EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: Tuberculosis is an important opportunist infection that can complicate the posttransplant course of solid-organ transplant recipients. Lung transplant recipients are at higher risk of tuberculosis after transplant than are other solid-organ transplant recipients. Significant drug-drug interactions between antituberculous medications, especially rifampin, and immunosuppressant medications render treatment in this patient population especially challenging. Data on the management of tuberculosis in lung transplant recipients with rifamycin-sparing regimens are so far limited. Therefore, we evaluated the incidence, clinical features, treatment, and outcomes of active tuberculosis in lung transplant patients from a single center in Riyadh, Saudi Arabia.

Materials and Methods: Cases of active tuberculosis in lung transplant recipients diagnosed between January 2005 and December 2017 at our center were included. Data on patient demographics, clinical presentations, diagnosis, treatment regimens, and outcomes were collected.

Results: Seven of 133 lung transplant recipients (5.3%) were diagnosed with active tuberculosis during the study period, corresponding to an incidence rate of 2147/100 000 person-years. Patients were diagnosed at median time of 94 days posttransplant. Fever and weight loss were the most common presenting symptoms. All patients were initially treated with a regimen consisting of isoniazid, ethambutol, pyrazinamide, and moxifloxacin. Isoniazid was later substituted with rifabutin in 2 patients with isoniazid-resistant tuberculosis. All patients were treated for a total of 9 to 12 months, without any adverse event-related interruptions. All patients were alive at 12 months after the diagnosis of tuberculosis. There was no evidence of relapse in any of the patients after a median of 32 (range, 9-51) months of follow-up after treatment.

Conclusions: Rifamycin-sparing regimens appear to be safe and highly efficacious in the treatment of active tuberculosis in lung transplant recipients.

Key words : Donor-derived, Mycobacterium tuberculosis, Rifabutin, Rifampin

Tuberculosis continues to be a significant challenge among solid-organ transplant (SOT) recipients. Active disease is mainly the result of the reactivation of a preexisting latent tuberculosis infection or is acquired through infected grafts.¹ The overall rate of tuberculosis in SOT recipients is approximately 2.4%; however, the rate may be considerably greater in areas with a high incidence of tuberculosis.^2,3 Compared with that for other SOT grafts, lung transplant is associated with a 5.6-fold increase in the risk of active tuberculosis.^4,5 In addition to the risk of the transmission of the infection, tuberculosis in SOT is associated with an increased risk of graft loss and death.^6,7 Furthermore, the treatment of tuberculosis in SOT recipients is associated with an increased risk of drug toxicities and significant drug-drug interactions.⁸

Triple immunosuppression regimens that include a calcineurin inhibitor (eg, tacrolimus), an antiproliferative agent (eg, mycophenolate mofetil [MMF]), and a corticosteroid are widely considered as standards of care for lung transplant recipients.⁹ Rifamycins are inducers of cytochrome P450, especially CYP3A, leading to a reduced bioavailability of coadministered medications that are metabolized through this system.¹⁰ Rifampin is an especially potent inducer of CYP3A, and its coadministration with immune suppressant drugs in SOT recipients has been reported as associated with acute rejection and graft loss.⁸ However, there are limited published data on the outcomes of lung transplant recipients treated for active tuberculosis, especially for those treated with rifamycin-sparing regimens. Herein, we evaluated the incidence, clinical features, treatment, and outcomes of active tuberculosis in lung transplant patients from a single center in Riyadh, Saudi Arabia.

Materials and Methods

Lung transplant recipients who were diagnosed with active tuberculosis between January 1, 2005 and December 30, 2017 were identified using the transplant database at King Faisal Specialist Hospital and Research Centre. Data on patient demographics, comorbidities, immunosuppressant medications, rejection episodes, time to tuberculosis diagnosis, microbiological results, tuberculosis treatment regimens, and outcomes were collected. After lung transplant, recipients underwent surveillance bronchoscopy at 2, 4, 6, 12, 24, and 48 weeks. Bronchoalveolar lavage (BAL) fluid was obtained at all of these time points and tested for cell counts, Gram staining, bacterial cultures, fungal staining and culture, acid-fast bacilli (AFB) staining, mycobacterial cultures, and Mycobacterium tuberculosis nuclear acid amplification test. The study was approved by our Institution’s Review Board. Informed consent was waived because of the retrospective nature of the study.

Statistical analyses
Continuous data are summarized as median and interquartile range. Categorical data are reported as frequencies. The incidence rate per person-year was calculated using the number of incident cases divided by the sum of the years of follow-up from the date of transplant. Follow-up was censored on December 30, 2017, diagnosis of tuberculosis, or death, whichever occurred first.¹¹

During the study period, 133 patients underwent lung transplant. Seven recipients (5.3%) were diagnosed with active tuberculosis, corresponding to an incidence rate of 2147 per 100 000 person-years. Most patients were male (57%), and the median age was 44 years (interquartile range, 31-48.5 years) (Table 1). Interstitial lung disease was the most common underlying indication for lung transplant (43%). The standard immunosuppression protocol consisted of methylprednisone and MMF for induction and tacrolimus, MMF, and prednisone for posttransplant maintenance. Only 1 patient (patient 2 in Table 1) had confirmed rejection episodes prior to the diagnosis of tuberculosis.

