History of posttransfusion hepatitis
Leslie H. Tobler1,a and Michael P. Busch1,2
1 Irwin Memorial Blood Centers, 270 Masonic Ave., San Francisco, CA
2 Department of Laboratory Medicine, University of California, San
Francisco, CA 94143.
a Author for correspondence. Fax 415-775-3859; e-mail
The risk of hepatitis virus transmission from transfusions 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 100 000. Although additional hepatitis viruses exist (e.g.,
hepatitis G virus), these appear to be minor contributors to clinical
PTH, which has been virtually eradicated.
early history of posttransfusion hepatitis (pth1 )
During World War II and the immediate postwar period the demand for
blood and blood components in the US increased substantially. This
resulted in the establishment and growth of blood banks, transfusion
services, and other blood and laboratory support services. The
technology for collection, processing, and storage of whole blood and
blood components materialized rapidly. By 1971, >5400 organizations were
involved in the field of transfusion medicine with >12 million annual
whole-blood donations and a nearly equal number of plasmapheresis
donations (Table 1 ) (1).
Table 1. Events in understanding and minimizing PTH.
HBV and paid vs. nonpaid donors
report of PTH
Retrospective study: paid vs nonpaid donors on rate of PTH
of HBV antigen (Australia antigen)
study evaluating the contribution of paid vs nonpaid donors to
the rate of PTH
marker for PTH
study: effectiveness of exclusion of commercial and HBsAg-positive
blood donors on the incidence of PTH
mandates screening of all blood donations for HBsAg
causative agent of PTH; NANBH defined
mandates an all-voluntary blood donor system
mandates use of a third generation HBsAg assay
Transfusion-Transmitted Virus Study results suggest use of ALT
as surrogate marker for PTH
NIH study confirm association between increased ALT
concentration in donor blood and the development of recipient
Implementation of surrogate marker testing
primary cause of NANBH
Classification of HCV as a single-stranded positive-sense RNA
virus belonging to the family Flaviviridae
and implementation of first-generation HCV screening
and implementation of second-generation HCV screening
of HCV supplemental testing
show declining value of surrogate markers
events post-HCV screening
Consensus Statement recommends discontinuation of ALT testing,
continuation of anti-HBc testing
40, 42, 43, 46
and partial implementation of third-generation HCV screening
PTH was first reported in the US by Beeson in 1943 (2). Seven cases of
PTH occurring 1–4 months after transfusion of blood or plasma were
reported. The author commented that the expanding number of blood and
plasma transfusions could lead to the occurrence of a considerable
number of PTH cases. In 1964 Grady and Chalmers (3) reported the results
of a retrospective study of PTH in nine Boston teaching hospitals,
1952–1962. In one of the hospitals 29% of the blood transfused was from
commercial sources, while in the other eight hospitals blood only from
volunteer blood donors was transfused. The incidence of clinically overt
(i.e., symptomatic or icteric) PTH in recipients of blood products from
volunteer blood donors was 0.6 cases/1000 units compared with 2.8
cases/1000 units in recipients of blood products from a mixture of
volunteer and commercial blood donors.
In 1970 scientists at the NIH reported the results of a prospective
study to determine the incidence of icteric and anicteric hepatitis in
patients undergoing open-heart surgery (4). During surgery the patients
were given blood from either commercial or volunteer blood donors.
Icteric and anicteric hepatitis developed in 51% of the recipients of
commercial blood, whereas no hepatitis occurred in patients who received
blood from volunteer donors. These authors estimated the hepatitis
carrier rate for commercial blood donors to be 6.3% and for volunteer
donors to be <0.6%. By 1971, the association between a paid blood donor
and an increased risk of PTH was accepted by most, but not all, experts
in the field. In early 1972, two states (California and Illinois)
considered legislation to specifically eliminate payment for blood. The
first law effective in eliminating paid blood donations was passed on
October 1, 1972 (i.e., The Blood Labeling Act of Illinois). By the end
of 1975, the Food and Drug Administration (FDA) mandated an
all-voluntary blood donor system in which blood donors could not receive
monetary payment for donations (Fig. 1 ) (1).
