Aforty-four-year-old man sustained a vertebral fracture during a snowmobile
accident on March 7, 1998. The patient was diagnosed with a burst fracture of
the lumbar spine at the L2 level. As a result, he underwent posterolateral
fusion of the spine from L1 to L3 on March 9, 1998, during which he received
an allograft of cancellous bone chips ranging from 4 to 10 mm in size. He
underwent a second operation on March 13, 1998, with L1-2 to L3 fusion and
reconstruction of the anterior vertebral column with use of an allograft of
femoral shaft bone. He received no blood or blood products during this
hospitalization and had received no such products at any other time in his
life. Documentation from the tissue-procurement organization noted that the
bone grafts had been processed by soaking in antibiotic, alcohol, and
detergent prior to freezing and that both bone-graft donors had tested
negative for hepatitis-C antibody.
Approximately six weeks later, on April 30, 1998, the patient was noted to
be jaundiced and underwent serological testing for hepatitis-A IgM,
hepatitis-B core antibody, hepatitis-B surface antigen, hepatitis-C antibody,
monospot, and antinuclear antibody; the results of all tests were negative
(Table I). The results of
abdominal ultrasonography and computed tomographic scanning were normal. A
second test for hepatitis-C antibody, performed on May 2, 1998, also was
negative. The patient recovered from the bout of acute hepatitis and was
reevaluated in August 1998. He was positive for hepatitis-C-virus RNA in
August 1998 and again in September 1998. A third test for hepatitis-C
antibody, performed in November 1998, was positive. A liver biopsy in
September 1998 showed chronic hepatitis. The patient's medical and surgical
history were otherwise unremarkable, and he had no risk factors for
acquisition of hepatitis C (that is, he had no history of receiving blood or
blood products, no tattoos, and no history of intravenous drug use). The
patient's spouse was negative for hepatitis-C-virus antibody.
Four factors indicate that this patient acquired the hepatitis-C virus
through the processed bone graft. First, the patient had no history of other
risk factors for acquisition of the hepatitis-C virus: his spouse tested
negative for hepatitis-C virus, he had no tattoos, he had no history of
intravenous drug use or administration of blood products, and he did not
receive blood or blood products during hospitalization or during any of the
operative procedures. Second, liver-function tests were normal prior to and at
the time of the accident, findings that were consistent with the absence of a
chronic hepatitis-C infection. Third, the patient's only known risk factor for
acquisition of the hepatitis-C virus was that he had received bone grafts,
which have been implicated in the transmission of viral disease. The most
likely source was the femoral shaft graft because such grafts contain
components of the bone marrow and therefore can be difficult to sterilize, as
discussed below. The average incubation time for hepatitis-C virus (the time
between exposure and the appearance of clinical symptoms of acute hepatitis)
is six to seven
weeks1, which is
exactly the same time-interval as that between the implantation of the bone
grafts and the presentation of symptoms of acute hepatitis C in this patient.
Fourth, the most compelling evidence that this patient acquired the
hepatitis-C virus through the processed bone graft is that the
hepatitis-C-antibody test was negative during the bout of acute hepatitis. In
fact, the hepatitis-C-antibody test was performed twice during the episode of
acute hepatitis and was negative both times. Thus, the likelihood of a
false-negative result is very remote. Within six months, the
hepatitis-C-antibody test was positive and the patient had documented viremia
as demonstrated by hepatitis-C-virus RNA on polymerase chain reaction testing.
This clinical scenario (that is, a negative hepatitis-C-antibody test during
an episode of acute hepatitis, followed by antibody seroconversion and
hepatitis-C-virus viremia) is diagnostic of acute hepatitis-C infection. The
negative hepatitis-C-antibody test during the acute hepatitis phase documents
that the patient had recently acquired hepatitis C, probably at the time of
implantation of the bone graft.
Clinically evident acute hepatitis C is quite rare. At our institution,
which is a major liver-transplant center and hepatology referral center, we
see only one or two cases of acute hepatitis C per year, compared with
hundreds of cases of chronic hepatitis C. Had he not had acute symptoms, the
patient probably would not have had serological testing, which was negative
for hepatitis-C antibody. The finding that the hepatitis-C-antibody test was
negative during the bout of acute hepatitis documents that the patient did not
have a long-standing hepatitis-C infection and provides convincing evidence
that he acquired hepatitis-C virus through the bone graft.
