Current status of pathogen inactivation methods

Abstract

Although improved donor selection criteria and tests of increasing sensitivity have dramatically reduced the risks of transfusion‐transmitted infectious disease, multiple potential means exist for a pathogen to escape detection and injure a recipient: a window period remains in which an infectious donor cannot be detected; some transmissions (e.g. bacterial contamination of platelets) have detection methods that are far from the desired capabilities; and ‘emerging’ pathogens continue to represent a risk to recipients until effective testing strategies are developed and implemented. Pathogen inactivation of labile blood components represents a means of addressing all three of these shortcomings simultaneously as they have for plasma derivatives. Multiple effective means of pathogen inactivation have been validated and put into use for plasma and for platelet components. While not yet universally implemented, these appear to have an acceptable toxicity profile and retain a clinically useful – although slightly diminished – degree of efficacy that is not associated with increased usage. Some of these techniques, such as solvent–detergent treatment of plasma, appear to offer benefits beyond avoidance of infectious disease; in this case, the pooling involved in the process, while creating a risk for dissemination of non‐enveloped viruses, appears to reduce the risk of TRALI considerably. Promising systems for pathogen inactivation of red blood cells and whole blood are under development and would complete the spectrum of treatment across all labile components. While some jurisdictions, most notably the United States, interpret the completed clinical trials as not yet presenting adequate benefit to balance perceived risks, the primary impediments to implementation would appear to fall more into the logistic than scientific category. Is there sufficient benefit to warrant implementation of pathogen inactivation for plasma and platelets before red cell treatment is feasible? How can the processes be accomplished while minimizing cost to the system? How will each country’s healthcare system accommodate the inevitably increased expense for this additional production step? What impact will a fully pathogen‐inactivated blood supply have on clinicians’ conception of transfusion risk and thus blood utilization? This review provides an overview of data available from clinical trials and attempts to identify a path towards improving transfusion recipient safety.

Meta‐analysis of the studies of bleeding complications of platelets pathogen‐reduced with the Intercept system

“…Other experts believe that further RCTs should be conducted before the Intercept system is adopted for routine use [37] because (1) capturing grade 1 (and/or 2) bleeding complications is difficult outside the framework of RCTs [12]; (2) the published surveillance studies [35, 36] that did not report increased bleeding also did not document the increase in platelet transfusions expected from the published RCTs [11]; it is possible that platelet transfusions had been overprescribed before the introduction of the Intercept system, thereby concealing an increased need for platelet transfusions [11] and perhaps also a higher risk of bleeding complications [12] following implementation of pathogen reduction; (3) there is an increase in clinically significant bleeding complications in association with treatment with Intercept when the SPRINT trial data are extracted from the expanded safety analysis of that study [4] (Fig. 2); and (4) in addition to being not blinded, the RCT of Kerkhoffs et al.…”

“…The RCT of Kerkhoffs et al . [1] questioned prevailing opinion [7–11] that the reduction in post‐transfusion platelet count increments (CCIs) caused by transfusion of platelets treated with Intercept (compared with untreated components) can be overcome by merely increasing platelet transfusions. These investigators [1] demonstrated an increase in bleeding complications in recipients of platelets treated with Intercept compared with controls, despite the fact that the recipients of treated platelets had also received more platelet transfusions to maintain a platelet count of ≥10 000/μl [1].…”

Risk-Reduction Strategies for Platelet Transfusion in the United States

“…If this is the case, contrary to what we had previously assumed [1,11,12,13], the platelet damage from PR cannot be overcome by merely increasing the platelet dose [14,16]. Introduction of PR in its current stage of development will result in an increase in mild and moderate, albeit perhaps not severe, bleeding complications, which we will have to explicitly tolerate to reap the benefits [1,11,12,13] conferred by PR.…”

“…For this reason, AABBaccredited U.S. blood establishments moved voluntarily toward reliance on single-donor platelets so that 87.5% of platelet doses transfused in the U.S. in 2006 were single-donor platelets [10]. In addition, the platelet pathogen-reduction (PR) systems [11,12,13] Intercept and Mirasol®, which use chemicals (respectively, amotosalen HCl along with ultraviolet-A light or riboflavin along with ultraviolet-B light) to inactivate nucleic acids in platelet concentrates, were licensed in Europe for the purpose of confronting the residual risk of TABS and TTIs. Thus, to mitigate the residual risks of TABS and TTIs from platelet transfusion, three alternative risk-reduction strategies may eventually reach the U.S. market: (1) transfusion of already-available non-pathogen-reduced single-donor (as opposed to PWBD) platelets, (2) transfusion of pathogen-reduced single-donor platelets, or (3) transfusion of pathogen-reduced PWBD platelets (if trials of this component are conducted in the U.S. in the future).…”

In reply

“…However, these observational studies also did not document the expected increase in the number of PLT transfusions owing to the PLT losses caused by PR. Most likely, PLT transfusions had been previously overutilized, so that the effective reduction in PLT dose caused by PR did not result in a visibly increased need for PLTs 10 . It is also possible that the expected increase in mild and moderate (as opposed to severe) bleeding complications might have gone unnoticed outside the framework of an RCT.…”