Rates of PTH are expressed as percent of recipient developing PTH. The
current risk of PTH because of HBV or HCV is estimated at less than 1 in
10 000/unit transfused (see text) (adapted from H. J. Alter).
role of hepatitis b virus (hbv) in pth
A viral etiology for PTH was long suspected. In 1965, Blumberg et al.
(5) first described the Australia antigen and stated that this antigen
could be identified in the sera of many hemophiliacs who had received
multiple transfusions. Subsequently retrospective studies indicated that
the presence of the Australia antigen in donor blood seemed to be
clearly associated with the occurrence of PTH (6). During an NIH
Conference in 1970, additional evidence was presented that linked the
presence of the Australia antigen to the occurrence of PTH. Furthermore,
during this conference it was stated that the Australia antigen was part
of an infectious agent, presumably a hepatitis virus (7). Nevertheless,
the screening of blood donors was not recommended. In a position paper
written by Alter et al. (8), the authors recommended testing and
deferral of blood donors based on the presence of the Australia antigen.
(The Australia antigen is now referred to as hepatitis B surface
antigen, HBsAg; ultimately the HBV was classified as a DNA virus in the
Hepadnaviridae.) These recommendations were not implemented because of
lack of consensus and concern over the general availability and variable
detection limits of early-generation HbsAg assays.
In 1970, Gocke et al. (9), using retrospective studies, estimated that
the exclusion of HBsAg-positive blood donors through either first- or
second-generation assays (e.g., agar gel diffusion or
counterelectrophoresis) would decrease the rate of PTH by ~25%. The
results of a prospective study on the effectiveness of exclusion of
commercial and HBsAg-positive blood donors on the incidence of PTH was
reported in 1972 (10). The exclusion of HBsAg-positive blood resulted in
a 25% reduction in the PTH rate, as predicted, while the elimination of
commercial donors resulted in a 70% reduction in the PTH rate. With the
simultaneous exclusion of commercial and HBsAg-positive donors, the PTH
rate was reduced to 7.1% of the prior rate.
On the basis of these studies, screening of blood donations for HBsAg
began in 1971 and became a US federal regulation in July 1972. The
initial methods used to detect HBsAg were relatively insensitive (i.e.,
immunodiffusion and counterelectrophoresis), and transfusion-associated
HBV cases continued to occur. In 1975, federal regulations were
implemented requiring the screening of all donor blood for HBsAg by one
of the third-generation tests [i.e., radioimmunoassay or enzyme-linked
immunoassay (EIA)], as well as the labeling of blood components with
respect to the volunteer or paid status of the donor. Since that time,
virtually 100% of all blood used in single-component transfusions has
been collected from volunteer donors. The transition to volunteer
whole-blood donors and routine third-generation HbsAg testing of all
blood donations resulted in a marked decrease in HBV-PTH, although
occasional cases continue to occur (11). In contrast to whole-blood
donors, donors of plasma for further manufacture into plasma derivatives
continue to be paid. The Cohen fractionation procedure used to prepare
plasma derivatives dramatically reduces viral infectivity, and over the
last decade, additional viral inactivation procedures (e.g., heating and
detergent treatment) performed on these products render contemporary
plasma derivatives virtually risk-free.
non-a, non-b pth and surrogate markers
In 1973, the causative agent of hepatitis A was detected by immune
electron microscopy on stools from patients with acute food-borne
hepatitis (12). The hepatitis A virus (HAV) was later classified as a
picornavirus closely related to the genus Enterovirus (13). HAV is
associated with acute resolving hepatitis without a chronic carrier
state. Retrospective studies involving multiply transfused thalassemia
patients indicated that these patients were at no greater risk of HAV
infection than nontransfused children (14). Similarly, analysis of donor
and recipient samples from cases of PTH showed no evidence of
involvement by HAV (15).
After implementation of specific screening tests for HBV and exclusion
of HAV as a cause of PTH, it became clear that a substantial proportion
of PTH cases continued to occur that were not caused by infections with
HBV or other known viral agents. Termed non-A, non-B hepatitis (NANBH),
this entity represented 90% of residual PTH cases in the US. In the late
1970s and early 1980s, rates of NANBH in multiply transfused patients
were reported to be as high as 10%.
