Infections Transmitted through Musculoskeletal-Tissue Allografts
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《新英格兰医药杂志》
The 2003 Institute of Medicine report Microbial Threats to Health: Emergence, Detection, and Response lists "advances in medical technologies, such as blood transfusions and organ transplants," as one reason for "new or enhanced microbial threats." Musculoskeletal allografts represent a form of technology that poses a risk of transmission of infection, and their use is increasing. In 2002, approximately 1 million such allografts were distributed in the United States. Unlike solid-organ allografts, most musculoskeletal allografts are used for life-enhancing rather than life-saving procedures, and as the report by Kainer et al. in this issue of the Journal (pages 2564–2571) demonstrates, their use has implications for patient safety.
(Figure)
Figure. Arthroscopic Photograph of an Infected Anterior-Cruciate-Ligament Allograft.
Courtesy of Michael J. Stuart, M.D., Mayo Clinic College of Medicine.
Historically, the concern about allograft-transmitted infection focused on human immunodeficiency virus (HIV), hepatitis B virus, and hepatitis C virus (HCV), since each of these viruses has been reported to be transmitted by this route. Since 1993, when it issued an interim rule (which was finalized in 1997) focusing on the screening of donors for these viruses, the Food and Drug Administration (FDA) has regulated musculoskeletal allografts. Musculoskeletal-allograft transmission of these viruses is now uncommonly reported. In 2002, however, HCV was transmitted to four recipients of musculoskeletal allografts from a seronegative donor. Although blood donors are screened with the use of nucleic acid testing for HCV, HIV, and West Nile virus, such testing is not required of tissue donors. The availability of approved nucleic acid testing for cadaveric serum should lead to further reduction of the risk of transmission of selected viruses through musculoskeletal allografts. The risk of transmissible spongiform encephalopathies, which have been transmitted through dura mater and corneal allografts, is currently assessed only through the evaluation of the donor's history.
Whereas musculoskeletal allografts may be contaminated with exogenous microorganisms during the harvesting or processing of the tissue (a hazard that is addressed with the use of an aseptic technique), the infections reported by Kainer et al. were probably caused by microbes that were present in the cadaveric tissue at the time it was harvested. During the dying process or thereafter, microorganisms may pass through the intestinal wall and seed the blood or tissue with normal intestinal flora (e.g., clostridium species or Enterobacteriaceae), and this process may involve multiple microbes. Even with refrigeration, the body temperature decreases slowly, allowing rapidly dividing organisms to proliferate. Low oxygen concentrations in cadaveric tissue may select for anaerobes, including clostridia. As nutrients become exhausted, clostridia sporulate, which allows them to persist for years (in the absence of sterilization), whereas small numbers of vegetative organisms may die over time. The use of spore-containing, unsterilized musculoskeletal allografts in patients presents a potentially ideal setting for clostridial infection: a closed wound, traumatized tissue, a devitalized allograft, and in some cases, a foreign body. By contrast, bone from living donors and solid organs are unlikely to be contaminated before harvesting because they are retrieved from donors with a beating heart.
There is no fail-safe means of excluding from donation potential cadaveric donors whose tissue might contain such organisms. The donors in the study by Kainer et al. had no obvious sepsis before death. In most cases, tissue was harvested within the recommended time limits; therefore, further studies of acceptable delays between death and the harvesting of tissue are warranted. Aseptic technique, although essential, does not provide protection against in situ microorganisms. The traumatic deaths of most of the donors in this study may have been a risk factor. The only definitive way to eliminate microorganisms is sterilization, which, unfortunately, has not been universally performed because of concern about adverse effects of gamma irradiation and ethylene oxide.
The use of cultures has limitations and cannot guarantee the sterility of musculoskeletal allografts, and culturing practices vary among tissue banks. Single cultures do not identify all bacteria that are potentially present; conversely, cultures are frequently positive for low quantities of skin commensals (e.g., coagulase-negative staphylococci). There is no established cutoff number (or percentage) of culture-positive specimens that warrants corrective action. The role of cultures of cadaveric blood, bone marrow, or both is unclear. Many tissue banks follow unique, often proprietary, methods for processing and disinfection. The antimicrobial treatment of tissue may not eliminate all microorganisms if there is a high burden of such organisms or spores and may be more active against surface contaminants than against organisms within the tissue.
