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Public Conference – Secondary Bacterial Screening of Platelet Components, 7/17/12

The Secondary Bacterial Screening of Platelets Public Conference was hosted by AABB on July 17, 2012, in North Bethesda, Md. Darrell Triulzi, MD, president of AABB, opened the conference by explaining that the objective of the meeting was to 1) discuss residual risk of bacterial contamination in apheresis platelets, 2) describe the use of secondary bacterial testing of platelet components using point-of-issue tests and 3) hear practical experiences from transfusion services using these tests in real life with whole blood-derived platelets. Triulzi noted that although the focus of the conference was residual risk associated with apheresis platelets and potential use of point-of-issue tests to reduce the risk even further, the experience that establishments have had with point-of-issue testing of whole blood-derived platelets would be helpful to the discussion.

Jay Epstein, MD, director of the Office of Blood Research and Review at the Center for Biologics Evaluation and Research of the Food and Drug Administration, stated his appreciation to AABB and the speakers for providing and participating in the public conference. He noted that, for the past several decades, FDA has been interested in and actively discussing the issues with various governmental advisory committees and, as early as 2001, began approving various products such as diversion pouches, which almost immediately effected a 50-percent decrease in the platelet contamination rate. Other product approvals that followed since that time include BacT/ALERT (BacT/ALERT), Pall Enhanced Bacteria Detection System (eBDS), Verax Platelet PGD Test (PGD), and BacTx Assay System (BacTx). FDA approved the PASSPORT protocol in 2003 in support of a path forward for seven-day apheresis platelets. Ultimately, sponsors closed the protocol. Approval of the eBDS system in 2005 occurred alongside a reversal of FDA's previous position on pre-pooled platelets. The latest approval, BacTx in 2012, is applicable only to whole blood-derived platelets.

There is no FDA requirement for testing of platelet products for bacterial contamination prior to transfusion. An AABB standard requiring accredited facilities to implement methods that limit and detect bacterial contamination in platelet products was implemented in 2004 and further modified in 2011 requiring that FDA approve test methods, or methods validated to provide equivalent sensitivity, to be used for detection. Data show that after the standards were put into place, septic transfusion reactions, or STRs, per 100,000 transfusions had decreased by 70 percent, and there was a similar decrease in septic fatalities. Epstein noted that culture testing of product before release to transfusion services and testing of pools prior to transfusion have resulted in improvements to patient safety. He further stated that the meeting was as an opportunity for robust dialogue among stakeholders to review data on residual risk for STRs, discuss the options available to favorably impact the current contamination rates, and possibly determine whether some testing options should become routine as a safety standard.

Steve Kleinman, MD, AABB's senior medical advisor, reviewed data from several published studies estimating the residual risk of bacterial contamination of apheresis platelets tested by early culture. He suggested the consideration for secondary testing of platelets is an increasingly important issue since apheresis platelets represent a growing percentage of the overall platelet supply. In 2004, apheresis platelets accounted for 79 percent of all platelets used in the United States, and in 2008, they represented 86 percent of the supply, according to National Blood Collection and Utilization Survey, or NBCUS, data. (The 2011 NBCUS data are not yet available.)

Data were presented that demonstrated an ongoing risk of bacterial contamination in apheresis platelets. Based on a review of a number of different studies performed in the U.S. and abroad, Kleinman reported that the per unit rate of bacterial contamination undetected by early culture appears to be approximatly 1 in 1500 units. A review of data from the conventional arms of two additional studies (PLADO and SPRINT) revealed that hematology-oncology patients receiving many units of apheresis platelets can have a risk as high as 1 in 250 of receiving a contaminated unit. Kleinman presented some preliminary data on apheresis platelets from the 2012 AABB member survey on methods to detect bacterial contamination in platelet components. He noted that most survey respondents reported using the BacT/ALERT culture system. A smaller number are using eBDS, and less than 1 percent use other methodologies. A small percentage of survey respondents use PGD testing. There was variation in the way establishments use PGD testing (e.g., batch testing or "as ordered" for transfusion), but all sent PGD-reactive units for confirmatory culture. Kleinman stressed that the data he shared were preliminary; his goal was to share some points that were informative to the discussion of the conference. A subgroup of the AABB Bacterial Contamination Task Force is completing an analysis of the survey and will make the results of the final analysis available at a later date.

Richard Benjamin, MD, PhD, FRCPath, chief medical officer of the American Red Cross, reported on his organization's experience with bacterial surveillance and hemovigilance. Benjamin described the change to inlet line diversion strategies and an increase in the culture inoculum to 8 mL as an important step at the Red Cross to reduce bacterial contamination, reporting that they have seen a significant (10-fold) decrease in STRs, and also in fatalities. He also explored the question of why culture testing fails, suggesting it could be due to sampling error or design weakness. Benjamin described the mathematical modeling that shows a larger sample volume may detect a greater portion of true-positive platelets, and that doubling the volume of a sample significantly increases sensitivity. He also commented that a report at the recent International Society of Blood Transfusion meeting noted that further increases in inoculum volume to 16 mL did not result in a greater yield in true-positive results but did result in a significantly higher false-positive rate.

