Photochemistry and Photobiology, 1997, 65(3): 428-431

Symposium-in-Print

Viral Risks Associated with Blood Transfusion

Elaine M. Sloand* National Heart, Lung, and Blood Institute, Bethesda, MD, USA

Received 1 July 1996; accepted 16 September 1996

ABSTRACT

Great strides have been made within the last decade to help ensure the safety of the blood supply. Additional tests to detect infectious agents, as well as development of improved donor screening and deferral techniques have helped make the risk of transfusion-transmitted dis- ease very low. Currently, blood banks perform seven tests to detect infectious agents. Prospective donors are carefully questioned about factors that place them at risk for transfusion-transmitted disease and donors known to test positive for certain viruses are permanently deferred. The risks of receiving a human immunodeficiency virus (H1V)-infected unit is now estimated to be 1 in 493000, while the risk of hepatitis B is 1 in 63000. However, changes in prevalence within the blood donor population brought about by changes in the factors that place an individual at risk for a transfusion-transmitted disease could significantly alter these risks. The American public continues to be concerned about the safety of blood transfusion. These concerns coupled with the fears that new viruses or new strains of viruses will be identified that escape detection has created the impetus for devel- opment of methods that will remove or inactivate viruses in cellular blood products.

INTRODUCTION

Great improvements have been made in transfusion safety in the last two decades. As a result, the risk of contracting a transfusion-transmitted infection in the United States is practically negligible today. Notwithstanding, the public continues to press for the institution of additional tests and the development of new ways to inactivate or remove infec- tious agents from cellular and noncellular components. De- spite some misconceptions regarding the risk associated with transfusion, part of the public’s concern is legitimate. Al- though the prevalence of transfusion-transmissible disease in the US. today is low, particularly in the blood donor pop- ulation, it is increasing globally. With the mobility of the

*To whom correspondence should be addressed at: 3 1 Center Drive, MSC 2490, Bldg. 31. Rm. 4Al1, Bethesda, MD 20892-2490, USA. Fax: 301-594-1290.

0 1997 American Society for Photobiology 003 1-8655/97 $5.00+0.00

population and new influxes of immigrants to the United States, it is likely that the prevalence of some transfusion- transmissible diseases will increase. The risks associated with receiving an infected unit of blood, which tests negative for infectious agents, are closely linked to the prevalence of the disease in the donor population. Should prevalence in- crease, the risks to the transfusion recipient could increase dramatically. For example, even assuming that testing meth- ods are as sensitive as in the U.S., the human immunodefi- ciency virus (HIV)-l? risk associated with transfusion in high prevalence areas such as the Ivory Coast of Africa is substantial (ranging from 0.5 to 1% in one study) (1). With this understanding this article reviews the current strengths and weaknesses of donor screening for transfusion-transmis- sible disease.

HEPATITIS B VIRUS (HBV) After the introduction of routine screening for hepatitis B in 1970, the frequency of posttransfusion hepatitis resulted in an 85% reduction in posttransfusion hepatitis (2). The resid- ual incidence of hepatitis B was 0.002% (3,4). These re- maining infections result from transfusion of blood testing negative for the hepatitis B antigen (HBsAg), which were nonetheless infected. The HBV DNA has been identified in a small percentage of HBsAg-negative samples from patients with chronic liver disease and infectivity of these samples has been demonstrated (5-10). Although the initial rationale for pretransfusion screening for hepatitis B core antibody (anti-HBc), initiated in early 1987, was to defer blood donors who were also at risk of transmitting non-A, non-B hepatitis (NANBH), testing also eliminated rare cases of transmission of hepatitis B in blood testing negative for HBV (1 1-13). Hepatitis core antibody may be present during the window period of acute HBV, after the disappearance of HBsAg, but before the appearance of protective antibody (anti-HBs). In one study Lander et al. (1 1) demonstrated that among 26

tAbbreviations: ALT, alanine aminotransferase; anti-HBc, hepatitis B core antibody; CMV, cytomegalovirus; EIA, enzyme immu- noassay; ELISA, enzyme-linked immunosorbent assay; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepa- titis C virus; HIV, human immunodeficiency virus; HTLV. human T-cell lymphotropic virus; NANB, non-A, non-B; PCR, polymer- ase chain reaction; REDS, Retroviral Epidemiology Donor Study; RIBA, recombinant immunoblot assay; TTV, transfusion-trans- mitted virus.

