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Blood Safety Monitoring Among Persons with Bleeding Disorders --- United States, May 1998--June 2002
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.
Reported by: 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.
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