Diagnosis and Management of Tuberculosis in Transplant Donors: A Donor-Derived Infections Consensus Conference Report

Authors


  • Endorsed by American Society of Transplantation, Canadian Society of Transplantation, and The Transplantation Society

Michele I. Morris, mmorris2@med.miami.edu

Abstract

Mycobacterium tuberculosis is a ubiquitous organism that infects one-third of the world's population. In previous decades, access to organ transplantation was restricted to academic medical centers in more developed, low tuberculosis (TB) incidence countries. Globalization, changing immigration patterns, and the expansion of sophisticated medical procedures to medium and high TB incidence countries have made tuberculosis an increasingly important posttransplant infectious disease. Tuberculosis is now one of the most common bacterial causes of solid-organ transplant donor-derived infection reported in transplant recipients in the United States. Recognition of latent or undiagnosed active TB in the potential organ donor is critical to prevent emergence of disease in the recipient posttransplant. Donor-derived tuberculosis after transplantation is associated with significant morbidity and mortality, which can best be prevented through careful screening and targeted treatment. To address this growing challenge and provide recommendations, an expert international working group was assembled including specialists in transplant infectious diseases, transplant surgery, organ procurement and TB epidemiology, diagnostics and management. This working group reviewed the currently available data to formulate consensus recommendations for screening and management of TB in organ donors.

Abbreviations: 
AFB

acid-fast bacilli

ATS

American Thoracic Society

BCG

Bacillus Calmette-Guerin vaccine

BMI

Body mass index

CDC

Centers for Disease Control

CNS

central nervous system

CXR

chest radiography

c/w

consistent with

ELISA

enzyme-linked immunosorbest assay

ELISPOT

enzyme-linked immunospot assay

GU

genitourinary

IDSA

Infectious Diseases Society of America

IGRA

Interferon-gamma release assay

INH

Isoniazid

LTBI

latent tuberculosis infection

Mm

millimeter

NA

not applicable

NAA

nucleic acid amplification

NTM

non-tuberculous mycobacteria

n

number

OPO

Organ procurement organization

OPTN

Organ Procurement and Transplantation Network

PPD

Purified protein derivative

QFT

QuantiFERON-TB Gold In-Tube assay

TB

tuberculosis

SOT

solid organ transplant

TST

tuberculin skin testing

UNOS

United Network for Organ Sharing

US

United States

Introduction

Solid-organ transplant (SOT) recipients have a significantly increased risk of developing infection with Mycobacterium tuberculosis compared with the general population (1,2); the infection may come from the transplant donor or recipient, or be community acquired. The risk of disseminated infection and death due to tuberculosis (TB) is higher in transplant recipients (3). Posttransplant TB is more common in lung recipients (2.6% in Spain) than in liver transplant patients (1.6% in Brazil), although the variation may depend on the local incidence of infection rather than the organ transplanted (4,5). Transplant candidates should be screened for latent tuberculosis infection (LTBI), i.e. dormant infection with Mycobacterium tuberculosis but without active tuberculosis. Pretransplant recipient screening protocols often include obtaining a history of potential prior exposure or LTBI treatment, tuberculin skin testing (TST) and chest radiography (CXR), though interferon-gamma release assays (IGRAs) are increasingly used (6,7).

While the majority of posttransplant TB cases occur secondary to reactivation in recipients with unrecognized or untreated LTBI, transmission of M. tuberculosis through the allograft can occur. Donor-derived TB is often unrecognized, especially in areas of low TB prevalence, resulting in significant morbidity and mortality (8). Global travel and immigration have resulted in an increasingly diverse transplant donor population in lower incidence countries, while organ transplantation has increased in some of the higher incidence regions, both factors affecting the overall incidence of donor-derived TB. The incidence of posttransplant TB varies greatly depending on the local prevalence of M. tuberculosis infection, ranging from 1% in Germany to 13.7% in India (9). Studies in the United States and Europe suggest that 0.35–6.6% of recipients develop TB, and 4% of those cases are donor derived (1). TB is one of the more common bacterial causes of donor-derived infection in the United States (10).

Solid-organ transplant centers in endemic areas may provide a model for screening and treatment of donors and recipients; nonetheless, little data exist to address the use of newer diagnostics in donor screening (11). Current screening and diagnostic modalities were designed to identify cases of latent TB infection. It is perhaps more essential that screening protocols identify donors with unrecognized active TB. To improve diagnosis and management of tuberculosis in transplantation, an international group of transplant physicians and TB experts convened a consensus conference to review the existing data and formulate recommendations for solid-organ donor TB screening (Tables 1 and 6, Figures 2 and 3). Recommendations were based on a thorough review of the best available evidence, recognizing that prospective randomized studies were generally not available; expert opinion was also included.