Michael Jacobs, MD, professor of pathology and director of clinical microbiology at University Hospitals Case Medical Center in Cleveland, Ohio, described his study of detection of bacterial contamination in prestorage culture-negative apheresis platelets on day of issue with the PGD test. Eighteen hospitals studied the PGD test by performing the test on the day of issue on 27,682 apheresis platelets released by collection centers as culture negative. The PGD test result was reported as reactive if two of three results were reactive. PGD results were reported reactive for 151 of the apheresis products. Nine were confirmed by culture, and 142 were culture negative. Three units that were reported nonreactive by PGD testing and transfused were later determined to be contaminated. Based on his study results, Jacobs concluded that application of PGD on day of issue can interdict contaminated units and prevent transfusion reactions.

International studies on the use of Verax PGD Assay were described by Mindy Goldman, MD, executive medical director of Canadian Blood Services, or CBS. Based on the studies she reviewed — a CBS study and a German study by Vollmer — clinically significant levels of contamination may be missed. The CBS researchers were able to increase accuracy of tests by implementing new practices, such as using a humid chamber and avoiding overlap of platelet units on an agitator in a laboratory, which may have been contributing to false positives. Additional comparison of international practices that may have an impact on contamination rates revealed variations in skin preps used, different sample volumes inoculated in cultures, and different times at which culturing is performed. These experiences suggest that maximizing culture sensitivity results in incremental improvements and that point-of-issue testing would likely be beneficial.

Continuous improvement strategies to reduce risk of bacterial contamination were described by Peter Tomasulo, MD, FACP, executive vice president of Blood Systems, Inc. Tomasulo described a process for determining a constant inoculum proportion to be used as the sample for culture rather than the current practice of a constant inoculum volume. Since this will result in a greater loss of product volume, Blood Systems, Inc would maintain its current dose per bag by decreasing its split rate. The organization also is considering culturing the platelets at 48 hours rather than 24 hours and releasing those products to inventory after 24 hours of incubation. The intent is to evaluate the data with FDA for the possibility of extended dating, coupled with constant inoculum proportion and later testing. Tomasulo suggested other strategies — some that require action on the part of device manufacturers — that could decrease the contamination rate, such as diversion of more than the first 30-50 mL of blood from the donor, use of pathogen reduction technologies, a move toward manufacture of buffy coat platelets, a needle that does not create a skin plug, a fluid path that does not pump blood to be transfused through the same tubing used to divert the initial blood collected, and designing filters that could reduce the bacterial load.

During the conference, two speakers discussed the logistics and cost issues of implementing secondary testing and stressed that the operational and financial burden of point-of-issue testing would likely vary among institutions. For smaller transfusion services, the additional cost of testing might require the institution to examine how to reduce costs in other areas. Louis Katz, MD, executive vice president of Medical Affairs at Mississippi Valley Regional Blood Center, said that hospital funds are "getting close to a zero sum game," and expressed concern that additional testing costs would take funds away from other important risk-reduction strategies in a hospital facility. Katz noted that there is no venue for regulators such as FDA, payers such as CMS and insurance companies, and practitioners to discuss issues of reimbursement and prioritization of safety interventions.

Louis Rossiter, PhD, research professor at the College of William and Mary, briefly reviewed lists from the Agency for Healthcare Research and Quality and the National Quality Forum of issues to improve patient safety that are examples of concerns and calls to action that compete for the attention of hospital administrators. He suggested that AABB and the FDA have analytical roles in the discussion and will have to consider that possibly other things are as important as assuring complete safety of the blood supply. Rossiter questioned whether the STRs under discussion would count as hospital-acquired conditions for which the Centers for Medicare and Medicaid Services will not reimburse. He also noted that currently no billing codes exist for point-of-issue tests performed by transfusion services and suggested that the cost of testing might be passed on to blood centers.

Five representatives from transfusion services shared their perspectives on point-of-issue testing. One presentation described work performed at two establishments. The presenters discussed implementation in their labs, the yield of true-positive contaminated units interdicted, as well as false positives, and the process they used in making a decision to use, or not use, a point-of-issue test. For a complete list of speakers at this session, please see the meeting agenda.

The conference included an open session to allow registrants to present additional information and share opinions. A wide range of perspectives were presented from hospital transfusion services, manufacturers, patient advocates, and other transfusion experts. Patient advocates supported secondary testing so that immunocompromised patients can receive platelets knowing that every safety measure has been taken. Manufacturers described the testing platforms currently marketed as well as a platform under development. Blood center and transfusion service speakers presented their experience with the testing systems as well as one study to find an optimal time for culture testing followed by transfusion within 24 hours, and another that compared the safety of triple apheresis collections with regard to bacterial contamination when compared to other apheresis components.

Attendees urged that the information gathered at the meeting be presented to advisory committees, such as the Blood Products Advisory Committee or the Advisory Committee on Blood Safety and Availability. There were differing opinions on whether there are currently enough data to create a new standard for secondary testing.

Triulzi concluded the meeting by expressing appreciation to the speakers and attendees for their contribution to the discussions of the day, whether it was sharing of data, operational logistics, or thoughtful questions that generated further discussion.