non-B Post-transfusion Hepatitis Research Articles

Recent breakthroughs to combat Hepatitis C virus infection

Following the discovery of hepatitis A and B viruses, it was almost certain that a third virus also attacked the liver. The main criteria for this thinking was the fact that, following blood transfusion, hepatitis with slightly different clinical features occurred in patients who were negative for both viruses, hence the disease was known as non-A, non-B post-transfusion hepatitis.

Transfusion-associated or nosocomial hepatitis G virus infection in patients undergoing surgery.

Despite blood donor screening, there are still cases of transfusion-associated hepatitis. From 1988 to 1992, a prospective study was conducted on the incidence of non-A, non-B posttransfusion hepatitis (PTH). The present investigation was designed to determine if transfusion recipients with PTH who are negative for hepatitis C virus (HCV) were positive for hepatitis G virus (HGV). Patients admitted for surgery who had normal liver tests and no transfusions during the previous 6 months were enrolled. Alanine amino transferase levels were determined monthly for 6 months after surgery and for 1 year in the case of PTH (defined as alanine aminotranferase twice the upper limit of normal in two consecutive assays). HGV RNA and E2 antibodies were tested for in samples from transfusion recipients with or without PTH and from nontransfused patients. Of the 308 blood recipients who were enrolled in the study, 21 (6.8%) had PTH. HGV RNA was detected at the onset of hepatitis in 3 patients with PTH (14%), 2 of whom were also anti-HCV and HCV RNA positive. One patient developed E2 antibodies without detectable HGV RNA. Three (10.7%) of 28 recipients of an allogeneic transfusion without PTH developed HGV infection. HGV RNA was also found in two nontransfused patients, which suggests nosocomial transmission of HGV. Some cases of PTH are associated with HGV; most cases of postoperative HGV infection are not associated with liver abnormalities; and most PTH cases are not associated with known hepatotropic viruses.

History of posttransfusion hepatitis

The risk of hepatitis virus transmission from tranfusions has declined dramatically from that of the 1940s when posttransfusion hepatitis (PTH) was first appreciated. Introduction of hepatitis B surface antigen screening and conversion to volunteer donors for whole-blood donations in the late 1960s and early 1970s led to substantial reduction in PTH cases. However, up to 10% of the recipients continued to develop PTH, most cases of which were attributed to an unknown non-A, non-B viral agent. Implementation of surrogate marker testing (i.e., alanine aminotransferase and anti-hepatitis B virus core antigen) for residual non-A, non-B hepatitis in the late 1980s reduced the per unit risk of PTH from 1 in 200 to about 1 in 400. Hepatitis C virus was discovered in 1989 and quickly was established as the causative agent of > 90% of non-A, non-B PTH. Introduction of progressively improved antibody assays in the early 1990s reduced the risk of PTH due to hepatitis C virus to about 1 in 100000. Although additional hepatitis viruses exist (e.g., hepatitis G virus), these appear to be minor contributors to clinical PTH, which has been virtually eradicated.

Incidence of post-transfusion hepatitis in Taiwan before and after introduction of anti-HCV testing.

The effectiveness of second-generation anti-hepatitis C virus antibody (anti-HCV) screening of blood donations for the prevention of non-A, non-B post-transfusion hepatitis (NANB PTH) was assessed. A prospective study of 192 transfusion recipients was performed to compare the incidence of NANB PTH after the introduction of the second-generation anti-HCV test with the incidence before its introduction. We used a polymerase chain reaction to detect HCV-RNA and HBV-DNA in the sera of patients with NANB PTH. The incidence of acute post-transfusion hepatitis C was 11% (8 of 71) before the screening for anti-HCV as compared with 2.5% (3 of 121) after the screening (p < 0.05). Viremia was detected within the first five weeks of infection in 10 patients with acute post-transfusion hepatitis C. However, there was no significant difference in the incidence of non-A, non-B, non-C (NANBNC) PTH before screening (3 of 71, 4.2%) compared with after screening (3 of 121, 2.5%). Usually, NANBNC PTH was not clinically important. Anti-HCV screening of blood donors significantly reduces the incidence of post-transfusion hepatitis C, but not the incidence of NANBNC PTH.