Table 1.  Summary consensus recommendations
Tuberculosis epidemiology recommendations:
 1. Organ donors can be divided into low, moderate and high-risk categories for risk of TB infection or LTBI based on detailed history and prior countries of residence/exposure. It should be noted that some donors thought to have LTBI may actually have undiagnosed active TB at the time they become an organ donor. Individuals with active TB will likely pose a greater risk for transmission; therefore, it is especially critical to identify these patients prior to donation.
 2. Risk stratification based on donor social and medical history may be predictive of TB infection (either LTBI or unrecognized active TB) in donors and hence possible risk of TB transmission to organ recipients.
 3. Diagnosis of LTBI and assessment of risk for transmission in organ donors optimally should be based on objective medical data such as prior historical results of TST, IGRA and CXRs
 4. The presence of TB disease in individuals currently residing in low risk countries is closely correlated with the donor's prior countries of origin and residence (33)
 5. Epidemiologic data can be used to target diagnostic evaluation of donors and recipients and formulate management algorithms. It therefore may be useful to include this information when evaluating donors.
 6. It is currently unknown how recipient history modifies the impact of donor epidemiologic risk factors on the probability of transmission of TB through transplantation. Factors such as recipient immunogenetics may confound donor risk stratification when evaluating transplant outcomes
Tuberculosis screening recommendations–all donors:
 1. Reasonable efforts must be made to rule out active TB in the donor with any identified historical or epidemiologic risk factors. For suspected or confirmed cases of active TB, donation should be deferred except in dire circumstances
 2. All SOT donors (living and deceased) should have a careful epidemiologic and personal medical history, physical and a chest radiograph
 3. TST and IGRA test results should be cautiously interpreted taking into consideration the epidemiologic history and chest radiograph findings. A negative result on an immunological test such as TST or IGRA does not rule out active TB
 4. For lung donors, bronchoscopy specimens should be obtained for mycobacterial testing for TB and atypical mycobacteria (AFB smear and culture at a minimum) prior to donation
 5. Molecular methods for mycobacterial culture and species identification are preferred to standard culture if available, due to the shorter turn-around time
 6. There is insufficient evidence to recommend IGRA testing of all SOT donors at this time. Further research into the utility of IGRAs in donors is needed. IGRAs have potential utility for identification of increased TB risk deceased donors (moderate or high risk)
 7. Donation need not be deferred for the diagnosis of latent TB in any SOT donor including lung donors
 8. Urinalysis with microscopy, genitourinary imaging and urine AFB smear and culture should be considered for all organ donors in intermediate- and high-risk countries. This is particularly important for kidney donors
Tuberculosis screening recommendations–deceased donors
 1. In deceased donors of solid organs other than lungs, who have an abnormal chest radiograph suspicious for active TB, specimens should be collected for AFB smear and culture, and specimens should be sent for nucleic acid amplification testing (34,35). The results of these tests can be used to guide further investigations and treatment in the recipients. Teams may have limited information when deciding whether to proceed to transplant (see Table 6 for further guidance)
 2. There is insufficient evidence to recommend routine IGRA testing of deceased donors. However, if IGRA testing is pursued, the following considerations should be taken into account
 a. IGRA results are not generally available for 24 h. Therefore, the decision to utilize the organs must be a clinical decision
 b. IGRAs have relatively high rates of indeterminate results in different subpopulations (0–16%) (23). Repeat testing of a donor is generally not feasible. Therefore, interpretation of these results must be done cautiously as it has possible therapeutic implications for the recipient(s)
 c. If an IGRA is positive or indeterminate and the deceased donor of any organ except lung is from an area of low incidence for TB but otherwise in a high risk group for TB, clinical history and chest imaging should be carefully reviewed for correlation. This should precede donation if the positive result is known prior to procurement. Regardless, the IGRA testing results alone should not influence suitability for donation, but may be used to guide follow up assessments or TB therapy in the recipient
 d. Literature suggests that cell-mediated immunity is depressed following head injury (36,37). Therefore, persons with head injury may not respond to mitogen. This situation has not been specifically studied with IGRAs
 e. There is minimal published information regarding the performance characteristics of IGRAs in infants and young children (38,39)
Tuberculosis screening recommendations–Living donors
General statements:
 1. When active TB is found in the donor, clinicians caring for the recipient must be rapidly informed in order for the recipient to be managed promptly; in cases involving ‘swaps’ of organs, the transplant centers and/or procurement organizations involved must notify the recipient centers as soon as possible
 2. Living donors with a positive TST or IGRA should be offered treatment for latent TB prior to donation or as per local or national guidelines. As completion of this treatment may delay the transplant and adversely impact the recipient, expert opinion was that each situation should be individualized, but the prophylaxis need not be completed before the transplant occurs. There are no data on optimal duration of LTBI therapy in this setting
 3. Information about living donor LTBI status and treatment history should be noted in the medical record of the organ recipient
 4. Chemoprophylaxis should be considered for recipients whose donor TB screening test (TST or IGRA) was positive, in cases where the donor did not receive either any or sufficient chemoprophylaxis. Recipient risk for INH toxicity must be weighed against the risk of donor-derived TB transmission; drug interactions with transplant medications and rifamycins (rifampicin, rifampin, rifabutin, rifapentine) should also be carefully considered after transplant. Clinicians should consider the impact of local TB resistance rates when developing effective chemoprophylaxis protocols, and should refer to local or national guidelines
Guidelines vary further with local TB risk, as specified here:
Low TB prevalence areas:
 1. We recommend that all living donors from areas with low TB prevalence be evaluated for TB with a directed history, physical examination, and CXR. TST or IGRA testing is recommended, with IGRA preferred in living donors with a history of prior BCG vaccination
Intermediate or High TB prevalence areas
