Research Article, Arch Transplant Vol: 4 Issue: 2

Tuberculosis Outcome in Solid Organ Transplant Recipients

Reem S Almaghrabi^1*, Reem Alameer¹, Nada Alshehri¹, Abdullah Almohaizeie², Abdulrahman A Alrajhi¹ and Ali S Omrani³

¹Section of Infectious Diseases, Department of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia

²Pharmaceutical Care Division, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia

³Communicable Diseases Center, Hamad Medical Corporation, Doha, Qatar

*Corresponding Author : Reem S Almaghrabi
Section of Infectious Diseases, Department of Medicine, King Faisal Specialist Hospital and Research Centre, 11211, PO Box 3354, MBC 46, Riyadh, Saudi Arabia
Tel: +966 11 4427494
Fax: +966 11 4427499
E-mail: ramaghrabi@kfshrc.edu.sa

Received: May 11, 2020 Accepted: May 22, 2020 Published: May 29, 2020

Citation: Almaghrabi RS, Alameer R, Alshehri N, Almohaizeie A, Alrajhi AA, Omrani AS (2020) Tuberculosis Outcome in Solid Organ Transplant Recipients. Arch Transplant 4:2. doi: 10.37532/at.2020.4(2).112

Abstract

Keywords: Tuberculosis; Solid organ transplant; Graft rejection; Clinical Presentation: Clinical outcomes; immunosuppressant

Introduction

Solid Organ Transplantation (SOT) is an established therapeutic option for end-stage dysfunction of a variety of organ systems [1]. In the year 2017, more than 139,000 SOT were performed worldwide [2]. Progressive development in surgical techniques, newer and safer immunosuppressant medications, as well as improved prevention, diagnosis and management of infectious complications have all contributed to improved clinical outcomes and survival of organ recipients [1,3]. Tuberculosis (TB) continues to be a major concern in many parts of the world. The most recent global World Health Organization report estimates that 10 million new TB cases occurred in the year 2018 [4]. In SOT recipients, the incidence of TB is 4–30 times higher than that in the general population [5]. The incidence of TB is also relatively high in individuals with end-stage end organ dysfunction patients who are awaiting transplantation [6]. Tuberculosis in SOT occurs as a consequence of reactivation of old infection or, less commonly, as donor derived infection [5]. Management of TB in SOT is challenging owing to atypical presentation, absence of the classical radiological signs and the significant drug-drug interaction between anti-tuberculous and immunosuppressant medication [7-9]. Hence, TB-associated mortality in SOT recipients is reported to be as high as 18-30% [6,7,10,11]. There are limited data on TB in SOT recipients from the Middle East and North Africa (MENA) region [12,13]. Our aim was to describe the epidemiology, clinical characteristics, treatment and outcome of TB in the setting of SOT in one of the largest transplant centers in the MENA region.

Methods

Details of kidney, liver or heart transplant recipients were retrospectively retrieved from the electronic database of the Organ Transplant Center at King Faisal Specialist Hospital and Research Centre, Riyadh. Patients of any age were included in the study if they received one of these organs during the period between January 1, 2005 and December 31, 2016 and were treated for active TB after the transplantation.

Active TB was defined as cases treated for TB based on microbiological results (positive acid-fast bacilli culture or Mycobacterium TB PCR (GeneXpert MTB/RIF, Cephid, Sunnyvale, California, USA), radiological and/or clinical features suggestive of TB. Clinical, laboratory and radiological data were extracted. Mortality at 30 days, 90 days and 12 months were collected. The study was approved and need for informed consent was waived by the Institutional Review Board.

Data were summarized using medians and ranges or numbers and frequencies, as appropriate. Chi-square and Mann Whitney tests were used to compare clinical characteristics of SOT recipients who survived for 12 months or more after initiation of anti-tuberculous therapy versus those who did not. Variables with an associated P value of less than 0.05 were included in a multivariate logistic regression analysis for all-cause mortality at 12 months. Kaplan-Meier curve was used to compare survival in recipients of different organ types. All analyses were performed using Statistical Package for the Social Sciences (SPSS) for Mac, Version 21 (IBM Corporation, Armonk, New York, United States).

Results

A total of 42 patients were included, 22 (52.4 %) were kidney, 16 (38.1 %) were liver and 4 (9.5%) were heart transplant recipients. The majority of the patients were males (34, 81.0%) with a median Charlson Comorbidity Score of 2 (range 0– 7) at the time of TB diagnosis. A summary the baseline demographic and clinical characteristics of the patients is presented in Table 1.