Identification and properties of the RNA-dependent RNA polymerase of hepatitis C virus.

Hepatitis C virus (HCV) is the major etiological agent of non-A, non-B post-transfusion hepatitis. Its genome, a (+)-stranded RNA molecule of approximately 9.4 kb, encodes a large polyprotein that is processed by viral and cellular proteases into at least nine different viral polypeptides. As with other (+)-strand RNA viruses, the replication of HCV is thought to proceed via the initial synthesis of a complementary (-) RNA strand, which serves, in turn, as a template for the production of progeny (+)-strand RNA molecules. An RNA-dependent RNA polymerase has been postulated to be involved in both of these steps. Using the heterologous expression of viral proteins in insect cells, we present experimental evidence that an RNA-dependent RNA polymerase is encoded by HCV and that this enzymatic activity is the function of the 65 kDa non-structural protein 5B (NS5B). The characterization of the HCV RNA-dependent RNA polymerase product revealed that dimer-sized hairpin-like RNA molecules are generated in vitro, indicating that NS5B-mediated RNA polymerization proceeds by priming on the template via a 'copy-back' mechanism. In addition, the purified HCV NS5B protein was shown to perform RNA- or DNA oligonucleotide primer-dependent RNA synthesis on templates with a blocked 3' end or on homopolymeric templates. These results represent a first important step towards a better understanding of the life cycle of the HCV.

Hepatitis C Virus Infection in Dialysis and Clinical Nephrology

Hepatitis C Virus (HCV), a single-strand RNA virus, has recently been cloned and sequenced. It causes nearly all cases of non-A non-B post-transfusion hepatitis (NANBH), and is responsible for most of the community-acquired NANBH. Considerable progress has been made in characterizing HCV and understanding the prevalence, transmission, and natural history of HCV infection.

Long-term course of non-A, non-B post-transfusion hepatitis

Source Citation Koretz RL, Abbey H, Coleman E, Gitnick G. Non-A, non-B post-transfusion hepatitis. Looking back in the second decade. Ann Intern Med. 1993 Jul 15;119:110-5.

Long-term Follow-up of Non-A, Non-B (Type C) Post-transfusion Hepatitis

Abstract One hundred and thirty-five patients who developed non-A, non-B post-transfusion hepatitis mostly after cardiac surgery, were followed for a mean (±S.D.) of 90±41 months (range: 13–180) to evaluate clinical and histological outcome. Thirty-one cases resolved within 12 months, while 104 (77%) progressed to chronicity. Twenty-one of 65 (32%) biopsied patients developed cirrhosis at the end of the follow-up, and one further progressed to hepatocellular carcinoma. One patient had a complete histological remission (1%). The remaining cases had chronic active (37%), chronic persistent (27%) or chronic lobular hepatitis (3%). About half of the cases with cirrhosis developed portal hypertension, and three of these died due to esophageal varices hemorrhage, one due to liver failure, and one due to hepatocellular carcinoma. Out of 26 patients with the initial histologic diagnosis of chronic hepatitis that were rebiopsied during follow-up, 13 (50%) progressed to cirrhosis. These patients were significantly older than patients who did not develop cirrhosis (mean age 57 and 45 years respectively; p During acute hepatitis anti-HCV was positive in all but one of the 114 patients tested. Percentages were similar for patients who recovered (95%) and those who developed chronic hepatitis (100%). However, during follow-up, 71% of the 1st generation and 21% of the 2nd generation ELISA test patients with acute resolved hepatitis became anti-HCV negative, while the same figures in chronic cases were only 8.5% ( p p =0.012). This suggests a correlation between anti-HCV antibody activity, hepatitis C virus replication, and the development of chronic liver disease.

