Nationwide tuberculosis outbreak linked to a single bone marrow donor

Outbreak Description

March-June 2021. Delaware, USA. An outbreak of tuberculosis occurred in 7 patients following spinal surgery in a Delaware hospital, the identity of which was not to be shared. The infection was linked to a single common exposure: implantation of FiberCel bone allograft material from a single product lot. 

Organism or Agent Involved 

In the 2021 outbreak in Delaware, Mycobacterium tuberculosis was found to be the main causative agent of tuberculosis disease. M. tuberculosis is an obligate intracellular pathogen that is responsible for almost all cases of tuberculosis in humans. Tuberculosis is primarily a respiratory disease that primarily spreads through the air via aerosol droplets that are inhaled into the lungs. (Smith 2003) Although tuberculosis is primarily a respiratory disease that spreads through aerosol droplets, in the Delaware outbreak, M. tuberculosis was transmitted through donor-transplanted bone marrow, which is a rare phenomenon but has been associated with increased virulence of the bacterium. 

Cases

March-April 2021: 

– Seven patients develop tuberculosis after spinal surgery at a Delaware acute care hospital. 

– Hospital staff identifies a single common exposure: implantation of bone allograft material (FiberCel product A) from a single product lot. 

May 25, 2021: 

– The Delaware Division of Public Health (DPH) is notified of the seven cases. – DPH notifies CDC, requests a field investigation, and issues a nationwide call for cases. 

June 2, 2021: 

– CDC deploys a team to Delaware to investigate the epidemiology of cases and opportunities for transmission. They provide prevention and treatment recommendations. 

– Another state health department notifies CDC about a person who developed tuberculosis after surgery involving the same product A lot. 

– The manufacturer (Aziyo Biologics Inc.), issues a voluntary nationwide recall. June, 2021: 

– By June 4, The CDC advised patients nationwide who had undergone surgery using the product A lot should be promptly evaluated and treated with the 4 drug regimen for tuberculosis, irrespective of whether or not they showed any symptoms. 

– On June 8th, the CDC recommended that all contacts of either the product A lot itself or product A patients undergo exposure evaluations. The CDC specifically recommended a risk assessment, symptom screens, interferon-gamma release assays (IGRAs), and tuberculin skin tests.

– By June 24, CDC identified 152 healthcare workers and 7 patients exposed to FiberCel product A. 

– June 25, 19 of the 23 surgery patients had laboratory or imaging evidence of tuberculosis in the spine or chest. 

– All 22 living patients begin standard four-drug treatment for tuberculosis 41 to 91 days after product implantation (median = 69 days). 

Ongoing: 

– The Delaware Division of Public Health (DPH) is working with CDC to investigate all future reports of TB following spinal surgeries. All members exposed to product A have been identified. As such, there is minimal risk of uncontrolled spread of M. tuberculosis. Patients exposed to FiberCel product A are on the 4 drug regimen for TB, which consists of nearly a dozen pills/day. In order for TB treatment to be effective, treatment must be maintained perfectly for a full year, such that DPH has required all patients to record and share themselves taking the medication daily. As the CDC deemed the investigation an emergency public health activity, institutional board review and informed consent were deemed unnecessary.

Diagnostics Used 

Since standard tuberculosis testing methods were inadequate in detecting M. tuberculosis in exposed tissues, unconventional technologies had to be used. In the outbreak involving product A, tissue recipients were tested for tuberculosis disease using smear microscopy, nucleic acid amplification, and clinical disease culturing. 

Smear microscopy is a microscopic examination technique used to detect acid-fast organisms, which are a group of bacteria that are able to resist decolorization by acids during laboratory staining. Considering that M. tuberculosis is categorized as an acid-fast organism, smear microscopy can be used as an initial screening tool. However, smear test results are directly proportional to the number of bacteria present in a sample, and are used primarily to identify the most infectious cases. “Smear-positive patients are 5-10 times more infectious than smear negative patients.” (Edwards, 2016) 

Nucleic acid amplification (NAA) tests are a fairly new method of testing for tuberculosis disease. NAA is a method of detecting genetic material in a specimen. It is incredibly accurate and very unlikely to produce a false-negative result. In the United States, there are two approved NAAs approved to test for M. tuberculosis, AMPLICOR and the Amplified MTD test. The Amplified MTD test is used for both smear-negative and positive specimens while the AMPLICOR test is only approved for smear-positive specimens. (Walter, Daley, 2012) Both tests are about 90-100% effective in detecting TB in previously smear-positive specimens and only cost around $7 per sample (Maritz, Presier, 2011). 

