ADDENDA Aug. 30, 2002

4. A transfusion medicine physician in Detroit reports that in the August 2002 issue of Transfusion, Werch et al present a simplified approach to screening platelet concentrates using urine reagent strips. Criteria for glucose and pH were set, and any platelet concentrate not meeting either or both of these criteria was not used. Thirty of 3093 platelets tested failed to meet criteria for glucose and/or pH. Only 2 of these 30 units actually grew bacteria when cultured. The Detroit physician wonders if the other 28 units have been OK to use, or if these 28 units were wasted. The Detroit physician adds that although the open letter calls for the "blood collection community" to begin platelet screening, this (in her opinion) is not realistic. She fears this burden will fall primarily, if not entirely, on hospital transfusion services, which are currently reeling from blood pricing increases and staffing shortages. In addition, delays in product release resulting from this testing will not be acceptable when need for platelets is emergent. She concludes with her opinion that "until a rapid, inexpensive and reliable method for screening platelet concentrates and apheresis units for bacteria is developed, that will have minimum impact on turnaround time of product release, this practice will NOT become the norm. Although we all agree with the need to make blood products as safe as possible, we must be realistic when setting our goals."

5. A transfusion medicine scientist from the East Coast wrote that it is his expectation that the AABB will provide a document that will cover the issues raised by the inquiring blood banker in response #1. In his opinion it will take a month or two, but the information will emerge in a timely fashion.

ADDENDA Sept. 4, 2002

6. Dr. Breanndan Moore of the Mayo Clinic has submitted the following letter for consideration by the e-network forum, in response to the letter by colleagues who call for immediate action to institute measures to detect bacterial contamination of platelet products.

According to Dr. Moore, "It seems to me that it may be somewhat "dangerous" for any blood banker to even attempt to make statements which might be construed as critical of the famous letter of exhortation. The danger is that one might immediately become the object of either ridicule or even invective for daring to question a letter which begs blood bankers to, as it were," do something" about a perceived threat to the integrity of blood transfusions.

While there are ample data demonstrating that systems to culture platelet aliquots can show growth in perhaps 1 in 2000-3000 such aliquots, the rarity of demonstrable clinical cases of resultant sepsis seems to be at variance with the culture data. I am well aware that many recipients are already on antibiotic medications but am still impressed by the "disconnect " between our actual clinical experience in a large tertiary care environment and the number of cases we should be seeing if the culture data truly reflected the frequency with which platelet units are in fact contaminated.

I am also well aware of the catastrophic nature of the cases of transfusion-mediated sepsis which have been reported and which have clearly motivated the writers of the now famous letter to institute measures to detect bacterial presence or growth in platelets. The fundamental problem seems to be that there is as yet no agreement on what can or should be instituted as a routine protective measure. It is usually the case that data are presented to FDA which demonstrate that a particular course of action is wise and that the FDA can logically mandate that all blood collectors institute such a course forthwith. In this particular situation there is no FDA mandate and no real consensus on what steps we should initiate. The presence of this letter of exhortation, however well intended, carries no regulatory "weight " and provides no clear path of action for those being exhorted. Such a situation, though, I am sure, not intended as such, is tantamount to moral blackmail since it implies a less than caring and concerned attitude on the part of any blood bankers who do not " do something ".

I certainly do not wish to convey the impression that I do not think that bacterial contamination is never a problem and a potentially fatal one if present. However, in the absence of clear recommendations or mandates from FDA, the presence of the famous letter is somewhat of a "loose cannon" which may frighten blood banks into taking a variety of different steps which will make it even more difficult in future to interpret their data and to plot a wise course where this issue is concerned.

Parenthetically, while in no way impugning the obviously well-meaning motivation of the writers of the letter in question, one would like to see a declaration of freedom from conflict of financial or other interest on the part of each of the writers concerned in sending out the letter, since huge amounts of money may well be involved in the widespread implementation of any measures such as those being taken by a few at this time."

ADDENDA Sept. 6, 2002

7. Ronald E. Domen, MD, Professor of Pathology, Medicine and Humanities and Medical Director, Blood Bank and Transfusion Medicine at the Milton S. Hershey Medical Center of Penn State University College of Medicine also read with interest the "Open Letter" concerning bacterial detection in platelets. Here is Dr. Domen's opinion:

"I also share concerns that a plea for mandatory bacterial detection has been made without sufficient information and discussion.

