Recommendation Issued to Tissue Banks Regarding the Risk of Mtb Transmission
Mycobacterium tuberculosis (Mtb) is one of the most common disease-causing infectious agents worldwide (WHO data) with high morbidity and mortality. It is one of the most common single causes of solid organ transplant infection derived from the donor (Nerac ref #10,16,17). Although rare, Mtb transmission via tissue transplant has occurred in the past through minimally processed bone, heart valves, and stem cells (Nerac ref # 1, 2, 6). Most recently, a tuberculosis outbreak was linked to a contaminated bone graft product containing live cells used in spinal surgery: https://www.cdc.gov/mmwr/volumes/70/wr/mm7036a4.htm?s_cid=mm7036a4
Tuberculosis is more prevalent in low to medium-income countries, most notably in Asia, Africa, and South America (WHO data, Nerac ref # 21). In low prevalence countries such as the United States, the majority of TB disease currently occurs in foreign-born individuals as a result of reactivation of old infections acquired in the prior area of residence (CDC data-TB statistics, Nerac ref # 16, 24).
Inhalation of bacteria results in Mtb inoculation of the lungs. In certain individuals, the bacteria can disseminate via the lymphatics and the bloodstream and establish itself in multiple tissues and organs other than the lungs. Mtb is an intracellular pathogen capable of infecting various cells, most notably the macrophages (Nerac ref #6). Studies have shown that Mtb DNA can be found in other diverse nonphagocytic cell types of both pulmonary and extrapulmonary locations such as fibroblasts, adipocytes and hematopoietic, and mesenchymal stem cells. This highlights the wide anatomical distribution of Mtb in infected individuals (Nerac ref #6).
Typically the host immune system eliminates the bacteria, but in some cases, the bacteria can persist inside the host cells in a latent, non-active form. The latent Mtb may later reactivate during the person's lifetime, depending on the person's immunological status and co-morbidities (Nerac reference #6, 7).
Both active and latent Mtb can potentially be transmitted by tissues that contain infected cells. Active replicating Mtb poses the more significant threat to recipients (Nerac ref # 16, 25, 26, 27, 29).
Currently, there is no approved accurate laboratory TB screening test for deceased donors. The current Interferon Gamma Release Assays (IGRA) available for living individuals require viable and intact immune cells to produce accurate results and has not been validated in deceased individuals. Such validation is unlikely to be feasible. IGRA use is not recommended for deceased donors as sensitivity and specificity are unknown given the lack of a gold standard in this setting, which can lead to diagnostic misclassification.
Direct testing of donor tissues for Mtb may be considered. PCR testing is available, could be used to test tissue samples, and has high specificity, but the application to various tissue types needs to be carefully validated by each individual establishment. Mtb cultures from tissues are considered the gold standard for TB diagnosis however, they take 6 to 8 weeks to finalize, which may not be a reasonable timeline for certain tissues (Nerac ref # 25).
The current donor data that are collected in the donor risk assessment interview (DRAI) that help assess TB risk include place of birth, travel history, personal history of TB or contact to TB, chronic illnesses that depress immunity such as diabetes, renal failure, liver disease, autoimmune diseases, rheumatological diseases, organ transplant, and use of immunosuppressive medications.
B. SUMMARY AND RECOMMENDATIONS:
In light of the recent transmission of Mtb, tissue banks may consider the following factors regarding the risk of transmission HCT/Ps:
- Tissue banks need to carefully consider their processing method, donor risk factors, and type of tissue to be able to determine its safety and suitability. Minimally processed tissues such as fresh grafts, live cells, stem cells, and any tissue with viable cells are considered the most at risk for transmitting Mtb if the cells harbor the bacteria. Decellularized tissues and those treated with a validated terminal sterilization process will carry the least risk.