Oversight of tissue-banking practices occurs at the levels of the FDA, the American Association of Tissue Banks (AATB), and the individual state. The FDA requires the preparation, validation, and following of written procedures to prevent contamination or cross-contamination with infectious diseases during processing. In 2001, the FDA proposed requirements for good tissue practices that cover procedures, facilities, personnel, equipment, supplies, reagents, process and labeling controls, process changes and their validation, storage, receipt and distribution, records, tracking, and handling of complaints. The AATB publishes quality standards for procuring and processing tissue (including time limits for retrieval) and for the screening of donors, as well as recommended procedures for the preservation, sterilization, preparation, evaluation, and labeling of tissues; these recommendations go beyond the requirements of the FDA. The AATB standards include recovery with the use of an aseptic technique, microbiologic testing (including aerobic, anaerobic, and fungal preprocessing cultures), and reporting of adverse outcomes. The AATB offers voluntary accreditation of tissue banks; in 2002, approximately 10 percent of musculoskeletal allografts were processed by banks that were not accredited by the AATB. At the state level, only Florida and New York require both the licensing and the inspection of tissue banks; a few states require state licensure alone.
Clearly, musculoskeletal allografts pose a risk of transmission of pathogens. Newer sterilization methods are needed. Infections may occur in multiple geographically dispersed recipients, and the number of allograft-transmitted infections may be underestimated because of incomplete reporting. Surgeons who use these allografts should be familiar with the techniques and standards for preparing them, in view of their effects on both the allograft's biomechanical properties and the risk of infection. When a postoperative infection develops, clinicians must be knowledgeable about the type of tissue used (a cadaveric allograft, an allograft from a living donor, or autologous tissue), consider the possibility of allograft-transmitted infection (especially with clostridial, gram-negative bacillary, enterococcal, or polymicrobial infections), and report such infections to the tissue processor and public health authorities. Empirical antimicrobial treatment should cover these microorganisms. Blood cultures should be obtained and, if appropriate, aerobic and anaerobic cultures of synovial fluid, tissue, or both.
The only definitive way to prevent allograft-transmitted bacterial infection is to sterilize all cadaveric allografts. The recommendations of Kainer et al. should serve as a basis for future regulations and standards. All tissue banks should be accredited by the AATB. There is a need for a standardized list of organisms that require corrective action when isolated from musculoskeletal allografts (e.g., clostridium species, Staphylococcus aureus, beta-hemolytic streptococci, Enterobacteriaceae, pseudomonas species, enterococci, and fungi), as well as a need for agreement on what action should be taken. Finally, a national registry for allograft-associated infections should be established.
Source Information
From the Division of Infectious Diseases, Department of Internal Medicine (R.P., A.T.), and the Division of Clinical Microbiology, Department of Laboratory Medicine and Pathology (R.P.), Mayo Clinic College of Medicine, Rochester, Minn.(Robin Patel, M.D., and An)
(Figure)
Figure. Arthroscopic Photograph of an Infected Anterior-Cruciate-Ligament Allograft.
Courtesy of Michael J. Stuart, M.D., Mayo Clinic College of Medicine.
Historically, the concern about allograft-transmitted infection focused on human immunodeficiency virus (HIV), hepatitis B virus, and hepatitis C virus (HCV), since each of these viruses has been reported to be transmitted by this route. Since 1993, when it issued an interim rule (which was finalized in 1997) focusing on the screening of donors for these viruses, the Food and Drug Administration (FDA) has regulated musculoskeletal allografts. Musculoskeletal-allograft transmission of these viruses is now uncommonly reported. In 2002, however, HCV was transmitted to four recipients of musculoskeletal allografts from a seronegative donor. Although blood donors are screened with the use of nucleic acid testing for HCV, HIV, and West Nile virus, such testing is not required of tissue donors. The availability of approved nucleic acid testing for cadaveric serum should lead to further reduction of the risk of transmission of selected viruses through musculoskeletal allografts. The risk of transmissible spongiform encephalopathies, which have been transmitted through dura mater and corneal allografts, is currently assessed only through the evaluation of the donor's history.
Whereas musculoskeletal allografts may be contaminated with exogenous microorganisms during the harvesting or processing of the tissue (a hazard that is addressed with the use of an aseptic technique), the infections reported by Kainer et al. were probably caused by microbes that were present in the cadaveric tissue at the time it was harvested. During the dying process or thereafter, microorganisms may pass through the intestinal wall and seed the blood or tissue with normal intestinal flora (e.g., clostridium species or Enterobacteriaceae), and this process may involve multiple microbes. Even with refrigeration, the body temperature decreases slowly, allowing rapidly dividing organisms to proliferate. Low oxygen concentrations in cadaveric tissue may select for anaerobes, including clostridia. As nutrients become exhausted, clostridia sporulate, which allows them to persist for years (in the absence of sterilization), whereas small numbers of vegetative organisms may die over time. The use of spore-containing, unsterilized musculoskeletal allografts in patients presents a potentially ideal setting for clostridial infection: a closed wound, traumatized tissue, a devitalized allograft, and in some cases, a foreign body. By contrast, bone from living donors and solid organs are unlikely to be contaminated before harvesting because they are retrieved from donors with a beating heart.
