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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE  
Year : 2015  |  Volume : 26  |  Issue : 1  |  Page : 6-11
Mycobacterial infection and the impact of rifabutin treatment in organ transplant recipients: A single-center study


1 Clinical Tuberculosis and Epidemiology Research Center; Mycobacteriology Research Center, National Research Institute for Tuberculosis and Lung Disease (NRITLD), Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
2 Clinical Tuberculosis and Epidemiology Research Center, National Research Institute for Tuberculosis and Lung Disease (NRITLD), Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
3 Lung Transplantation Research Center, National Research Institute for Tuberculosis and Lung Disease (NRITLD), Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran

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Date of Web Publication8-Jan-2015
 

   Abstract 

Tuberculosis (TB) is a frequently encountered infection among organ transplant recipients in developing countries, and the incidence of infection after the first year of transplantation is considerably high. In this study, the impact of rifabutin treatment on organ transplant recipients with TB infection was evaluated with respect to the trend of infection, management and outcome. The medical records of 26 post-transplant patients who received an organ transplant between 2004 and 2012 and later diagnosed with TB of different organs were reviewed retrospectively. We retrieved data regarding clinical features as well as treatment and outcomes. The median time interval between transplantation and TB was 36 months (IQR 12-101 months). The most common form of infection was pulmonary/pleural TB. All our subjects received rifabutin instead of rifampin in the anti-TB treatment regime as rifabutin is a less-potent inducer of cytochrome P-450. All patients responded satisfactorily to the treatment and maintained excellent allograft function. Moreover, we did not have any mortality among our recipients. Drug-induced hepatitis was observed in nine (35%) patients. Rifabutin is an excellent alternative medication to rifampin in the setting of TB management. Hepatotoxicity is a potential risk for treatment because of the potential additive toxicity of immunosuppressive drugs.

How to cite this article:
Tabarsi P, Farshidpour M, Marjani M, Baghaei P, Yousefzadeh A, Najafizadeh K, Sharifkashani B, Javanmard P, Mansouri D, Masjedi M, Velayati A. Mycobacterial infection and the impact of rifabutin treatment in organ transplant recipients: A single-center study. Saudi J Kidney Dis Transpl 2015;26:6-11

How to cite this URL:
Tabarsi P, Farshidpour M, Marjani M, Baghaei P, Yousefzadeh A, Najafizadeh K, Sharifkashani B, Javanmard P, Mansouri D, Masjedi M, Velayati A. Mycobacterial infection and the impact of rifabutin treatment in organ transplant recipients: A single-center study. Saudi J Kidney Dis Transpl [serial online] 2015 [cited 2019 Dec 9];26:6-11. Available from: http://www.sjkdt.org/text.asp?2015/26/1/6/148710

   Introduction Top


Tuberculosis (TB) is one of the leading opportunistic infections among organ transplant recipients. The incidence of TB in solid organ transplant recipients is reported to be 36-74 times higher than that in the normal population due to the use of immunosuppressive agents and reactivation of latent infection. [1],[2] While the estimated incidence of TB in Iran is reported to be 21 per 100,000 inhabitants, this rate can be expected to be much higher among transplant recipients. [3] Previous studies have reported that the prevalence of TB among organ transplant recipients ranges between 1.7% and 3.9% in Iran. In addition, TB causes considerable morbidity and mortality among this group. [4],[5],[6] The management of TB in this setting is difficult due to the side-effects of anti-TB agents and their potential interactions with immunosuppressive medications. Therefore, in this particular study, we investigated the trend of TB infection in organ transplant receipts and the impact of using rifabutin in their management.


   Materials and Methods Top


The clinical records of all organ transplant recipients admitted at the National Research Institutes of Tuberculosis and Lung Diseases (NRITLD), Masih Daneshvari Hospital in Iran from January 2004 to February 2012 were reviewed. Because only heart and lung transplants are being performed in our center, renal transplant cases were those referred to our hospital from other transplant centers. The diagnosis of TB was defined as a positive result for acid fast bacilli (AFB) on a sputum smear examination, culture and/or chronic granulomatous inflammation by histopathology. Those with a positive TB polymerase chain reaction (PCR) on samples were also considered as positive. [1] TB was categorized according to the type and extent of involvement. Consequently, pulmonary infection was described as lung involvement only and extrapulmonary TB indicated the involvement of a single extrapulmonary location. Disseminated TB signified the concomitant involvement of at least two separate sites.

Lung transplant recipients received cyclosporine (CsA) before the transplant, methyl prednisolone during the transplant and CsA plus mycophenolate mofetil (MMF) and prednisolone (PRD) after the transplant as immunosuppressive agents. Most heart transplant recipients as well as kidney transplant recipients were administered methyl prednisolone and anti-thymocyte globulin (ATG) as the induction immunosuppressive agents as the maintenance agent. Maintenace therapy was with CsA or tacrolimus, cellcept or sirolimus(SRL) and PRD. In patients taking CsA, the dose was adjusted and monitored aiming for a trough serum concentration of 100-200 ng/mL.

