Cesium cessation? An advantage of pathogen reduction treatments

Transfusion-associated graft-versus-host disease (TA-GVHD), when severe, is characterized by the relentless, devastating destruction of host tissues and organs orchestrated by activated and proliferating donor lymphocytes and abetted by the host. Since there is no effective treatment for TA-GVHD and reported mortality of severe cases is greater than 90%, prevention of this clinically horrific process is essential.1 TA-GVHD is a terrible tragedy, but is thoroughly preventable. It has been more than 40 years since Graw and colleagues2 suggested that allogeneic blood components should be irradiated before transfusion to immunosuppressed patients. Thus, the longstanding method for preventing TA-GVHD has been to subject blood components that are known to contain large numbers of viable T cells (all units of whole blood, red blood cells [RBCs], platelets [PLTs], granulocytes, and fresh liquid plasma) to a sufficient dose of irradiation to damage DNA in multiple ways thereby paralyzing the cells' proliferative potential.3-6 (Frozen plasma contains viable mononuclear cells and the possibility of irradiating these components has been raised.)7 While the likelihood of TA-GVHD is related to the number of transfused lymphocytes, the threshold dose is not known and the disease has been reported after the transfusion of nonirradiated leukoreduced (LR) components.8, 9 The 2009 Nationwide Blood Collection and Utilization Survey report (2008 US data) indicates that 10% of 15,014,000 RBC components transfused were irradiated, 44% of 1,761,000 apheresis PLTs transfused were irradiated, and 22% of 1,300,000 individual whole blood–derived PLT concentrates transfused were irradiated. In total, more than 2,500,000 components were irradiated.10 The US Nuclear Regulatory Commission (NRC) reported that cesium-137 chloride (CsCl) blood irradiators are used in more than 90% of blood component irradiation procedures because the devices are the “most reliable, efficient, and require low maintenance.”11 All CsCl used in the United States comes from a single source in Russia. X-ray is an alternative form of irradiation; however, the NRC states that “stakeholders have indicated that X-ray irradiators create hardship for the sterilization industry because of their significant limitations compared to CsCl irradiators, such as low reliability, slow throughput, high initial costs, high operating costs, high maintenance requirements, and shorter working life.”11 A total of 575 blood irradiators containing CsCl are in use in the United States.11, 12 Despite its popularity, CsCl in blood irradiators is of growing concern because it is a compressed powder that is water soluble and easily dispersible. If ingested or inhaled, it is delivered throughout the body. CsCl could be an appealing target for terrorists wishing to use it in a radiologic dispersal device or employ it for other malevolent uses. Thus, in the United States, rigorous security measures have been required by the NRC that create infrastructure challenges and expense. This editorial focuses on the principal regulatory, technical, and clinical challenges associated with using a free-standing CsCl source irradiator to treat blood components and presents some of the evidence supporting pathogen reduction treatment (PRT) as an alternative means of preventing TA-GVHD. The issues raised by the use of CsCl in blood irradiators are not trivial. The reader is referred to other sources for more broad-based discussions of TA-GVHD.13-15 With respect to the regulation of blood irradiation in the United States, facilities with blood irradiators must be licensed by the NRC and have a radiation safety officer. Much has happened since November 14, 2005, when the NRC issued orders requiring compliance with increased controls of CsCl source irradiators.16 The NRC stated that the loss of control of the CsCl could constitute a threat to public health.16 Since 2005, the NRC has issued a series of communications that contain both binding requirements and voluntary suggestions for reducing the risk of terrorist activity directed at obtaining and using the CsCl. (The NRC intends to put the requirements into 10 CFR Part 37.) The components of security requirements and recommendations currently in place address personnel, security of the facilities housing the units (e.g., high-security locks on doors, multiple locked doors, secured facility schematics), security of the units themselves (including “hardening” and security enhancement initiatives), tracking of transfers and shipments, and preplanning with local law enforcement.11 Briefly, some of the requirements are: Limiting access to the irradiator to approved individuals who need to use the device in performing work activities. Security clearance for all persons having unescorted access to CsCl irradiators, including employment background checks, personal references, and fingerprinting with Federal Bureau of Investigation criminal history record checks