By Richard R. Watkins, MD, MS, FACP, FIDSA, FISAC
Professor of Internal Medicine, Northeast Ohio Medical University, Rootstown, OH
SYNOPSIS: An 80-year-old man with undiagnosed tuberculosis (TB) became a bone tissue donor after his death from a cardiac arrest. Bone graft product was given to 113 recipients in 20 states, of whom three died of TB. All living recipients were started on treatment for TB at a median of 69 days after bone product implementation.
SOURCE: Schwartz NG, Hernandez-Romieu AC, Annambhotla P, et al. Nationwide tuberculosis outbreak in the USA linked to a bone graft product: An outbreak report. Lancet Infect Dis 2022;22:1617-1625.
Tuberculosis (TB) transmission is known to occur from organ and/or tissue donors with undetected or latent infection. When such transmission occurs, it results in significant morbidity and mortality. Schwartz et al described a TB outbreak in the United States from a single bone tissue product donor that affected more than 100 patients in 22 states.
The donor was an 80-year-old man who lived in the United States but previously had lived and frequently traveled to a country with an annual TB incidence > 20 cases/100,000 people. The country was not identified. The donor did not have a known history of TB infection or latent TB, illicit drug use, homelessness, incarceration, or alcoholism. His medical history included end-stage kidney disease requiring hemodialysis, type 2 diabetes, congestive heart failure, and coronary artery disease. The donor presented to the hospital with a two- to three-week history of worsening dyspnea, cough, orthopnea, and lower extremity edema following multiple missed hemodialysis sessions. He also reported a 35-kg weight loss over the preceding two years, which he attributed to dietary changes.
The initial chest radiograph showed patchy bilateral airspace disease with a small pleural effusion. During the hospital course, he was treated with antibiotics for community-acquired pneumonia and underwent hemodialysis. He developed bradycardia and cardiac arrest, and then had extended cardiopulmonary resuscitation. Three days after the cardiac arrest, he was transitioned to comfort care and died. No mycobacterial testing was performed during the hospitalization. Medical records attributed his cough and dyspnea to heart and kidney failure.
Subsequent work by the outbreak investigators determined that the donor had a negative tuberculin skin test four months prior at the dialysis center. At that time, he completed a TB risk assessment form and answered no to all the questions. Standard donor testing at the time of bone tissue procurement was negative for human immunodeficiency virus (HIV), hepatitis B and C, syphilis, and human T-lymphotrophic virus.
The long bones of the upper and lower extremities and pelvis were recovered from the donor. These were turned into a product that included demineralized cortical bone and cancellous bone processed to retain live cells. The manufacturer performed testing for bacteria and fungi on samples collected during processing and on the final product but did not test for Mycobacterium tuberculosis.
The bone product was subsequently used in 113 human recipients. Their median age was 61 years (range 52-71 years), 57 (50%) were men, 12 (11%) were immunocompromised, and almost all (112/113) had bone grafts implanted in the spine. Furthermore, 87/113 (77%) developed microbiological or radiographical evidence of TB. Disease at the surgical site was present in 83 (73%) recipients and 28 (25%) had disseminated disease. The median time from product implantation to microbiological or imaging evidence of TB was 65 days (range, 49-78 days). After recognition of the outbreak, investigators attributed three deaths to TB and three to unrelated causes. The bone product was recalled by the manufacturer, while all 105 living recipients started active treatment for TB at a median of 69 days (range, 56-81 days) after product implantation. Investigation of the outbreak was ongoing as of July 2022.
COMMENTARY
In this outbreak of donor tissue-derived TB, standard screening methods failed to detect infection in the donor. TB developed rapidly and disseminated in one-quarter of the recipients. This likely was because of several factors. First, the bone product was found to contain a high mycobacterial load. Second, the mycobacteria were directly inoculated into skeletal sites, thus bypassing the immune defenses of the respiratory system. Third, the contents of the bone product, such as live cells and bone proteins, could have facilitated mycobacterial growth. Finally, post-operative vascular permeability may have helped the mycobacteria to disseminate.
So, what lessons can be learned from this unfortunate event? The donor’s tuberculin skin test performed four months prior to his hospitalization likely was a false-negative result. Other testing methods, such as an interferon-γ release assay or nucleic acid amplification testing (NAAT), should be considered for donors with risk factors for TB, such as residing in a country with a high incidence of TB like the donor had. However, NAAT for M. tuberculosis is only currently Food and Drug Administration-approved for sputum samples. Based on the results of this study, the American Association of Tissue Banks recommended that polymerase chain reaction (PCR) testing be considered for tissues obtained from donors with TB risk factors or minimally processed tissues at highest risk for transmitting TB, including any tissue with viable cells.
This study highlights the ongoing need to improve safety in tissue transplantation. Currently there are no requirements to perform mycobacterial testing on bone donor samples or products in the United States. At a minimum, this should be reconsidered given the devastating consequences of donor-derived TB. It also is hoped that clinicians involved with transplantation will carefully assess for risk factors for TB in donors to mitigate the risk of future outbreaks.