 1. We recommend that living donors be tested for active TB in areas with intermediate or high incidence of TB using CXR. Testing the donor for LTBI can be considered and can help guide the risk of donor transmission. Either the TST or IGRA (or both) may be used for screening for LTBI, depending on history of BCG vaccination and cost plus availability of testing options
 2. INH treatment based only on transplant recipient screening (i.e. without donor screening) is reasonable in high incidence TB countries. Posttransplant INH treatment in high incidence countries may prevent reactivation, donor transmission and de novo infection during the posttransplant period of maximal immunosuppression, and may be justified in highly endemic areas. The optimal duration of such treatment is not known, and programs should weigh risk of toxicity with benefit of ongoing chemoprophylaxis
Table 6.  Recommendations for clinical management
Clinical scenarioRisk for transmissionRecommendation-living donorRecommendation-deceased donor
Latent TB   
 History of TB exposure or significant risk factors for TB -not testedVariableTest (refer to diagnostics section)Insufficient data on testing; monitor clinically
 History of latent TB-treated appropriatelyLowerMonitor recipient clinicallyMonitor recipient clinically
 History of latent TB-treated insufficiently or not treated or treatment details not clear OR new diagnosis of latent TB-positive TST/PPD or Interferon gamma release assay found during pretransplant evaluation; evaluation finds no evidence of active TBModerateConsider deferring transplant if possible until donor has taken some/all of chemoprophylaxis and consider chemoprophylaxis of recipient; monitor clinicallyMonitor recipient clinically; consider chemoprophylaxis of recipient with clinical monitoring. Recommend chemoprophylaxis for lung transplant recipients
 Unexplained pulmonary apical fibrosis in donor without cavitation and without additional testingVariableDefer donation pending further evaluationConsider testing donor (Diagnostics section). If tests are pending, consider whether high or low risk for TB before deciding whether to proceed; depends on local prevalence (Table 3), risk factors, quality of data available. If all definitive tests for TB are negative, accept as organ donor, but consider other possible causes of apical fibrosis (endemic mycoses, malignancy, etc). Consider chemoprophylaxis and/or clinical monitoring in higher risk TB donors
Active TB: history of active TB   
 History of active TB-site remote from transplant (i.e. pulmonary in a kidney donor)-treated appropriately over 2 years ago (Majority of relapses occur within first 2 years; see the text for details)Lower to moderateMonitor recipient clinically; consider cultures of previous TB sites if possible. Verify adequate treatment. May consider TB prophylaxis of recipientSame as living donor
 History of active TB-site remote from transplant (i.e. pulmonary in a kidney donor)-treated appropriately within 2 yearsLower to moderateMonitor recipient clinically; consider cultures of previous TB sites if possible; Consider/suggest chemoprophylaxis of recipient, particularly if adequacy of prior donor treatment cannot be fully verifiedSame as living donor
 History of active TB-site remote from transplant (i.e. pulmonary in a kidney donor)-treated insufficiently and/or with other than standard regimenHigherDefer live donors until adequately treated; consider consult with infectious disease specialist; recommend cultures of previous TB sites prior to transplant if possibleMonitor clinically; Recommend chemoprophylaxis (as per national guidelines); recommend cultures of previous TB sites; consider consult with infectious disease specialist
 Excluding disseminated or CNS TBIncreased risk if less than 2 years since active TB diagnosis  
 History of active TB-site same as transplant (i.e. renal TB in a kidney donor)-treated appropriately Organ should be carefully evaluated for function, as tuberculous lesions may result in scarring and be inappropriate for transplantModerateVerify treatment; monitor clinically; recommend chemoprophylaxis for recipient (as per local guidelines); recommend cultures of previous TB site(s); consider consult with infectious disease specialistSame
 History of active TB-site same as transplant (i.e. GU TB in a kidney donor)-treated insufficiently and/or with non-standard treatment.Organ should be carefully evaluated for function, as tuberculous lesions may result in scarring and be inappropriate for transplantHigherReject or defer live donors until adequately treated; recommend consult with infectious disease specialist; recommend cultures of previous TB sites either before (optimal) or at time of transplant; consider chemoprophylaxis versus treatment for active TB in recipient (as per local guidelines); monitor recipient clinicallyRecommend rejecting; in dire circumstances, accept and treat recipient for active tuberculosis with informed consent and involvement of infectious disease specialist
Active TB: microbiologic or pathologic diagnosis   
 Active TB at time of proposed donation-same site as transplant or site remote from transplant (i.e. pulmonary in a kidney donor) OR Positive TB culture/NAA positive from same site as transplant or from site remote from transplant (i.e. pulmonary in a kidney donor) recognized pretransplantHigherReject; may reevaluate after full treatment for active TB completed as per aboveStrongly recommend rejecting, particularly if TB is in same site as transplant organ; in dire circumstances accept and treat recipient for active tuberculosis with informed consent and involvement of infectious disease specialist
 Findings c/w possible active TB but no special cultures/NAA available pretransplant (i.e. AFB smear + in a deceased donor with TB vs NTM still undefined with a fibrotic CXR)-same site as transplant or site remote from transplantHigherDefer until further evaluation completedRecommend rejecting; in dire circumstances accept and treat recipient for active tuberculosis with informed consent and involvement of infectious disease specialist. Strongly recommend additional testing of donor, consider including IGRA if available; biopsy of affected organ can be taken for pathologic examination and NAA during organ procurement. Decision regarding recipient treatment versus chemoprophylaxis will depend on final outcome of donor cultures
 Positive AFB stain/TB NAA/TB Culture only known posttransplant-same site as transplant or site remote from transplant (i.e. pulmonary in a kidney donor)HigherTreat recipient (and donor) for active TB; recommend consult with infectious disease specialist.Report test results to the OPO and UNOS immediatelyTreat recipient for active TB; recommend consult with infectious disease specialist.Report test results to the OPO and UNOS immediately
 Findings c/w TB but no cultures (i.e. path only), data only known posttransplant-same site as transplant or site remote from transplant (i.e. pulmonary in a kidney donor)HigherFavor treating recipient (and evaluating donor) for active TB. Pursue molecular testing where possible. Adjust recipient treatment as needed based on results of donor testing. Recommend consult with infectious disease specialist. Report test results to the OPO and UNOS immediatelyFavor treating recipient for active TB. Pursue molecular testing where possible. Recommend consult with infectious disease specialist.Report test results to the OPO and UNOS immediately
Figure 2.