The results of the multicenter prospective Transfusion-Transmitted
Viruses Study were published in 1981 (16). Two major goals of this study
were to define the incidence of PTH and to evaluate the factors
influencing its occurrence. The data reported indicated a substantial
association between recipients with NANBH and donor alanine
aminotransferase (ALT) concentrations. Another independent study
conducted at NIH confirmed an important association with an increased
ALT concentration in donor blood and the development of NANBH in
recipients of that blood (17). Furthermore, in 1984 Stevens et al. (18),
representing the Transfusion-Transmitted Viruses Study, reported an
important association between the occurrence of NANBH in recipients of
blood that tested positive for antibody to the core protein of HBV
(anti-HBc). The research group at NIH confirmed this observation (19).
This study showed that anti-HBc testing of donors, in concert with ALT
testing, might eliminate 30–50% of recipient NANBH. Primarily on the
basis of these studies, in 1986–87 blood collection agencies began
screening donated blood for surrogate markers of NANBH (anti-HBc and
ALT) (20). The rate of PTH among recipients dropped subsequently to as
low as 2–3% (21).
hcv as major etiological agent of nanbh
Extensive research was conducted in the 1970s and 1980s to identify the
etiological agent(s) of NANBH. More than 25 preliminary reports of
associated agents were determined to be false. Then, in 1988, the
hepatitis C virus (HCV) was identified with molecular biology techniques
by M. Houghton and associates at Chiron, in collaboration with D. W.
Bradley of the Hepatitis Branch of the Centers for Disease Control (22).
The process of virus discovery involved construction of a cDNA
expression library in the bacteriophage gt11 by using high-titer plasma
from a chimpanzee inoculated with PTH plasma. The library was then
screened for rare clones expressing viral antigen with serum from a
chronic NANBH patient as a presumed source of viral antibodies.
Screening of this library led to the identification of the positive cDNA
clone 5-1-1 (Fig. 2 ) (23).
The major open reading frames are shown in the upper box, with putative
properties of each generation shown above (deduced from parallels with
other flaviviruses). Major antigens used in antibody detection systems
are shown below (from H. J. Alter (21)).
HCV is a single-stranded positive-sense RNA virus with a genome of ~9500
bases coding for ~3000 amino acids. This small RNA lipid-envelope (24)
virus has been classified in the family Flaviviridae. The entire viral
genome was sequenced within 1 year, and antigens were expressed for
development of antibody detection assays. Early studies established that
HCV was the etiological agent of at least 80–90% of residual NANBH (21).
hcv screening assays and residual risk of hcv-pth
Blood collection agencies in the US implemented donor screening
immediately after licensure of the first-generation anti-HCV enzyme
immunoassay (HCV 1.0 EIA) in 1990. This EIA detected antibodies to an
antigenic protein (c100-3) of HCV (Fig. 2). Even though this assay
facilitated the screening of blood donors for anti-HCV antibodies, it
did not detect all infectious blood donations (25) and had a protracted
window of infectivity ranging from 12 weeks to >26 weeks postinfection
(26). Nevertheless, a prospective study of patients receiving
transfusions before and after mid-1990 found that the risk of
transfusion-associated HCV infection per unit dropped from 0.36% (1 in
274) before anti-HCV screening to 0.07% (1 in 3300) for donations
screened with both surrogate markers and first- generation anti-HCV
tests (27)(28). It has since been estimated that this test prevented
transmission of HCV to 40 000 patients per year in the US (21).
A second-generation anti-HCV EIA (HCV 2.0 EIA) was licensed and rapidly
implemented in 1992. This test incorporated two additional proteins, one
structural (c22-3) and one nonstructural (c33c) (Fig. 2). This test was
substantially more sensitive than HCV 1.0 EIA in detecting acute and
chronic HCV infections. Antibodies to these proteins generally appear
much earlier than those to c100-3, so the seroconversion window period
could be shortened by 10–20 days. In addition, parallel studies
comparing first- and second-generation tests showed that HCV 2.0 EIA
detected additional HCV chronically infected donors at a rate of 1 in
1000 (25). This increased yield translated into prevention of an
additional 13 000 HCV transmissions per year by transfusion (21).
Conflicting estimates existed regarding the residual risk of HCV after
implementation of the second-generation assay. Projections based on
incidence-window period models suggested that the risk of HCV PTH had
dropped to as low as 1 in 100 000 per unit (29), whereas extrapolation
from historical PTH studies suggested a risk of up to 1 in 5000 (30).
