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Perspectives on Modern Orthopaedics

Musculoskeletal Allograft Risks and Recalls in the United States

Mroz, Thomas E. MD; Joyce, Michael J. MD; Steinmetz, Michael P. MD; Lieberman, Isador H. MD; Wang, Jeffrey C. MD

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Journal of the American Academy of Orthopaedic Surgeons: October 2008 - Volume 16 - Issue 10 - p 559-565
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Abstract

Allograft tissue is used in almost all of the orthopaedic surgical subspecialties. Allograft tissue is an attractive alternative to autogenous tissue because its use obviates recovery of tissue from the patient, thereby avoiding host-related morbidity. Approximately 1 million musculoskeletal allografts were distributed for use in the United States in 2004.1 These bone and soft-tissue grafts were used for limb reconstructive surgery, spinal surgery, orthopaedic sports medicine surgery, oral-maxillofacial surgery, and plastic surgery.

Recent reports of disease transmission following the implantation of contaminated allografts have raised concern over the issue of patient safety among allograft tissue recipients.2-6 Reports of allograft infections include those involving transmission of Clostridium species, group A streptococcus, hepatitis C virus (HCV), and human immunodeficiency virus (HIV). Bacterial transmission accounts for most instances of disease transmitted from cadaveric sources. Most incidents involved allografts used in soft-tissue reconstruction associated with sports medicine. In 2002, the Centers for Disease Control (CDC) reported on 26 bacterial infections arising from contaminated allograft tissue over the preceding 7 years.4 A case of Streptococcus pyogenes infection was reported in 2003; it followed the implantation of a contaminated patellar tendon allograft for an anterior cruciate ligament reconstruction.2 The only subsequent reported musculoskeletal allograft-associated bacterial infection in the past 4 years occurred in September 2006. This infection was related to Chryseobacterium meningosepticum and occurred after a soft-tissue allograft was used for knee ligament reconstruction.7,8

Allograft-associated infections caused by viruses are uncommon. The first case of HIV transmission from allograft bone to a spinal fusion recipient was reported in 1988;6 this was a donor case that occurred before the onset of serologic testing of blood and tissue donors in March 1985. The only other reported case of HIV transmission from allograft musculoskeletal tissue occurred in 1985, from a donor who was seronegative for HIV antibody but infectious.9 This led to the transmission of HIV to three recipients of musculoskeletal tissue. The risk of HIV transmission from an allograft has been estimated to be approximately 1 in 1.6 million,10 assuming that all available measures have been taken to screen and test the donor tissue. There has been one reported case of hepatitis B virus (HBV) transmission11 and two instances of HCV transmission from musculoskeletal allografts, the most recent of which was reported in 2002.3,12,13

These reported numbers may seem to portray a small relative risk, but they may be understated. In contrast to comprehensive regulation of the use of medical devices, drugs, biologics, and vaccines, the mechanism for reporting to the FDA complications or adverse reactions arising from or subsequent to allograft implantation was poorly defined until 2005. Therefore, it is likely that several cases of bacterial and, possibly, viral infection via allograft have gone unreported. The investigation by the CDC serves to point out that allograft transmission represents a public health risk that merits further investigation and increased regulatory oversight.4 Recent initiatives by the FDA through its Current Good Tissue Practice rule, and by the Joint Commission (formerly, the Joint Commission on the Accreditation of Hospital Organizations) and the American Association of Tissue Banks (AATB), have advanced tissue safety measures within the United States.14,15

Methods

We searched all available databases to collate and report the recall of tissue that had been distributed by registered tissue banks. The FDA collects and publishes weekly reports on regulated product recall. These data are specific to product type, manufacturer, reason for recall, volume of product, and geographic distribution of recalled products. For this review, we analyzed all allograft-tissue recall data collected from the period of January 1994 (when such data collection began for tissue products) to June 30, 2007. Recalls involved 63 domestic tissue banks. All musculoskeletal allograft recalls were included. These include bone as well as soft tissues. All data were obtained directly from the FDA recall Website (http://www.fda.gov/opacom/Enforce.html). The reasons for recall and the quantities, as well as trends and implications for patient safety, were analyzed.