Recommended algorithm for screening and management of deceased donor candidates.*Results of recommended testing may be pending in deceased donors at the time of decision making and consultation with a transplant infectious disease specialist is recommended when possible to determine whether to proceed with donation. Consider other possible causes of radiographic abnormalities (endemic mycoses, malignancy, etc.). See Table 6 for further information. **Chemoprophylaxis is recommend in lung transplant recipients, others should be determined on a case-by-case basis.

Figure 3.

Recommended algorithm for screening and management of living donor candidates.

Donor-derived tuberculosis cases

Recent US reports of donor-derived TB transmission demonstrate some of the key features of the epidemiology and outcomes. These reports include 22 donors potentially affecting 55 recipients; of these, 16 recipients had confirmed transmission with two attributable deaths (8,10,12,13). Since there are no approved assays for screening donors for TB, it is critical to depend on the donor history and assessment for the presence of risk factors. For example, in several of the transmission events, the donor was born in an area of high TB endemicity; in most cases the transmitted TB could be typed to strains from the area where there donor was born (10,12). In another case, the donor had multiple risk factors for TB (alcoholism, homelessness and recent incarceration) and presented with recurrent pneumonia and findings suspicious for TB meningoencephalitis (8). In several transmission events, appropriate cultures for TB were sent but became positive well after the transplants had occurred (8,10,13). Unfortunately, communication of information to the procurement organization and the transplant centers regarding positive cultures was sometimes delayed, even though failure to report donor cultures is a violation of Organ Procurement and Transplantation Network (OPTN) policy, which requires reporting of positive results within 24 h. Lastly, although primary pulmonary TB can be a presenting illness in the recipient, fever of unknown origin, sepsis and organ dysfunction are more typical of transmission from nonpulmonary organs or in donors with disseminated disease at the time of donation (8,10).

