The following letter has been received (full titles and affiliations of authors may be found in the original text)

August 16, 2002

Open letter to the Blood Collection Community

A recent FDA workshop in Bethesda, Maryland held on August 7 and 8, 2002 addressed the safety and efficacy of methods for reducing pathogens in cellular blood products used in transfusion. At this meeting, the consensus of opinion was that bacterial contamination of platelets represents the largest transfusion transmitted disease risk.

The focus of this meeting was a discussion of inactivation strategies that targeted nucleotides as a means of achieving pathogen reduction. However, it is unclear when such inactivation technologies will be available. Bacterial detection technology, however, is currently available and screening via bacterial culture has been shown to be practical and effective.

In the interim, given the current risk of bacterial contamination of platelets of approximately 1/1000-1/2000 per unit, we call for the blood collection community to immediately initiate a program for detecting the presence of bacteria in units of platelets.

Respectfully,

Mark E. Brecher, M.D.
James AuBuchon, M.D.
Roslyn Yomtovian, M.D.
Paul M. Ness, M.D.
Morris A. Blajchman, M.D., F.R.C.P.(C.)

The following responses were received.

1. A colleague reports that after reading the August 16, 2002 "Open letter to the Blood Collection Community" (copy attached), his first impression was that the authors provided insufficient information for him to take an informed position on the issue, as no references were provided, and he respectfully requests that the authors of the letter provide references justifying their position. In particular, the references should provide data on risk of clinical sepsis and death from contaminated platelets, as those outcomes are far more important than the mere risk of bacterial contamination, reported in the letter to be approximately 1/1000-1/2000 per unit. The inquiring blood banker would also be interested to know which organisms cause clinical sepsis or death, the age of implicated platelets, as well as if the contaminated platelets are more likely to be apheresis or random concentrates. Finally, the inquiring blood banker requests information on the efficacy of the various bacterial screening methods that might be implemented to interdict contaminated units.

2. Editor's note: All five of the authors of the attached letter are subscribed to the e-Network Forum; see the response from Dr. Brecher (and Ness) in response #3, (received Aug. 30). Previous e-network and related discussions germane to this topic include the following:

• Single Donor Platelets are associated with fewer Septic Reactions than Platelet Concentrates
• Case report of a pediatric patient who received a transfusion of a pool of four platelet concentrates and experienced rigors and a rise in temperature to 40C
• Kuehnert MJ et al.  Transfusion-transmitted bacterial infection in the United States, 1998 through 2000. Transfusion 2001;41:1493-1499

3. According to Dr. Mark Brecher, "In the US, approximately 4 million units of platelets are transfused per year (3 million random concentrates, 1 million single donor apheresis). Given the current risk of bacterial contamination of platelet concentrates of approximately 1/1,000 to 1/2,000 per unit, this would mean we transfused 2,000-4,000 contaminated bags per year. It is thought that 1/4th to 1/6th result in clinical sepsis (N=333-1,000 cases per year) and perhaps 1/3rd are fatal (N=111-333 deaths per year, i.e., 1/36,000 - 1/120,000 bags lead to death). Current estimates of fatality based on clinical experience are 1/50,000 bags (Roslyn Yomtovian's data, University Hospitals of Cleveland) and 1 per 16,000 random pool doses and 1 per 71,000 apheresis doses from Johns Hopkins (Paul Ness' data). Here at UNC, we have had one death in the 10 years that I have been here, with approximately 20,000 apheresis platelets transfused. It is anticipated that the AABB will be issuing an interim standard (for comment) on bacterial detection in the next few weeks. This should be accompanied with some guidance.

In terms of method of detection, there are multiple choices, as summarized below. See Mitchell KT, Brecher ME. Approaches to the detection of bacterial contamination in cellular blood products. Trans Med Rev 1999;13:132-144 (no abstract).

Culture

Becton Dickinson (BacTec) and Biomerieux (formerly Organon Teknika - BacTAlert) offer automated liquid culture systems that are widely used in clinical micro labs around the world. However, only the BacTAlert is FDA-approved for in-run quality control of sterility for apheresis platelets. This was approved in February (but the original bottles licensed have now been upgraded and they are awaiting approval of equivalence with their new bottles). Published validation studies in platelets show detection at 10 CFU/mL in <24 hours for a wide range of organisms. See the following references:

• Brecher ME, Means N, Jere CS, Heath D, Rothenberg S, Stutzman LC. Evaluation of the BacT/ALERT 3D Microbial Detection System for platelet bacterial contamination An analysis of 15 contaminating organisms. Transfusion 2001;41477-482.
• Brecher ME, Heath D, Hay S, Rothenberg S, Stutzman LC. Evaluation of a new generation culture bottle using the BacT/ALERT 3D Microbial Detection System on 9 common contaminating organisms found in platelet components. Transfusion 2002, 42;774-779.
• AuBuchon JP, Cooper LK, Leach MF, Zuaro DE, and Schwartzman JD.  Experience with universal bacterial culturing to detect contamination of apheresis platelet units in a hospital transfusion service. Transfusion 2002; 42: 855 (July)

Pall is trying to bring to market a simplified aerobic culture system called the Pall Bacterial Detection System (BDS). This system entails pushing over 2 mLs of platelets through a filter that captures platelets but lets about 1/2 of the bacteria through. This is stored in a separate bag with enhancement chemicals (SPS) at 35C for 24 hours and then the pO2 is measured in the head space. This is submitted for approval.

Multireagent dipsticks:

An easy and inexpensive method is the use of multireagent strips looking for decreases in pH and glucose. However, this method is not very sensitive (10⁷ CFU/mL with notable exceptions). Nevertheless, it did detect two B. cereus-contaminated units in >3000 random platelet concentrates screened at MD Anderson. See Werch JB, Mhawech P, Stager CE, Banez EI, and Lichtiger B. Detecting bacteria in platelet concentrates by use of reagent strips. Transfusion 2002;42:1027-1031 (also cited in response #4).

Staining (Gram or Wright)

Staining has been used but is labor-intensive and insensitive (10⁶-10⁷ CFU/mL).

Jim AuBuchon at Dartmouth and we at UNC have been culturing our apheresis platelets (on day 2 of storage) with the BacTAlert. At both institutions a sample bag is attached via a sterile connection to sample the main platelet bag. The sample bag is separated from the main bag, sampled and bottle(s) inoculated. At Dartmouth an aerobic bottle is inoculated; at UNC both aerobic and an anaerobic bottles are inoculated. We do not quarantine the platelets while the cultures are pending. Both of us have interceded on multiple contaminated bags (at UNC, we found three contaminated apheresis bags already this year). For the rare random platelets at UNC we use multireagent strips. In Europe, culturing is mandatory in Norway, the Netherlands and the Flemish-speaking part of Belgium.

Ideally, the FDA could greatly facilitate detection strategies in the U.S. by allowing:

1. Pre-pooling of random platelets with culture
2. An extension of the shelf-life of cultured platelets to 7 days.

Of course, data to justify such modifications to the regulations would be required.

For a general review of this problem, we recommend the article by Depcik-Smith ND, Hay SN, Brecher ME, J Clin Apheresis 2001."

(Editor's note:  Dr. Paul Ness indicates that the above response mirrors his thoughts and includes his data.)

Please submit comments to the e-Network Forum.

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