The AATB was established in 1976 and has been a voluntary accrediting agency for tissue banks since 1986. The AATB sets forth quality standards for tissue screening, recovery, processing, preservation, sterilization, and labeling. In the United States, there are approximately 800 tissue facilities and more than 500 reproductive tissue facilities registered with the FDA. As of 2007, the AATB had accredited 99 tissue banks, 11 of which are reproductive only. Hence, only a little more than 10% of tissue facilities involved with musculoskeletal allografts are accredited by the AATB. In 2002, it was estimated that approximately 10% of allograft tissue originated from tissue banks not accredited by the AATB.16

A 2002 CDC report on allograft infections in the United States4 suggests that many allograft-associated infections remain unreported and are a public health risk that merits further investigation and increased regulatory oversight. Few tissue banks in the United States have the means of reducing the risk of allograft infections through tissue sterilization, which was called for in a recent article by Kainer et al.17 Despite improvements in the regulation of the tissue banking industry regarding allograft tissue, several issues remain. A report issued by the Department of Health and Human Services in 2001 revealed the scope of the matter.18 In January 2001, there were 156 domestic tissue banks identified by the FDA. Only 118 (75.6%) of these banks, however, had been inspected by the FDA. In more than half of these inspections, deficiencies requiring reformatory action were discovered. In 72 of the inspections, the FDA issued a recommendation to the companies for their voluntary remediation. In comparison, for 2005, 1,970 tissue banks were registered with the FDA, and only 270 (13.7%) had been inspected by the FDA. In 18% of these inspections, notices of observed deficiencies were given.

Results

From January 1, 1994, to June 30, 2007, 61,607 tissue specimens (ie, musculoskeletal, skin, cardiovascular, dura, corneal, sclera) were recalled. Of those, 59,476 (96.5%) were musculoskeletal allografts. From January 2006 through June 2007 alone, 33,483 musculoskeletal allograft tissues were recalled. The largest musculoskeletal recall (approximately 28,000) pertained to five involved tissue banks that had received tissue from one recovery company. Although the number of annual recalls increased from 1994 to 2007 (Table 1), we were not able to determine the absolute trend incidence because the total number of tissues distributed each year over the study period was not available. The remaining allograft tissues recalled comprised 842 (1.37%) cardiovascular specimens (eg, cardiac valves, vein conduits), 711 (1.15%) corneas, and 253 (0.41%) dura mater specimens.

Table 1
Table 1:
Number of Tissues, Agencies, and Musculoskeletal Recalls, FDA, 1994-2007

The categories for recall reporting changed over the study period (Tables 2 and 3). In years before 1999, improper or inadequate donor selection and positive serology were reported together; they were considered separately in subsequent years. From 1994 through 1998, insufficient or improper donor evaluation and positive serology accounted for 96.4% of musculoskeletal recalls. From 1999 through June 2007, improper donor evaluation accounted for 67.2% of recalled specimens. Contamination (21.5%) and recipient infections (9.79%) were other major reasons for musculoskeletal recalls. One recipient Chryseobacterium infection from a contaminated anterior cruciate ligament graft resulted in the FDA's recalling 4,805 allograft specimens in April 2007, after there had already been a tissue bank voluntary recall in 2006.

Table 2
Table 2:
Reasons for FDA Musculoskeletal Allograft Tissue Recalls (1994-1998)
Table 3
Table 3:
Reasons for FDA Musculoskeletal Allograft Tissue Recalls (1999-June 30, 2007)

Discussion

Bacterial infections resulting from allograft contamination may have serious and even fatal consequences.2,4 In 2002, the CDC reported on 26 bacterial infections associated with the use of allograft tissue.4 Thirteen patients developed Clostridium species infections, and 14 of the overall cases were associated with a single tissue bank. In 11 of the 13 infections, further work-up implicated an allograft as the ultimate contaminant. Involved allografts were tendons (8), osteoarticular segments (2), bone (2), and meniscus (1). Eleven of the 13 allografts had been frozen, and 2 were fresh. All of the allografts had been processed aseptically but not sterilized. Eleven of the 26 patients had gram-negative bacillus infections, and 2 had negative cultures.4 In 2003, an S pyogenes (ie, group A streptococcus) infection was reported in a recipient of a hemipatella tendon allograft for an anterior cruciate ligament reconstruction.2 A soft-tissue musculoskeletal allograft-associated Chryseobacterium meningosepticum infection was reported by the Minnesota Department of Health.8

