Kills 99% of known germs

In 2007 the Canadian Blood Services Consensus Conference on Pathogen Inactivation recommended that blood services move toward adopting pathogen reduction techniques for blood components as a defense against emerging transfusion-transmitted infections.1 Recently Vamvakas and Blajchman2 reviewed their six top-ranked risk reduction measures for blood services. Pathogen reduction technology (PRT) remains a high priority on their list. PRT of plasma and platelet (PLT) components is gaining momentum in Europe. Recent Vox Sanguinis international fora on pathogen reduction3 and on stock management4 indicate that more than half of European countries have adopted at least some form of PRT of blood components. In contrast, 3 years after the Canadian consensus meeting, two processes have been licensed but not yet adopted in Canada and licensing remains a challenge in the United States. In this issue of TRANSFUSION, Goodrich and colleagues5 review the performance of PRT and discuss whether the performance of those technologies is appropriate to meet the needs of the blood transfusion community. While they cover many aspects in their review, the emphasis is on the impact such technology has for pathogens for which screening is already in place (in the developed world). In practice the practical benefits, in terms of risk reduction, are most likely to be in reducing the incidence of bacterial and parasitic infections6-8 rather than for known or emerging lipid-enveloped viruses. This limitation is at least in part due to the lower expected pathogen load at the time of intended pathogen reduction processing, in most cases being orders of magnitude less for bacterial and parasitic agents than for viral pathogens. Effectiveness of current technologies for nonlipid viruses, bacterial spores or prion diseases is less certain or not present. PRT also has benefits in terms of white cell inactivation that may provide greater security in preventing graft-versus-host disease than gamma irradiation. At present, PRTs seem to be on a slow march toward market acceptance, in a process a little reminiscent of the adoption of virus inactivation processes of fractionated products in the 1970s and 1980s and of leukoreduction in the 1980s and 1990s. The problems of cost, toxicity, and loss of efficacy are once again under scrutiny as part of the assessment of the future utility of a new technology. For plasma for clinical use, PRT has gained a high degree of penetration in Europe: amotosalen, solvent/detergent, and methylene blue are well-established technologies, and balance has probably begun to shift toward having to justify not doing PRT for plasma rather than having to justify its use. Massive-dose plasma therapies in thrombotic thrombocytopenic purpura will probably give adequate reassurance both of safety and of efficacy comparable to that of untreated FFP. The real dividend for PRT will arrive when all three labile components (four in those countries where cryoprecipitate is still in use) can be treated either as a single process for whole blood or as individual components. At that point serious consideration can be given to stripping out certain technologies: testing for cytomegalovirus (CMV), human T-lymphotropic virus Types I and II (HTLV-I/II), and hepatitis B core antibodies; malaria and Chagas disease deferrals; irradiation; and bacterial testing for PLTs. Two other benefits would also accrue: protection of recipients from at least some infectious agents present but not known, appreciated, or understood—such as xenotropic murine leukemia virus–related virus (XMRV), monkey pox, or Simian foamy virus in recent years and early, proactive defense, at no extra cost, against new epidemics: West Nile virus (WNV), Chikungunya, Congo Crimea virus, influenza, severe acute respiratory syndrome, Rift Valley fever, and babesiosis. This protection is already in effect for plasma and for PLTs. For example, the appearance of WNV in South Texas is of no concern for the users of plasma from that region in Ireland, and PRT has been used to good effect in dealing with the large Chikungunya epidemic in La Réunion. A major potential advantage for PRT would be a solution for safe blood in rural communities in the developing world, where problems of economics, logistics, and high microbiologic threat present problems on an overwhelming scale. Ideally, a pathogen inactivation technology would be applied to whole blood, with preparation of individual safe (red blood cell [RBC], PLT, and plasma) components applied thereafter, rather than to the individual components being treated as is currently the case (Table 1). Preliminary studies suggest that a whole blood process may be feasible.9,10 The questions asked by Goodrich and colleagues are therefore of extreme importance—what is the target for PRT? At what point can we draw the line that best addresses the unholy trinity of cost, toxicity, and effectiveness? We may discount cost for the time being: costs for technology fall with market penetration. In addition, accepted norms of health economics in the developed world have often been abandoned for blood transfusion in the face of political necessities, which is not, in the end, unreasonable: the threat from infections through blood transfusion is often seen more as a civil problem than as simply a health issue. At the same time, any cost increase is beyond the reach of many economies where PRT would be especially life-saving, so that a different method of ensuring return for commercial interests will be required. Toxicity is a problem in two places: to the product (impairing efficacy) and to the recipient (residual material, or metabolites, causing harm). The discipline and science of toxicology continues to evolve, generally replacing fear with scientific definitions and measurements of real hazards. For policy purposes, users