Non-A, Non-B Post-Transfusion Hepatitis: Looking Back in the Second Decade

To determine the long-term course of non-A, non-B post-transfusion hepatitis. Follow-up in 1989 to 1992 of patients prospectively identified as having contracted non-A, non-B post-transfusion hepatitis between 1972 and 1980. A university hospital. Patients who were prospectively followed from receipt of blood products and in whom otherwise unexplained abnormalities in their serum alanine aminotransferase levels developed without serologic evidence of exposure to hepatitis A or B. The presence or absence of clinical evidence of liver failure or symptoms of chronic hepatitis. Of 90 patients identified in the 1970s, 80 were recontacted and evaluated between 1989 and 1992. Based on the current status of these 80 patients and on the last known status of the remaining patients, the following observations were made: 1) Although about 40% had some symptoms during the early phase of the disease, none subsequently experienced significant clinical problems related to hepatic inflammation; 2) eight patients (seven with chronic hepatitis) developed hepatic failure; and 3) life-table analysis showed that the probabilities of developing clinical evidence of cirrhosis after 16 years of disease in the entire cohort, in the subgroup who developed chronic hepatitis, in the patients who had hepatitis C, and in those with chronic hepatitis C were 18%, 21%, 17%, and 20%, respectively. For most of the study patients, non-A, non-B post-transfusion hepatitis was a biochemical and histologic disease that had not yet caused hepatic symptoms. If hepatic failure does occur, it is usually seen only after 10 or more years of disease. Before that time, many infected persons die due to other disease processes.

Clinical significance of antibodies to nonstructural and core proteins of hepatitis C virus in posttransfusion hepatitis patients during long‐term follow‐up

To clarify the long-term clinical significance, antibody to hepatitis C virus (HCV) was examined using core (p22) and nonstructural (C100-3) protein assays in sera of 18 patients with non-A,non-B posttransfusion hepatitis (PTH-NANB) who were selected retrospectively. Each patient had been followed for more than 5 years after the development of the disease. They were divided into three groups according to clinical outcome: acute hepatitis that resolved within 1 year, group 1 (n = 3); chronic hepatitis that resolved within 1-4 years, group 2 (n = 4); and chronic hepatitis that persisted for 5 years or longer, group 3 (n = 11). Sixteen of the 18 were positive for anti-C100-3 and anti-p22, one was positive for anti-p22 alone, and one was negative for both. In ten of the 16 (62.5%), anti-p22 appeared before anti-C100-3. The anti-C100-3 titer peaked about 12 months after disease onset in all cases and thereafter declined gradually, finally becoming negative in groups 1 and 2, while the titer fluctuated in group 3. The mean titer in group 3 at 12 months (69.2 units) significantly exceeded that of groups 1 (4 units) and 2 (8.2 units). Group 1 was seronegative for HCV antibodies and HCV RNA at the last examination, suggesting the cessation of HCV replication. Group 3 remained positive for those markers, indicating the continued replication of HCV.(ABSTRACT TRUNCATED AT 250 WORDS)

Non-A, non-B posttransfusion hepatitis: Comparing C and non-C hepatitis

Using assays to detect antibodies against antigens (C-100, 5-1-1, C-22 and C-33) of the hepatitis C virus, we tested stored sera from 40 patients prospectively identified as having non-A, non-B posttransfusion hepatitis. The 28 patients who demonstrated seroconversion ("documented hepatitis C") had more severe initial disease; all 20 cases of chronic hepatitis occurred in this subgroup. Only 2 of the 12 patients who did not demonstrate such seroconversion even had symptoms. In the group of patients with documented hepatitis C, chronic hepatitis was more commonly seen in men (89%) than in women (40%). The patients in whom antibody to the C-100 antigen developed were younger and had received more blood than had those patients who had hepatitis C diagnosed by demonstration of antibodies to the 5-1-1, C-22 or C-33 antigen (or all three). The proportion of cases of posttransfusion hepatitis that could be associated with antibody sero-conversion decreased around the time that blood banks switched to an all-volunteer system. The hepatitis seen in patients who failed to demonstrate serological evidence of hepatitis C virus exposure was usually clinically unimportant; it may or may not have been due to viral infection.

