A cluster of fatal donor-derived arenavirus cases was reported in Australia in 2008, in which the infectious agent was a previously unidentified LCMV-related arenavirus. The donor in this cluster was a 57-year-old man who died of cerebral hemorrhage 10 days after returning to Australia from a 3-month visit to the former Yugoslavia, where he had travelled in rural areas. No viral nucleic acids were detected in the donor, and no history of acute infectious disease was reported; however, IgG and IgM antibodies were present. He donated his liver and both kidneys to 3 recipients, all of whom developed febrile illness with varying degrees of encephalopathy and proceeding to death within 4 to 6 weeks of transplantation. Bacterial and viral cultures, NAT, and viral and panmicrobial oligonucleotide microarray assays revealed no candidate pathogens, and therefore, RNA was extracted from the brain, cerebrospinal fluid (CSF), serum, liver, and kidney of one of the kidney recipients, and from the CSF and serum of the liver recipient. High-throughput sequencing of amplified RNA samples and examination of Vero E6 cells inoculated with homogenized fresh-frozen kidney tissue revealed the presence of an arenavirus with an identical but previously uncharacterized genetic sequence in the recipients.
The case above highlights the challenges of identifying central nervous system infections particularly in donors dying from CVA and the potential for rare and uncharacterized infectious agents to be transmitted by organ transplantation. To aid decision making in this context, the United States OPTN has formulated a guidance document for recognizing central nervous system infections in potential deceased organ donors. Issues for consideration highlighted by this document are listed in Table 27.
The number of tuberculosis notifications in Australia in 2016 was 1217 (5.1 per 100 000 population, National Notifiable Disease Surveillance System 2016 data set). The vast majority (approximately 90%) of these cases occurred in Australia's overseas-born population, among which the incidence of tuberculosis is approximately 20 times that of the Australian-born, non-Indigenous population (18.4 vs 0.7 notifications per 100 000 in 2013 respectively). NSW and Victoria account for more than 50% of all tuberculosis cases in Australia, whereas the Northern Territory has the highest jurisdiction-specific notification rate (17.1 per 100 000 in 2013). Tuberculosis incidence in ATSI peoples was 4.6 cases per 100 000 in 2013.
The most frequently reported countries of birth for tuberculosis cases in Australia in 2013 were India, Vietnam, the Philippines, and China. Relative to population size, the highest rates of tuberculosis in 2013 were reported for Australian residents born in Somalia, Nepal, Myanmar, Afghanistan, Papua New Guinea, and Sudan. Of those diagnosed within 4 years of arrival in Australia, international students accounted for 21% of tuberculosis cases in 2013. The contribution of international students and the demographics of the Australian resident migrant population (median age, 37 years; ABS 34120DO001_201415) would account for the bimodal distribution of tuberculosis notifications seen in Figure 11.
Major risk factors contributing to notified cases of tuberculosis in Australia in 2013 were past travel or residency in a high-risk country (81% of cases), household, or other close contact with tuberculosis (11% cases), or current or previous employment in the health industry (7%). Other risk factors that were present in a small proportion of cases (5%) included current or prior incarceration, current or prior residence in an aged care facility, current or prior employment at a correctional facility, aged care facility or homeless shelter, current or prior homelessness, parent born in a high-risk country, or being treated with immunosuppression.
Australia has had very few cases of multidrug-resistant tuberculosis, and these have occurred almost exclusively in the overseas-born population. Of cases where drug sensitivity testing was performed in 2013, 0.3% had resistance to rifampicin alone, 5.2% to isoniazid alone, and 2.4% to both rifampicin and isoniazid (MDR-TB). Zero cases of extensively drug-resistant tuberculosis were reported in 2013:only 2 cases of XDR-TB have been reported since 1995. Figure 12 shows trends in the proportion of tuberculosis cases that were multidrug-resistant since 1995. The spike in 2010 is accounted for by 10 patients with MDR-TB from Papua New Guinea accessing healthcare services in the outer Torres Strait Protected Zone.
Incidence of tuberculosis among solid-organ transplant recipients is much higher than the general population, especially among lung transplant recipients. Tuberculosis most commonly appears in the transplanted population due to reactivation of latent infection:an audit at Westmead Hospital Sydney estimated that 30% of waitlisted patients had latent tuberculosis (personal communication: A Webster):but it may also be acquired as a de novo infection posttransplant, or be transmitted via the donor organ. In the United States, tuberculosis is one of the most common donor-derived bacterial infections. Data from Europe and the United States indicate that 0.4% to 7% of solid-organ recipients develop tuberculosis, and donor-derived transmission accounts for less than 5% of these cases. Risk factors for tuberculosis among potential donors include (1) social factors:country of origin or prior residence in an endemic country, history of homelessness, incarceration or alcoholism, and/or contact with persons infected with tuberculosis; and (2) medical risk factors:history of untreated tuberculosis, radiographic evidence of prior tuberculosis, body mass index less than 18.5, diabetes mellitus, and/or cigarette smoking.
