Objectives: Tuberculosis remains an important problem in solid-organ transplant patients due to their immunocompromised state. The objective of the present study was to report the incidence, demographic characteristics, and various presentations of tuberculosis in solid-organ transplant recipients.

Materials and Methods: We evaluated a total of 999 patients (male/female = 665/334, 661 renal and 338 liver transplants) who underwent solid-organ transplant between 2003 and 2013. The medical records of all patients were retrospectively reviewed. Patients’ demographics, transplant type, primary site of tuberculosis specimen culture and pathology results, chest radiograph, and thoracic computed tomography findings, total blood count and chemistry were all recorded.

Results: Among the 999 subjects, 19 patients (1.9%) (male/female: 15/4, mean ± SD age, 42 ± 18.5 y) were diagnosed with tuberculosis. The majority of patients (85%) were diagnosed with tuberculosis within 6 months after transplant, and 15% were diagnosed within 3 months. Most diagnoses of tuberculosis were based on histopathologic examination of biopsy material. Of these patients, 9 were diagnosed with pulmonary tuberculosis, 8 had extrapulmonary tuberculosis, and 2 had both. Nontuberculosis mycobacteria infections were detected in 3 patients.

Conclusions: Even with a negative exposure history, tuberculosis can manifest as different clinic presentations in solid-organ transplant patients on immunosuppressive drugs, particularly in the first 6 months after transplant. Therefore, clinicians should always consider tuberculosis as the potential cause of an infectious disease with unknown cause to successfully diagnose and manage solid-organ transplant recipients.

Key words : Pulmonary complication, Infection, Transplant

Introduction

Tuberculosis (TB) is an opportunistic infection with high morbidity and mortality, and persistent diagnostic difficulties often result in delayed treatment.¹ According to the World Health Organization, more than one-third of the world’s population is infected with Mycobacterium tuberculosis.² Among those who carry the bacterium, 10% have active (primary or reactivated) TB, with a considerably higher rate among immunosuppressed individuals.

The reported incidence of TB disease is 0.2% to 6.4% in developed countries and is predicted to be as high as 15% in highly endemic countries.^3-6 The prevalence of active TB disease among solid-organ transplant (SOT) recipients was estimated to be 20 to 74 times higher than that of the general population.^7-9 Although rare, TB infection presents as various clinical manifestations with increased frequency and severity in transplant recipients.¹⁰ Consequently, TB mortality is also higher (up to 31%) in SOT patients than in immunocompetent individuals (0-24 cases per 100 000 for the USA and Western Europe, and > 1% in South Africa).^3,5,11,12

Tuberculosis clinical presentation is often atypical, with more than half of SOT recipients presenting with extrapulmonary or disseminated disease.⁸ Therefore, a high degree of suspicion for M. tuberculosis infection based on clinical experience remains the cornerstone of TB diagnosis. Furthermore, TB treatment is highly problematic in these patients because they are at high risk for multiple adverse effects of first-line anti-TB drugs, drug-drug interactions, and acute allograft rejection due to the increased clearance rate of immuno­suppressant drugs.^7,8,13,14

Tuberculosis management in SOT recipients remains complex and challenging. In this study, we report the frequency, clinical features, risk factors, and primary outcomes of TB in SOT patients.

Materials and Methods

This study was conducted in Baskent University Hospital, and was approved by the Ethical Review Committee of the Institute. All of the protocols conformed with the ethical guidelines of the 1975 Helsinki Declaration. Written informed consent was not required due to the retrospective nature of the study. All SOT recipients who underwent transplant between January 1, 2003, and December 31, 2013, were enrolled, and their medical records were reviewed to determine whether or not the patients had TB after SOT. The retrospectively collected data included patient demographics and characteristics, comorbidities, type of organ transplant, immuno­suppressive regimen, prior TB contact, and/or infection history, primary site of TB, clinical presentation, laboratory (biochemistry, microbiology, and histopathology) findings, radiographic features, diagnostic procedures, clinical outcomes, and mortality.