In 1996, a third-generation screening test (HCV 3.0 EIA) was licensed
that detected antibodies to an even greater number of HCV-encoded
epitopes. This test differs in antigen content from the
earlier-generation screening assays with deletion of the c-100
recombinant protein and addition of the NS-5 recombinant protein (Fig.
2). This allows detection of antibodies to a greater number of HCV-encoded
epitopes. HCV 3.0 EIA has consequently narrowed the seroconversion
window by about 10 days relative to the HCV 2.0 EIA (31)(32). This
window period reduction is projected to detect 1–2 additional
seroconverting donors per million units screened. Although the impact of
the HCV 3.0 EIA on residual HCV risk has not been prospectively
quantified, the ongoing NIH prospective study of PTH has failed to
detect any HCV transmissions among >650 patients transfused with >2500
units of blood screened by second-generation HCV EIA since late 1992 (H.
Alter, personal communication).
hcv confirmatory assays
Given the low prevalence of viral infection in preselected volunteer
donors, it is important that confirmatory assays are developed and used
to discriminate between true and falsely positive EIA-reactive donors.
The Chiron RIBATM HCV 2.0 strip immunoassay (RIBA 2.0) was licensed on
June 27, 1993. The RIBA 2.0 is an immunoblot assay in which four
recombinant HCV-encoded antigens fused to human superoxide dismutase are
immobilized on nitrocellulose strips. A negative, indeterminate, or
positive interpretation is based on the reaction pattern present on the
strip. About 89% of RIBA 2.0-positive specimens are HCV RNA-positive by
PCR tests, while ~19% of RIBA 2.0-indeterminate specimens are HCV
RNA-positive by PCR tests (25).
The HCV 3.0 EIA companion supplemental test, Chiron RIBA HCV 3.0 SIA (RIBA
3.0), is now pending licensure from the FDA. This assay uses a mixture
of peptides, rather than recombinant antigens, for the 5-1-1/c-100 and
c22-3 regions of the HCV genome. The use of peptides, when appropriate,
eliminates those amino acid sequences that are a source of nonspecific
cross-reactivity with other antigens (33)(34). On the basis of data from
Europe (35), these changes have substantially improved this assay's
lowest detection limits and specificity.
The prevalence of anti-HCV antibody in US blood donors, as determined
with HCV 2.0 and 3.0 EIA confirmed by RIBA 2.0 and 3.0, respectively,
ranges from 0.2% to 0.4% (21). At least 70% of seropositive donors are
viremic (25). Similar rates have been observed in Europe, and higher
rates in Japan and other Asian countries. Importantly, these rates are
in highly selected blood donors (26). The prevalence of HCV infection in
the general population of the US is currently estimated to be between 1%
and 2% (36).
retention of surrogate tests
With virtual elimination of NANBH by HCV screening, the issue of whether
surrogate tests should be retained has surfaced. Although the direct
cost of ALT testing is low, the indirect cost is very high because >1%
of units test positive and are discarded. Anti-HBc screening has a
higher direct cost and results in ~0.5% unit loss. Furthermore, the
donors of these units are either temporarily or permanently deferred.
The preponderance of available data indicates that, in the presence of
anti-HCV testing, retention of ALT testing prevents few if any residual
PTH cases (30)(37). Therefore, a 1995 NIH Consensus Statement
recommended that ALT testing of volunteer blood donors be discontinued.
On the other hand, the consensus conference recommended that anti-HBc
testing be retained, at least temporarily, for the following reasons:
possible prevention of some PTH HBV cases and possible prevention of
some cases of transfusion-transmitted HIV from donors who test negative
for anti-HIV during the window phase of infection (20). Recent studies
suggest that these applications of anti-HBc have a very low predictive
value and very poor cost effectiveness (37). Therefore, discontinuation
of anti-HBc is being actively reconsidered.
hepatitis g virus (hgv) and other putative pth agents
Evidence indicates that additional viruses that explain rare residual
PTH cases may exist. Indeed, before HCV was identified there was strong
suspicion that more than one blood-borne viral agent was causing NANBH
(26). However, it has now become clear that reinfection by different HCV
strains is not uncommon, which explains many of the cases of recurrent
PTH that led to speculation regarding multiple agents. In addition, the
rate of non-ABC hepatitis in recipients is now comparable with that in
nontransfusion controls (i.e., <0.8% in both US and Canadian studies,
similar to background values) (20). Nevertheless, the search for
additional agents has continued.