to try to establish the trustworthiness and reliability of all employees with unescorted access. (The author is aware of one transfusion service medical director who has no fingerprints and must be escorted in her own institution's blood bank.) Escorting all service providers. Monitoring the facility and the irradiator and having a means for detecting and immediately responding to unauthorized access. Documenting monitoring and personnel activities. Immediate response plans in the event of any attempted theft, sabotage, or diversion of the CsCl. Development of a plan for assistance from supporting authorities in the event of theft, sabotage, or diversion. Documenting any attempt at theft, sabotage, or diversion of the CsCl. The NRC has acknowledged that the near term replacement of CsCl blood irradiators is not practicable or necessary due to implementation of the requirements above and considering the current lack of a disposal capacity, but it has called for efforts to develop and use alternate forms of cesium (e.g., the less dispersible cesium-137 ceramic) that would reduce the safety risks. In addition, the NRC is also encouraging the manufacturers to implement design improvements that further mitigate or minimize the radiologic consequences of misuse or malevolent acts.17 The NRC has also introduced voluntary, federally funded initiatives, including a “hardening program” that aims to increase the security of blood irradiators through the installation of security plates that significantly increase the time required to illicitly gain access to the CsCl.11 In addition, a facility security enhancement program has been developed.18 In response, with federal support, some institutions have placed the irradiator within its own room with a heavily reinforced ceiling. Entry (not through the ceiling) requires three elements: a unique biologic identifier, something the employee possesses, and something he or she knows (e.g., fingerprint, badge, PIN). In this setting, a window can be placed in the door to the irradiator room that allows operation of the irradiator without entry, thus precluding access to the CsCl source. A variety of other security measures including motion detectors, cameras, physical sensors, and alarms has been used. The NRC is also working with other countries to coordinate development of international security.19 The US Energy Policy Act of 2005 established an Interagency Task Force on Radiation Source Protection and Security. The task force has noted that the near-term replacement of CsCl irradiators is not practicable and would be “disproportionately detrimental to patient health.”20 It has suggested, contingent upon the availability of both alternative technologies and disposal pathways, that the NRC consider whether the use of new cesium sources should be discontinued and also should investigate options such as a voluntary, incentivized program for the replacement of CsCl sources.20 However, decommissioning a CsCl irradiator can cost more than $100,000.21 These issues are described in communications from the NRC and the task force.11, 12, 16, 18-23 Other entities have had input as well. The National Academies24 also weighed in at the request of Congress concluding that the US government should provide incentives for the development of means to replace CsCl in medical and research equipment. The Food and Drug Administration (FDA) considers blood irradiation manufacturing, and this activity alone requires facility registration. There is a considerable expense and there are many technical requirements associated with purchasing, installing, maintaining, and operating a free-standing CsCl irradiator. The weight of this device (up to 5000 lbs) limits the locations in which it may be placed. In some institutions, floor reinforcements may be required.11 The capital cost is US$200,000 to US$300,000 depending on the model and accessories. Operating and service expenses combined can exceed $20,000 annually.21, 25 Procedures must be written and reviewed that address instrument operation, maintenance, alarm response, and the management of individual irradiated components and overall inventory. Furthermore, there must be procedures to insure that blood components are not irradiated more than once. Operators are required to have training in how to use the device as well as in radiation safety. Annual retraining in the hazards of radiation is required by the NRC. Periodic competency assessments or reviews of operation and security with staff may be implemented. Documentation of component irradiation must be scrupulously recorded and maintained. Arrangements must be made for back-up when the irradiator is not working as few institutions have more than one device. This contingency plan can be logistically problematic and major repairs can incur a large, unbudgeted expense.26 An emergency response plan for security breaches must be in place and, as noted above, a responsible head for radiation safety appointed. The intended dose of irradiation delivered must be a