Epidemiology

Understanding TB epidemiology and the net risk to the recipient is crucial for both appropriate donor screening and posttransplant management of symptomatic and asymptomatic recipients. Tuberculosis risk can be stratified by various social and medical risk factors, including organ transplanted and country of origin (Tables 2 and 3, Figure 1). The United States is among the nations with the lowest rates of TB (3.6/100 000), with most cases occurring in individuals who are foreign born (14). Thus in the United States, it is more likely that donor-derived TB may be associated with donors who were born or lived for a significant period of time in TB endemic countries.

Table 2.  Risk factors for tuberculosis (40)
Country of OriginIncidence ≥100/100 000
Social risk factorsHomeless
 Incarceration
 Alcohol
 Known TB contact
Medical risk factorsHistory of untreated TB
 Radiographic evidence prior TB
 BMI<18.5
 Diabetes mellitus
 Cigarette smoking
Organ transplanted ? Lung
Table 3.  Tuberculosis incidence by country of origin (41)
>300/100 000100–299/100 00050–99/100 00025–49 000<25/100 000
Africa with exceptionsAngolaChinaSpainNorth America
 notedTanzaniaSouth KoreaPortugalAustralia
CambodiaSomaliaLithuaniaEstoniaEurope with exceptions
 IndiaLatviaPoland noted
 PakistanIraqSaudi ArabiaJapan
 Southeast Asia with exceptionsYemenTurkeyLibya
  notedMoroccoSouthEgypt
 South PacificAlgeriaAmerica with exceptions 
 RussiaEcuador noted 
 MongoliaPeru  
 North KoreaBolivia  
 BelarusGuyana  
 UzbekistanSuriname  
 Turkmenistan   
 Czech Republic   
 Afghanistan   
Figure 1.

World Health Organization global TB incidence (41).

Issues that confound optimal epidemiologic risk stratification include the following:

  • • Donor exposure timing and the changing incidence of TB in geographic locales.
  • • Different TB reactivation risk based on the organ transplanted and the choice of immunosuppressives.
  • • The impact of prior TB exposure and genetic factors in the recipient.

Annual review of TB epidemiology is recommended to more accurately assess donor TB transmission risk.

Diagnosis

The increasing diversity of the organ donor population makes TB screening essential, even in countries with a low incidence of TB. The current method for donor screening for both latent and active TB includes history (prior TB exposures, history of active TB, travel or residence in endemic regions and past TST results), physical examination (pneumonia, unexplained cachexia or lymphadenopathy), cultures and thoracic imaging (old granulomatous disease, apical scarring, new infiltrates). For living donors, TST or IGRA screening may also be used. Specimens sent for acid-fast bacilli (AFB) staining and culture may be helpful when active TB is suspected, although cultures can take up to 8 weeks before turning positive. Nucleic acid amplification assays may identify M. tuberculosis in clinical specimens in individuals with active infection only. Deceased donors frequently have abnormal pulmonary findings due to unrelated causes, further confounding the evaluation.

The currently FDA approved screening methods for LTBI in the United States include the TST and the IGRAs: QuantiFERON-TB Gold in Tube assay (QFT) and T-SPOT.TB (Table 4). None of these tests differentiate active from latent TB, and it is not uncommon for any of these tests to be negative during times of active infection (15). A total of 10–25% of people with active TB do not react to PPD with 5 mm or greater of induration, patients with disseminated TB have a false negative test rate of approximately 50%.

Table 4.  Comparison of TST and IGRAs.
TestAvailabilityTATAdvantages/disadvantagesFeasibility
  1. There are no data yet on the clinical utility or test performance of IGRAs in the deceased donor population, or similar populations such as critical care unit patients or patients with head injury. It is unknown whether brain death may impact the performance of this assay.