Studies of bacteriologic cultures on preprocessed musculoskeletal allograft tissues have also reported high rates of bacterial contamination in processed musculoskeletal allograft tissue. Malinin et al19 reported an 8.1% incidence of Clostridium species contamination, most commonly Clostridium sordellii, in musculoskeletal allograft tissue. The authors concluded that the occurrence of infection was correlated to increasing time between donor death and time of recovery. Others have reported similar findings of higher contamination rates associated with prolonged period of time for tissue recovery.20

Deijkers et al21 demonstrated a 3% contamination rate of highpathogenic organisms and a 50% contamination rate of low-pathogenic organisms in bone allografts. Further, they found that the contaminant source is largely exogenous and that the rates of contamination are strongly influenced by the methods used by the recovery team. The methods used for culturing donor tissue are critical. Surface swabbing has been considered an industry standard; however, this test is limited in the ability to detect microbial contamination. Techniques that improve safety and accuracy include solution extraction and destructive testing of companion tissue.

The incidence of HIV transmission from an allograft to recipient remains low and is roughly estimated at 1 in 1.6 million.10 Because approximately 1 million musculoskeletal allografts are implanted in the United States each year, this estimate represents a potential of approximately 1 to 2 cases of HIV via allograft every 2 years. This estimate does not take into account such factors as human error in recovery, processing, or distribution, and it presumes adherence to a screening and testing regimen that may not be practiced by all tissue banks. Even so, transmissions of HCV from organ and tissue donors and of West Nile virus from organ donors to recipient have underscored the need for updated guidelines for screening donors and, more than ever, the need to adopt new sterilization technologies in tissue processing.16

As such, new FDA guidelines initially published in February 2007 and updated in August 200722 mandated that nucleic acid testing for HIV/HCV be implemented for all new tissue donors by August 2007. The reason for the mandate is related to experience. In 2002, the CDC reported on four cases of hepatitis C infection that had resulted from transplantation of musculoskeletal tissues donated from a seronegative but non-nucleic acid testing-screened donor: one patient received a tendon allograft and three received bone-tendon allografts.3 In August 2002, West Nile virus infection developed in four organ recipients of solid organs from a common donor.5 To date, there have been no reported cases of West Nile virus transmission via musculoskeletal allografts in the United States. However, it is reasonable to assume that such an occurrence is possible under the current tissue screening policies.

Donor blood is routinely screened by use of nucleic acid testing assays for HCV, HIV, and West Nile virus, and important steps have been taken to standardize nucleic acid testing screening of donated musculoskeletal tissue for HIV and HCV. In December 2003, the FDA approved the first nucleic acid testing serology for HIV to screen cadaveric serum, and in June 2004, a combined HIV/HCV test was approved. Since March 2005, the AATB has required AATB-accredited tissue banks to include serologic testing of donor tissue for nucleic acid testing serology for HIV, and HCV. A formal federal government policy requiring tissue banks to routinely screen donors using cadaveric specimens for nucleic acid testing for HBV was adopted in August 2007. There are no requirements for serologic screening of musculoskeletal donors for West Nile virus.

Important conclusions can be drawn from this review. First, existing tissue regulatory guidelines do not fulfill the objective of setting standards for complete elimination of transmission of infection to tissue recipients. Many of the recalled grafts reported here were recalled after processing and distribution, which means that many such tissues were already “on the shelf” and poised for surgical implantation into patients.

