Since 1998, CDC has collaborated with approximately 140 federally funded
hemophilia treatment centers (HTCs) in the United States and its territories
through the Universal Data Collection (UDC) surveillance project to monitor
blood product safety and detect new viral hepatitis and human immunodeficiency
virus (HIV) infections. This report presents findings of investigations conducted
during May 1998–June 2002 of 1,149 seroconversions* for hepatitis viruses
identified among persons with bleeding disorders who were enrolled voluntarily
in UDC; 99% of hepatitis A virus (HAV) seroconversions and 90% of hepatitis
B virus (HBV) seroconversions were attributed to vaccination programs against
HAV or HBV. None of these cases was attributable to blood products received
during this time, which indicates that the virally inactivated blood factor
concentrates used to treat bleeding disorders are unlikely to transmit viral
hepatitis. Regular monitoring of patients ensures the continued safety of
blood and blood products.
HTC staff obtain informed consent from each UDC participant and collect
a standard set of clinical data and a plasma specimen. Data presented on standardized
registration, annual, and laboratory forms are sent to CDC along with annual
blood specimens from all UDC patients. Specimen remainders are stored in a
blood-safety repository for future investigations of blood safety. All plasma
specimens are tested for hepatitis viruses at Baylor College of Medicine.
UDC participants are tested for hepatitis at enrollment according to algorithms
that determine whether patients have been exposed to or infected with a virus.
Participants who test negative for a virus are retested in subsequent years
to monitor for seroconversions. Possible seroconversions are evaluated for
HAV by testing for IgM antibody to HAV and total antibody to HAV; for HBV
by testing for antibody to hepatitis B surface antigen (anti-HBs), antibody
to hepatitis B core antigen (anti-HBc), and hepatitis B surface antigen (HBsAg);
and for hepatitis C virus (HCV) by testing for antibody to hepatitis C (anti-HCV),
which is confirmed with recombinant immunoblot assay and/or HCV-RNA by polymerase
chain reaction when needed.
Systematic investigations were conducted when patients were confirmed
as seropositive after having tested seronegative in a previous UDC specimen.
Laboratory results were compared with information about past infections and
vaccinations and with data about exposure to blood components or plasma derivatives.
If the change in laboratory results could not be explained on the basis of
these data, CDC contacted HTC staff for additional information on other potential
risk factors for infection and on the setting of potential transmission, including
blood-product manufacturer and lot number. Resolution of discrepancies generally
required repeat testing of previously drawn specimens; less often, repeat
testing was performed on newly drawn specimens. Patients' identities were
not disclosed by HTCs.
During May 1998–June 2002, a total of 11,171 patients with hemophilia
and other bleeding disorders were enrolled in UDC; 6,931 (62%) had hemophilia
A, 1,866 (16%) had hemophilia B, 2,078 (19%) had von Willebrand disease, and
296 (3%) had other congenital bleeding disorders. A total of 6,219 (56%) patients
were newly enrolled in UDC and so had been tested only once; these persons
will be tested again in subsequent years. Of the 4,952 (44%) patients who
had blood testing in ≥2 years, 1,149 (23%) had seroconversions to hepatitis
viruses: 896 (18%) to anti-HAV; 252 (5%) to anti-HBs, anti-HBc, or HBsAg;
and one (<1%) to anti-HCV. Because 896 (99%) HAV seroconversions and 227
(90%) HBV seroconversions could be attributed to vaccination programs, and
the remainder could be attributed to other sources, no seroconversions were
attributed to exposure to blood derivatives used during the surveillance interval.
No participants who seroconverted to anti-HAV were IgM-positive when
the tests were performed. Being IgM-positive is a marker of acute infection
with HAV that persists for 3-6 months in the majority of patients.1
Of 896 persons who seroconverted to total anti-HAV in the second year
of testing, 890 (99%) had completed the hepatitis A vaccination series, had
received a booster injection, or were in the process of being vaccinated.