Results

A total of 999 SOT recipients (male/female: 665/334) were enrolled in this study. Sixty-six percent had received kidney transplants, whereas 34% had received liver transplants. Tuberculosis was diagnosed in 19 of these patients (1.9%). The prevalence rates of TB among renal and liver SOT recipients were 2.1% and 1.5%. The demographic features and laboratory findings of SOT recipients with TB are listed in Table 1. The majority of patients (57.9%) were ex-smokers with a history of renal transplant (73.7%) and from a living donor (73.7%). There were various comorbidities in 13 patients (68.4%). Four had multiple comorbidities (1 patient had diabetes mellitus and hypertension; 1 patient had chronic obstructive pulmonary disease, coronary artery disease, hypertension, and congestive heart failure; and 2 patients had coronary artery disease and hypertension).

Various combinations of immunosuppressive drugs were administered posttransplant. The most commonly used agent was prednisolone (84.2% of SOT recipients with TB), but mycophenolate mofetil (73.7%), sirolimus (52.6%), tacrolimus (47.4%), and cyclosporine (10.5%) also were administered.

None of the patients had any known prior history of TB exposure and/or infection (Table 2). Tuberculosis prophylaxis with isoniazid was given pre- (1 patient) or postoperatively (2 patients). Upon radiologic examination, sequel lesions were found on computed tomography scans and/or chest radiograph in 10 patients (1 patient had sequel lesions on both imaging modalities). Tuberculosis involvement was pulmonary in 9 patients (47.4%), extrapulmonary in 8 (42.1%), and both in 2 SOT recipients with TB (10.5%).

The most commonly used diagnostic tool was histopathologic examination (n = 10, 52.6%), followed by specimen culture for TB (n = 4, 21.1%), and clinical suspicion (n = 5, 26.3%). Most patients (n = 17, 89.5%) were diagnosed with TB more than 6 months after transplant. None of the M. tuberculosis isolates were resistant to first-line anti-TB drugs. All patients were given combination therapy including isoniazid, rifampicin, pyrazinamide, and etham­butol. None of the patients developed hepatotoxicity due to these medications. Non-TB mycobacterial infections were found in 3 patients (0.3%). Neither death nor organ rejection was recorded during the management of TB disease in our study population. Three of the patients died because of other causes (independent of TB) 4 to 14 years after transplant. Five rejections were recorded 6 to 20 years after transplant.

Discussion

Patients undergoing SOT require potent and generally prolonged immunosuppressive treatment after surgery, which increases their risk several states opportunistic infections.^15,16 Tuberculosis is one of the most serious diseases that they can develop as it is associated with high morbidity and mortality in SOT recipients.^3,4 Many studies have described TB as a factor that facilitates organ rejection due to drug-drug interactions between anti-TB and immuno­suppressive agents.^17-19 Therefore, TB remains an important topic for both clinicians and patients in the posttransplant period.

The literature reports that the prevalence for TB in SOT recipients in low-endemicity areas is between 0.2% and 6.4%.^3-6 In the present study, TB frequency was 1.9% in 999 SOT patients. This high prevalence could be attributed to our strict preoperative pulmonary evaluation strategies for excluding the risk of reactivation TB in these patients.⁸ Another factor could be The National Stop Tuberculosis Strategy, which led to decreased TB rates in Turkey within the last 10 years (the annual change in the rate of new TB cases were 28.5 and 22.5 in 2005 and 2010).²⁰

Most TB occurs within 12 months after transplant.15 The median time interval between transplant and TB diagnosis has been reported as 9 to 31 months in the literature.^1,9,15,21 In our study group, 16 patients (85%) developed TB 6 months after transplant; TB was detected within the first 3 months after transplant in just 3 patients. Interestingly, all 3 of these patients received pulse steroid therapy within 1 month after transplant. All of these earlier cases also had radiographic evidence of latent TB. This leads us to speculate that, patients with a history of prior M. tuberculosis exposure develop TB earlier than patients without an exposure history, which is in accordance with the literature.²² In addition, none of the SOT recipients who developed TB had a prior known TB history, even though they had sequel lesions on either chest radiographs or computed tomography scans. Interferon-γ release assays are valuable for diagnosing latent TB infection in this population. The purified protein derivative skin test is not useful in Turkey because Bacillus Calmette–Guérin vaccination is routine. In our center, we began to perform interferon-γ release assays for all transplant candidates and initiate preventive therapy in those with positive reactions.