TSTWidely available48–72 hLow costLiving Donors but not
   Need to return to have test reading feasible in deceased
   HCW expertise in administering and reading test donors
   False negative in immunosuppression 
   False positive after BCG vaccination, NTM 
Quantiferon-TB GoldCommercially available∼24 h+CostLiving or deceased donors
 (Cellestis Inc.,FDA approved No need for second visit 
 Victoria, Australia)Widely available Indeterminate results in immunosuppression 
   Lymphopenia may affect test 
   Not evaluated in deceased donors 
T-SPOT.TBCommercially available∼24 h+CostLiving or deceased donors
 (Oxford Immunotec,  No need for second visit 
 Oxford, U.K.)  Indeterminate results in immunosuppression 
   Not evaluated in deceased donors 

Laboratory assays to detect specific cellular immunity toward M. tuberculosis share many basic principles with skin testing, yet have different performance characteristics, specificity and sensitivity (16,17). The principle of these assays is to first stimulate peripheral blood cells with specific antigens; T cells recognizing these antigens are rapidly activated and secrete a variety of cytokines within hours after stimulation. These assays have been termed interferon-gamma release assays (IGRA), as interferon-gamma is measured to indicate pathogen-specific activation of T cells. An ELISPOT (enzyme linked immunospot) assay can determine the percentage of blood cells releasing interferon-gamma; an ELISA (enzyme-linked immunosorbent assay) can measure the quantity of interferon-gamma released into the plasma. Both assays are commercially available (ELISPOT as T-SPOT.TB by Oxford Immunotec, UK, ELISA as QuantiFERON-TB Gold In-Tube by Cellestis, Australia). A flow-cytometry based assay can detect the intracellular production of interferon-gamma by TB-specific T cells (18). Proper handling of specimens for cellular assays is imperative for optimal results; when initiating the use of such assays, programs should proceed carefully.

IGRAs have been shown to be of increased specificity compared with TST due to the use of highly specific antigens derived from M. tuberculosis, which are absent in all strains of Bacillus Calmette-Guerin (BCG) and most environmental mycobacteria including M. avium complex, thus a specific T cell response toward those antigens is a more specific marker for true M. tuberculosis infection than a TST-response towards PPD (17). In people who have received vaccination with BCG, a common practice in TB endemic areas, IGRAs have clear advantages over TST, given the increased specificity of the results.

The positive predictive value of IGRA responses for the development of TB has recently been studied, demonstrating that the rate of progression to active TB among those who are QFT positive (14.6%) is higher than in those that were TST positive (2.3%) (19). A study among HIV positive individuals in a low endemic area demonstrated a very high negative predictive value of IGRAs (20,21). IGRAs do not provide a major increase in sensitivity compared with TST. ELISPOT-based assays do appear to have higher sensitivity in immunocompromised patients compared to studies that used ELISA (16,17).

Use of immune-based tests in deceased donors

While TST is not feasible in deceased donors (due to the delay in development of a reaction), whole blood assays may be performed. In a deceased donor, it is important to assess whether antigen presenting cells and T cells are functional enough to produce an appropriate immune response. Therefore, a potential advantage of IGRAs in the deceased donor setting is that specific stimulation reactions are accompanied both by a negative control that allows assessment of nonspecific background reactivity, and also by a mitogen stimulus that is used as a positive control to assess general T cell responsiveness. This may allow for interpretable results. Unfortunately, there are no data yet on the clinical utility or test performance of IGRAs in the deceased donor population, or similar populations such as critical care unit patients or patients with head injury. It is unknown whether brain death may impact the performance of this assay.

Another issue in testing for LTBI (both TST and IGRAs) in the deceased donor population is that the donor may be from a potentially low risk population. Positive tests in a low risk population may represent a false positive result rather than true latent infection (22). Donors with an indeterminate or positive IGRA should not be excluded from donation, although they should be carefully screened for active disease. In these cases, OPOs may wish to procure tissue and blood for additional testing; such samples have been helpful with prior TB transmission investigations (8).

While both the TST and IGRAs are positive in the majority of patients with active TB, both tests may be negative in a substantial proportion of such patients (Table 5), and false negative results may also occur in miliary or disseminated TB (15,23,24). Therefore, neither IGRAs nor TST should be relied upon to exclude active TB disease.

Table 5.  Evidence supporting available TB diagnostic modalities. Comparison of sensitivity and specificity of TST and IGRAs in patients with active TB and low risk controls/TB suspects, including those who received BCG vaccination
Test type/criteriaType of patientsSensitivitySpecificityReference
  1. TST = tuberculin skin test; TB = tuberculosis; QFT-G = Quantiferon Gold; BCG = Bacillus Calmette Guerin vaccine recipients; NA = not applicable.