minimum of 25 Gy targeted to the central portion of the container and 15 Gy must be the minimum dose at any point.5, 6 Irradiation-sensitive devices must be employed with each use to demonstrate that an adequate dose of irradiation to each batch of components was accomplished.6 A dose map must be determined routinely (e.g., annually and after major repair, parts replacement, or instrument relocation). In addition, the time of radiation must be adjusted periodically owing to isotopic decay (e.g., semiannually) because the half-life of CsCl is 30.17 years. The turntable, timer, and alarms need to be checked at regular intervals (e.g., quarterly). (The turntable is also checked visually with each use.) In addition, various components must be maintained or changed as directed by the vendor. A film badge may be placed on the irradiator to monitor for radiation leakage and checked periodically (e.g., semiannually). The vendor will also periodically perform more extensive preventive maintenance. The NRC performs routine inspections to ensure that proper security measures are in place and, as best as can be determined, are being followed. Technical aspects of blood component irradiation have been addressed in greater depth elsewhere.27 There are significant clinical considerations associated with blood irradiation. The 24-hour in vivo recovery of stored, irradiated red blood cells is reduced compared to nonirradiated red cells.28-30 Longer storage of irradiated red blood cells is associated with progressively reduced recovery compared to nonirradiated cells.30 However, the long-term red cell survival is comparable between control and irradiated red cells.30 Irradiated red cells are also more rigid than nonirradiated cells, which poses a risk of compromised oxygen delivery and may account for their decreased in vivo recovery.31-34 However, prestorage LR (PLR) ameliorates the reduced recovery.35 This finding strongly suggests leukocytes play a role in the red cell damage from gamma irradiation. Owing to the reduced 24-hour recovery, in 1993 the US FDA recommended that the permissible maximum storage for irradiated RBCs and whole blood be no longer than 28 days from the date of irradiation, regardless of when the irradiation was performed, or the original outdate, whichever is earlier.5 AABB standards align with this stipulation.6 (In 2000, the FDA issued a guidance “pilot program for licensing” for irradiating blood that was withdrawn in 2006 leaving the 1993 guidance as the FDA's latest public document on this matter.) Irradiated red cells, regardless of irradiation source, undergo an increased loss of potassium during storage.28-30, 35-40 At any storage age, RBC units contain approximately twice as much extracellular potassium as nonirradiated units. Free hemoglobin levels are also modestly increased; however, hemolysis is not greater than 1% at any storage age.28-30, 39 Red cell ATP is slightly but significantly decreased.29, 30 PLR was shown to significantly reduce the effect of gamma irradiation on hemolysis, but not on the enhanced potassium release.39 The absolute amount of potassium in irradiated units is not a concern in most clinical situations. Posttransfusion, this potassium will be diluted and also may be absorbed by the potassium-depleted transfused red cells. Concerns have arisen, however, because of the possible cardiotoxicity from hyperkalemia that could result from large-volume (i.e., >25 mL/kg) transfusions to neonates and infants. Hyperkalemic posttransfusion fatalities in neonates have been reported.41 No uniform practice exists in this setting with respect to permissible storage times after irradiation.42 This complex decision depends upon many variables including the clinical status (e.g., hyperkalemia, renal function, acid-base status, metabolic rate, medications), age of unit irradiated, anticoagulant-preservative (CPD units have higher potassium concentrations), and the anticipated rate and volume of transfusion. Additionally, short postirradiation storage times in this setting may lead to increased donor exposures. The interested reader is referred to a sophisticated analysis of this issue.43 Platelets and granulocytes are not sufficiently affected by the irradiation doses used to have outdates shortened.44-46 Irradiation can lead to a delay in transfusion. If irradiation is not performed in house, there may not be irradiated units available. This delay can be a practical matter for patients who have had hematopoietic stem cell transplant procedures far from their community hospitals where they may be receiving transfusions posttransplant. Alternatively, there may be a queue for blood to be irradiated in house. Additionally, there is always a possibility of failure to irradiate when indicated which can arise when either the patient's correct diagnosis has not yet been made47 or because the need for irradiation in a particular clinical circumstance has not yet been recognized.48 Japan and a small number of hospitals in the United States (mostly oncology