The World Health Organization (WHO) recently presented its post-2015 global tuberculosis (TB) strategy, which aims to reduce deaths from TB by 95% and to cut the number of new cases by 90% before 2035.1 Traditionally, appropriate early treatment of active TB cases has been the main policy for reducing the spread of the infection. Now, for the first time, tackling latent TB infection (LTBI) has become an integral part of the global strategy to end the pandemic.2
The huge number of latently infected individuals—at least one third of the world’s population—serves as a reservoir for future cases of TB. With only a 10% rate of progression from latent to active disease over the lifetime,3 and the need for lengthy TB preventive therapy, universal treatment for all latent infections is neither affordable nor feasible at present. In the absence of tests that can directly diagnose LTBI and identify those at risk of progression to active TB, an individual risk-driven approach based on targeting people for preventive therapy is needed.4 In their recent guidelines, the WHO provided evidence-based recommendations on the management of LTBI, including its diagnosis and treatment, and for the monitoring of adverse effects. The WHO guidelines intend to help national stakeholders to adopt the most appropriate strategies for specific groups at risk for TB, based on their local epidemiologic characteristics.
Transplant-related immunosuppression is a well-known risk factor for developing active TB. In addition to the public health risk, transplant-associated TB poses a significant risk for both graft loss and death.5,6 Screening for LTBI, followed by treatment as necessary, is therefore widely recommended for all transplant candidates. Still, the significant differences in incidence depending on the type of transplant and especially on the background endemicity of TB5,6 precluded a more selective approach to LTBI management in the WHO guidelines, which were primarily targeted at high-income countries with an estimated TB incidence rate of less than 100 per 100 000 population.1 Because increased global mobility and migration have resulted in a growing diversity of the donor pool, transplant-related TB now requires a comprehensive approach.7
In this overview, we aim to evaluate the previous experience and to compare and contrast the main current guidelines on the prevention and treatment of TB in both solid organ transplantation (SOT) and hematopoietic stem cell transplantation (HSCT).
Prevention of TB in Transplant Recipients
In SOT and HSCT, the rationale for active surveillance and treatment of LTBI is that the high prevalence of TB in transplant recipients is mostly due to the reactivation of a previously acquired infection, and that active TB can be prevented by treating the infection. Transmission from the donor and de novo infection after transplantation may constitute important routes of transmission in high TB-burdened countries.
The risk of TB is linked to the background endemicity of both the donor and the recipient (Table 1). Prevalence reports in SOT range from 0.48% in low-endemic countries such as Spain8 to 15.2% in high-endemic countries.9-13 Different types of transplant pose different risks of developing TB, with lung transplantation carrying the highest risk among SOT (1.32% to 6.5%).8,14 As for HSCT, the risk of developing active TB is lower than that in SOT, probably because of a limited period of immunosuppression. Although autologous HSCT showed rates of TB ranging from 0.05% to 0.26%, which is comparable to that of the general population,15 allogeneic recipients have a higher risk.15-17
The effectiveness of treatment for preventing the development of active TB has been consistently demonstrated in high-risk groups,18 such as close contacts of TB cases,19 people living with human immunodeficiency virus,20 individuals with old untreated TB,21 and those treated with TNF antagonists.22 However, the evidence in transplant recipients is quite limited.23,24
Assessment for LTBI in Transplant Candidates
There is a general agreement among the guidelines on the need to assess TB infection in transplant candidates.25-31 Only 1 set of guidelines suggests universal preventive therapy for transplant candidates in high-endemic areas (≥100 cases per 100 000 population)25 (Table 2). Assessment of living donors is recommended in the 4 most comprehensive guidelines,25-28 but is not recommended in 1 set,31 and is not even mentioned in 2 more.29,30
After the initial TB risk assessment, which includes accurate recording of data on prior TB and verification of appropriate therapy (both prophylaxis and treatment), all but 2 guidelines recommend screening all transplant candidates for TB infection with either the tuberculin skin test (TST) or an IFN-γ release assay (IGRA). These 2 exceptions to this rule suggest that screening should be based on individual TB risk assessment30 or on the background endemicity of TB.25
Diagnosis of TB Infection in Transplant Candidates