Table 1: Demographic and clinical characteristics of the patients with active tuberculosis following liver: kidney or heart transplantation. *At time of TB diagnosis; ATG: anti-thymocyte globulin; CCS: Charlson Comorbidity Score

Active TB was diagnosed in 16 (1.7%) out of a total of 918 patients who underwent liver transplantation during the study period. Chronic viral hepatitis (8, 50.0%) was the commonest indication for liver transplantation, followed by schistosomiasis (3, 18.8%), autoimmune hepatitis (3, 18.8%) and cryptogenic liver cirrhosis (2, 12.5%). The median Model for End-Stage Liver Disease (MELD) score at the time of liver transplantation was 19 (range 13 - 44). Over one half (9, 56.3%) of the liver recipients with active TB received grafts from living-related donors. Among those, 2 (12.5%) of the donors had undergone pretransplant QuantiFERON-TB Gold (QFT) (Qiagen, Germantown, Maryland, United States) testing; and both donors had negative tests. The remaining 7 (43.8%) liver recipients received organs from deceased donors; 2 in China from Chinese donors, while the nationalities of the other 5 donors are not available. The majority (11, 68.8 %) of the liver recipients received induction immunosuppressive regimen; 3 with basiliximab, 5 with methylprednisone and 3 with both agents. Ten patients (62.5%) were on triple immunosuppressant medications with tacrolimus, mycophenolate mofetil and prednisone, while the other 6 patients (37.5%) were on 2 immunosuppressants at the time of TB diagnosis.

Twenty-two (1.2%) out of 1,906 individuals who underwent kidney transplantation during the study period were diagnosed with posttransplant active TB. Most had end-stage renal disease secondary to diabetes mellitus (5, 22.7 %), hypertension (10, 45.5%), or idiopathic causes (7, 31.8%). Glomerulonephritis, vesicoureteral reflux, druginduced kidney injury and congenital causes contributed to 5 (22.7%) cases. The median time on dialysis prior to transplant was 7 months (range 0 – 84). Nineteen patients (86.4%) had organs from living donors. Eight patients (36.3%) received induction immunosuppression with anti-thymocyte globulin (ATG) in 5 patients, methylprednisone in 2 patients and both agents in 1 patient. Other patients had no clear documentation of receiving induction immunosuppression therapy, mostly because they were transplanted in centers outside Saudi Arabia (9, 40.9%). Fifteen patients (61.2%) were on triple immunosuppressant medications with tacrolimus (or cyclosporine), mycophenolate mofetil and prednisone, while 7 (31.8%) patients were on 2 (9.1%) immunosuppressants at the time of TB diagnosis.

Only 4 (1.8%) out of 218 patients who underwent heart transplantation during the study period developed post-transplant TB. Three (75.0%) patients had idiopathic cardiomyopathy and 1 (25.0%) patient had dilated cardiomyopathy. All patients received induction immunosuppression with ATG; 3 patients received concomitant methylprednisone induction. All 4 patients were on triple immunosuppressant medications with tacrolimus (or cyclosporine), mycophenolate mofetil and prednisone at the time of TB diagnosis.

Overall, the median time between transplant and TB diagnosis was 14.6 months (0.5–255.8). A total of 17 patients (42.5%) were diagnosed within the first 12 months after transplant; 11 (64.7%) of these received 1 induction immunosuppressive agent, while 2 patients received 2 agents. Liver transplant recipients constituted 47.1% of the patients who were diagnosed in the first year. Only 5 (29.4%) patients were transplanted abroad (2 in Pakistan, 1 in Lebanon, 1 in China and 1 in the Philippines). Five out of the 17 (29.4%) patients had positive QFT prior to transplant and never received TB chemoprophylaxis.

Among the 25 patients who were diagnosed after the first year of transplant, 11 patients (44%) were on triple immunosuppressant medications at the time of TB diagnosis. Three patients had positive QFT and were diagnosed during the second year of transplant. One patient had a positive tuberculin skin test (TST). This patient received TB chemoprophylaxis at the time of transplantation but developed active TB 20 years later.

Majority of patients (29,69.0 %) of the patients in this cohort were on 3 immunosuppressant medications at the time of TB diagnosis; (29, 69.0 %) were on tacrolimus-based immunosuppressant regimens while (13, 31.0 %) were on cyclosporine-based regimens.

Lungs were the most common site of involvement (29, 69.0%); 13 (44.8%) of these had isolated pulmonary involvement. Graft involvement was seen in only 3 (7.1%) patients, 2 patients with liver transplant and 1 patient with kidney transplant. Both liver transplant patients received organs from deceased donors. Kidney transplant recipients constituted 90.0% (4 out of 5) of those who presented with miliary and 63.6% (7 out of 11) of those with multifocal TB.