Viral risks of blood transfusion

Summary, Viral complications of modern blood transfusion are negligible, but transfusion can never be called totally safe. The most important risks are transmission of hepatitis and human immunodeficiency (HIV) viruses. Systematic screening of blood donors for HBsAg greatly reduced the incidence of post-transfusion hepatitis B, but virus transmission is still possible in the convalescence period when HBsAg test has become negative. To avoid this possibility, some countries have started additional screening for anti-HBc. The decision depends on the prevalence of hepatitis B, and no universal recommendation can be given. The great majority of non-A, non-B post-transfusion hepatitis cases seem to be caused by hepatitis C virus (HCV). The second generation tests for anti-HCV are very useful for screening blood donors, and surrogate testing (e.g. ALT and anti-HBc) is not needed anymore. Careful donor selection and other preventive strategies including systematic laboratory testing for anti-HI V have greatly reduced the risk of HIV transmission, but in the seronegative phase of the disease transmission of infection is still possible in donated blood. Antigen screening in donors does not solve this problem. Cellular products may transmit HTLV and CMV. In the latter case, depletion of blood products of leukocytes is as good a strategy as using seronegative donors. The prevention of transmission of all viruses includes, in addition to donor selection and laboratory screening, viral inactivation of products. This has been achieved with most plasma derivatives, and research is active with cellular products. Different preventive strategies should be used simultaneously to minimize the risk as much as possible.

European Acute Transfusion Hepatitis Interferon Study (EATHIS)

Since 1989, a prospective, multicentric and collaborative study, named European Acute Transfusion Hepatitis Interferon Study (EATHIS), involving 16 blood centres in France is coordinated by a task force in collaboration with the Viral Hepatitis and Recipients working groups of the French National Society of Blood Transfusion. A phase of recipient screening may be completed by a therapeutic interferon protocol. Among 1,476 transfused recipients receiving an average of 4.4 blood components, 1,011 were followed up at least four months. The incidence of non-A, non-B post-transfusion hepatitis (PTH) was varying from 0.1 to 6% at the different locations. Out of 15 hepatitis cases, 10 were diagnosed as post-transfusional. These preliminary data indicate a reduced incidence of PTH, with a mean of 1% for the period 1989-1991. It emphasises the importance of a transfusion vigilance program including follow up and testing for transaminases and specific viral markers.

Development of antibody to hepatitis C virus (HCV) in acute and chronic non-A, non-B post-transfusion hepatitis.

The antibody to hepatitis C virus (anti-HCV) was measured by an immunoassay in 507 serum samples from 94 patients with acute and chronic post-transfusion non-A, non-B hepatitis (NANB) and in 436 healthy blood donors. Anti-HCV was found in 70.8 of patients with acute hepatitis, in 78.2 with chronic hepatitis, and in 1.4 of healthy blood donors. In acute hepatitis, anti-HCV appeared in the serum from 4 to 34 weeks after transfusion and from 1 to 30 weeks after the onset of the overt disease. Three patients with resolving hepatitis (21%) and 2 who developed chronic hepatitis (10%) lost anti-HCV during a mean follow-up period of 28 months. Among the 36 patients with chronic hepatitis, 2 (6%) lost anti-HCV after 12 months and 8 years respectively. These data indicate that in recent years HCV has been the major etiologic agent of acute and chronic transfusion-associated hepatitis (TAH) in our geographical area. The late appearance of anti-HCV from the onset of clinical and biochemical signs of acute hepatitis in more than 70% of patients limits the diagnostic utility of this assay for an earlier serological diagnosis of acute NANB hepatitis. Additional studies are required to determine the diagnostic significance of this antibody in chronic NANB hepatitis.