The diagnosis of LTBI relies on these 2 immune-mediated tests, the TST and the IGRAs. At present, there is no consensus on the best strategy for TB screening: that is, whether the TST should be used, or an IGRA, or both. This uncertainty is reflected in the inconsistency of the recommendations in different risk groups, including SOT and HSCT (Table 2). Two guidelines recommend the use of an IGRA as first option,25,30 2 recommend the TST,27,28 2 recommend either the TST or IGRA,29,30 and 1 recommends both when available26; in yet another, no consensus was reached.31 In the American guidelines, an IGRA is also recommended in addition to the TST for patients without immunosuppression and those vaccinated with the Bacillus Calmette-Guérin (BCG).28 The Spanish27 and the American28 guidelines recommend the 2-step TST method to provide a “boosting” effect, as do the European Society of Clinical Microbiology and Infectious Diseases Study Group for Infections in Compromised Hosts guidelines when the IGRA test is not available.26 This strategy, which consists of repeating the TST 7 to 14 days after a negative first test, is intended to improve sensitivity by bolstering a waning response to the purified protein derivative in TB-infected people with immunosuppression or with a long-standing acquired infection. However, the benefit of this practice has not been proven in any group of patients—and still less so in transplant candidates. The helpfulness of this second test is usually low, and although it may identify some infected patients, it also increases false-positive rates and leads to overtreatment, as has been demonstrated in other risk groups.32
Currently, 2 IGRAs are commercially available: the QuantiFERON-TB-Gold In-Tube test (QFT-GIT), which is based on an enzyme-linked immunoabsorbent assay, and the TSPOT.TB test (T.SPOT), which is based on an enzyme-linked immunospot.33 Many studies have directly compared the performance of both IGRAs with the TST in nontransplant populations. In a meta-analysis, the sensitivity of the TST was 0.77, and its specificity was 0.59 and 0.97 for BCG-vaccinated and nonvaccinated people, respectively. For IGRAs, the corresponding figures for sensitivity were 0.81 (QFT-GIT) and 0.88 (T-SPOT.TB) and for specificity 0.99 (BCG-vaccinated) and 0.96 (nonvaccinated) when tested with QFT-GIT, and 0.93 when tested with T-SPOT.TB (pooled data including both vaccination statuses).34 However, the value of these tests would be greater if they could predict the development of active TB. So far, prospective observational studies have shown a nearly 100% negative predictive value but a very poor positive predictive value for the progression to active TB, with IGRAs showing slightly better results than TST.35 As for transplant recipients, although IGRAs are equally poor at predicting the development of TB, transplant candidates with a negative IGRA on pretransplant testing have also shown a very low risk of subsequently developing active TB17,36-42 (Table 3). However, a negative IGRA does not rule out active TB or imply “zero risk” for developing TB in the posttransplant period; several series of SOT and HSCT recipients have reported culture-proven TB presenting with negative IGRA test results.17,38-42
Indeterminate results are the main drawback of IGRAs in immunosuppressed patients. Indeed, these range from 1% to 7% in most series,43 but are as high as 20% when performed after transplantation.44 Whenever possible, screening should be performed before the transplant procedure, as the subsequent immunosuppressive therapy diminishes the host's responsiveness to Mycobacterium tuberculosis antigens and purified protein derivatives, reducing the sensitivity of both the TST and the IGRAs. Several studies to date have confirmed the TST to be more negatively affected by immunosuppressive drugs.45-48
Detailed baseline chest imaging studies are also recommended, in search both of pulmonary lesions suggestive of previously untreated TB and of radiographic findings indicative of active TB. Some researchers favor the use of computed tomography scans when screening transplant candidates.49
Treatment of LTBI in Transplant Candidates and Recipients
Most published guidelines agree that treatment for LTBI should be offered to all SOT recipients with a positive immunodiagnostic test (TST or IGRA) (Table 2). Treating patients in the absence of an immunodiagnostic test (or with a negative result) is recommended in 3 circumstances: known history of contact with an infectious case of TB,25-28,30,31 chest radiograph findings suggestive of old untreated TB,25-28,30 and the receipt of a graft from a known latently-infected donor.25,27,28 In these scenarios, treating a recipient of a lung transplant is probably the most efficient strategy, because the lungs are more likely to harbor the main load of silent TB foci than other grafts. Although offering treatment in these particular situations is accepted by most guidelines, the actual benefit of this practice is unknown.
