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
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.
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.
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.
Volume : 13
Issue : 1
Pages : 214 - 218
DOI : 10.6002/ect.mesot2014.P16
From the 1Department of Pulmonary Diseases, Baskent University
Ankara; the 2Department of Pulmonary Diseases, Baskent University
Istanbul; and the 3Department of General Surgery, Baskent University
Acknowledgements: The authors declare that they have no sources of funding for this study, and they have no conflicts of interest to declare.
Corresponding author: Gaye Ulubay, MD, Baskent University, Department of Pulmonary Diseases, Fevzi Çakmak Cd. 10. Sk. No: 45, Bahçelievler, Ankara, Turkey
Phone: +90 312 212 6868
Fax: +90 312 223 7333
Table 1. Demographics and Laboratory Findings of 19 SOT Recipients with TB
Table 2. TB Characteristics