The current level of safety of the blood supply is unparalleled. However, a small degree of risk of transfusion-transmitted disease remains (see TMU, December, 1993). The residual risk of viral transmission is due to the absence of detectable serological markers during the brief "window period" which occurs after exposure and the absence of recognized or acknowledged risk factors in some infected donors. The next significant step in improving the safety of transfusion entails the introduction of manufacturing procedures which inactivate viruses which may be present despite the extensive safety screening already in place.

An effective viral inactivation procedure would eliminate any concerns about window period viral infectivity. Furthermore, depending upon the nature of the virus, viral inactivation may be effective against any new, unknown, or unrecognized viral pathogens which could infect the blood supply. Eventually, the need for extensive laboratory testing of blood

A number of protein constituents of human plasma have important therapeutic utility. Currently, licensed derivatives include albumin/plasma protein fraction (PPF), coagulation factor concentrates, and immune globulin preparations (IV and IM formulae). These derivatives are manufactured from large pools of human plasma, primarily by the Cohn cold ethanol fractionation method. This involves the sequential precipitation of specific proteins under varying conditions of ethanol and pH conditions. The separated fractions are harvested by centrifugation or by filtration. Additional purification steps are specific for each derivative. For many years, the safety of albumin preparations has been further insured by an additional viral inactivation step, heating for 10 hours at 60° C (pasteurization). Cohn fractionation itself has been shown to result in antiviral effects by physical partitioning as well as direct virucidal activity from ethanol treatment. In 1986, the Centers for Disease Control (CDC) and the Food and Drug Administration (FDA) determined that intravenous immune globulin (IVVIgG) prepared by Cohn fractionation contained no discernible risk of HIV. This was based on in vitro studies indicating >10 log clearance of HIV when added to starting material. Tragically, this was found not to be the case for coagulation factor concentrates produced in the early 1980s, which were prepared by similar methods. Subsequently, the addition of several viral inactivation procedures to factor concentrates proved to be highly effective in eliminating the risk of viral transmission. These measures include wet or vapor heating, and solvent/detergent treatment (S/D) (see TMU, November, 1992).

Although Cohn fractionation has proven highly effective for the inactivation of HIV, recent evidence suggests that this method alone may not be as effective for other types of viruses, such as hepatitis C. While intravenous immune globulin preparations have generally been considered to be safe, there have been several reports of HCV transmission over the last decade. Recently, one IVIgG preparation had to be withdrawn from the market because of reports of HCV infection. Thus, it appears, that a small risk of HCV transmission by some IVIgG products remains. As a result, current recommendations to manufacturers from regulatory agencies are that all immune globulin products be subjected to specific viral inactivation procedures subsequent to fractionation. Several IVIgG preparations which utilize S/D viral inactivation are now commercially available, and additional inactivation procedures are being developed. Patients treated at Central Blood Bank with IVIgG now receive an S/D treated product.

Whether the small risk of HCV transmission associated with IVIgG extends to intramuscular immune globulin is unclear. However, HCV transmission has not been specifically linked to intramuscular IgG, and there are notable differences between the techniques used in the preparation of these two IgG formulae.

To date, 127 patients (including six treated at Central Blood Bank) have received nearly 2,500 units of this product as part of a multicenter trial of its safety and efficacy. The treated patients were those primarily who had coagulopathy due to liver disease or congenital factor deficiency. The overall reaction rate, 1.4% per unit, was comparable to that seen with FFP and consisted mainly of urticaria. No evidence of viral seroconversion has been found in 25 previously untransfused patients.

Definitive viral inactivation steps are being rapidly introduced into the manufacturing of plasma products and derivatives. These techniques have proven to be highly effective with respect to the viral safety of clotting factor concentrates. Practical antiviral treatment of cellular blood products awaits further investigation. While implementation of a new technology, such as S/D plasma, is expected to further the goal of a reduced risk blood supply, its high incremental cost will also need to be examined in light of competing pressures to contain health-care expenditures.