The recently issued WHO guidelines recommend that 1 of the following options be used in the treatment of LTBI1: isoniazid (INH) for 6 or 9 months, weekly rifapentine plus INH for 3 months, INH plus rifampin for 3 to 4 months, and rifampin alone for 3 to 4 months. In transplant recipients, the experience is primarily restricted to INH, so guidelines tend to recommend this drug for 6 to 9 months.25-31 The largest body of evidence accumulated on efficacy (though still limited) has been in kidney23,41 and liver24,50-53 transplantation. In a meta-analysis of 6 observational studies54-59 and 4 randomized controlled trials (RCTs),60-63 INH was the preventive therapy used in renal transplant recipients. Pooled data from the 4 RCTs, which included 709 patients, showed a significant reduction in the incidence of posttransplant TB in patients treated with INH as compared with untreated patients (relative risk, 0.31; 95% confidence interval, 0.15-0.51) (Table 4). All RCTs were conducted in high-endemic countries (India and Pakistan), as were most of the observational studies.56-59 In a recent study of renal transplant candidates without risk factors for TB infection in a low-to-intermediate endemic country, none of the 131 patients allocated to INH developed TB, whereas 3 (2%) of the 132 of nontreated patients developed the disease.41
In liver transplantation, treatment of TB infection poses additional complexity because of its potential to cause severe liver toxicity. Anti-TB drugs may worsen liver function when administered during the candidacy period, or may make it difficult to distinguish between toxicity, rejection, and infectious complications when given after transplantation. Moreover, rifamycins, which are a less hepatotoxic group of drugs, cannot be used because of their major interactions with most immunosuppressants.64-66 Supporting evidence on the efficacy and safety of LTBI treatment in liver transplant recipients comes from case series and observational studies using INH. A meta-analysis that included 7 observational studies showed a benefit of INH treatment for 6 months or longer when compared with no treatment in 224 TST-positive liver transplant candidates. In that study, none of the 61 treated patients developed TB, compared with 7 (5.1%) of the 143 untreated patients24; however, in 5 (6%) of 84 patients treated with INH, including 7 with negative or unknown TST results, INH was discontinued because of hepatotoxicity. Since then, 5 more observational studies50-53 and 1 RCT67 have reported the effectiveness and safety of preventive therapy with INH in liver transplant recipients. Overall, the pooled data showed that none of the 281 pretransplant or posttransplant patients developed active TB after treatment, and 1 of 40 nontreated patients (2.5%) developed TB after average follow-up periods ranging from 34 months to over 5 years.24,50-53,67 Notably, however, there was considerable inconsistency in the completion rates, which ranged from 44% to 92%.53,67
Despite the low completion rates for INH, alternative treatments in transplant candidates and recipients have not been widely explored. The systematic review, which reported the treatment recommendations for the WHO guidelines found no differences in efficacy for preventing TB between INH for 6 months and the rifamycin-containing regimens, observing only that the latter added a better safety profile.18 The addition of (or substitution by) a rifamycin allows a shorter regimen and, thus, encourages better adherence and compliance to the treatment.68 The main disadvantage of rifamycins, however, is their interaction with most immunosuppressive agents. This interaction limits their use in posttransplant patients, because it may bring the immunosuppression down to dangerously low levels and cause graft loss.64-66 Still, 2 studies have reported data on a small number of liver transplant candidates and recipients treated with rifampin,69,70 in which none of the 29 patients treated with rifampin developed TB after a median follow-up of more than 5 years. Tolerability was excellent and, in one of the studies, liver enzymes did not increase above baseline levels in any of the 5 patients treated with rifampin.70 No details were provided on the 24 patients treated in the other study.69
Two drugs in the rifamycin group could may play an important role in this scenario: rifapentine and rifabutin. Rifapentine has a longer half-life than either rifampin or rifabutin, which allows for once- or twice-weekly dosing and thus, favors adherence to treatment.68 A recently published analysis of the PREVENT TB cohort showed the weekly rifapentine-INH regimen to have a lower risk of liver toxicity than daily INH for 9 months.71 To date, 2 RCTs have demonstrated the noninferiority of a 12-week weekly rifapentine plus INH schedule when given under directly observed therapy compared with INH for either 9 months72 or for 6 months.73 In view of these findings, the same regimen was examined in a small study of 17 SOT candidates.74 Of these, 13 (76%) completed a full course of treatment. Among the 7 liver transplant candidates, treatment was discontinued in only 1 during the ninth week because of worsening ascites and fluid overload. The other 3 patients were kidney transplant candidates who discontinued treatment for reasons other than hepatotoxicity. No cases of active TB developed over a mean follow-up of 20.4 months after transplant.