Fever was present at presentation in most patients (30, 71.4%). One half (21, 50.0%) of the patients presented with both fever and weight loss. Cough was present in 8 (44.4%) of those with pulmonary involvement, while both cough and shortness of breath were reported in 19 (65.5%) patients with lung involvement. Fever accompanied by weight loss and anorexia were the commonest presenting symptoms (27, 64.3%) in patients with miliary or multifocal TB.

TB was suspected clinically in the majority of patients (31, 73.8%) and was confirmed microbiologically in 36 (85.7%) of the patients in this cohort. Results of the microbiological tests are summarized in Table 2. Among patients with pulmonary involvement, sputum Ziehl- Neelsen (ZN) stain was positive in 13 (46.4%) out of 28 patients. Interestingly, sputum ZN was positive in 3 (60.0%) patients with miliary TB. PCR and mycobacterial cultures were positive in 7 (24.1%) and 24 (82.8%) out of 29 patients with pulmonary involvement, respectively. The diagnosis in the remaining 4 patients was achieved by positive Broncho-alveolar lavage (BAL) cultures in 2 patients and positive cultures from other sites in 2 patients. In patients with miliary TB, the disease was confirmed microbiologically in 4 out of 5 patients. All 4 had positive sputum cultures and 3 had positive BAL cultures. Two kidney transplant patients with miliary TB had positive urine cultures as well. The 2 patients with liver allograft infection had positive ZN stain and culture from liver tissue. Biopsy for histology was done in 15 out of 42 patients (35.0%). Necrotizing granulomatous changes were reported in biopsies from 10 (66.7%) patients and positive ZN stain on histology from 7 (46.7%) recipients.

Table 2: Microbiological confirmation of tuberculosis in recipients of liver: kidney or heart transplantation. BAL: bronchoalveolar lavage; PCR: polymerase chain reaction; ZN: Ziehl-Neelsen

The majority of patients received modified first line therapy (26, 62.0%). Treatment regimens are summarized in Table 3. All liver transplant recipients received modified first line therapy; the majority of which did not include pyrazinamide (PYZ). Fluoroquinolones (FQ) were used as a substitute for PYZ in 16 patients (8 liver, 7 kidney and 1 heart transplant recipient) and as substitute for rifampin (RIF) in 7 patients (4 liver transplant, 1 kidney and 2 heart transplant). Hepatotoxicity developed in 13 (31.0%) recipients (5 liver and 8 kidney transplant recipients). Management of patients who developed hepatotoxicity is summarized in Table 4. Notably, agents that were associated with hepatotoxicity were successfully re-introduced in 7 (53.8%) of those 13 recipients.

Table 3: Modified anti-tuberculous regimens received by patients with active tuberculosis following liver: kidney or heart transplantation ATT anti-tuberculous therapy; CNI: calcineurin inhibitors; CsA: cyclosporine; CS: cycloserine; EMB: ethambutol; INH: isoniazid; IS: immune suppressant; LZD: linezolid; LFX: levofloxacin; MXF: moxifloxacin; PYZ: pyrazinamide; RIF: rifampin; FQ: fluoroquinolones; PYZ: pyrazinamide; RIF: rifampin

Table 4: Treatment of the 13 patients who developed hepatotoxicity

Smear conversion was documented in 9 (69.2%) patients with positive initial ZN stains: while mycobacterial culture conversion was demonstrated in 16 (66.7%). Patients were treated for a median duration of 9.5 months (1–36). Six patients were treated for less than 6 months; 3 died within 90 days and 3 died within the first year of transplant.

Overall: 6 (14.3%) patients died within the first year of diagnosis. Compared with those who survived for more than 12 months after diagnosis of TB: patients who died were significantly older (median age 60 versus 51 years: P = 0:033) and had higher median Charlson Co-morbidity Scores (6 versus 2: P = 0.001) (Table 5). Age (adjusted odds ratio 0.892: 95% confidence interval 0.827–0.961; P 0.003) and Charlson Comorbidity Score (adjusted OR 2.866: 95% CI 1.331–6.174; P 0.007) were independently associated with all-cause mortality at 12- months. All-cause mortality at 36 months was higher in liver transplant (25.0%) compared with kidney transplant (9.1%) and heart transplant recipients (0%): but the difference was not statistically significant (log rank P 0.51) (Figure 1).