Second, not all allograft tissues are processed in the same manner, and not all tissue banks in the United States have the ability to sterilize tissue routinely. For example, although tissue may be processed aseptically, this does not equate to sterilization. Aseptic technique implies that it is unlikely for any new organisms to be introduced during cadaveric tissue recovery or during the handling of tissues during the processing and post-processing phases at the tissue bank. Aseptic processing does not absolutely guarantee sterility, although it does significantly reduce endogenous contamination and occult exogenous contamination. Validation of aseptic processing implies that after handling, presterilized products yield negative bacteriologic cultures for an end-product sample.

Sterilization is a process that eliminates bacteria, spores, fungi, and, at times, viruses (if validated for viruses) through processing with one of the following sterilization technologies: low-temperature chemical sterilization, gamma or electron beam irradiation, and ethylene oxide. Ethylene oxide has a limited potential to penetrate tissue and has been associated with adverse patient outcomes.23,24 Allograft bone that is lyophilized, irradiated, and/or treated with ethylene oxide has been associated with decrements in biomechanical integrity and osteoinductive potential.25,26 Chemical sterilization has recently been identified as one of the new sterilization technologies with a zero attributable risk of infection to date. Low-temperature irradiation, with some methods using radiation protectants, is now being used to sterilize tissue with a purported lesser adverse effect on the tissue and long-term outcomes.

The findings of this review indicate that donor evaluation and abnormal serologic tests are responsible for the great majority of the musculoskeletal allograft tissue recalls overseen by the FDA in the United States. Prior to 1993, recovery, processing, and distribution of allograft tissue were not actively regulated by the US federal government. In the early 1990s, two sentinel events heightened concerns regarding the use of allograft tissue. The first episode was the transmission of HIV from an infected seronegative 1985 donor (screened with a first-generation HIV antibody assay) to several recipients of allograft tissue. One patient reported on in 1992 underwent a spine fusion with bone from a femoral head.9 The second event was the recognition by the FDA that various domestic tissue banks were accepting imported tissues from international donors that were neither accurately screened nor accurately tested serologically for HIV, HBV, or HCV.

Thus, in December 1993, the FDA published an Interim Rule for Human Tissue for Transplantation (21 CFR Part 1270).27 The rule outlined specific donor suitability and screening requirements for all human tissues. It also detailed the inspection of tissue banks and the recall of unsafe donor tissues. The rule was finalized to guide donor screening and testing, and the Final Rule was published in July 1997.28 These regulations gave the FDA the authority to perform on-site inspections and to recall, retain, or destroy any tissues that were not obtained or processed in compliance with FDA policy. The FDA recently instituted refinements in its regulatory oversight of the tissue-banking industry through the Current Good Tissue Practice rule.28-31 As of 2007, the major oversight of the tissue banking industry is performed by the FDA, as well as by the Joint Commission (for handling tissue grafts in the hospital or surgical center), the AATB, and several state governments.

Two important regulatory advancements in the tissue banking industry occurred in 2005. First, on May 25, 2005, the FDA finalized the Current Good Tissue Practice requirements.17,29-31 This mandate, supported both by Congress and the tissue banking industry, implemented several noteworthy changes to ensure the safety of allografts used in the United States. Current Good Tissue Practice now requires organizations that donate human cells, tissues, and cellular- and tissue-based products to recover, process, store, and distribute those products in a manner that prevents disease transmission. Tissue banks must also practice stringent recording and complaint evaluation, investigate all adverse reactions related to human cells, tissues, and cellular- and tissue-based products, and report to the FDA any serious adverse reaction involving a communicable disease. Adverse reactions are defined by the FDA as fatal, life-threatening, resulting in permanent impairment of a body function or permanent damage to body structure, or necessitating medical or surgical intervention, including hospitalization. Current Good Tissue Practice marks the first federally mandated requirement for reporting adverse reactions associated with allograft tissue.

Second, on July 1, 2005, the Joint Commission implemented new standards that apply to accredited organizations that store or process tissue (ie, not tissue banks).15 These standards require such organizations (ie, hospitals and surgical centers) to use or provide the following: oversight responsibility for tissue programs, standardized procedures for all tissue handling, record maintenance for tissue traceability, and a defined algorithm to investigate and report any adverse events associated with allograft tissue.