There is no fail-safe means of excluding from donation potential cadaveric donors whose tissue might contain such organisms. The donors in the study by Kainer et al. had no obvious sepsis before death. In most cases, tissue was harvested within the recommended time limits; therefore, further studies of acceptable delays between death and the harvesting of tissue are warranted. Aseptic technique, although essential, does not provide protection against in situ microorganisms. The traumatic deaths of most of the donors in this study may have been a risk factor. The only definitive way to eliminate microorganisms is sterilization, which, unfortunately, has not been universally performed because of concern about adverse effects of gamma irradiation and ethylene oxide.
The use of cultures has limitations and cannot guarantee the sterility of musculoskeletal allografts, and culturing practices vary among tissue banks. Single cultures do not identify all bacteria that are potentially present; conversely, cultures are frequently positive for low quantities of skin commensals (e.g., coagulase-negative staphylococci). There is no established cutoff number (or percentage) of culture-positive specimens that warrants corrective action. The role of cultures of cadaveric blood, bone marrow, or both is unclear. Many tissue banks follow unique, often proprietary, methods for processing and disinfection. The antimicrobial treatment of tissue may not eliminate all microorganisms if there is a high burden of such organisms or spores and may be more active against surface contaminants than against organisms within the tissue.
Oversight of tissue-banking practices occurs at the levels of the FDA, the American Association of Tissue Banks (AATB), and the individual state. The FDA requires the preparation, validation, and following of written procedures to prevent contamination or cross-contamination with infectious diseases during processing. In 2001, the FDA proposed requirements for good tissue practices that cover procedures, facilities, personnel, equipment, supplies, reagents, process and labeling controls, process changes and their validation, storage, receipt and distribution, records, tracking, and handling of complaints. The AATB publishes quality standards for procuring and processing tissue (including time limits for retrieval) and for the screening of donors, as well as recommended procedures for the preservation, sterilization, preparation, evaluation, and labeling of tissues; these recommendations go beyond the requirements of the FDA. The AATB standards include recovery with the use of an aseptic technique, microbiologic testing (including aerobic, anaerobic, and fungal preprocessing cultures), and reporting of adverse outcomes. The AATB offers voluntary accreditation of tissue banks; in 2002, approximately 10 percent of musculoskeletal allografts were processed by banks that were not accredited by the AATB. At the state level, only Florida and New York require both the licensing and the inspection of tissue banks; a few states require state licensure alone.
Clearly, musculoskeletal allografts pose a risk of transmission of pathogens. Newer sterilization methods are needed. Infections may occur in multiple geographically dispersed recipients, and the number of allograft-transmitted infections may be underestimated because of incomplete reporting. Surgeons who use these allografts should be familiar with the techniques and standards for preparing them, in view of their effects on both the allograft's biomechanical properties and the risk of infection. When a postoperative infection develops, clinicians must be knowledgeable about the type of tissue used (a cadaveric allograft, an allograft from a living donor, or autologous tissue), consider the possibility of allograft-transmitted infection (especially with clostridial, gram-negative bacillary, enterococcal, or polymicrobial infections), and report such infections to the tissue processor and public health authorities. Empirical antimicrobial treatment should cover these microorganisms. Blood cultures should be obtained and, if appropriate, aerobic and anaerobic cultures of synovial fluid, tissue, or both.
The only definitive way to prevent allograft-transmitted bacterial infection is to sterilize all cadaveric allografts. The recommendations of Kainer et al. should serve as a basis for future regulations and standards. All tissue banks should be accredited by the AATB. There is a need for a standardized list of organisms that require corrective action when isolated from musculoskeletal allografts (e.g., clostridium species, Staphylococcus aureus, beta-hemolytic streptococci, Enterobacteriaceae, pseudomonas species, enterococci, and fungi), as well as a need for agreement on what action should be taken. Finally, a national registry for allograft-associated infections should be established.
Source Information
From the Division of Infectious Diseases, Department of Internal Medicine (R.P., A.T.), and the Division of Clinical Microbiology, Department of Laboratory Medicine and Pathology (R.P.), Mayo Clinic College of Medicine, Rochester, Minn.(Robin Patel, M.D., and An)