Table 5: Bivariate analysis for all-cause mortality at 12 months after diagnosis of active TB in liver: kidney or heart transplant recipients ATT: Anti-Tuberculosis Therapy; CCS: Charlson Comorbidity Score; TB: Tuberculosis

Discussion

To the best of our knowledge, this is the largest report of post-SOT TB from the MENA region. Over 11 years, there were 42 cases of active TB in kidney, liver or heart transplant recipients, corresponding to an incidence rate of 1.4%. This is lower than rates reported in SOT recipients from Asian (2.4%) or African countries (3.3%) [10]. This is likely to be in part due to the higher incidence of TB in these countries compared with that in Saudi Arabia [4].

Evaluation of latent TB in potential SOT recipients is usually based on history of any known prior TB exposure, previous personal history of TB, in addition to TST or interferon gamma release assays (IGRA) [14]. A considerable proportion of the patients included in this report had documented risk factors; history of TB exposure (5, 11.9%), positive pre-transplant QFT or TST (9, 21.4%) or prior personal history of TB (5, 11.9%) (Table 1). However, only 1 patient received TB chemoprophylaxis. In a recent review of TB is SOT recipients, only 140 out of 364 cohort studies reported the risk factors for development of post-transplant TB. Of those, only 25% received TB chemoprophylaxis [10]. This represents an important missed opportunity for prevention of TB in this high-risk population and highlights the need for effective pre-transplant risk stratification and multidisciplinary discussion to decide if TB chemoprophylaxis is required and its most appropriate timing in relation to the transplant procedure. Moreover, the evaluation of transplant candidates on high-dose corticosteroid and those with history of diabetes mellitus or are living in areas with higher rates of TB should include routine chest x-rays in addition to computed tomography (CT) scans, where necessary [14,15]. Noting a higher than expected rate of post-transplant TB in our center, we implemented a policy of universal TB chemoprophylaxis for all Kidney transplant recipients with allografts from deceased donors [13].

A recent systematic review and meta-analysis compared the performance of IGRA against TST in SOT recipient. No significant difference was found in patients with clinical risk factors, prior TB or BCG vaccinations. However, the authors concluded that IGRA-based tests performed better in patients with radiological evidence of past TB [16].

Compared with renal transplant candidates, liver transplant candidates are more likely to have indeterminate QFT results [17,18]. Higher Model for End-Stage Liver Disease (MELD) scores have been shown in some studies to be associated with higher rates of indeterminate QFT results, probably due to anergy [19,20]. Thus, caution should be exercised when interpreting QFT results in SOT candidates from countries with high endemicity for TB. Additional tools such as chest imaging, history of known prior exposure should be part of the assessment. Decisions on chemoprophylaxis should be based on the overall assessment instead of one particular test or another [18,19].

The majority of our patients who were diagnosed within the first year of transplant had received induction immunosuppressive regimens. Anti-thymocyte globulin (ATG) was received by approximately one third of patients in this series. Use of lymphocyte depleting agents and/or treatment of rejection episodes were among the identified risk factors for active TB in heart transplant recipients [10]. Most (28, 66.7 %) of our patients were on tacrolimus-based regimens. In a large cohort study from India, the incidence of TB was remarkably lower in SOT recipients who received tacrolimus-based immune suppression regimens compared with cyclosporine (6.1% versus 19.9%, P <.001) [21]. In the same study, tacrolimus-based regimens were also associated with more disseminated disease. In the current study we did not evaluate the incidence of TB in both group and cannot make a conclusion on risk difference of TB between the different immunosuppressant regimens.

The majority of patients in this cohort received modified antituberculous therapy. Pyrazinamide-sparing regimens were the most common modification; most often in Liver transplant patients. Fluoroquinolones were part of the first line therapy in a considerable number of patients. Current American Society of Transplantation (AST) guidelines for the treatment of TB in SOT recipients recommend that regimens similar to those used in non-transplant patients [14]. Patients who develop hepatotoxicity or impaired liver test can be treated with FQ-based therapy. Around 30% of our patients developed hepatotoxicity and underwent further modification of antituberculous therapy. None of the patients developed rejection while on anti-TB therapy, including patients who were on rifampin. This may suggest that rifampin can be used in the setting of transplantation with close monitoring of immunosuppressant levels.

Conclusion

In conclusion, post-transplant TB is relatively uncommon in SOT recipients in MENA but should be considered in the differential diagnosis in SOT recipients who present with subacute respiratory or constitutional symptoms, especially in endemic regions, or in the presence of risk factors. Risk assessment prior to transplant should include epidemiologic risk factors, results of the screening tests for latent TB and adequate radiological assessment. Caution is required when interpreting screening results. Moxifloxacin-based ATT in SOT recipients is associated with low rates of hepatotoxicity-related interruptions. Overall, clinical outcomes are acceptable, given the complexities of immune suppression and drug-drug interactions in this setting.

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