or pediatric) have adopted universal irradiation for all cellular transfusions. In addition to expense, one concern that arises from such a policy is related to the reduced red cell recovery. There is the theoretical risk of exacerbating iron overload due to increased transfusion requirements for patients receiving chronic transfusion support (e.g., those with sickle cell disease or β-thalassemia for whom blood irradiation is typically not indicated). Transfusing PLR units soon after irradiation would help address this concern. Ambruso and colleagues49 recently demonstrated that prestorage gamma irradiation enhanced priming of neutrophil oxidase activity in PLT components collected by apheresis. Neutrophil priming is a marker for biologically active compounds in stored components that may cause adverse transfusion-related events including lung injury. PRT did not enhance this activity. Viral reactivation has been reported as a consequence of low-dose gamma irradiation.50 However, no reports exist of this occurrence from irradiated blood components used clinically. The amount of radiation used for this purpose very likely substantially exceeds the amount that could cause such reactivation.5 Radiation of nucleated cells can result in malignant transformation.51 There are no reports of nonautologous malignancy in irradiated blood recipients. In vitro studies indicate that the amount of irradiation used for blood completely abolishes lymphocyte proliferation.52 The FDA has also stated that the available data show a “very low risk” of this occurrence.5 In this issue of and report a series of in which blood mononuclear cells from blood cells collected from the of an blood were after either PRT or gamma irradiation. The and to the of In the that treatment and gamma irradiation reduced cell very in a used to response by and in The also studies in and and determined that treatment significantly reduced in the of or after and cells comparable Additionally, were to proliferative in allogeneic cells were not of but not T cells in a The work by and suggests that the could be used in place of gamma irradiation for the prevention of TA-GVHD. While the are in their by that their that gamma irradiation could be with this work to an of and clinical evidence that the as well as PRT Blood are effective in preventing and reported treatment of before into completely The safety and of the for PLTs have been demonstrated in a recently reported large clinical of the clinical in this irradiation during the for with than of patients who were transfused with control PLT This process the for apheresis and PLTs in and for plasma in This an for use for the of in these with this are in countries and parts of the of this more than PLT transfusions have been as a of routine At many institutions using the are not PLTs that would undergo this No TA-GVHD has been reported with this The is not available in the United The is being further for the treatment of whole blood, a single PRT and by the use of the as whole blood or into In a clinical in vitro that may 24-hour survival of red cells in vivo were established and used to design the of the studies are currently to in the United States an FDA approved The a that into DNA and and upon with a with to form and Additionally, the has been shown to both to the of for a and TA-GVHD in vivo using a transfusion The for PLTs and in after a clinical in this did not irradiate PLTs for TA-GVHD The for plasma was in A for treatment to replace gamma irradiation for prevention of TA-GVHD in in and the use of the in of gamma irradiation for the prevention of TA-GVHD. A described more than patients in one in who multiple transfusions of either apheresis or PLTs with the that were not gamma irradiated and were with a active No TA-GVHD was Additionally, a report has data for more than of whom were who more than transfusions of PLTs than of which were not no TA-GVHD was In most blood using the have discontinued using gamma more than have been to PLT components in 15 countries in the and No cases of TA-GVHD have been reported by institutions using the The is not available in the United has also a PRT for RBCs a that has been in and clinical A process has been and a recently clinical the of 24-hour recovery FDA studies with this are currently for and studies in the United States will be performed an A more of the use of the and to provide pathogen reduction and TA-GVHD prevention has been The in the use of CsCl in blood irradiators are regulation is a instrument and an threat costs, and of in this is a There is clinical and evidence that both the and the can be used to TA-GVHD. Thus, in addition to the prevention of CsCl blood irradiators should be an of PRT when the and of PRT are all the technical, and challenges associated with CsCl irradiation of blood is is that a and alternative means of preventing the of TA-GVHD is very much The author for support and and for very and principal for clinical lead author and on to data monitoring on to of of principal for registration.