Long-term follow-up of non-A, non-B (type C) post-transfusion hepatitis

One hundred and thirty-five patients who developed non-A, non-B post-transfusion hepatitis mostly after cardiac surgery, were followed for a mean (±S.D.) of 90±41 months (range: 13–180) to evaluate clinical and histological outcome.Thirty-one cases resolved within 12 months, while 104 (77%) progressed to chronicity. Twenty-one of 65 (32%) biopsied patients developed cirrhosis at the end of the follow-up, and one further progressed to hepatocellular carcinoma. One patient had a complete histological remission (1%). The remaining cases had chronic active (37%), chronic persistent (27%) or chronic lobular hepatitis (3%). About half of the cases with cirrhosis developed portal hypertension, and three of these died due to esophageal varices hemorrhage, one due to liver failure, and one due to hepatocellular carcinoma. Out of 26 patients with the initial histologic diagnosis of chronic hepatitis that were rebiopsied during follow-up, 13 (50%) progressed to cirrhosis. These patients were significantly older than patients who did not develop cirrhosis (mean age 57 and 45 years respectively; p<0.01).During acute hepatitis anti-HCV was positive in all but one of the 114 patients tested. Percentages were similar for patients who recovered (95%) and those who developed chronic hepatitis (100%). However, during follow-up, 71% of the 1st generation and 21% of the 2nd generation ELISA test patients with acute resolved hepatitis became anti-HCV negative, while the same figures in chronic cases were only 8.5% (p<0.0001) and 1.4% (p=0.012). This suggests a correlation between anti-HCV antibody activity, hepatitis C virus replication, and the development of chronic liver disease.

Incidence of anti-hepatitis C virus antibodies in non-A, non-B post-transfusion hepatitis in an area of northern Italy.

A total of 210 patients consecutively submitted to heart surgery at the Parma University Hospital and transfused with 1,898 units of blood were followed after transfusion in order to evaluate both the incidence of anti-hepatitis C virus (HCV) seroconversion in non-A, non-B post-transfusion hepatitis (PTH-NANB) cases and the usefulness of the screening for anti-HCV in comparison with that for serum glutamic pyruvic transaminase (SGPT) values in preventing PTH-NANB transmission. Fifteen recipients developed PTH-NANB (group A); ten of them (66.6%) showed anti-HCV seroconversion within 3-12 months. Eight of the ten anti-HCV positive patients developed chronic hepatitis, but none of the five PTH-NANB anti-HCV negative did. None of the 15 controls (group B) randomly chosen among the patient population showed anti-HCV seroconversion. A close correlation with the transmission of PTH was showed by anti-HCV positivity but not by SGPT elevation in blood donors. Eleven of 172 blood products transfused to group A but none of 139 products transfused to group B were anti-HCV positive. The incidence of elevated SGPT values was similar between the two groups of the transfused blood products. Nevertheless, the correlation observed between anti-HCV positivity and SGPT levels in the blood products involved in PTH confirms the need to exclude blood donors with abnormal SGPT values. On the whole, anti-HCV screening of donors showed a predictive value higher than that of SGPT (100% vs. 53.3%), allowing a minor blood donation exclusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Hepatitis C virus infection in Japan

Because of the high incidence of non-A non-B post transfusion hepatitis and its relation to hepatocellular carcinoma, HCV antibody screening for blood transfusion was begun in November 1989. Seroepidemiological studies revealed the great magnitude of HCV infection in acute hepatitis, chronic hepatitis, liver cirrhosis and hepatocellular carcinoma in Japan. Approximately 1.6 million HCV antibody-positive persons are now in Japan. Major routes of infection are considered to be horizontal blood borne infection in the past and blood transfusion.

Low incidence of non-A, non-B post-transfusion hepatitis in London confirmed by hepatitis C virus serology

