Infections Associated with Musculoskeletal-Tissue Allografts
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《新英格兰医药杂志》
To the Editor: We are grateful to the Journal for putting on the record1 the undisclosed conflicts of interest of two of the authors of the report by Kainer et al. (June 17 issue).2 Specifically, the associations were Dr. Archibald's employment with Regeneration Technologies (the manufacturer of BioCleanse, which was mentioned in the article) and Dr. Kainer's retention as an expert witness on behalf of plaintiffs' counsel in lawsuits against CryoLife (Tissue Bank A in the article). It is critical for readers to review the work in light of this context.
BioCleanse has yet to be clinically proven as a sterilizing method for soft-tissue musculoskeletal allografts. No documented evidence supports short-term or long-term maintenance of the structural integrity of BioCleanse-processed soft-tissue grafts. Given the poor clinical history of previous soft-tissue musculoskeletal-allograft "sterilization" methods, to, in effect, promote the use of BioCleanse in the absence of critically assessed clinical data is irresponsible and ethically questionable.
The authors' implication that Tissue Bank A knowingly released tissue with a positive culture result after processing (Table 1 of the article) is inaccurate and misleading. They report one culture result as negative, eight results as unknown, and five as positive. Tissue Bank A certifies that every one of the cultures after processing was negative, and this information was provided to the Centers for Disease Control and Prevention (CDC). Tissue Bank A has never intentionally released tissue contaminated with any organism. Furthermore, there have been reports of clostridial infections associated with musculoskeletal allografts from other tissue banks, and the data appear to have been presented selectively in a manner that omits all but those connected to Tissue Bank A.3,4 The report by Kainer et al. is based on data published two years ago.3 Since then, Tissue Bank A has developed and validated numerous new procedures to enhance safety. The recommendations listed in Table 4 of the report ("Recommendations to Reduce the Risk of Allograft-Associated Infections") have been substantially put into practice by Tissue Bank A.
J. Robin De Andrade, M.D.
Gregory S. Ray, M.D.
CryoLife
Kennesaw, GA 30144
References
Kainer MA, Archibald LK. Correction: infections and musculoskeletal-tissue allografts. N Engl J Med 2004;351:397-398.
Kainer MA, Linden JV, Whaley DN, et al. Clostridium infections associated with musculoskeletal-tissue allografts. N Engl J Med 2004;350:2564-2571.
Update: allograft-associated bacterial infections -- United States, 2002. MMWR Morb Mortal Wkly Rep 2002;51:207-210. [Medline]
Food and Drug Administration. Manufacturer and user facility device experience database. (Accessed August 26, 2004, at http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfMAUDE/Detail.CFM?MDRFOI_ID=400733.)
To the Editor: We agree with Kainer et al. that standardized sterilization procedures for musculoskeletal allografts are necessary to reduce the risk of allograft-associated infections. Validating the sterilization of bone-tissue transplants with peracetic acid–ethanol, we showed that spores of Bacillus subtilis and Clostridium sporogenes, as well as enveloped and nonenveloped viruses, were inactivated effectively. Only hepatitis A virus appeared to be resistant.1 We observed no bacterial or viral infection with the use of allografts treated with peracetic acid–ethanol in approximately 100,000 transplantations.2 Tissues that do not allow sufficient penetration of chemical sterilization solutions (i.e., massive allografts) should be gamma-irradiated whenever possible; the minimal doses are 25 kGy for inactivation of nonviral microorganisms3 and 34 kGy for viral inactivation.4 For validation of the tissue-sterilization process, we recommend a reduction of 5 log10 colony-forming units per milliliter for bacteria, spores, and fungi and 4 log10 tissue-culture infectious doses (50 percent) per milliliter for viruses. In addition, testing of the donors for viral markers and single polymerase-chain-reaction analysis for at least the human immunodeficiency virus, hepatitis C virus, and hepatitis B virus are mandatory.
Axel Pruss, M.D.
Ulf B. G?bel, M.D., Ph.D.
Charité, University Medicine Berlin
D-10098 Berlin, Germany
axel.pruss@charite.de
Georg Pauli, Ph.D.
Robert Koch Institute
D-13353 Berlin, Germany
References
Pruss A, G?bel UB, Pauli G, et al. Peracetic acid-ethanol treatment of allogeneic avital bone tissue transplants -- a reliable sterilization method. Ann Transplant 2003;8:34-42.
Pruss A, Perka C, Degenhardt P, et al. Clinical efficacy and compatibility of allogeneic avital tissue transplants sterilized with a peracetic acid/ethanol mixture. Cell Tissue Bank 2002;3:235-43.