TST at 5 mmSensitivity: active TB patients75–90%NAHuebner (42)
TSTSensitivity: active TB patients70%NADiel (43)
T-SPOT.TBSpecificity: low risk controls88%86% 
QFT-G or QFT G in tube 81%99% 
TSTSensitivity: active TB patients77%97% (59% BCG)Pai (16)
T-SPOT.TBSpecificity: low risk controls90%93% 
QFT-G or QFT G in tube 70%96% 
TSTSensitivity: active TB patients65%75%Sester (15)
T-SPOT.TBSpecificity: TB suspects with diagnosis other than TB81%59% 
QFT G in tube 80%79% 

Use of immune-based tests in living donors

Living donors are generally healthy but may be from an area of high prevalence of TB or have received BCG vaccine. In general, the epidemiologic history is more reliable compared with decreased donors. TST is routinely recommended to screen for LTBI in living donors (6). For living kidney and liver donors, transplant can often be delayed until a full evaluation of possible latent or active TB is performed. Although there are no formal studies of TST or IGRAs in the living donor population, test characteristics in living donors should be similar to those of healthy adults.

Management

The evaluation and management of TB in all organ donors requires accurate historical, clinical and laboratory data, which can be challenging especially with deceased donors. Many experts felt that verification of appropriate therapy (both prophylaxis and treatment) was essential, but that this can be a major challenge in the evaluation and decision making, especially with deceased donors.

About one-third to one-half of all cases of active TB after transplantation are disseminated or occur at extra-pulmonary sites, compared to about 15% of cases in immunocompetent persons (25). Clinicians should be cognizant of the risk of donor-derived, reactivation and de novo infection, and when clinically indicated, test for disease in the allograft and elsewhere, using cultures, nucleic acid amplification tests, radiology, pathology (with AFB stains) and clinical acumen, maintaining a low threshold to clinically diagnose this disease. TST and IGRAs are much less sensitive in the diagnosis of new TB exposure after SOT.

In the United States, OPTN policy requires that information regarding donors found to have active TB be communicated promptly to the recipient transplant centers (26). Such policies may not exist or may not be feasible in endemic regions. Prompt reporting of positive test results across many centers may be complicated; conference participants recommended that centers report these results emergently to the organ procurement organization, transplant centers and transplant agencies such as the OPTN in the United States. Examples of positive test results that should be reported include AFB stains, cultures, molecular diagnostics and other findings suggestive of TB (i.e. histopathology in the absence of cultures). Unfortunately, specimens from deceased donors are not always recognized to be associated with organ donation, resulting in significant reporting delays. A system in which such laboratory specimens are flagged as originating from organ donors is needed to optimize communication of critical test results.

Recommendations for the management of donors with suspected or confirmed TB are presented in Table 6 and in Figures 2 and 3. Consensus on management of latent TB was easily achieved, as experts felt this group could be divided into higher and lower risk categories. Compliance with treatment of latent infection is notoriously poor; clinicians should be cautious about assuming completion of therapy. In a recent North American study fewer than half of the people starting LTBI treatment finished the recommended course of therapy. Some centers in endemic regions with high rates of LTBI in donors and recipients (as well as increased risk for de novo infection in recipients) use universal prophylaxis with isoniazid for varying periods of time after organ transplantation, while others opt to monitor the recipients closely (27–29). Data regarding the use of chemoprophylaxis for LTBI in TST or IGRA positive living donors in TB endemic countries are limited and have not been shown to improve recipient outcomes; for these reasons, it is not routinely recommended. Whether isoniazid toxicity in recipients may outweigh the benefit of such prophylaxis is unknown. In addition, many of the intermediate- or high-risk TB countries have a high rate of INH resistance, decreasing the potential benefit of INH prophylaxis; alternative prophylactic regimens have not been well studied in the transplant setting.

Management of current or prior active TB was divided into recent and remote infection, based on the fact that the majority of relapses after treatment for active TB occur within the first year. Recurrence of TB may occur either as reactivation disease (more common in low prevalence regions) or exogenous infection (more common in endemic regions). In a review of 15 TB treatment trials initiated by the British Medical Research Council between 1970 and 1983 in Africa and East Asia, of 574 relapses, 78% occurred within 6 months of stopping treatment and 91% within 12 months (25). The joint ATS/CDC/IDSA US guidelines on TB management also state that relapse is most common within the first 6–12 months (30). Donors who had active TB within the previous 2 years are thus at higher risk for relapse of disease with subsequent transmission via the organ graft; chemoprophylaxis should be more strongly considered in such circumstances. In addition, these donors are at higher likelihood of transmitting drug-resistant TB and clinicians should take this into consideration when administering medications both as prophylaxis and treatment.

In addition, management of active TB was further categorized as infection in the organ being considered for transplant or remote (i.e. lung in a kidney donor), with concerns for transmission highest in those with infection at the site of the allograft. Some specialists would not use a kidney from a donor with previous renal TB due to concerns about potential poor function from granulomas and scarring, even with a normal creatinine. A strong recommendation was made to reject donors with active TB in any location An exception might be made for critically ill recipients or in other dire circumstances, especially since unrecognized tuberculosis in recipients urgently transplanted can be treated if promptly identified (31); centers should then treat the recipients for active TB with informed consent and involvement of an infectious disease specialist.