While I think that we all agree that bacterial contamination of platelets is a real possibility, what does the estimated incidence of 1/1000-2000 per unit mean in terms of the incidence of actual patient infection, morbidity, or mortality? If cultures are performed, how should iatrogenic contamination as a result of the culturing process be separated from a real bacterial contamination. Although I have seen one or two real bacterial contaminations that resulted in patient morbidity over the past 10-plus years, this represents a very small number compared to the tens-of-thousands of platelet transfusions over this same period of time. Back in the "old" days (i.e., the early 1980's) bacterial contamination seemed to be a greater problem when we were using 7-day storage bags/protocols. I think before a "call to arms" is made on this issue, we need to answer some basic questions, such as:

• What is the relationship between culture-positive units and infection/reaction in the recipient?
• What is the incidence of false-positive cultures/contamination?
• How many deaths related to bacterial contamination have been seen/reported?
• While platelets are being singled out as the worst for bacterial contamination, are there truly any differences between blood components that are associated with bacteria-associated morbidity/mortality?
• What method(s) is(are) recommended for bacterial screening and what is the sensitivity/specificity?
• What has been done to identify the root cause(s) of bacterial contamination?
• The authors of the "open letter" need to declare any potential conflicts of interest surrounding this issue.
• Finally, once the data is collected and analyzed, should there not be a consensus conference by the AABB and/or the FDA detailing the magnitude of the problem and recommended approaches to deal with it?"

ADDENDA Sept. 11, 2002

8. One of the signers of the letter, Dr. Morris A. Blajchman, offers this response:

• Several recent CBBS e-network respondents to the letter about the bacterial contamination issue appear to be unaware of much of the Transfusion Medicine literature, over the past 20 years, that deals specifically with the risk of serious septic events associated with contaminated blood products. For this reason, I have attached a short selection of 15 relevant articles describing the morbidity and mortality risks of contaminated blood products (1-15). Moreover, the FDA (1,2), the SHOT Program in Britain (10), the Hémovigilance System in France (9), and recently, the BaCon study (15) have all shown that transfusion-associated bacterial sepsis is the greatest current microbiological risk for recipients of blood products, particular for platelet recipients. Moreover, the FDA has held 3 workshops on this topic, including one in early August 2002. Most importantly, such data show clearly that septic transfusion reactions are often mis-diagnosed and as a consequence under-reported.
• One of the respondents, despite claims to the contrary, tries to impugn those of us who have signed the recent letter about bacterial safety, by raising the conflict-of-interest canard. On behalf of those who signed the letter, I would assure CBBS e-network readers that those who signed the letter did so only because of concern about the bacterial risk for recipients of blood products; that is, in order to enhance blood product safety.
• I agree with the suggestion of convening a consensus conference, to make recommendations to try to deal with the issue of transfusion-transmitted bacterial sepsis. On several occasions over the past five years I have suggested to various individuals associated with the FDA, NHLBI, as well as Canadian authorities to encourage them to convene such a consensus conference; but to no avail. I feel, therefore, that a non-recriminant and potentially satisfactory outcome of this debate would be the convening of a consensus conference to deal with this important blood safety issue. If properly convened, such a consensus conference could contribute significantly to the common goal of all of us engaged in Transfusion Medicine, that of enhancing the safety of the world's blood supply.