While approximately 150,000 bone allografts are used each year in the
United States, transmission of hepatitis-C virus through bone graft is very
uncommon for several reasons. A small proportion of bone-graft donors test
positive for hepatitis-C virus. In a study from Australia, eight (0.4%) of
2176 people who wished to be bone-graft donors were rejected as donors because
of hepatitis-C
virus5. In a report
from Finland, only one (0.2%) of 560 bone grafts was positive for hepatitis-C
virus between 1972 and
19956. Because of
the risk of transmission of hepatitis-C virus (and other viral disease)
through bone grafts, extensive safeguards are in place to prevent the
transmission of communicable diseases. The current recommendations for the
prevention of transmission of viral disease through tissue transplantation
were formulated by the American Association of Tissue Banks, whose published
criteria regarding "donor suitability" are available for
review7. With use of
these criteria, approximately 90% of inappropriate potential donors are
rejected on the basis of the standardized screening
history8. Several
steps of donor evaluation are in place to prevent disease transmission through
organ and tissue transplantation. Donor history is used to determine social
and sexual history, and physical examination is used to assess for evidence of
high-risk behavior and signs of human immunodeficiency virus, hepatitis-C
virus, and bacterial or other viral
infection9.
According to the criteria of the American Association of Tissue Banks,
"cells and/or tissue shall not be distributed from donors who have
engaged in behaviors defined as high risk for viral disease transmission. This
information shall be obtained via interview, physical examination and review
of relevant medical records. All human cells and/or tissue intended for
transplantation shall be recovered from donors who are tested and found to be
negative for: antibodies to HIV type 1 and 2, hepatitis B surface antigen,
hepatitis C antibody, human T-lymphotropic virus type 1 and 2 and
syphillis."7
To minimize the risk of disease transmission, processing techniques (including
soaking the bone in antibiotic, alcohol, and detergent prior to freezing) are
used to remove blood and bone marrow from the bone graft. Bone grafts that
contain marrow are associated with the highest risk of transmission of viral
disease, whereas cancellous chips that have been processed to remove the
marrow are associated with the lowest risk. The patient in the present report
received a graft of cancellous chips and a graft of femoral shaft bone, the
latter of which was the most likely source of the infection with hepatitis-C
virus.
To our knowledge, the first reported case of transmission of hepatitis
through bone allograft was described in 1954 by
Shutkin10. In that
report, hepatitis developed ten weeks after the patient had received a bone
graft consisting of cancellous and cortical chips. (Serological testing for
hepatitis B and C was not yet available in 1954, so the type of hepatitis
acquired by this patient could not be specified.) We are aware of three
reported cases of transmission of hepatitis-C virus through unprocessed bone
graft. The first case occurred in a patient who had received an unspecified
type of bone graft from a donor who tested positive for hepatitis-C
antibody2. The
patient had received no blood products and had no risk factors for hepatitis-C
virus, but hepatitis C was diagnosed twenty-two weeks after surgery on the
basis of elevated values on liver-function tests and a positive
hepatitis-C-antibody test. The second case was documented in an analysis of
stored sera from tissue and organ donors; in that case, a recipient of an
unspecified type of bone graft with no history of liver disease tested
positive for hepatitis-C antibody after having received a bone graft from a
donor who was positive for hepatitis-C
antibody3. The third
case was documented in a retrospective review of tissue transplants from
donors who were positive for hepatitis-C
antibody4. In that
report, a recipient of a proximal femoral graft who had received no blood
products during surgery acquired hepatitis-C virus after surgery. Nucleotide
sequence analysis of the hepatitis-C virus from the donor and recipient proved
that the recipient had acquired hepatitis-C virus from the donor.
In summary, we have described the case of a patient with no other risk
factors for acquisition of the hepatitis-C virus in whom acute hepatitis C
developed approximately eight weeks after the implantation of a processed bone
graft. While the implantation of a bone graft is not a recognized risk factor
for acquisition of the hepatitis-C virus, physicians should be aware of this
possible association.