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Photochemistry and Photobiology, 1997, 65(3) 429

cases of posttransfusion HBV infection, most resulted from transfusion of HBsAg negative, anti-HBc-positive blood. Similarly, in the transfusion-transmitted virus (TTV) (12) study, 15 of 1151 recipients of blood were infected with HBV; of these 8 received anti-HBc-positive blood. In the U.S. the latest data from the Retroviral Epidemiology Donor Study (REDS) supports a transfusion risk of HBV of 1 per 88000 units of blood transfused (14). This risk currently exceeds that of any other viral infection.

NANB VIRUS Before the introduction of surrogate testing, posttransfusion hepatitis, unrelated to hepatitis A or B (NANBH) still oc- curred in as many as 20% of patients (15) receiving trans- fusion. Before the development of a specific test for NANBH, surrogate testing was introduced in the late 1970s and 1980s. Two surrogate tests measured the alanine ami- notransferase (ALT) and anti-HBc. Although the anti-HBc was specific for hepatitis B, the rationale for implementing it was that individuals who were at risk for hepatitis B were also at risk for NANBH. Studies by two independent groups of investigators demonstrated that recipients of blood from donors with abnormal ALT had a three-fold higher risk of developing NANBH than recipients of blood from donors with normal ALT concentrations (16.17). Subsequently, it was shown that the presence of the other surrogate marker, anti-HBc, correlated significantly with the occurrence of NANBH in the recipient (18).

After the identification of the hepatitis C virus (HCV) gene sequences an enzyme immunoassay to detect antibody to HCV was developed and testing instituted in May of 1990. It was soon apparent that HCV accounted for 90% of NANBH (19,20). Second generation tests (21) were able to identify infected donors within 4 weeks of infection with HCV. A positive confirmatory test or recombinant immu- noblot assay (RIBA) has been shown to correlate with HCV infection, the presence of liver disease and detectable vire- mia defined by polymerase chain reaction (PCR) viral RNA (22-27). Eighty to ninety percent of recipients of blood from individuals testing positive for HCV seroconvert (27). In a recent study of patients transfused for cardiac surgery the risk of posttransfusion hepatitis C was found to be 1 per 103 000 screened units of blood transfused (14,28).

HUMAN T-CELL LYMPHOTROPHIC VIRUS (HTLV) TYPE I AND TYPE II Both HTLV I and I1 can be transmitted by transfusion of cellular blood components. The HTLV-I infection is asso- ciated with a small but significant incidence of T-cell leu- kemiallymphoma in Japan, as well as spastic paraparesis, a degenerative neurological disease primarily found in areas of the Caribbean, where HTLV is endemic. However, the risk of developing an HTLV-associated disease is very small even to those with long-term infection. In the U.S. the trans- mission rate (i.e. the number of individuals who seroconvert after transfusion of a seropositive unit) is significantly lower (20%) than in Japan (60%) (29,30) where the virus is en- demic and where the number of leukocytes in blood com- ponents is substantially higher and the storage time is shorter than in the U.S. Longer storage time and fewer leukocytes

are inversely related to the transmission rate (31.32). Sero- prevalence of HTLV in the U S . population ranges from 0.025 to 0.08. The risk of receiving an infected unit was 0.02% prior to screening and 0.001% following.

One of the difficulties with some of the initial enzyme- linked immunosorbent assays (ELISA) for HTLV-I is that they were less sensitive for HTLV 11, although it was esti- mated that the HTLV I enzyme immunoassay (EIA) identi- fied about 90% of individuals infected with HTLV-I1 (33,34). Previously, the absence of a specific disease asso- ciation for HTLV I1 similar to HTLV I (which is associated with HTLV and tropical spastic paraparesis) provided little incentive for developing and requiring sensitive and specific screening tests. However recent reports of the association of tropical spastic paraparesis in individuals with HTLV-I1 in- fection may likely cause a reevaluation of the issue (35-37).