Unfortunately, detailed data on the donors’ exposure histories were not available. However, all 7 donors were from endemic areas for tuberculosis (India, Nepal, Bangladesh, Philippines, and Somalia). A pretransplant QuantiFERON-TB Gold (Qiagen, Germantown, MD, USA) test was negative in 6 recipients. One recipient (patient 6 in Table 1) had a positive result and was started on isoniazid after transplant. There were no documented pre- or posttransplant exposures to active tuberculosis in any of the 7 recipients.

Most patients (86%) were diagnosed within the first year posttransplant. The median time to tuberculosis diagnosis was 94 days (interquartile range, 65.5-103.8 days). The site of tuberculosis was the mediastinal lymph nodes in 1 patient, the pleura in 1 patient, and the lungs in 4 patients. One patient had multifocal disease involving the lungs, pleura, and mediastinal lymph nodes (Table 1).

Fever was the most common presenting symptom (83.3%), followed by weight loss and cough (42.9% each). None of the patients reported a history of hemoptysis. One patient (patient 3 in Table 1) was asymptomatic and was diagnosed when a routine BAL fluid test was positive for tuberculosis by polymerase chain reaction and culturing. Patient 7 received an allograft from a donor with known granulomatous pulmonary lesions. Tuberculosis in the donor was confirmed shortly after transplant, and antituberculous therapy was started. The details of this case were previously reported.¹²

Radiological abnormalities in 3 of the patients with pulmonary involvement included bilateral upper lobe changes. None of the patients had cavitary lesions. A mixture of ground-glass opacities, tree-in-bud appearances, and consolidation were observed in this series. All patients had radiological changes corresponding to the site of their tuberculosis infection (Table 1). Tuberculosis was microbiologically confirmed in all 7 patients: by cultures and M. tuberculosis polymerase chain reaction (GeneXpert MTB/RIF, Cephid, Sunnyvale, CA, USA) in 6 patients and by AFB smears and a probe assay (BD ProbeTec, Becton Dickinson, Franklin Lakes, NJ, USA) in 1 patient. Sputum AFB smears were negative in all patients, whereas 3 patients had positive BAL fluid smears. Six patients (86%) underwent biopsies as part of the work-up. Histological findings are summarized in Table 1.

Isolates of M. tuberculosis from all but 2 patients were susceptible to isoniazid. All isolates were susceptible to rifampin, pyrazinamide, ethambutol, and moxifloxacin. All patients were initially treated with rifamycin-sparing regimens consisting of isoniazid, pyrazinamide, ethambutol, and moxifloxacin. Once susceptibility results were available, rifabutin was substituted for isoniazid in the 2 patients with isoniazid-monoresistant tuberculosis. None of the patients developed hepatotoxicity or any other complication that would lead to a modification or interruption of their antituberculous therapy. Patients were treated for a total duration of 9 to 12 months (Table 2).

All 7 patients achieved clinical and radiological cures, evident by the resolution of symptoms and/or radiological signs of infection. Microbiological clearance was documented in all 5 patients with pulmonary involvement. There was no evidence of relapse during the follow-up of 10 to 52 months after tuberculosis treatment completion. All patients were alive at 12 months after their diagnosis with active tuberculosis.

The risk of tuberculosis after SOT is linked to the endemicity of tuberculosis in the general population. In areas of low endemicity (in which the tuberculosis rate in the general population ranges between 0 and 24 per 100 000 person-years), post-SOT tuberculosis rates are reported to range between 0.5% and 6.5%.7 From 1991 to 2010, the overall incidence rate of tuberculosis in Saudi Arabia declined from 14 to 17 per 100 000 person-years to around 10 per 100 000 person-years, according to the latest World Health Organization Global Tuberculosis Report.^13,14

Intense immunosuppression after lung transplant is one of the major risk factors for the development of active tuberculosis. Lymphocyte-depleting agents are associated with higher rates of tuberculosis after SOT.^5,7,15 However, none of our patients received a lymphocyte-depleting agent for induction immunosuppression. One patient had several rejection episodes and received antithymocyte globulin for the treatment of rejection within 1 year before diagnosis of active tuberculosis.

Similar to that shown in previous reports, most patients in our series were diagnosed within the first 6 months of transplant (median of 94 days). Given the negative pretransplant interferon-gamma release assays in most of these patients, the early presentations suggest donor-derived tuberculosis.² In June 2017, universal tuberculosis chemoprophylaxis with isoniazid for 6 months became policy at our center for all deceased donor allograft recipients. No cases of active tuberculosis have been diagnosed in lung transplant recipients since the implementation of this policy.