Rifabutin has better intrinsic activity than rifampin against M. tuberculosis,75 more rapid sterilizing activity in animal models,76 and less potent induction of the CYP3A4/5 enzyme.77,78 Although it is used in the treatment of active TB, rifabutin is not mentioned in any of the guidelines as an alternative treatment for LTBI. Although clinical experience is limited,79,80 rifabutin may turn out to be a valid choice for preventive therapy in transplant candidates and recipients when rifampin cannot be given.
Fluoroquinolones are considered as alternative treatments when there is intolerance to the major antituberculous drugs, but again, direct evidence supporting their use is scarce. Recently, an RCT on the treatment of TB infection in liver transplantation compared the efficacy and safety of levofloxacin (500 mg daily per 9 months) initiated before transplantation against 9-month INH initiated after transplantation.67 The study was discontinued prematurely when an unexpectedly high incidence of severe tenosynovitis developed in the levofloxacin arm (18%). However, 55% of patients in the levofloxacin arm completed a full course of treatment, compared with only 44% of those treated with INH, and there were no cases of TB after a median follow-up of 270 days. A subsequent retrospective study reported better results: fluoroquinolone-related adverse events occurred in 14 of 25 liver transplant candidates, and only 2 patients required permanent withdrawal.81
Although most of the published guidelines recommend starting treatment for TB infection before transplantation,25-31 some suggest that posttransplant treatment may be better tolerated.26-28 In a retrospective study of SOT patients in Canada, although patients treated in the posttransplant phase were less likely to complete treatment (odds ratio, 0.47; 95% confidence interval, 0.24-0.92), completion rates were better in patients treated after transplant (54%, vs 18% those treated pretransplant) for the subset of liver transplant recipients.69
There is no consensus on how best to monitor adverse events, particularly liver toxicity. Many experienced clinicians make their first assessment after 3 or 4 weeks of treatment and then monthly thereafter, or when there is any clinical suggestion of toxicity. A careful regular evaluation before and during the treatment period, using liver function tests, clinical assessment and proper counseling has been shown to be effective for controlling LTBI-treatment risks in other groups.82
Prevention of Donor-Derived TB
The assessment of transplant donors for SOT is addressed in 4 guidelines.25-28 The American Society of Transplantation, the Canadian Society of Transplantation, and the Transplantation Society endorsed a consensus that focuses specifically on the diagnosis and management of TB and LTBI in transplant donors.83 There is little information on this particular issue,42 and guidance in this context largely relies on expert opinions. Although there is indirect evidence of the risk of donor-derived TB, and although several well-documented case reports have been described in high endemic countries, the extent of the risk and the difference between reactivation and reinfection in high-incidence TB countries remains unclear. In these countries, a universal preventive therapy is recommended in recipients of SOT and HSCT during their maximum immunosuppression period.