The issue of counseling individuals with HTLV-ID1 infec- tion is a difficult one, as the actual risk of developing a disease as a consequence of infection is extremely low (38) and it is unclear whether alteration of lifestyle to prevent transmission is warranted.

HIV-1 Since the widespread institution of screening for HIV-1 in the spring of 1985, the risk of receiving a unit of blood that is infected and yet tests negative by pretransfusion testing has fallen to 1 in 413000 (14). This low risk, which varies greatly with geographic location, results from improvements in donor screening, which identifies and defers high-risk do- nors, as well as from testing blood for specific infectious diseases. The importance of donor deferral measures can be seen from statistics showing that the risk for HIV decreased dramatically in San Francisco after high-risk donors were deferred, before the introduction of screening in 1985 (39). A prospective study conducted in two high-risk areas of the country, Baltimore and Houston (40). found that two sero- conversions occurred in a group of cardiac surgery patients receiving a total of 1 10000 units of screened blood. Another study in a high-prevalence area employed HIV-I cultures with PCR augmentation and found 1 in 120000 screened units contained infectious HIV-I (41). Although the sero- conversion rate after transfusion of infected blood testing positive by EIA is over 90%, washed components and units stored for more than 21 days resulted in lower transmission rates than other components (42).

Although there were initial reports of window periods as long as 6 months following infection, these have not been substantiated. Most investigators agree that seroconversion generally occurs within 6-8 weeks (43-47). The develop- ment of more sensitive EIA has decreased this to 3 weeks, and recent initiation of the p24 antigen test is likely to nar- row this by 5 days (48). The utility of the PCR technology in further improving blood safety is being continually re- examined. Currently, tests based on the PCR technology would result in a small decrease in the window period but at great expense and with loss of uninfected units of blood that test false negative (49).

CYTOMEGALOVIRUS (CMV) Almost 80% of the normal adult population has been in- fected with this cell-associated herpes virus (SO). Although

430 Elaine M. Sloand

usually asymptomatic in the normal population, CMV infec- tion may be life-threatening in immunosuppressed individ- uals. Cytomegalovirus is only transmitted via cellular com- ponents, and blood that has been leukodepleted has a greatly decreased risk of transmitting CMV infection (5 1-54). Transfusion of blood that is CMV seropositive to seroneg- ative individuals may result in CMV infection and transfu- sion of seronegative, immunosuppressed patient with CMV seronegative blood is generally recommended (55). Al- though superinfection of a seropositive donor with a second strain of C M V has been reported in seropositive recipients of seropositive organs, this phenomenon is yet t o be dem- onstrated by transfusion. Activation of latent CMV infec- tions in seropositive recipients of either seronegative or se- ropositive blood does occur (probably as a result of upreg- ulation of viral production in latently infected recipient lym- phocytes result ing from exposure to allogenic donor lymphocytes). T h e utility of leukodepletion of blood trans- fused to immunocompromised patients is currently being studied in an NIH-sponsored trial.

CONCLUSION Although the U.S. blood supply is as safe as it has ever been, it is important to continue to develop more sensitive tests t o detect viruses and to develop procedures that would suc- cessfully inactivate viruses in cellular blood products, in or- der to guarantee continued safety. The question of how to counterbalance safety with adequacy and cost-effectiveness was addressed in a conference held by the Institute of Med- icine in 1989. Although much anguish was expressed by both blood users and blood providers, there was no clear answer. T h e question of whether to add expensive and high- ly technical blood tests using PCR technology has also been addressed in a public forum and it is unclear whether the increased costs, the longer turnaround time and the increased number o f false positives generating anxiety in the donor population will justify its institution. Certainly effective methods to remove o r to inactivate viruses or bacteria in cellular components would offer a greater measure of safety, if the methodology was relatively inexpensive and easy to use. Such expertise would be of particular value to the Armed Forces and to the third world where prevalence is much greater and increased storage t ime and greater safety would be facilitated by such methodology.

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