To see whether the introduction of screening tests for post-transfusion non-A, non-B hepatitis (NANBH) in the UK would be worth while, the incidence of such hepatitis was assessed among patients receiving blood during operations at five hospitals served by the North London Blood Transfusion Centre. 387 patients, who each received blood or blood components from an average of 3 donors were followed up prospectively and blood samples were taken every 2 weeks for 3 months and then each month for a further 3 months. 229 patients also provided a sample at 12 months. All available patient and donor samples were tested for alanine aminotransferase concentrations and for antibody to hepatitis C virus (anti-HCV) by ELISA. Repeatedly anti-HCV positive samples were submitted to supplementary HCV assays. 1 of the 387 patients showed biochemical evidence of acute post-transfusion NANBH after exclusion of non-viral causes. Anti-HCV developed in this patient and the seroconversion was confirmed by recombinant immunoblot assay and polymerase chain reaction. Serum from 1 of the 8 donors whose blood he received was positive for anti-HCV by all three methods. In another patient HCV seroconversion was shown by ELISA but alanine aminotransferase concentrations remained normal throughout follow-up. His samples and those of his 2 donors were negative for HCV by the polymerase chain reaction. A third patient showed rises in alanine aminotransferase compatible with post-transfusion NANBH, but serology and polymerase chain reaction assays for HCV were negative for her samples and those of her donors. Anti-H CV reactivity likely to be false positive (negative by both confirmatory tests and no adverse effects in recipients) was seen in 6 of 1283 donors. This study, despite its being carried out in the part of the UK with the highest frequency of infectious markers in blood donations, has shown a very low incidence of post-transfusion NANBH.

Antibody to Hepatitis C Virus in Post-Transfusion Hepatitis

To evaluate the prevalence of antibodies to hepatitis C virus (anti-HCV), their relation to outcome, and the seroconversion rate in patients with post-transfusion non-A, non-B hepatitis. Retrospective analysis of prospectively collected serum specimens. A referral-based university hospital. Sixty-three consecutive patients who developed non-A, non-B post-transfusion hepatitis after open-heart surgery. All patients had follow-up with serial serum testing and clinical evaluation. The mean (+/- SD) duration of follow-up after hepatitis onset was 81 +/- 33 months (range, 13 to 132 months). Seventeen patients recovered after acute-phase illness, whereas 46 developed chronic disease which, in 30 cases, was confirmed histologically. Of 32 patients tested before transfusion, 1 (3.1%) had anti-HCV. Fifty-nine (93%) patients were anti-HCV positive during acute-phase hepatitis: Patients with "early" seroconversion (less than 15 days after hepatitis onset) did not differ from those with "late" seroconversion (greater than 60 days after onset) in epidemiologic, clinical, and biochemical features. The rate of anti-HCV positivity during acute-phase illness was not significantly different among patients who recovered (76%) compared with those who developed chronic disease (95%). At 6 to 12 months, patients whose disease resolved had lower antibody activity than those with progressive disease. Further, during long-term follow-up (1 to 9 years), 53% of patients whose disease resolved but only 6.9% of patients who had progressive disease became anti-HCV negative. Hepatitis C virus is the major cause of post-transfusion hepatitis in Italy. The time to anti-HCV seroconversion varies widely after hepatitis onset and is not significantly associated with acute-phase features or outcome of disease.

Significance of antibody to hepatitis C virus in Japanese patients with viral hepatitis: Relationship between anti‐HCV antibody and the prognosis of non‐A, non‐B post‐transfusion hepatitis

In a retrospective study, antibody to hepatitis C virus (anti-HCV antibody) was measured in 80 patients with acute viral hepatitis (type A, 18; type B, 21; type non-A,non-B, 41). Anti-HCV antibody was found in 12 of 20 patients (60%) with non-A,non-B post-transfusion hepatitis (NANB-PTH) and in 9 of 21 patients (43%) with sporadic NANB hepatitis (NANB-SPO). Patients with acute hepatitis type A or type B did not have anti-HCV antibody. The number of patients who developed chronic hepatitis was greater in the group with anti-HCV antibody than in the anti-HCV negative group in both NANB-PTH and NANB-SPO. The difference was significant in those with NANB-PTH (P less than 0.05). To investigate the relationship between the long-term prognosis of NANB-PTH and the course of anti-HCV, we studied anti-HCV antibody in 12 patients who developed chronic type C hepatitis (C-CH) after PTH and followed them for more than 5 years after the development of PTH. One year after the development of PTH, all 12 had anti-HCV antibody. Five lost anti-HCV antibody (group 1) while 7 remained positive (group 2) at the final examination. Four of the 5 patients in group 1 had normal serum transaminases; however, abnormal transaminase persisted in all 7 patients in group 2 until the end of follow-up (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)