IAEA Code of Practice for the radiation sterilisation of tissue allografts: requirements for validation and routine control. In: Phillips GO, ed. Advances in tissue banking 2004. Vol. 7. Cardiff, United Kingdom: World Scientific Publishers, 2004:211-65.
Pruss A, Kao M, Gohs U, Koscielny J, von Versen R, Pauli G. Effects of gamma irradiation on human cortical bone transplants contaminated with enveloped and non-enveloped viruses. Biologicals 2002;30:125-133.
To the Editor: Kainer et al. recommend the monitoring of allograft-associated adverse events; we would like to explain how to report them. Health care providers are encouraged to report adverse events (including infections) for which there is a reasonable possibility that the transplanted tissue caused the event. Reports should be made to the laboratory that made the tissue available for distribution; to the Division of Health Care Quality Promotion, CDC (telephone, 800-893-0485); and to the Food and Drug Administration (FDA). The FDA MedWatch reporting form and instructions are available at www.fda.gov/medwatch/report/instruc.htm and at the back of the Physicians' Desk Reference.1 It has been proposed that manufacturers of tissue available for distribution be required to report to the FDA certain adverse events involving a communicable disease.2
Jacquelyn A. Polder, M.P.H.
Jennifer J. Wood, Ph.D., M.P.H.
M. Miles Braun, M.D., M.P.H.
Food and Drug Administration
Rockville, MD 20852
polder@cber.fda.gov
References
Physicians' desk reference. Montvale, N.J.: Thompson PDR, 2004.
Food and Drug Administration. Current good tissue practice for manufacturers of human cellular and tissue-based products; inspection and enforcement; proposed rule. 66 FR 1508. January 8, 2001.
The authors reply: Polder and colleagues provide information on reporting adverse events associated with transplanted tissue. Detailed guidelines should also be developed for the process that tissue banks use after receiving such reports (e.g., what information is provided to surgeons who have implanted tissue from the same donor and how tissue banks ensure that clinicians receive that information).
Our letter1 outlines the circumstances regarding the perceived conflicts of interest referred to by De Andrade and Ray. We did communicate Dr. Archibald's new affiliation to the Journal in revised manuscripts; unfortunately, it failed to appear in print. The retention of Dr. Kainer as an expert witness by patients and Dr. Archibald's affiliation with Regeneration Technologies did not constitute conflicts of interest, in our view, since these events occurred after the completion of the manuscript and after their tenures with the CDC.
We identified only two other cases of musculoskeletal-tissue allograft–associated clostridium infection (in 1986).2 We chose our study period (January 1998 to March 2002) because of available denominator data for estimating risks and because of concerns regarding the accuracy of case ascertainment before this period. Culture results of tissue from any anatomical site are presented in Table 1 of our article and were compiled with inspection reports from New York state regulatory authorities, the FDA, and warning letters. Although Tissue Bank A discarded tissue from anatomical sites that yielded a positive culture, it distributed tissue from implicated donors, despite the isolation of clostridium or bowel flora from other anatomical sites.
De Andrade and Ray are correct in suggesting that there are few published data on the efficacy of new sterilization methods. We determined that some tissues from implicated donors were processed with the use of gamma irradiation or BioCleanse. No infections developed in recipients of tissue that was subjected to either of these sterilization methods. We reported the results of the public health investigation of this naturally occurring experiment to contribute to the scientific literature.
Pruss and colleagues describe the use of peracetic acid–ethanol to sterilize bone. They correctly state that chemical solutions must penetrate adequately to be effective. Gamma irradiation has excellent penetration; other methods also effectively penetrate tissue.3
Testing of donors for viral markers is important. Transmission of hepatitis C from an antibody-negative donor has been described4; tissues that underwent gamma irradiation did not transmit the virus. This finding constitutes further evidence that tissue sterilization provides an additional safety barrier when the donor-screening process does not identify contaminated tissue because of testing limitations. Patients and providers expect tissue to be safe and sterile; informed consent should be obtained before the implantation of nonsterile tissue.
Marion A. Kainer, M.B., B.S., M.P.H.
Tennessee Department of Health
Nashville, TN 37247
marion.kainer@state.tn.us
William R. Jarvis, M.D.
135 Dune Lane
Hilton Head Island, SC 29928
References
Kainer MA, Archibald LK. Correction: infections and musculoskeletal-tissue allografts. N Engl J Med 2004;351:397-398.
Update: allograft-associated bacterial infections -- United States, 2002. MMWR Morb Mortal Wkly Rep 2002;51:207-210.
Mills CR, Roberts MR, Chang JY, Bianchi JR, Summit MC. Method to determine germicidal inactivation in allograft processing. In: Schutte E, Picciolo GL, Kaplan DS, eds. Tissue engineered medical products (TEMPs). West Conshohocken, Pa.: ASTM International, 2004:54-8.
