The Risk to Human Islet Cell Transplant Recipients of Acquiring Variant Creutzfeldt-Jakob Disease: A Provisional Quantitative Risk Assessment

Human islet cell transplantation is a procedure for the treatment of type 1 diabetes practiced by several health centers worldwide. In this procedure, patients receive islet cells harvested from at least one donor pancreas (cadaveric donor pancreases or an autograft from the patient themselves). The purified islet cells are injected into the recipient's hepatic portal vein during a nonsurgical procedure, which can be repeated up to three times. The cells migrate to the liver where they produce insulin. Follow-up treatment with antirejection drugs is necessary because the transplants of islet cells have the same immunological properties as solid organ transplants (1). The concept was tested in animal models during the 1970s (2); however, a successful human transplant was not performed until 1990 (3). To date, approximately 500 patients have undergone islet cell transplantation world wide (4). The islet cell isolation procedure introduces a unique, potential exposure pathway for human infection with the bovine spongiform encephalopathy (BSE) agent because of the digestion of donor tissue with an enzyme blend purified from crude collagenases of the bacterium Clostridium histolyticum produced in a fermentation process. Certain manufacturers used a growth medium that contained brain-heart infusion (BHI) to grow C. histolyticum. BHI is made from brain and other specified risk materials sourced from cattle. The result of the manufacturing process is a semipurified enzyme cocktail derived from tissues potentially contaminated with BSE agent. The enzyme preparation might then contaminate donor tissue during dissociation of islet cells prior to transplantation. BSE is a rare, progressive, neurodegenerative, and invariably fatal brain disease that affects both humans and animals (5). In humans, oral exposure to the BSE agent is believed to manifest as variant Creutzfeldt- Jakob disease (vCJD) (6). A quantitative risk assessment was conducted on the islet cell manufacturing process, including the sourcing and production of collagenases to quantify this potential exposure pathway for vCJD. The risk assessment critically analyzed what was known about the manufacturing process of the enzyme but had to use data gathered from expert opinion and past work with “biopharm” materials (7) to contend with large information gaps. Because of limitations in the input data, the assessment must be used with caution and perhaps is best viewed as a learning and pioneer exercise. Since the research described in this article was performed, an alternative source of collagenase prepared with plant-based growth media (without BHI) was implemented for clinical use. Although current manufacturing processes no longer use bovine materials for collagenase production, this investigation, within the limitations noted above, is relevant for those patients who previously received islet cell transplants. Importantly, all patients undergoing this procedure are exposed to the very low risk that the islet cell donor pancreas may be from a person who was harboring CJD or vCJD but was not showing signs of illness; this irreducible source of risk from transplantation of human tissues was not evaluated in this assessment, but is acknowledged. Monte Carlo simulation was chosen for scenario analysis because of its ability to model low probability occurrences. Major information gaps were covered by using worst-case scenarios for missing data resulting in a conservative estimate of risk. Estimation of the potential risk of infection per treatment, Ppi/etr, was conducted based on the values of the input parameters collected from different sources (Tables 1 and 2). The general framework of the Monte Carlo protocol was implemented using Crystal Ball 7 software (Decisioneering Inc., Denver, CO) by generating the parametric model y=f(x1, ..., xq), where “y” represents the final output of the model, P(pi/etr). Variables x1, ..., xq are the inputs required to calculate P(pi/etr). The complete set of data inputs used for the equations are listed in Table 2. Sensitivity analysis showed that the level of risk was strongly correlated with the mass of infected tissue in a batch (Table 2, variable W) and the number of animals in a batch (Table 2, variable Nb). Additional details of the model development and Monte Carlo simulation can be found in the full risk assessment available from the Public Health Agency of Canada (contact the corresponding author Dr. ElSaadany, [email protected], for the full islet cell risk assessment report).TABLE 1: MCS risk assessment model equations with outcomes and ranges of uncertaintyTABLE 2: The vCJD parametric risk model inputs used for the equations found in Table 1The model predicts a potential risk of vCJD infection per single human islet cell treatment of approximately one in 100 million (1.12×10−8). The 95% confidence interval around the uncertainty of this result is three orders of magnitude (3×10−9, 1×10−6). The assessment indicates that even using worst-case scenarios for the assessment inputs, the risk of contracting vCJD from a single islet transplantation procedure is extremely low. ACKNOWLEDGMENTS The authors thank Dr. Abdel El-Shaarawi for his consultation and quantitative review of the model. Within the Public Health Agency of Canada (PHAC), the authors also thank Ms. Caroline Desjardins and acknowledge the role of Dr. Robert Gervais for his role in completing the risk assessment. Susie ElSaadany1 Michael G. Tyshenko2 Tamer Oraby2 Andrew J. Malcolm3 Peter Senior3 A. M. James Shapiro3 Angela Catford1 Tarek Salem2,4 Jun Wu1 Daniel Krewski2 Robert G. Rohwer5,6 1Blood Safety Surveillance and Health Care Acquired Infections Division Public Health Agency of Canada, Ottawa ON, Canada 2McLaughlin Centre for Population Health Risk Assessment University of Ottawa, Ottawa ON, Canada 3Clinical Islet Transplant Program, Edmonton AB, Canada 4Clinical Trials Group 1 Health Canada, Ottawa ON, Canada 5Medical Research Service Veterans Affairs Medical Center Baltimore, MD 6Rohwer Technical Counseling, LLC Ellicott City, MD

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