There is general agreement that active TB should be investigated in the donor, and that if present, organ donation is contraindicated. The presence of fibrotic or calcified lesions on chest radiography, suggesting old untreated TB, is a formal contraindication for lung transplantation, but not for other organs. It is also agreed that donor assessment should focus on epidemiological risk factors and on personal histories of latent and active TB and treatment. It is frequently difficult to obtain these data from a deceased donor’s family. A recent study focused on the cell-mediated immune response against M. tuberculosis in deceased individuals, in which IGRAs are the only assays that can be applied.84 A positive result might be especially valuable in lung transplantation, because lungs are more likely than other grafts to harbor the main load of silent TB foci. Prescribing preventive therapy to the recipient of an IGRA-positive lung donor with no evidence of active TB is probably the most efficient intervention,85 and perhaps the only situation in which the donor's latent infection may represent a risk to a SOT or HSCT recipient.
In contrast, assessment of living donors is feasible and more reliable, because an immunodiagnostic test can be administered. If they are diagnosed with LTBI, there is no consensus regarding treatment: 2 guidelines recommend offering preventive therapy to the donor,28,83 whereas the other 2 advocate treatment of the recipient.25,27
If either living or deceased donors are reported to have had active TB in the last 2 years, and if completion and adherence to treatment cannot be ensured, some authors advocate for preventive therapy for the recipient.83
Donor-derived TB has not been reported in HSCT, even with active nondisseminated disease. This suggests that the risk is insignificant. Interestingly, the American Society of Blood and Marrow Transplantation does not recommend screening for TB infection in the donor, and in the case of active TB, recommends that transplantation be deferred until the disease is stable and noncontagious and the donor is fully recovered, in the interest of safety.
Prevention of de Novo Infection After Transplantation
In high-endemic countries, where the high positive rates of TST and IGRAs limits their usefulness for selecting individuals at risk of developing active TB, a universal preventive therapy strategy has been proposed for patients in transplantation programs, at least during the period of maximum immunosuppression.86 This strategy may prevent the reactivation of a previous latent infection or the acquisition of a new infection from a risky environment. However, there are no data supporting the benefit of this universal coverage, and the risk of masked monotherapy for active TB should be considered.
Treatment of Active TB in Transplant Recipients
Treatment of active TB in transplant recipients is challenging because of the potential for toxicity and for interactions between rifampin and immunosuppressive drugs. Published guidelines differ regarding the use of a rifamycin as a part of the anti-tuberculous regimen, as well as the duration of standard therapy (Table 5). Although 3 guidelines recommend the use of standard therapy for 6 months (2 months of INH, rifampin, pyrazinamide (PZA) and ethambutol (EMB), followed by 4 months of rifampin and INH)25,28,30 2 others advise against the use of rifamycins unless severe or disseminated forms of TB are present, and if so, they recommend a 9-month regimen (2 months INH+RMP+PZA+EMB/7 months RMP +INH).26,27
Although rifamycins are the cornerstone of treatment for TB, there are concerns about their ability to lower the levels of most immunosuppressants (thus inducing graft dysfunction). As a result, some authors advise against their use in the transplant population.87
As stated above, rifabutin is a less potent inducer of the CYP3A4/5 enzyme system. Its efficacy for treating pulmonary TB has been shown in both immunocompetent88 and human immunodeficiency virus–infected patients receiving protease inhibitors,89 with no differences found in cure and relapse rates between the rifabutin and rifampin groups.89 Favorable outcomes in terms of survival and graft function have also been reported in transplant recipients with TB treated with rifabutin-containing regimens.90-92 At our institution, our experience has also been satisfactory: of the 24 SOT TB cases in the last 15 years, 8 were treated with rifabutin for a mean duration of 9.1 months, with a favorable outcome and no evidence of allograft dysfunction or death (data not published). Recently, the RIFAQUIN trial also showed that a 6-month weekly regimen with high-dose rifapentine and moxifloxacin was as effective as the standard 6-month rifampin-containing regimen for the treatment of pulmonary TB in immunocompetent patients.93
The optimal duration of treatment for active TB in transplant recipients is also controversial. Although 3 of the guidelines recommend that treatment be continued for 6 months,25,29,30 2 suggest extending treatment to 9 months based on reports in small series of higher relapse rates and deaths with shorter regimens in the 1990s.26-28 Once again, however, no clinical trials or prospective observational studies have addressed this issue.