Hepatitis C virus transmission from an antibody-negative organ and tissue donor -- United States, 2000-2002. MMWR Morb Mortal Wkly Rep 2003;52:273-4, 276.
Related Letters:
Correction: Infections and Musculoskeletal-Tissue Allografts
Kainer M. A., Archibald L. K.
BioCleanse has yet to be clinically proven as a sterilizing method for soft-tissue musculoskeletal allografts. No documented evidence supports short-term or long-term maintenance of the structural integrity of BioCleanse-processed soft-tissue grafts. Given the poor clinical history of previous soft-tissue musculoskeletal-allograft "sterilization" methods, to, in effect, promote the use of BioCleanse in the absence of critically assessed clinical data is irresponsible and ethically questionable.
The authors' implication that Tissue Bank A knowingly released tissue with a positive culture result after processing (Table 1 of the article) is inaccurate and misleading. They report one culture result as negative, eight results as unknown, and five as positive. Tissue Bank A certifies that every one of the cultures after processing was negative, and this information was provided to the Centers for Disease Control and Prevention (CDC). Tissue Bank A has never intentionally released tissue contaminated with any organism. Furthermore, there have been reports of clostridial infections associated with musculoskeletal allografts from other tissue banks, and the data appear to have been presented selectively in a manner that omits all but those connected to Tissue Bank A.3,4 The report by Kainer et al. is based on data published two years ago.3 Since then, Tissue Bank A has developed and validated numerous new procedures to enhance safety. The recommendations listed in Table 4 of the report ("Recommendations to Reduce the Risk of Allograft-Associated Infections") have been substantially put into practice by Tissue Bank A.
J. Robin De Andrade, M.D.
Gregory S. Ray, M.D.
CryoLife
Kennesaw, GA 30144
References
Kainer MA, Archibald LK. Correction: infections and musculoskeletal-tissue allografts. N Engl J Med 2004;351:397-398.
Kainer MA, Linden JV, Whaley DN, et al. Clostridium infections associated with musculoskeletal-tissue allografts. N Engl J Med 2004;350:2564-2571.
Update: allograft-associated bacterial infections -- United States, 2002. MMWR Morb Mortal Wkly Rep 2002;51:207-210. [Medline]
Food and Drug Administration. Manufacturer and user facility device experience database. (Accessed August 26, 2004, at http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfMAUDE/Detail.CFM?MDRFOI_ID=400733.)
To the Editor: We agree with Kainer et al. that standardized sterilization procedures for musculoskeletal allografts are necessary to reduce the risk of allograft-associated infections. Validating the sterilization of bone-tissue transplants with peracetic acid–ethanol, we showed that spores of Bacillus subtilis and Clostridium sporogenes, as well as enveloped and nonenveloped viruses, were inactivated effectively. Only hepatitis A virus appeared to be resistant.1 We observed no bacterial or viral infection with the use of allografts treated with peracetic acid–ethanol in approximately 100,000 transplantations.2 Tissues that do not allow sufficient penetration of chemical sterilization solutions (i.e., massive allografts) should be gamma-irradiated whenever possible; the minimal doses are 25 kGy for inactivation of nonviral microorganisms3 and 34 kGy for viral inactivation.4 For validation of the tissue-sterilization process, we recommend a reduction of 5 log10 colony-forming units per milliliter for bacteria, spores, and fungi and 4 log10 tissue-culture infectious doses (50 percent) per milliliter for viruses. In addition, testing of the donors for viral markers and single polymerase-chain-reaction analysis for at least the human immunodeficiency virus, hepatitis C virus, and hepatitis B virus are mandatory.
Axel Pruss, M.D.
Ulf B. G?bel, M.D., Ph.D.
Charité, University Medicine Berlin
D-10098 Berlin, Germany
axel.pruss@charite.de
Georg Pauli, Ph.D.
Robert Koch Institute
D-13353 Berlin, Germany
References
Pruss A, G?bel UB, Pauli G, et al. Peracetic acid-ethanol treatment of allogeneic avital bone tissue transplants -- a reliable sterilization method. Ann Transplant 2003;8:34-42.
Pruss A, Perka C, Degenhardt P, et al. Clinical efficacy and compatibility of allogeneic avital tissue transplants sterilized with a peracetic acid/ethanol mixture. Cell Tissue Bank 2002;3:235-43.
IAEA Code of Practice for the radiation sterilisation of tissue allografts: requirements for validation and routine control. In: Phillips GO, ed. Advances in tissue banking 2004. Vol. 7. Cardiff, United Kingdom: World Scientific Publishers, 2004:211-65.
Pruss A, Kao M, Gohs U, Koscielny J, von Versen R, Pauli G. Effects of gamma irradiation on human cortical bone transplants contaminated with enveloped and non-enveloped viruses. Biologicals 2002;30:125-133.