In this specific outbreak, NAA tests were conducted primarily for the purpose of data collection and contact tracing. All living recipients of the product A lot were treated for TB disease, irrespective of their initial test results. Tuberculin skin tests were then used to monitor the need for further treatment. 

Clinical disease culturing was used to further confirm test results as it is considered to be the most sensitive method for detecting the presence of M. tuberculosis bacteria. It is not used as an initial disease testing method due to the higher costs associated with culturing over other mass producible tests (Dowdy, Lourenço, Cavalcante, et. al., 2008). 

Following the diagnoses, all recommended TB treatments were followed. Primarily, TB treatment consists of a 4 drug regimen, consisting of “isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin.” (Herchline, Amorosa, 2020) In bone tuberculosis, revision surgery may also be required to “obtain diagnostic specimens and manage complications.” (Lee, 2015) In this case, all patients underwent antibiotic treatment with some undergoing revision surgery. (Pradelli, Mettendorf, 2021)

Impact on Society and Public Health 

The tuberculosis outbreak stemming from the product A lot is considered to be the “largest recorded tissue-derived tuberculosis outbreak.” (Schwartz, Hernandez-Romieu, Annambhotla, et. al., 2022) The conventional screening process failed to identify any signs of infection in both donor and donated tissues. Prior to the 2021 bone graft tuberculosis outbreak, the FDA regulated Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) using a risk-based approach. This meant that the donor was to be screened for possible disease transmission, the manufacturing process was to be free of contamination, and there was to be a demonstration of safety in high-risk tissues. (FDA, 2019) In this case, there could have been a failure in any of these steps. Considering the donor was deceased, it could have been difficult or impossible to adequately screen them for possible disease contact. There could have also been a failure in the manufacturing process, where a source of contamination may have been present.

This investigation revealed the high attack rates of spinal tuberculosis after surgical implantation, as well as several chances for exposure to M. tuberculosis during surgery and patient care. It also revealed the willingness of the CDC to forgo existing informed consent and institutional board review practices. 

Following the outbreak, FDA introduced several new rules for the regulation of HCT/Ps in their Guidance for Industry document. Specifically, it established more stringent safety standards for HCT/Ps and granted the FDA the authority to enforce and inspect compliance with these regulations. (FDA, 2022) This was a significant change from previous regulations, which were criticized as being too lax and allowing for too much self-policing by industry participants. 

The number of reported tuberculosis cases in the United States has been decreasing since 1993. However, in 2021, the number of cases increased by 9.4%, partially due to delayed diagnoses of cases from the previous year. The recent outbreak in Delaware accounted for only a small percentage of this increase. Specifically, while Delaware had an increase from 17 cases in 2020 to 43 cases in 2021, the total number of cases in the United States rose from 7173 in 2020 to 7860 in 2021. Therefore, the Delaware outbreak only contributed to a maximum of 3.78% of the overall increase in cases. 

Summary

Between March and April 2021, seven patients contracted tuberculosis after spinal surgery at a Delaware hospital that used FiberCel bone allograft material from a single product lot. The culprit was Mycobacterium tuberculosis, which was transmitted through transplanted bone marrow from a donor – a rare occurrence. As a precautionary measure, the CDC advised all patients who received tthe CDC advised all patients who received the same product lot to undergo evaluation and treatment for tuberculosis, regardless of their symptoms. Additionally, all individuals who had contact with either the product or the patients were recommended to undergo exposure evaluation. The CDC identified 152 healthcare workers and 7 patients who were exposed to the product, and 19 of the 23 surgery patients had evidence of tuberculosis in their spine or chest. All living patients began treatment for tuberculosis 41-91 days after product implantation, regardless of test results. The Delaware Division of Public Health is collaborating with the CDC to investigate future reports of tuberculosis following spinal surgeries. 

To diagnose tuberculosis disease in the exposed tissues, smear microscopy, nucleic acid amplification, and clinical disease culturing were utilized. Tuberculin skin tests were then continuously used to assess the need for further treatment. Clinical disease culturing was used to confirm test results, as it is the most sensitive method for detecting the presence of M. tuberculosis bacteria.