Because up to one-third of the world’s population has latent TB infection, the main mechanism of TB development in SOT recipients is the reactivation of dormant bacilli in other parts of the body.¹ Other sources of TB are primary infection from post­transplant exposure and acquired infection via an infected donor organ.^5,11 Donor-derived disease transmission is rare, complicating less than 1% of transplants.^23-25 Based on their radiologic findings, the basic mechanism in our 10 SOT recipients with TB could be reactivation of latent TB. However, the cause was not clear for the rest of the patients because they had neither prior history of TB nor radiologic findings. The source of TB in this group could be exposure to TB during the posttransplant phase.^21,26

Transplant type was found to be related with TB occurrence. In the present study, most TB patients were renal recipients (73.7%), which is in accordance with the literature.^5,21,22 This could be partially attributed to the predominance of renal recipients in our center (renal/liver: 661/338). Another explanation could be that renal recipients are at high risk of TB exposure from dialysis units.²⁷ Additionally, reactivation of latent TB might occur more frequently in patients with end-stage renal disease before transplant who have weakened immune systems due to renal failure. Collectively, our findings suggest that renal transplant recipients should be evaluated with more attention paid to TB risk compared with liver transplant recipients.

The most commonly used diagnostic method was histopathologic examination in our SOT recipients with TB, all of whom were diagnosed with extra­pulmonary TB (typically in the lymph nodes and bones). Therefore, while searching for the cause of an extrapulmonary infection, we recommend that all histopathologic specimens from SOT recipients should be evaluated for TB. In 4 patients, TB was treated based on clinical suspicion resulting in clinical, radiologic, and laboratory evidence. This supports the general opinion that empirical anti-TB treatment should be immediately administered to SOT recipients with high clinical suspicion of TB to reduce related complications and mortality.

Extrapulmonary TB occurs in approximately 20% of TB patients in a normal population.28 The clinical presentation of extrapulmonary TB in SOT patients is highly variable; they may have no symptoms and may be accidentally diagnosed by routine control testing. Hence, extrapulmonary TB presents more of a diagnostic and therapeutic problem than pulmonary TB, emphasizing the importance of clinical experience in this field.²⁸ Although there are some controversial results in our immunocompromised study population, the fre­quencies of pulmonary and extrapulmonary TB were similar (47.4% and 42.1%).^29-35 Therefore, extrapulmonary TB should be considered in the differential diagnosis of all extrapulmonary infections in SOT recipients.

The mortality rates due to TB in SOT recipients were reported between 13% and 40%.^1,36 In our study, this rate was 0%. Similarly, transplanted organ rejection did not occur during TB management. The Health Ministry of Turkey reported the national TB treatment success rate as 91%.²⁰ Thus, these satisfactory outcomes for SOT recipients with TB could be attributable to the government’s successful national treatment strategy, which has made Turkey one of the leading countries in global TB control.³⁶

Atypical mycobacterial infections may occur more often in immunocompromised hosts. The characteristics of a significant non-TB mycobacterial infection include positive culture of the pathogen from a normally sterile site or repeated isolation of potential mycobacterial pathogens from nonsterile sites.^15,37 The current frequency of the disease because of various non-TB mycobacteria species is unknown in immune-compromised patients.^28,38 Determining the incidence and prevalence of non-TB mycobacterial lung disease is actually quite difficult because it is not required to be reported in many countries. In our study, microbiologic test results revealed that 3 of the 999 SOT recipients (0.3%) had non-TB mycobacterial lung disease. Correctly differentiating between non-TB and TB infections is very important because some non-TB mycobacteria species do not respond well to anti-TB therapies.^15,28,38

In conclusion, TB is an important complication in SOT recipients and can increase mortality and morbidity rates. Reactivation TB can develop any time during the posttransplant period but is more common in the first few months after transplant. Additional immunosuppressive treatments against organ rejection may facilitate TB occurrence. Histopathologic analyses play an important role in diagnosing TB in patients with extrapulmonary involvement.