- TB risk factors:
- Donors on immunosuppressive medications such as corticosteroids, tumor necrosis factor alpha (TNFa) inhibitors, rituximab, mycophenolate, cyclophosphamide, tacrolimus, and various other drugs used to suppress immunity
- Donors with chronic kidney disease on dialysis (hemodialysis or peritoneal dialysis)
- Donors with chronic liver disease
- Donors with uncontrolled diabetes
- Donors who had an organ transplant
- Donors with a history of TB or close contact with a person with active TB
- Donors born in an area with a high prevalence for tuberculosis, particularly if those donors also have one of the conditions listed above
- There are no assays suitable for deceased donor testing, so adequate medical and social history is required. Current IGRA assays are not appropriate in this setting.
- Tissue testing for Mtb by PCR may be considered for tissues obtained from donors with increased risk profiles as outlined above or from recovered tissues that will be minimally processed. PCR application and methodology for various tissues will need to be validated by each bank.
There is no one accurate and reliable method to detect and prevent tuberculosis transmission. It is the consensus of the Panel that consideration of all the above factors combined should reduce the risk. Each establishment needs to consider the best approach to minimizing the risk of transmission of Mtb via HCT/Ps.
This document has been prepared by Sally Alrabaa MD, Melissa Greenwald MD, Dan Schultz MD, Hannis Thompson MD, James Alexander MD, Matthew Kuehnert MD, and Roman Hitchev MD under the administrative moderation of Beverly Bliss and the support of the following Panel members: Anna McDonald MD, Tim Maye, Dr. Shab Namin, Dr. Alyce Jones.
- Khanna S, Ross J, Monro J. Homograft aortic valve replacement: seven years' experience with antibiotic-treated valves. Thorax. 1981;36(5):330-7.
- James JI. Tuberculosis transmitted by banked bone. The Journal of bone and joint surgery British volume. 1953;35 B(4):578.
- Mayito J, Andia I, Belay M, Jolliffe DA, Kateete DP, Reece ST, et al. Anatomic and cellular niches for mycobacterium tuberculosis in latent tuberculosis infection. Journal of Infectious Diseases. 2019;219(5):685-94.
- Gupta RK, Calderwood CJ, Yavlinsky A, Krutikov M, Quartagno M, Aichelburg MC, et al. Discovery and validation of a personalized risk predictor for incident tuberculosis in low transmission settings. Nature Medicine. 2020;26(12):1941-9.
- Abad CLR, Razonable RR. Donor derived Mycobacterium tuberculosis infection after solid-organ transplantation: A comprehensive review. Transplant infectious disease : an official journal of the Transplantation Society. 2018;20(5):e12971.
- Jones JM, Vikram HR, Lauzardo M, Hill A, Jones J, Haley C, et al. Tuberculosis transmission across three states: The story of a solid organ donor born in an endemic country, 2018. Transplant Infectious Disease. 2020;22(6).
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- World Health Organization. Use of high burden country lists for TB by WHO in the post-2015 era: Summary: World Health Organization,; n.d.
- Available from: https://www.who.int/tb/publications/global_report/high_tb_burdencountrylists2016-2020summary.pdf? ua=1#:~:text=The%2030%20TB%20HBCs%20(those,%2C%20Russian%20Federation%2C%20Sierra%20Leone%2C
- Warwick RM, Magee JG, Leeming JP, Graham JC, Hannan MM, Chadwick M, et al. Mycobacteria and allograft heart valve banking: an international survey. Journal of Hospital Infection. 2008;68(3):255-61.
- Anyanwu C, Nassau E, Yacoub M. Miliary tuberculosis following homograft valve replacement. Thorax. 1976;31(1):101-6.
- Edathodu J, Alrajhi A, Halim M, Althawadi S. Multi-recipient donor-transmitted tuberculosis. The international journal of tuberculosis and lung disease: the official journal of the International Union against Tuberculosis and Lung Disease. 2010;14(11):1493-5.
- Shingde R, Habachou LI, Calisa V, Craig JC, Tong A, Chen SC, et al. Unexpected donor-derived infectious transmissions by kidney transplantation: A systematic review. Transplant infectious disease : an official journal of the Transplantation Society. 2018;20(2):e12851.
If you have questions, please contact Beverly Bliss, Vice President of Accreditation and Standards, at firstname.lastname@example.org.