To the Editor: Kainer et al. recommend the monitoring of allograft-associated adverse events; we would like to explain how to report them. Health care providers are encouraged to report adverse events (including infections) for which there is a reasonable possibility that the transplanted tissue caused the event. Reports should be made to the laboratory that made the tissue available for distribution; to the Division of Health Care Quality Promotion, CDC (telephone, 800-893-0485); and to the Food and Drug Administration (FDA). The FDA MedWatch reporting form and instructions are available at www.fda.gov/medwatch/report/instruc.htm and at the back of the Physicians' Desk Reference.1 It has been proposed that manufacturers of tissue available for distribution be required to report to the FDA certain adverse events involving a communicable disease.2
Jacquelyn A. Polder, M.P.H.
Jennifer J. Wood, Ph.D., M.P.H.
M. Miles Braun, M.D., M.P.H.
Food and Drug Administration
Rockville, MD 20852
polder@cber.fda.gov
References
Physicians' desk reference. Montvale, N.J.: Thompson PDR, 2004.
Food and Drug Administration. Current good tissue practice for manufacturers of human cellular and tissue-based products; inspection and enforcement; proposed rule. 66 FR 1508. January 8, 2001.
The authors reply: Polder and colleagues provide information on reporting adverse events associated with transplanted tissue. Detailed guidelines should also be developed for the process that tissue banks use after receiving such reports (e.g., what information is provided to surgeons who have implanted tissue from the same donor and how tissue banks ensure that clinicians receive that information).
Our letter1 outlines the circumstances regarding the perceived conflicts of interest referred to by De Andrade and Ray. We did communicate Dr. Archibald's new affiliation to the Journal in revised manuscripts; unfortunately, it failed to appear in print. The retention of Dr. Kainer as an expert witness by patients and Dr. Archibald's affiliation with Regeneration Technologies did not constitute conflicts of interest, in our view, since these events occurred after the completion of the manuscript and after their tenures with the CDC.
We identified only two other cases of musculoskeletal-tissue allograft–associated clostridium infection (in 1986).2 We chose our study period (January 1998 to March 2002) because of available denominator data for estimating risks and because of concerns regarding the accuracy of case ascertainment before this period. Culture results of tissue from any anatomical site are presented in Table 1 of our article and were compiled with inspection reports from New York state regulatory authorities, the FDA, and warning letters. Although Tissue Bank A discarded tissue from anatomical sites that yielded a positive culture, it distributed tissue from implicated donors, despite the isolation of clostridium or bowel flora from other anatomical sites.
De Andrade and Ray are correct in suggesting that there are few published data on the efficacy of new sterilization methods. We determined that some tissues from implicated donors were processed with the use of gamma irradiation or BioCleanse. No infections developed in recipients of tissue that was subjected to either of these sterilization methods. We reported the results of the public health investigation of this naturally occurring experiment to contribute to the scientific literature.
Pruss and colleagues describe the use of peracetic acid–ethanol to sterilize bone. They correctly state that chemical solutions must penetrate adequately to be effective. Gamma irradiation has excellent penetration; other methods also effectively penetrate tissue.3
Testing of donors for viral markers is important. Transmission of hepatitis C from an antibody-negative donor has been described4; tissues that underwent gamma irradiation did not transmit the virus. This finding constitutes further evidence that tissue sterilization provides an additional safety barrier when the donor-screening process does not identify contaminated tissue because of testing limitations. Patients and providers expect tissue to be safe and sterile; informed consent should be obtained before the implantation of nonsterile tissue.
Marion A. Kainer, M.B., B.S., M.P.H.
Tennessee Department of Health
Nashville, TN 37247
marion.kainer@state.tn.us
William R. Jarvis, M.D.
135 Dune Lane
Hilton Head Island, SC 29928
References
Kainer MA, Archibald LK. Correction: infections and musculoskeletal-tissue allografts. N Engl J Med 2004;351:397-398.
Update: allograft-associated bacterial infections -- United States, 2002. MMWR Morb Mortal Wkly Rep 2002;51:207-210.
Mills CR, Roberts MR, Chang JY, Bianchi JR, Summit MC. Method to determine germicidal inactivation in allograft processing. In: Schutte E, Picciolo GL, Kaplan DS, eds. Tissue engineered medical products (TEMPs). West Conshohocken, Pa.: ASTM International, 2004:54-8.
Hepatitis C virus transmission from an antibody-negative organ and tissue donor -- United States, 2000-2002. MMWR Morb Mortal Wkly Rep 2003;52:273-4, 276.
Related Letters:
Correction: Infections and Musculoskeletal-Tissue Allografts
Kainer M. A., Archibald L. K.