References:

1. Hopewell PC, Maeda MK. Tuberculosis. In: Mason RJ, Broaddus VC, Martin TR, King TE, Schraufnagel DE, Murray JF, Nadel JA, eds. Textbook of Respiratory Medicine. 5th ed. Philadelphia, PA: Saunders Elsevier; 2010:754-792.
2. World Health Organization. Global Tuberculosis Control 2009: Epidemiology, Strategy, Financing (WHO/HTM/TB/2009.411). Geneva, Switzerland: World Health Organization; 2009.
3. Torre-Cisneros J, Doblas A, Aguado JM, et al. Tuberculosis after solid-organ transplant: incidence, risk factors, and clinical characteristics in the RESITRA (Spanish Network of Infection in Transplantation) cohort. Clin Infect Dis. 2009;48(12):1657-1665.
4. Morales P, Briones A, Torres JJ, Solé A, Pérez D, Pastor A. Pulmonary tuberculosis in lung and heart-lung transplantation: fifteen years of experience in a single center in Spain. Transplant Proc. 2005;37(9):4050-4055.
5. Holty JE, Sista RR. Mycobacterium tuberculosis infection in transplant recipients: early diagnosis and treatment of resistant tuberculosis. Curr Opin Organ Transplant. 2009;14(6):613-618.
6. Eyüboğlu FÖ, Küpeli E, Bozbaş SS, et al. Evaluation of pulmonary infections in solid organ transplant patients: 12 years of experience. Transplant Proc. 2013;45(10):3458-3461.
7. Chen CH, Shu KH, Ho HC, et al. A nationwide population-based study of the risk of tuberculosis in different solid organ transplantations in Taiwan. Transplant Proc. 2014;46(4):1032-1035.
8. Bumbacea D, Arend SM, Eyuboglu F, et al. The risk of tuberculosis in transplant candidates and recipients: a TBNET consensus statement. Eur Respir J. 2012;40(4):990-1013.
9. Graham JC, Kearns AM, Magee JG, et al. Tuberculosis transmitted through transplantation. J Infect. 2001;43(4):251-254.
10. Gasink LB, Blumberg EA. Bacterial and mycobacterial pneumonia in transplant recipients. Clin Chest Med. 2005;26(4):647-659, vii.
11. Aguado JM, Torre-Cisneros J, Fortún J, et al. Tuberculosis in solid-organ transplant recipients: consensus statement of the group for the study of infection in transplant recipients (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology. Clin Infect Dis. 2009; 48(9):1276-1284.
12. Currie AC, Knight SR, Morris PJ. Tuberculosis in renal transplant recipients: the evidence for prophylaxis. Transplantation. 2010;90 (7):695-704.
13. Köseoğlu F, Emiroğlu R, Karakayali H, et al. Prevalence of mycobacterial infection in solid organ transplant recipients. Transplant Proc. 2001;33(102):1782-1784.
14. Sun HY, Munoz P, Torre-Cisneros J, et al. Mycobacterium tuberculosis-associated immune reconstitution syndrome in solid organ transplant recipients. Transplantation. 2013;95(9):1173-1181.
15. Young JH, Weisdorf DJ. Typical and atypical mycobacterium infections after hematopoietic stem cell or solid organ transplantation. In: Bowden RA, Ljungman P, Snydman DR, eds. Transplant Infections. 3rd ed. Phladelphia, PA: Wolters Kluwer/Lippincott Williams & Wilkins: 2010:282-294.
16. Myobacterium tuberculosis, in Guidelines for the prevention and management of infectious complications of solid organ trans­plantation. Am J Transplant. 2004;4(suppl 10):37-41.
17. Aguado JM, Herrero JA, Gavaldá J, et al. Clinical presentation and outcome of tuberculosis in kidney, liver, and heart transplant recipients in Spain. Transplantation. 1997;63:1278-1286.
18. Muñoz P, Rodríguez C, Bouza E. Mycobacterium tuberculosis infection in recipients of solid organ transplants. Clin Infect Dis. 2005;40:581-587.