Treatment of latent or active TB varies by region, in part based on drug availability, local resistance patterns and other factors. In addition, potential drug interactions with transplant medications (especially with the rifamycins, including rifampin/rifampicin and rifabutin) require careful evaluation and monitoring, and usually preclude use of rifamycins except for treatment of active TB. A recent metaanalysis found that randomized and nonrandomized studies support the value of isoniazid as prophylaxis in renal transplant recipients at risk for active TB, but that the evidence for the benefit of isoniazid prophylaxis in renal transplantation was not robust, and a large multicenter trial of isoniazid prophylaxis in kidney transplantation in endemic areas is needed (32). There was strong agreement that transplant centers should refer to local guidelines regarding prophylaxis and treatment of TB in their donors and recipients.

Future research

In a survey of 20 attendees regarding priorities for future research areas, 50% (n = 10) felt that a study of IGRAs in living and/or deceased donors should be done, 30% (n = 6) elected prospective evaluation and outcomes of recipients receiving organs from donors that have a high risk for latent TB and 20% (n = 4) chose nucleic acid amplification testing of body fluids in high risk TB donors. Multiple participants felt that all were important research topics, with the suggestion that they could be combined in a single study done at high-risk centers. In addition, standardizing the system for case reporting and data collection would augment the level of research in the field.

Conclusions

Donor-derived TB remains an important infectious complication of solid-organ transplantation, despite the availability of new diagnostic assays and sensitive imaging techniques. Increased awareness of donor risk factors may allow targeted testing for latent and unrecognized active TB in potential donors, but research is required to better understand the performance of newer assays in deceased donors. Given the significant mortality of posttransplant TB, communication between transplant centers of any suspicion for donor-derived TB should occur without delay, and appropriate evaluation and management of recipients with the support of transplant ID specialists is recommended. The increasing diversity of the transplant donor population that has occurred with globalization has resulted in donor-derived TB in low, moderate and high TB risk areas. A further study is needed to optimize early diagnosis and treatment and lower the significant morbidity and mortality of transplantation-associated TB.

Table 7.  Definition of donor-derived TB
Proven transmissionProbable transmissionPossible transmission
  1. Criteria are adapted from the classification system for determining the likelihood that an infection has been transmitted from a transplant donor to the organ recipient, and are adapted to use in TB infection cases from the criteria of the Organ Procurement and Transmission Network ad hoc Disease Transmission Advisory Committee (OPTN/DTAC) (10,13).

Requires confirmed evidence of transmission including all of the followingRequires strong evidence of transmission including the followingThe available evidence suggests but does not prove donor-derived transmission of infection
• Suspected transmission through transplantation• Suspected transmission through transplantation• Suspected transmission through transplantation
• Laboratory evidence of M. tuberculosis infection in the donor• Laboratory evidence of M. tuberculosis infection in a recipient• Laboratory evidence of M. tuberculosis infection in a single recipient
• Laboratory evidence of M. tuberculosis in a recipientAND at least ONE of the following criteria must also be present• Other data that strongly suggest but do not prove that a transmission has occurred
• Laboratory evidence of M. tuberculosis infection in other recipients of the same donor• Laboratory evidence of M. tuberculosis infection in another recipient of the same donor 
• If possible, demonstration of clonally or molecularly identical isolates both in the donor and at least one recipient • Pretransplant testing, if performed, must indicate that the recipient had no evidence of M. tuberculosis infection prior to transplantation• Laboratory evidence of M. tuberculosis infection in the donor • Pretransplant testing, if performed, must indicate that the recipient had no evidence of M. tuberculosis infection prior to transplantation 

Acknowledgments

Funding for the Donor-Derived Infections Consensus Conference on Mycobacterium tuberculosis was provided by the American Society of Transplantation, the Canadian Society of Transplantation and The Transplantation Society.

The authors wish to thank the following participants who assisted in the Consensus Conference process: Willie Bower, Centers for Disease Control, Atlanta, GA, Shahid Husain, University Health Network, Toronto, Canada, Patricia Muñoz, Servicio de Microbiologia-Enfermedades Infecciosas Hospital General Universitario Gregorio Marañon, Madrid, Spain, Debbie Seem, Centers for Disease Control, Atlanta, GA, Dorry Segev, Johns Hopkins University School of Medicine, Baltimore, MD. For CDC Participants: Participation was primarily to serve as a technical resource for the conference and not to provide the official position of the CDC.

Disclosure

D.K. and A.H. have received research funding from Cellestis Inc. All other authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

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