of any emerging technology, including users of mobile phones and microwave ovens, must at times deliver themselves into the hands of the safety industry. There have been failures of commission and omission (witness the failure to distinguish fear from risk in the ongoing saga around the use of the plasticizer DEHP). Nevertheless, it is probably reasonable to assume that recipients of products treated with all current PRTs will be adequately protected by good toxicologic assessments. For current plasma and PLT products continuing hemovigilance studies suggest that recipient toxicity is not a problem,1-13 although untoward antibody formation has been reported for two, now abandoned, RBC PRT processes. Toxicity to the product is a separate issue that can only be resolved by careful and extensive study of a stable technology. It has taken years to tease out the albumin story, for example; RBC storage is still a matter of debate and optimum PLT dosing has not been defined. It will take time, and as an industry we should remain committed, but patient. The regulatory concerns are valid, and it is probably reasonable that a higher bar for these products is required over and above the historical, and lax, requirements for untreated labile components. All current processes result in some loss of product potency and/or efficacy. Based on what has been deemed acceptable by some early adopters of the PRT in Europe, a 15% loss of dose/efficacy may be acceptable, whereas a 30% loss would probably not be, unless the variable involved is not regarded as clinically critical, for example, Factor VIII content of plasma, or can be circumvented by giving a larger dose. Acceptability in this arena depends on the clinical end points under consideration. Taking PLTs as an example, a reduction in count increment may be acceptable, but an increase in breakthrough bleeding may not be.4-16 Given the fairly crude dosing for these products that is the norm in clinical practice, potency issues may be addressed adequately through dosing changes, in much the same way as was done for fractionated products subjected to sterilization. Immunogenicity has been a problem for RBCs that must be addressed and resolved, but does not seem to be an issue for PLTs and plasma. Given that cost and toxicity (to the patient and to the product) are issues that can be addressed separately, the problem of efficacy (of microbiologic sterilization) remains to be defined. A purchaser of PRT would expect robust security: From the known problems—window period donations for services that have testing in place for human immunodeficiency virus, hepatitis C virus, and hepatitis B virus using nucleic acid technology (NAT); From known transfusion-transmissible infections we do not test for: CMV, parvovirus B19, Chikungunya virus, dengue, malaria, babesiosis, (WNV, Chagas, HTLV-I/II); From agents in the community that cause concern rather than known disease—simian foamy virus, XMRV, other emerging retroviruses; And from the unknown unknowns: there are many diseases with a probable, but unknown, environmental cause that may need to be covered in the future. Processes should also be robust enough to confer real protection in the setting of developing countries, bearing in mind that it may then permit nonadoption of other technologies such as NAT. The article by Goodrich and colleagues usefully identifies the likely load for different types of pathogen in infected blood units. The ability of PRT to reduce the risk associated with such donations depends on the total dose (= volume × titer) of pathogen as well as the efficacy of the pathogen inactivation step for that agent, usually expressed as a log reduction factor (RF). This ratio of the total pathogen dose after processing to that before is on a log scale, never reaching a residual risk of zero. For example a 300-mL PLT product containing 100 bacteria/mL has a bacterial load of 30,000 bacteria. A process that reduces 5 logs means that the residual load is in the order of 0.3 bacteria per unit, or one bacterium in every third unit after processing. If incubated, such a unit could grow bacteria to high titers again in a relatively short time. In practice the demonstrable RF for pathogen reduction processes is often limited by the available titer of the pathogen available to add to the component under assessment and data is cited as a log RF of greater than some number (e.g., >6 log means all 6 logs added was inactivated) The process may well have considerably more capacity but would require a higher concentration of pathogen than was available to prove the case. For some PRT, for example, prion filters for RBCs, expressing pathogen reduction as log RF is inappropriate, since for these the extent of pathogen reduction is not independent of pathogen load (there is an absolute limit set by filter capacity), whereas RF is appropriate for processes such as heat treatment or irradiation, which exhibit zero order kinetics with respect to pathogen concentration. Unlike fractionated plasma products the application of multiple inactivation steps that act by independent mechanisms (orthogonal) to single donation blood components is probably not a realistic approach. Finally, PRT represents our best bet for the future. Testing will struggle to keep pace with emerging infections and in any event becomes more difficult for the developing world to maintain. The costs of PRT will fall, and the technology will almost certainly evolve. At present, only the commercial sector has the capability of developing PRT to the point of clinical use; if the current initiatives fail to gain acceptance there may be great reluctance on the part of the commercial sector to try again, and an opportunity for a considerable enhancement to the safety of an essential therapy may be lost. None.

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