19. Doblas A, Alcaide F, Benito N, Gurguí M, Torre-Cisneros J. Tuberculosis in solid organ transplant patients. Enferm Infecc Microbiol Clin. 2012;30(suppl 2):34-39.
20. The 2012 Report of War Against Tuberculosis in Turkey. Health Ministry Report of Turkey; 2013. http://tuberkuloz.thsk.saglik. gov.tr/Dosya/Dokumanlar/raporlar/turkiyede_verem_savasi_2012_raporu.pdf. Accessed 31 October, 2014.
21. Lopez de Castilla D, Schluger NW. Tuberculosis followingsolid organ transplantation. Transpl Infect Dis. 2010;12(2):106-112.
22. Singh N, Paterson DL. Mycobacterium tuberculosis infection in solid organ transplant recipients: impact and implications for management. Clin Infect Dis. 1998;27:1266-1277.
23. Ison MG, Nalesnik MA. An update on donor-derived disease transmission in organ transplantation. Am J Transplant. 2011;11(6): 1123-1130.
24. Morris MI, Daly JS, Blumberg E, et al. Diagnosis and management of tuberculosis in transplant donors: a donor-derived infections consensus conference report. Am J Transplant. 2012;12(9):2288-2300.
25. Subramanian AK. Tuberculosis in solid organ transplant candidates and recipients: current and future challenges. Curr Opin Infect Dis. 2014;27(4):316-321.
26. Patel R, Paya CV. Infections in solid organ transplant recipients. Clin Microbiol Rev. 1997;10(1):86-124.
27. Linquist JA, Rosaia CM, Riemer B, Heckman K, Alvarez F. Tuberculosis exposure of patients and staffs in an outpatient hemodialysis unit. Am J Infect Control. 2002;30:307-310.
28. Charles LD, Griffith DE. Nontuberculous mycobacterial infections. In: Mason RJ, Broaddus VC, Martin TR, King TE, Schraufnagel DE, Murray JF, Nadel, JA eds. Textbook of Respiratory Medicine; vol 1. 5th ed. Philadelphia, PA: Saunders Elsevier; 2010:793-810.
29. Centers for Disease Control and Prevention. Reported Tuberculosis in United States, 2007. Atlanta, GA: Centers for Disease Control and Prevention; 2007.
30. Holty JE, Gould MK, Meinke L, Keeffe EB, Ruoss SJ. Tuberculosis in liver transplant recipients: a systematic review and meta-analysis of individual patient data. Liver Transpl. 2009;15(8):894-906.
31. el-Agroudy AE, Refaie AF, Moussa OM, Ghoneim MA. Tuberculosis in Egyptian kidney transplant recipients: study of clinical course and outcome. J Nephrol. 2003;16(3):404-411.
32. Ghafari A, Makhdoomi K, Ahmadpoor P, Afshari AT, Fallah MM, Rezaee K. Tuberculosis in Iranian kidney transplant recipients: a single-center experience.Transplant Proc. 2007;39(4):1008-1011.
33. Boubaker K, Gargah T, Abderrahim E, Abdallah TB, Kheder A. Mycobacterium tuberculosis infection following kidney trans-plantation. Biomed Res Int. 2013;2013:347103.
34. Chen CH, Lian JD, Cheng CH, Wu MJ, Lee WC, Shu KH. Mycobacterium tuberculosis infection following renal transplantation in Taiwan. Transpl Infect Dis. 2006;8(3):148-156.
35. Bodro M, Sabé N, Santín M, et al. Clinical features and outcomes of tuberculosis in solid organ transplant recipients. Transplant Proc. 2012;44(9):2686-2689.
36. World Health Organization. Global Tuberculosis Control: WHO Report 2011. Geneva, Switzerland: World Health Organization; 2011.
37. William AB, Rodrigo EM, John BB. Tuberculosis and disease caused by atypical mycobacteria. In: Albert RK, Spiro SG, Jett JR, eds. Clinical Respiratory Medicine. 2nd ed. Maryland Heights, MO: Mosby; 2004:321-339.
38. Griffith DE, Aksamit T, Brown-Elliott BA, et al. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med. 2007;175(4):367-416.