Also, the data were analyzed for the mean time of onset of TB after transplantation, immunosuppressive drugs administered during TB treatment, anti-TB regimen, graft rejection as well as success, failure and duration of TB treatment. Transplant recipients with documented TB had received the standard protocol regimen of our institution including isoniazid (INH) (5 mg/kg/ day), rifabutin (5 mg/kg/day), pyrazinamide (20-30 mg/kg/day) and ethambutol (15-25 mg/kg/day) for the first two months, followed by INH and rifabutin for another 10 months. However, patients diagnosed with resistance to rifampin had received cycloserine (750-1000 mg/day), ofloxacin (400-800 mg/day) and prothionamide (750-1000 mg/day) for two years and amikacin (15 mg/kg/day for the first six months. Rifampin was not used given the fact that it is a potent inducer of the cytochrome P-450 microsomal enzyme system that is accountable for metabolizing cyclosporine, SRL and prednisolone.

After discharge from the hospital, treatment was continued at a peripheral center of the national health care system. Patients were also followed-up and re-evaluated every six months at our referral clinic. Adverse drug reactions were monitored based on clinical symptoms and signs. Blood urea nitrogen, creatinine and liver function tests were performed every 15 days in the hospital and monthly thereafter. Demographic and clinical data were analyzed using mean and standard deviation and range depending on normality of the data. The study was conducted with the approval of the National Research Institutes of Tuberculosis and Lung Diseases Ethics Committee.


   Results Top


Characteristics and demographic factors of 26 organ transplant recipients identified and reviewed are given in [Table 1]. The mean age was 38 ± 10 (range 25-62) years. Fifteen (58%) of the patients were male and 21 (81%) had renal transplantation, three (11%) lung, one (4%) heart and one (4%) underwent bone marrow transplantation. Furthermore, nine (35%) patients were diabetic and 13 (50%) were hypertensive. All patients were negative for human immunodeficiency virus (HIV) infection; however, two (8%) of our subjects were chronically infected, one with hepatitis B and the other with C virus. The median time interval between the transplantation and TB was 36 months [interquartile range (IQR) 12-101 months]. Pulmonary TB was found in 19 (73%), extra-pulmonary TB in two (8%) and disseminated TB in five (19%), among which one had miliary shadows on chest X-ray. Extra-pulmonary TB occurred only in renal transplant recipients, and the most common site of involvement in our study was the cervical lymph nodes, a total four (15%) cases. Furthermore, one (4%) patient was infected with Mycobacterium simiae. Cough and sputum were the most common presentations in posttransplantation TB, and this was observed in 19 (73%) of our patients. Fever was also frequent among the patients [Table 1].
Table 1: Characteristics and demographic factors of 26 organ transplant recipients.

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Twenty (77%) patients who received transplants had been taking triple therapy with CsA plus MMF and prednisolone (PRD). Others were treated with double therapy consisting of SRL or TAC plus PRD.

In our study, the acid-fast staining to detect bacilli in sputum specimens was the most frequently employed method for the diagnosis of pulmonary TB, used in 19 (73%) patients. Histopathological examination was performed in tissue samples obtained from the cervical lymph nodes in nine (35%) patients and, finally, the drug susceptibility test (DST) was established in all possible specimens if drug resistance was suspected. In addition, the PCR, which can amplify genetic materials from sputum, was positive in ten (38%) recipients.

Twenty-four (92%) patients were treated with the standard protocol regimen of our institution. Two (8%) patients who had received renal transplant were diagnosed with rifampin resistance and administered cycloserine, ofloxacin and prothionamide for two years and amikacin for the first six months.

Moreover, drug-induced hepatitis was observed in nine (35%) patients. After withdrawal of INH, rifabutin and pyrazinamide, serum transaminase levels rapidly returned to normal in the first week and all the above-mentioned medications were re-administered except for pyrazinamide. Following reinstitution, no increase in serum transaminase was detected. Additionally, five (19%) patients experienced severe thrombocytopenia and rifabutin was subsequently excluded from their regimen immediately.

One of our patients had an infection with Mycobacterium simiae, which was treated with the combination of clarithromycin, ofloxacin and Co-trimoxazol. He was also diagnosed with cytomegalovirus (CMV) enteritis. Also, we discovered other co-infections in five (19%) patients as given below: CMV, pneumonitis (in a patient with renal transplant), H1N1 (in a patient with heart transplant and diabetes mellitus), CMV enteritis, aspergillosis (in a patient with lung transplant) and E. coli urosepsis (in a renal transplant recipient).

All our patients were treated with anti-TB medications and there was neither mortality nor organ rejection among our subjects. The mean time of follow-up was 10 ± 7 months. Subsequently, five (19%) patients died, one each due to renal failure, massive hemoptysis and hepatic encephalopathy, and information regarding the cause of death for the remaining two was not available.