Only Florida, Maryland, California, and New York perform on-site inspections for tissue-banking companies licensed in their states, and less than 10% of all US tissue banks are accredited by the AATB; there is low incentive to seek accreditation. Additionally, the FDA's regulation of the industry is not a funded mandate, which limits the agency's ability to enforce policy. It is hoped that Current Good Tissue Practice and the Joint Commission regulations will dramatically increase the safety of tissue products by addressing many of these and other outstanding issues.

The safety of allograft tissue is predicated on several variables, including enforcement of regulatory guidelines; adherence to proper tissue retrieval, processing, storage, and distribution protocols; and meticulous surgical implantation. However, much of the burden rests with surgeons, who should take an active role to help optimize the safety of the allografts used in their respective institutions. Joyce32 emphasized the need for surgeons to thoroughly understand the practices of their contracted tissue banks. Table 4 provides further guidelines for surgeons. The author emphasized the importance of understanding the following seven key points about the tissue bank:

Table 4
Table 4:
Surgeon Checklist: Key Points and Guidelines for Safe Use of Musculoskeletal Allograft

1. Tissue-recovery sources (eg, operating rooms, morgues, funeral homes). The biologic contamination profile can vary with the source and circumstance of the donor's death. Does the tissue processor have a validated system to qualify and quantify the contamination present on arrival at the processing facility?

2. Methods used during tissue processing to detect microorganisms (ie, surface swabbing and/or solution extraction method and/or destructive testing of companion tissues).

3. Methods used during tissue processing to reduce or preferably eliminate biologic contamination (ie, ethylene oxide, electronic beam radiation, gamma irradiation, chemical sterilization). Is the graft at risk of being structurally or biologically compromised because of the type of sterilization? Does the bank validate its employed technique? Is there a sterility assurance level?

4. Knowledge and expertise of personnel. Is the medical director of the processor a physician? The release of allograft tissue for use in patients requires careful review of donor social and medical histories, examinations, and document and serology results, and, hence, requires astute medical judgment.

5. Protocol for reporting and investigating surgeon complaints and adverse events. Does the tissue bank comply strictly with the Current Good Tissue Practice mandate?

6. AATB accreditation and FDA compliance. Has the tissue bank voluntarily become accredited by the AATB? When was the bank last formally inspected by the FDA? What were the results of that inspection? For example, were remedial steps recommended/implemented?

7. Nucleic acid test screening for HIV and HCV. Since March 9, 2005, AATB-accredited tissue banks have been mandated to perform nucleic acid screening for HIV and HCV using FDA-validated licensed tests for cadaveric blood. More recently, the FDA guidelines of August 2007 insist on NA screening for HIV/HCV for donors recovered after that time.22 It is imperative that all surgeons using allograft tissue completely understand the Current Good Tissue Practice and AATB regulations as well as the practices of the tissue bank that provides them with allograft tissue.

Summary

The overall risk of disease transmission via musculoskeletal allograft tissue remains very low, but when an episode occurs, there can be substantial morbidity and even mortality. Tissue recalls by the FDA are relatively common and are predominantly linked to inadequate donor screening or abnormal serologic tests. Therefore, it is imperative that clinicians properly inform patients of these risks. Further, the FDA, the AATB, the Joint Commission, individual states, and physicians must work together in taking the necessary steps to ensure the safe use of allograft tissue through enhanced guidelines, further research, the implementation of a reporting system for adverse events associated with allograft tissue implantation, and potential requirements for additional protective measures such as sterilization procedures for tissues without impact on graft strength or incorporation. A future analysis of allograft recall and disease transmission from allograft tissue after the implementation of the Current Good Tissue Practice and the Joint Commission guidelines will certainly provide more insight into the safety of musculoskeletal tissue. Ultimately, the optimization of allograft tissue safety will be predicated on a streamlined participation of all parties involved, including the FDA, the Joint Commission, the AATB, the tissue-banking industry, individual states, hospitals, and surgeons.

References

Citation numbers printed in bold type indicate references published within the past 5 years.

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4. Centers for Disease Control and Prevention: Update: Allograft-associated bacterial infections. United States, 2002. MMWR Morb Mortal Wkly Rep 2002;51:207-211.
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