References

Aziyo Biologics Inc. (2019, October). FiberCel. Aziyo. Retrieved April 26, 2023, from https://www.aziyo.com/wp-content/uploads/2020/07/IFU-0021-Rev03-FiberCel.pd f 

Centers for Disease Control and Prevention. (2021, September 9). Notes from the field: Tuberculosis outbreak linked to a contaminated bone graft product used in spinal surgery – Delaware, March–June 2021. Centers for Disease Control and Prevention. Retrieved April 22, 2023, from 

Centers for Disease Control and Prevention. (2022, March 25). Tuberculosis – United States, 2021. Centers for Disease Control and Prevention. Retrieved April 22, 2023, from https://www.cdc.gov/mmwr/volumes/71/wr/mm7112a1.htm 

Dowdy, D. W., Lourenço, M. C., Cavalcante, S. C., Saraceni, V., King, B., Golub, J. E., Bishai, D., Durovni, B., Chaisson, R. E., & Dorman, S. E. (2008). Impact and cost-effectiveness of culture for diagnosis of tuberculosis in HIV-infected Brazilian adults. PloS one. Retrieved April 22, 2023, from 

Edwards, C. (2011, February 11). AFB Smear Microscopy. APHL. Retrieved April 22, 2023, from 

https://www.aphl.org/programs/infectious_disease/tuberculosis/TBCore/TB_AFB_ Smear_Microscopy_TrainerNotes.pdf 

FDA. (2019, May 7). Tissue and tissue product questions and answers. U.S. Food and Drug Administration. Retrieved April 22, 2023, from 

https://www.fda.gov/vaccines-blood-biologics/tissue-tissue-products/tissue-and-ti ssue-product-questions-and-answers 

Food and Drug Administration. (2020, July). Regulatory considerations for human cells, tissues, and cellular and …Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use. Retrieved April 22, 2023, from https://www.fda.gov/media/109176/download 

Food and Drug Administration. (2022, November). Regulation of human cells, tissues, and cellular and tissue-based …Regulation of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps). Retrieved April 22, 2023, from https://www.fda.gov/media/70689/download 

Lee, J. Y. (2015, April 2). Diagnosis and treatment of extrapulmonary tuberculosis. Tuberculosis and Respiratory Diseases. Retrieved April 22, 2023, from http://e-trd.org/journal/view.php?doi=10.4046%2Ftrd.2015.78.2.47 

Madison B (2001). “Application of stains in clinical microbiology”. Biotech Histochem. 76 (3): 119–25. doi:10.1080/714028138. PMID 11475314.

Maritz, J., & Preiser, W. (2011, April). Cost-effectiveness of nucleic acid amplification tests for identifying acute HIV infections. Journal of clinical microbiology. Retrieved April 22, 2023, from 

Parrish, N. M., & Carroll, K. C. (2011, March). Role of the clinical mycobacteriology laboratory in diagnosis and management of tuberculosis in low-prevalence settings. Journal of clinical microbiology. Retrieved April 22, 2023, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3067741/ 

Pradelli, C., & Mettendorf, C. (2021, June 25). Investigation: Lawsuit alleges delaware woman, others exposed to tuberculosis during surgery. 6abc Philadelphia. Retrieved April 22, 2023, from 

https://6abc.com/tuberculosis-lawsuit-cdc-outbreak-delaware-bone-repair/108278 06/ 

Ryan KJ; Ray CG, eds. (2004). Sherris Medical Microbiology (4th ed.). McGraw Hill. ISBN 0-8385-8529-9. 

Schwartz, N. G., Hernandez-Romieu, A. C., Annambhotla, P., Filardo, T. D., Althomsons, S. P., Free, R. J., Li, R., Wyatt Wilson, W., Deutsch-Feldman, M., Drees, M., Hanlin, E., White, K., Lehman, K. A., Thacker, T. C., Brubaker, S. A., Clark, B., Basavaraju, S. V., Benowitz, I., Burton Glowicz, J., … Haddad, M. B. (2022, November). Nationwide tuberculosis outbreak in the USA linked to a bone graft product: An outbreak report. The Lancet. Infectious diseases. Retrieved April 22, 2023, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9605268/ 

Smith I. (2003). Mycobacterium tuberculosis pathogenesis and molecular determinants of virulence. Clinical microbiology reviews, 16(3), 463–496. 

Snyder, A. (2018, August 27). Bone tuberculosis: Symptoms, causes, and treatment. Healthline. Retrieved April 22, 2023, from 

Sun, L. H., & Bernstein, L. (2021, June 18). CDC investigating TB cases linked to tainted bone repair product used in more than 100 patients. The Washington Post. Retrieved April 22, 2023, from 

Talbot, E. A., & Raffa, B. J. (2014, September 29). Mycobacterium tuberculosis. Molecular Medical Microbiology (Second Edition). Retrieved April 26, 2023, from https://www.sciencedirect.com/science/article/pii/B9780123971692000925 

Thomas E Herchline, M. D. (2022, March 4). Tuberculosis (TB) treatment & management. Approach Considerations, Treatment During Pregnancy, Treatment in Children. Retrieved April 22, 2023, from 

Walter, N., & Daley, C. L. (2012, September 14). Tuberculosis and nontuberculous mycobacterial infections. Clinical Respiratory Medicine (Fourth Edition). Retrieved April 22, 2023, from