Because none of the six participants who seroconverted in the absence of vaccination
had received blood products between tests, these infections were presumed
to be community-acquired.
Of 252 persons who seroconverted to one or more HBV markers, 227 (90%)
who seroconverted only to anti-HBs had received either a full, partial, or
booster vaccination between their first- and second-year tests. The remaining
25 who tested negative in initial UDC testing for anti-HBs, anti-HBc, or HBsAg
and then tested positive subsequently were documented by HTC staff to have
a previous history of HBV infection caused by past exposure to blood products.
All these 25 participants also were HIV-infected from blood products used
before enrollment in UDC.
One seroconversion for HCV occurred 6 months after collection of an
initial negative UDC specimen. Local health authorities investigated this
seroconversion and determined that the most likely source of this infection
was injection-drug use; the patient's HIV status was negative.
FB Hollinger, MD, Baylor College of Medicine, Houston, Texas. A Kirtava,
MD, M Oakley, DVM, M Soucie, PhD, B Evatt, MD, Div of AIDS, STD, and TB Laboratory
Research, National Center for Infectious Diseases, CDC.
HTCs provide care to 70% of persons in the United States with bleeding
disorders. UDC is the largest data collection system monitoring persons receiving
plasma derivatives, and infections transmitted by blood and blood products
often are identified first in this sentinel population.2 A
high risk for bloodborne viral infections (including HBV and HCV) among persons
with bleeding disorders was associated with the use of clotting factor concentrates
prepared from large pools of human plasma manufactured during the 1970s and
early 1980s before the development of viral inactivation procedures.3,4 In the early 1990s, several outbreaks
of HAV associated with the receipt of clotting factors were reported in Europe
and the United States.5,6
Investigations of seroconversions during May 1998–July 2002 did
not document new cases of viral hepatitis infections that were attributed
to blood products received during the time interval between laboratory tests.
The majority of seroconversions for HAV and HBV were associated with vaccination
(99% and 90%, respectively). The other seroconversions probably were caused
either by community-acquired infection (for the six HAV infections) or by
fluctuations in antibody levels that occur among HIV-infected patients (for
the 25 persons with HBV seroconversions who also were infected with HIV).7
This report suggests that currently available blood factor concentrates
most likely do not transmit HBV or HCV. Transmission of HAV remains a remote
risk because the viral inactivation procedures used for plasma derivatives
are unable to inactivate non-enveloped viruses such as HAV completely.8 Sporadic cases occur when plasma obtained from
an asymptomatic donor who is incubating the infection is added inadvertently
to a plasma pool used to manufacture derivatives. Because of the wide distribution
of these products, such sporadic product-related cases can be identified only
by monitoring large populations for clusters of cases that occur at the same
time and that are associated with the use of a single product lot.
The findings in this report are subject to at least two limitations.
First, because not all persons with bleeding disorders participated in the
surveillance, some seroconversions might have been missed. Second, because
patient or health-care provider reports of vaccination were used instead of
medical record documentation, some seroconversions might have been attributed
incorrectly to vaccination.
UDC promotes prevention and reduction of the complications of bleeding
disorders and provides health agencies with timely risk data to support policy
decision making. In addition, UDC has led to high levels of vaccination coverage,
which is recommended for persons with bleeding disorders.9,10 Regular
testing of patients with bleeding disorders through UDC monitors the safety
of blood and blood products and provides the national repository of stored
serum for assessment of potential new threats to the blood supply.
This article is based on data supplied by the staff of federally funded
hemophilia treatment centers who enrolled patients in the surveillance system
and assisted with the investigations.
*A change of test results from negative in year one of testing to positive
in the subsequent year of testing for any reason (e.g., vaccination or other
risk factors). Seroconversion is an expected outcome for vaccination.
Blood Safety Monitoring Among Persons With Bleeding Disorders—United States, May 1998–June 2002. JAMA. 2003;289(5):541-543. doi:10.1001/jama.289.5.541