Adherence to Guidelines
Transplant recipients are at high risk of active TB, as well as the added risks of reduced survival and reduced graft viability. In addition, although limited, there is both direct and indirect evidence that preventive therapy halts the development of active TB in transplant recipients. Therefore, systematic risk assessment, screening, and treatment of TB infection before transplant appears straightforward. However, transplant teams may be reluctant to follow the guidelines issued, particularly in the context of liver transplantation. The reasons for this may include fear of drug toxicity, uncertainty of how to interpret test results, and a sense that the perceived harm of LTBI treatment outweighs the potential benefits in this particular transplant population.
It is unclear how far transplant teams adhere to guidelines for the prevention of TB in transplant patients. Data available from countries with guidelines in place suggest that adherence is at best suboptimal.24,27,94,95 In the Spanish Network for the Research of Infection in Transplantation cohort, only 40.5% of patients undergoing SOT underwent a TST in the period between 2003 and 2006, and only 43.5% of those considered infected with M. tuberculosis (ie, with a positive TST) finally received treatment.27 In a study of liver transplant recipients (mostly from the United States), only 31% of patients had undergone a TST.24 A survey of the management by UK kidney transplant units showed that 74% had a protocol in place and that 84% performed TB risk assessment, but that only 21% performed an IGRA.94 Another survey of HSCT in Europe revealed that only 10% of centers systematically screened their patients with the TST, and that figure rose to just 50% in the case of risk factors for TB infection.83,95
In our view, any preventive strategy should be individualized according to known epidemiologic factors (ie, prevalence of TB and TB infection) and to the given patient's characteristics (age, type of transplant, and risk factors for toxicity). Specifically trained staff with knowledge of TB, together with the transplant team, should then discuss the risks and benefits of treatment, plus any alternatives, with patients.69 Adherence to treatment and adverse events should be closely monitored throughout treatment. Routine clinical practice should include comprehensive counseling for the disease and its treatment, including access to on-demand appointments and direct telephone contact with the treatment team. Clinical assessment and blood tests should be performed at least fortnightly in the first 2 months, then monthly, and then whenever needed thereafter.
We provide a simple algorithm for the prevention of transplant-related TB for both donors and recipients of SOT and HSCT (Figure 1). The aim of this algorithm is to gather together the recommendations common to the main guidelines, and to decide on the options available for special situations.
Conclusions and Further Research
To prevent the development of active disease, the main guidelines agree on the need for assessment of active and latent TB in both donors and recipients. However, there is an important gap between the recommendations and their implementation in clinical practice, mainly because of the paucity of robust evidence. Recommendations in transplant-associated TB face 2 main difficulties. The first is the intrinsic limitation of the immunodiagnostic tests. Further research should be undertaken to investigate the development of biomarkers that can distinguish between latent and active TB, and to select the subjects with the greatest risk of progression to active TB.
The second is the limited range of antituberculous treatments currently available: there is an urgent need for clinical trials with better-tolerated drugs, such as rifampin, rifabutin, and weekly therapy with RPT plus INH, to assess their efficacy, safety, and adherence in transplant candidates and recipients. As for active TB, well-controlled prospective studies are needed to assess the outcomes of TB treatment with the rifamycins, particularly rifabutin, in this population. Table 6 lists the specific areas on which research should concentrate in the coming years.
Until diagnostic methods become more accurate and better treatments are developed for LTBI, guidelines and consensus statements should aim to be straightforward and to correspond to the local TB epidemiology. Moreover, there needs to be a move toward involving TB specialists in the decision-making process for the prevention and treatment of TB, and toward optimizing counseling, adherence, and adverse-event monitoring. Finally, we must take care to discuss the therapeutic alternatives with patients, especially when a high risk of toxicity is anticipated.
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