Our series included 2 patients with isoniazid-resistant tuberculosis (patients 3 and 6 in Tables 1 and 2). Both patients received grafts from donors from the Philippines, a country with high rates of drug-resistant tuberculosis.¹⁴ Our original intention was to use rifamycin-sparing regimens to avoid a potential drug-drug interaction with the calcineurin inhibitor.^15-17 However, we substituted isoniazid with rifabutin in these 2 patients, once resistance to the former agent was reported. Multiple studies have demonstrated rifabutin as equally safe and effective as rifampin in the treatment of active tuberculosis in nontransplant settings.¹⁸ Compared with rifampin, rifabutin is a weaker inducer of CYP3A and, thus, has fewer drug-drug interactions.¹⁰ However, clinical experience with rifabutin in SOT-associated tuberculosis is limited.^19,20 We identified 4 previous reports describing a total of 5 lung transplant recipients with active tuberculosis who were treated with rifabutin-based regimens.^21-24 One report described a 73-year-old male patient who was diagnosed with pericardial tuberculosis at 4 months after lung transplant and who died within 1 month of starting a quadruple antituberculous regimen, in which rifampin was substituted with rifabutin.²² However, rifabutin-based antituberculous therapy was successful in the remaining 4 patients, 3 of whom had pulmonary disease and 1 of whom had tuberculosis of the oral cavity and colon.^21,23,24 Rifabutin-based antituberculous therapy was successful in both patients in the present series, suggesting that this agent may be useful in the setting of lung transplant-associated tuberculosis.

Outside of SOT settings, rifamycin-sparing antituberculous regimens are usually used in the context of rifampin-resistant tuberculosis. In rifampin monoresistant tuberculosis, 12-month fluoroquinolone-based regimens have shown high success rates.²⁵ More recently, shorter treatment regimens have also been recommended for multidrug-resistant pulmonary tuberculosis, subject to specific criteria.²⁶ The shorter treatment regimen for multidrug-resistant tuberculosis comprises an intensive phase of kanamycin, moxifloxacin, prothionamide, clofazimine, pyrazinamide, high-dose isoniazid, and ethambutol for 4 to 6 months, followed by a 5-month continuation phase of moxifloxacin, clofazimine, ethambutol, and pyrazinamide. Extrapulmonary tuberculosis and risk of toxicity or drug-drug interactions are among the exclusion criteria for this short rifamycin-sparing antituberculous regimen.²⁷ The complexity and critical importance of immune suppressive therapy in SOT recipients limit the utility of these shorter rifamycin-sparing approaches in the current setting.

Use of a rifamycin-sparing regimen for the treatment of lung transplant-associated tuberculosis has been previously reported (Table 3). In 2 cases, rifamycin resistance was the reason for use of a rifamycin-sparing regimen,^28,29 whereas in the remaining 28 cases rifamycin was proactively omitted to avoid potential drug-drug interactions.^4,24,28-35 The sites of tuberculosis in the 4 reported cases who died while on rifamycin-sparing antituberculous regimens were pulmonary (n = 2), disseminated (n = 1), and pericardial (n = 1).^4,30,35 In the latter 2 cases, death occurred within 48 hours after start of antituberculous therapy.^30,35 Among the 26 patients with successful outcomes with rifamycin-sparing antituberculous regimens for lung transplant-associated tuberculosis, the majority received triple or quadruple regimens containing isoniazid and a fluoroquinolone, and the treatment duration was 12 to 24 months.^{4,28,29,32-34} In our series, 5 patients, all with localized tuberculosis, were successfully treated with moxifloxacin and isoniazid-based regimens, without a rifamycin, for a total duration of 9 to 12 months. These outcomes suggest that such regimens may allow a shorter duration of treatment in lung transplant-associated tuberculosis.

Treatment recommendations for active tuberculosis in SOT recipients are based on data from nontransplant populations, case series, and expert opinions.^{2,19,20,36,37} The inclusion of a rifamycin in tuberculosis treatment regimens is generally considered highly desirable because of their rapid sterilizing activity, shorter treatment course, and association with high rates of treatment success.^20,37,38 However, maximizing tuberculosis treatment efficacy needs to be balanced against the risk of graft rejection as a result of potential drug-drug interactions with rifampin. Current guidelines advocate the avoidance of rifampin in the treatment of localized, nonsevere forms of tuberculosis in SOT recipients. An allowance is made for using rifampin when necessary, but only with careful therapeutic drug monitoring of the immunosuppressant agents.^19,20 Decisions need to be individualized based on the patient’s specific needs and the availability of ready access to therapeutic drug monitoring and logistical support, enabling a prompt clinical review and dose adjustments when required.

In our report on a series of patients with lung transplant-associated tuberculosis, excellent clinical response and completion of a tuberculosis treatment course were achieved without significant interruption or serious adverse events. All patients survived for more than 1 year after the diagnosis of active tuberculosis. Notwithstanding the small size of the study, our experience supports the use of rifamycin-sparing regimens for the treatment of nonsevere forms of active tuberculosis in lung transplant recipients. The small number of included patients and lack of lung donor screening for tuberculosis are limitations of this study. However, as a result of this work, Saudi national policy was changed in November 2019 to require tuberculosis screening for all lung donors, using a combination of AFB staining and mycobacterial cultures of airway samples.

Volume: 19 Issue: 4 April 2021

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