REFERENCES

1. Honig CL, Bove JR. Transfusion-associated fatalities: Review of Bureau of Biologics reports 1976-1978. Transfusion 20:653-661, 1980.
2. Sazama K. Reports of 355 transfusion-associated deaths: 1976 through 1985. Transfusion 30:583-590, 1990.
3. Morrow JF, Braine HG, Kickler TS, et al. Septic reactions to platelet transfusions. JAMA 266:555-558, 1991.
4. Barrett BB, Anderson JW, Anderson KC. Strategies for the avoidance of bacterial contamination of blood components. Transfusion 133:228-233, 1993.
5. Yomtovian R, Lazarus HM, Goodnough LT, et al. A prospective microbiologic surveillance program to detect and prevent the transfusion of bacterially contaminated platelets. Transfusion 33:902-909, 1993.
6. Blajchman MA, Ali AM, Richardson HL. Bacterial contamination of blood components. Vox Sanguinis 67 (Suppl. 3):25-33, 1994.
7. Blajchman MA. Editorial: Transfusion-associated bacterial sepsis: The phoenix rises yet again. Transfusion 34:940-942, 1994.
8. Chiu EKW, Yuen KY, Lie AKW, et al. A prospective study on symptomatic bacteremia from platelet transfusion and its management. Transfusion 34:950-965, 1994.
9. Noel L, Debeir J, Cosson A. The French Haemovigilance system. Vox Sang (Suppl. 2) 74:441-445 1998.
10. Williamson L, Cohen H, Love E, et al. The Serious Hazards of Transfusion (SHOT) initiative: The UK approach to haemovigilance. Vox Sang 78 (Suppl. 2): 291-295, 2000.
11. Goldman M, Blajchman MA. Bacterial contamination. In: Transfusion Reactions. Popovsky M (ed), 2nd edition; AABB, Bethesda, MD: pp 133-159; 2001.
12. Ness PM, Braine HG, King KE et al. Single donor platelets reduce the risk of septic transfusion reactions. Transfusion 41:857-861, 2001.
13. Blajchman MA, and Goldman M. Bacterial contamination of platelet concentrates: Incidence, significance and prevention. Seminars in Hematology 38:20-26, 2001.
14. Goldman M, Delage G, Beauregard P et al. A fatal case of transfusion-transmitted Staphylococcus epidermidis sepsis. Transfusion 41: 1075-1076, 2001. (Letter).
15. Kuehnert MJ, Roth VR, Haley R et al. Transfusion bacterial infection in the United States, 1998 through 2000. Transfusion 41:1493-1499, 2001.

ADDENDA Sept. 13, 2002

9. Dr. Roslyn Yomtovian, another of the letter-signers, adds: "I am obviously biased - not by financial interests related to any of the tests which might be implemented since I hold no stock or stake in any of the companies - but by data derived from my practice through the years showing the prevalence of bacterial platelet contamination and the frequent associated clinical sequelae which, as Dr. Moore points out, are likely blunted often by the widespread use of antibiotic therapy in those receiving platelets. Nonetheless, our data and those of others clearly shows a recurrent, ongoing pattern of morbidity and mortality associated with bacterial platelet contamination which is many times more common than other infectious complications of blood transfusion. That this doesn't seem as frequent in some institutions probably relates, not to a lack of occurrence, but to a lack of recognition. I say this largely from personal experience - in the years during which we conducted intense prospective surveillance we uncovered far more cases - and, surprisingly many with associated signs and symptoms (including positive blood cultures) - than in the years where the typical passive or transfusion reaction surveillance was employed. SEEK AND YE SHALL FIND. It is not really surprising, in a very ill patient population, that sepsis associated with platelet transfusion would not be thought of and thus attributed to another etiology. I suspect this is quite common. However, now, finally, for the first time, at the urging of the FDA, the apparent means to prevent the majority of such cases are becoming available. It would have been better, to say the least, for the FDA at this time to take the lead in recommending some action in dealing with this problem which continues to harm and injure people every day in the US. Perhaps this will happen. In the meantime, as many have discovered the hard way over the last 30 years, bacterial contamination of platelets is inevitable and will lead to harm in a subset of patients. It is time that action replace inaction."

ADDENDA Sept. 16, 2002

10. And yet another letter-signer, Dr. James AuBuchon, writes: "The issue of conflicts of interest has been raised in the debate over how (or whether) to address the issue of bacterial contamination of platelets. To make the record clear I hold no equity interest in any biomedical company. I am a consultant to several, but the fees involved are modest and the lack of having a stake in the company allows me to tell them exactly what I think is appropriate. I receive research support from several companies, but, thankfully, I am in a position in which I feel comfortable about speaking my mind. In short my position advocating for us to reduce the risks of bacterial contamination has absolutely no financial consequences for me. On a related issue one of the forums discussed pooled platelet units in which I was referenced. Steve Wagner's lab (ARC) and ours have both investigated the growth rates and final concentrations in platelet concentrates before and after pooling. He found that pooling concentrates would allow a larger inoculum to be obtained because of the larger volume. We found this to be true also - but inconsistently so. (In a small study, only half of the pooled units had higher inocula.) From a practical point of view does infusing 1x10⁸ vs 6x10⁸ bacteria make any difference? My guess is, probably not. (Note prestorage pooling was common in Europe long before culturing was introduced.)"

ADDENDA Mar. 10, 2003 (updated August 2003)

11. Editor's Note: see related AABB Association Bulletin of August 29, 2003 (AABB Membership required to access); and e-Network Forum issue posted Mar. 10, 2003.

Please submit comments to the e-Network Forum.

Ira A. Shulman, MD
CBBS e-Network Forum Editor & Moderator