In 1995, researchers at Abbott Laboratories reported the isolation of
three viral agents [GB viruses (GBV) A, B, and C] from tamarins
inoculated with serum from a surgeon "GB" who had contracted acute
icteric hepatitis 20 years earlier (38)(39). Only one of the isolates (GBV-C)
proved to be a human viral hepatitis candidate; the other two were
tamarin agents incidentally infecting the animals at the time of the
experiments. A second independent group of researchers from GeneLabs
performed molecular cloning with plasma from a patient designated
PNF2161, who was originally identified by the CDC as having NANBH. The
virus cloned by these researchers was designated HGV (40). Given the
amino acid sequence matching of 95% between GBV-C and HGV, these viruses
are therefore considered to be different strains of the same virus,
tentatively termed GBV-C/HGV (41). GBV-C/HGV is a positive-stranded RNA
virus classified in the Flaviviridae, the same family as HCV. Only 32%
amino acid homology exists between GBV-C/HGV and HCV. Therefore,
although GBV-C/HGV is distantly related to HCV, this agent is not a
different serotype of HCV.
GBV-C/HGV RNA has been detected at a high prevalence (2–25%) among
various high-risk groups, e.g., intravenous drug users, hemophiliacs,
and hemodialysis patients. About 1–2% of blood donors have also been
found to be RNA-positive (42). A recent study, using PCR technology,
clarified the relationship of GBV-C/HGV and the occurrence of hepatitis
(43). PCR was performed on selected patients from a surveillance study
of acute viral hepatitis in four US counties. The patients included in
this study were: 45 patients with a diagnosis of non-A-E hepatitis, 116
patients with hepatitis C, 100 patients with hepatitis A, and 100
patients with hepatitis B. The results of this study indicated that HGV
was implicated as a potential etiological agent in only 0.3% of cases.
These HGV cases had only mild liver enzyme increases. Furthermore,
coinfection by HGV did not affect the clinical course in patients with
hepatitis A, B, or C.
Initial studies involving the prevalence of GBV-C/HGV infection were
hampered by the absence of an antibody detection system; therefore, the
diagnosis of GBV-C/HGV infection depended on the use of PCR to detect
GBV-C/HGV RNA. Recently an antibody test has been developed that has
demonstrated seroconversion associated with viral RNA clearance in about
two-thirds of infected persons (44)(45).
GBV-C/HGV is unequivocally a highly prevalent transfusion-transmissible
agent (46). However, a causal relationship between HGV infection and
hepatitis or other diseases has not been established (41)(43). GBV-C/HGV
appears to explain only a small fraction of either transfusion- or
community-acquired hepatitis cases, and these cases are very mild
(43)(46). Thus at present, it is unclear whether screening of blood
donors for GBV-C/HGV will be recommended.
The overall risk of PTH has declined markedly over the past 2 decades
with virtual elimination of transmission of HBV and HCV infections. The
advances in prevention of PTH have been not only extraordinary with
regard to recipient safety, but also highly cost-effective. Indeed, the
cost of screening the blood donor population for HCV is more than offset
by the reduced healthcare costs achieved by prevention of PTH cases
(30). Unfortunately, many infections did occur before the availability
of screening assays. The tragedy of the transfusion AIDS epidemic also
echos loudly. Thus, the current priority of infectious disease blood
banks is further enhancement of blood safety, through elimination of
rare residual cases of virally transmitted hepatitis by implementation
of nucleic acid screening assays (47) and avoidance of complacency
through proactive surveillance of the blood supply for new or emerging
1 Nonstandard abbreviations: PTH, posttransfusion hepatitis; HAV,
hepatitis A virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HGV,
hepatitis G virus; GBV-C, GB virus C; HBsAg, hepatitis B virus surface
antigen; EIA, enzyme-linked immunoassay; NANBH, non-A, non-B hepatitis;
ALT, alanine aminotransferase; PCR, polymerase chain reaction.
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