.8), and this risk increased substantially if the patient also had a history of heavy alcohol abuse (odds ratio, 31.1). Although numerous reports have identified a strong role of alcohol in promoting progression of liver disease among persons with chronic HCV infection (4-12), our findings provide a quantitative measure to assess the strength of this association. Some patients who were originally classified as having acute non-A, non-B hepatitis tested negative for HCV infection. These patients developed cirrhosis more frequently than controls, but not significantly so. This finding suggests that the elevated ALT levels observed during the original prospective studies were caused by intrinsic liver disease. It remains to be determined, however, whether these patients had been infected with a virus other than hepatitis A, B, or C virus or whether the elevated enzyme levels resulted from other causes (for example, nonviral infection

Hepatitis B virus infection and transfusion medicine : science and the occult

O ccult hepatitis B virus (HBV) “infection” has been characterized as an obscure, covert, concealed, or hidden disease entity that is recognized in a hepatitis B surface antigen (HBsAg)-negative person whose blood and/or liver tissue is found to contain HBV DNA. While there is general consensus for this definition, uncertainty exists as to what other hepatitis B serologic criteria should be included in this description and whether hepatitis C virus (HCV) or human immunodeficiency virus (HIV) should be excluded from the equation. This has created some confusion depending on whether one is dealing with a healthy blood donor or a patient with liver disease. Additional critical issues are whether these individuals are viremic and at risk for progression of their disease or are capable of transmitting HBV to another individual. To place this in perspective, an overview of the current methods used for detecting HBV followed by a summary of the serologic patterns accompanying hepatitis B infection seems to be warranted concluding with a discussion of occult infection based on recently published articles. CURRENT MOLECULAR BIOLOGY OF HBV AND DIAGNOSTIC METHODOLOGY

Factors influencing the immune response to hepatitis B vaccine, booster dose guidelines, and vaccine protocol recommendations

The clinical course and immunodiagnosis of hepatitis B infection is discussed. Immunization is necessary to prevent the clinical disease, the development of carriers, and the transmission of the hepatitis B virus to susceptible persons. Host factors that can curtail the immune response include increasing age, obesity, smoking cigarettes, and having a medical condition that compromises the immune system. Increasing the dose of vaccine, administering the inoculations intramuscularly, and giving the vaccine more frequently can enhance the immune response. The duration of immunity following vaccination has not yet been defined, but booster dose guidelines for selected groups are provided. Finally, recommendations for developing and implementing hepatitis B immunization protocols are presented.

Immunization of seronegative infants with hepatitis A vaccine (HAVRIX®; SKB): a comparative study of two dosing schedules

Hepatitis A virus (HAV) infection is of public health significance among infants and diapered children. Although two licensed HAV vaccines are available, they have not been assessed widely in children under the age of 2 years and are not currently licensed for this age group. The purpose of this study was to evaluate the immunogenicity and reactogenicity of HAV vaccine in seronegative infants. Fifty-three healthy infants were immunized with 360 ELISA Units (EL.U.) of an inactivated HAV vaccine at 2, 4, and 6 (Group 1) or 2, 4, and 15 months of age (Group 2). These injections were not received on the same day that participants received their routine childhood immunizations. HAV serum antibodies were detected using a modified radioimmunoassay procedure and concentrations were calculated using a World Health Organization serum anti-HAV reference standard. No serious-systemic or local reactions were noted among the immunized infants. Three months following the third immunization, seroconversion rates were 100% and 93% in groups 1 and 2, respectively. No significant differences were observed in the geometric mean anti-HAV concentrations between the two groups at comparable time points, i.e. 2 months after the second dose, 3 months after the third dose, and 19 months after the first dose. Three infants, not included in the data presented above, had preexisting maternal antibodies; one never responded to the vaccine and the other two did not respond until maternal antibody levels had become reduced. The results indicate that the inactivated HAV vaccine is highly immunogenic in seronegative infants and could be included in the routine harmonized infant immunization schedule.

A comparative study of human immunodeficiency virus culture, polymerase chain reaction and anti-human immunodeficiency virus immunoglobulin A antibody detection in the diagnosis during early infancy of vertically acquired human immunodeficiency virus infection.

The infection status of 91 infants born to mothers with human immunodeficiency virus (HIV) infection was determined. Twenty-eight (31%) infants had confirmed HIV infection and 63 (69%) had seroreverted to HIV and lack evidence of infection. During the first 6 months of life HIV culture had a sensitivity and specificity for diagnosis of HIV infection of 80 and 100%, respectively. False negative HIV cultures were observed in only 7 of 35 specimens, 6 from among the 12 infected infants tested at birth. The sensitivity and specificity of polymerase chain reaction (PCR) detection of HIV were 95 and 93%, respectively. A single false negative PCR test result was observed among the 19 tests performed on specimens from HIV-infected infants. False positive PCR test results were observed occasionally throughout the first 6 months of life. Detection of HIV-specific IgA antibody lacked diagnostic sensitivity; positive test results were observed in only 53% of specimens obtained from infected infants. Culture and PCR detection offer excellent sensitivity and specificity for diagnosis of HIV infection during the first 6 months of life; however, false-negative HIV cultures sometimes are observed, particularly during the newborn period, and either false negative or false positive PCR test results may be noted occasionally. For purposes of clinical decision-making, any positive test result should be confirmed with a second HIV culture or PCR test performed on a separate blood specimen.