A recent matched cohort study comparing the clinical features and outcomes of tuberculosis in transplant recipients versus the Spanish general population found that time from clinical suspicion of tuberculosis to diagnosis (positive acid-fast bacilli smear, histopathological pattern of tuberculosis, positive NAT or M. tuberculosis culture) was longer in transplant recipients than in the general population (median, 14 days vs 0 days) and more often required invasive procedures. This study also found that rates of tuberculosis-related mortality were higher among transplant recipients than the general population (18% vs 6%), as were rates of toxicity associated with antituberculosis treatment (38% vs 10%). Tuberculosis in transplant recipients often resists timely diagnosis and is associated with worse outcomes than observed in the general population.
One of the challenges for the detection of donor-derived tuberculosis is that disease in donors and recipients may not present as a primary respiratory infection and, therefore, may not be recognized straight away, contributing to delays in diagnosis and reporting. Pulmonary disease accounts for approximately 60% of cases in the Australian general population, with 40% being extrapulmonary. By comparison, extrapulmonary disease accounts for closer to half of tuberculosis cases in the transplant population, and disseminated tuberculosis is substantially more common. Where the donor was born in, or recently travelled to, an endemic country, or where other tuberculosis risk factors are present, the possibility of extrapulmonary tuberculosis should be considered in recipients presenting with an infection of unknown origin. This is of course dependent on the availability of a detailed, accurate donor history, which will not exist in all circumstances.
In living donors, it is possible to perform tuberculosis screening in accordance with recommended guidelines; however, in potential deceased donors, this is problematic because there are no proven methods for screening deceased donors for tuberculosis. Chest X-ray and direct microscopy of BAL for acid-fast bacilli have a low sensitivity, and cultures may take up to 8 weeks to turn positive. Tuberculin skin testing is also impractical in the context of deceased donation given a turnaround time of at least 48 hours. NAT can identify M. tuberculosis in clinical specimens from donors with active infection only. Therefore, when these tests are performed, a negative/normal result does not definitively rule out infection with M. tuberculosis, due to the high rate of false negatives and because organisms can remain dormant in the host without causing disease for decades, without any detectable radiographic abnormality. Conversely, abnormal pulmonary findings from a range of causes are common in deceased donors and may confound donor evaluation.
Interferon-gamma release assays (IGRAs) might theoretically be useful given their shorter turnaround time (~24 hours). These assays work by stimulating peripheral blood cells with specific antigens; in response, T cells recognizing these antigens are rapidly activated and secrete a variety of cytokines, of which interferon gamma is measured to indicate the pathogen-specific activation of T cells. Interferon gamma release assays are available commercially as T-SPOT.TB (Oxford Immunotec, UK) and QuantiFERON-TB Gold in-Tube (Cellestis, Australia). Drawbacks of these tests include high cost and indeterminate results in immunosuppressed persons; moreover, IGRAs have not yet been validated for use in deceased donors, and it is not known whether brain death impacts the performance of this assay. Further, false-positive results will be common in low-risk populations, whereas false-negative may occur in cases of miliary or disseminated tuberculosis. Therefore, the results of IGRAs cannot be relied upon to either definitively exclude active disease nor as grounds for rejecting a given donor.
Given the limitations of tuberculosis screening tools in deceased donors, it is important to evaluate social and medical risk factors in the potential deceased donor. Country of origin and/or prior residence in a highly endemic country is a key risk factor. Tuberculosis country profiles can be reviewed at www.who.int/tb/data., Although difficult to obtain, patient histories for possible contacts with persons infected with M. tuberculosis are important.
Given the global challenges of tuberculosis screening in potential organ donors, an international consensus group was formed to provide expert recommendations on this subject. A summary of the recommendations of this group is provided in Table 28.
Current UK and European donor screening guidelines make the following recommendations with respect to tuberculosis and organ donation:
SaBTO: Donation of organs, tissues and cells is contraindicated from donors with active disease or within the first 6 months of antituberculosis treatment. However, organs can be considered for transplant if a recipient has received a 6-month course of chemotherapy, unless the isolate is found to be resistant to appropriate antituberculosis drugs. If there is a history of tuberculosis at the site of the organ to be used for donation, use of that organ is contraindicated by the donation of other organs is acceptable.
EDQM: Organs from donors with disseminated tuberculosis should not be used. Organs from donors with a history of TB and with successful treatment for at least 6 months may be considered, with prophylaxis and/or empiric treatment considered for the recipient in accordance with international guidelines.