   Discussion Top


TB has an important impact on renal transplant recipients, particularly in endemic countries due to the mortality, morbidity and treatment that requires the utmost attention to antimicrobial therapy and their interaction with immunosuppressant agents. Active TB infection in those patients could be due to airborne spread in the community or transmission through the transplanted organ; however, in general, the disease is assumed to develop because of the reactivation of pre-existing dormant lesions. [7]

Additionally, the presence of co-existing diseases in this group, such as CMV, Pneumocystis jirovecii, nocardia, hepatitis C infection and diabetes mellitus are closely associated with the development of TB. [8],[9]

Previous studies have reported that the prevalence of TB in organ transplant patients ranges between 1.7% and 3.9% in Iran, which is moderately high compared with developed western countries, where the prevalence of TB ranges from 1-4%. [10],[11] This is probably because of the relatively high frequency of TB in Iran. Additionally, reports have shown that the over-all mean age is 35 years at the time of TB infection and the interval between transplantation and diagnosis is 54 months. [12],[13] In our study, TB occurred at a slightly older age and TB happened earlier after transplantation compared with previous data.

Often, there is difficulty in the diagnosis of TB in immunosuppressed patients due to the atypical clinical and laboratory findings, and this may cause a delay in treatment. [14] In our work, productive cough and fever were common symptoms among the patients, and this statement is consistent with an earlier report that has shown 30% of patients presented with fever. Therefore, in developing countries, TB could be regarded as a presumable cause of fever of unknown origin in transplant organ recipients, particularly after the first year of transplantation. [15] Additionally, pulmonary involvement is the most common form of presentation of TB in the post-transplant period, and this was consistent with our experience in which pleural- pulmonary infection was the most common form of TB in our patients. [16]

Overall, the mortality rate among organ transplant recipients is between 11% and 23% in Iran, 29% in the United states and 28% among those from Europe. [12],[13],[16] Predictors of mortality in transplant recipients with TB could be disseminated TB compared with localized TB, prior rejection episodes compared with no prior rejection and receipt of muromonab-CD3 (OKT3) or anti-T cell antibodies compared with not receiving OKT3 or anti-T cell antibodies. [16]

Interestingly, there was no mortality among our patients during the study period, and all of our patients were cured. In addition, none of our subjects were diagnosed with an organ rejection episode during the treatment with anti-TB therapy. This finding might be due to the use of rifabutin instead of rifampin in our regimen. Rifampin deserves special attention in the management of organ transplant recipients who develop TB due to its induction of the hepatic cytochrome P-450 system. When cyclosporine is administrated in conjunction with rifampin, its serum level has to be monitored strictly. In this study, we used rifabutin, which has greater activity against M. tuberculosis, has a much longer half-life (35 h compared with 3.5 h) and is a less-potent inducer of the cytochrome P-450 system than rifampin. [17],[18] Subsequently, with dose adjustments made as required, serum levels of cyclosporine were maintained within the therapeutic range and no acute rejection was noted in our recipients.

Another significant problem in these patients is anti-TB drug-induced hepatotoxicity. Our data demonstrated that clinically significant hepatotoxicity occurred in 35% of renal transplant recipients compared with 2.5% in previous studies. [16] It has been shown that administration of INH together with rifampicin enhances the risk of hepatotoxicity up to 8% in non-transplant patients and a fatal course occurred in 4.6% of patients. [19] The reason behind the high prevalence of drug-induced hepatitis in our subjects is still unclear and further investigations are needed to address this issue.

This study has some limitations. First, it is based on retrospective data from a single center. Different hospitals or populations could be anticipated to have diverse outcomes. Moreover, pre-hospital information was not accessible for several of our patients hence limiting our ability to analyze them.


   Conclusion Top


This review summarizes the overall effect of M. tuberculosis in organ transplant recipients and highlights key features such as TB being a frequent cause of infection among organ transplant recipients in developing countries. Additionally, the incidence of infection after the first year of transplantation is considerably high. Rifabutin is an excellent alternative medication to rifampin in the setting of management of TB in patients with organ transplantation on immunosuppressive medications. Hepatotoxicity is a potential risk during treatment.

Conflict of interest: None

 
   References Top

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2.
Sakhuja V, Jha V, Varma PP, Joshi K, Chugh KS. The high incidence of tuberculosis among renal transplant recipients in India. Transplantation 1996;61:211-5.  Back to cited text no. 2
    
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WHO TB burden estimates and ′Global tuberculosis report 2012′. Available from: http://www.who.int/tb/publications/global_report. [Last accessed on 9/5/2013.  Back to cited text no. 3
    
4.
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;15:894-906.  Back to cited text no. 4
    
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Canet E, Dantal J, Blancho G, Hourmant M, Coupel S. Tuberculosis following kidney transplantation: Clinical features and outcome. A French multicentre experience in the last 20 years. Nephrol Dial Transplant 2011;26:3773-8.  Back to cited text no. 5
    
6.
Grassi C, Peona V. Use of rifabutin in the treatment of pulmonary tuberculosis. Clin Infect Dis 1996;22 Suppl 1:S50-4.  Back to cited text no. 6
    
7.
Samhan M, Panjwani DD, Dadah SK, Kumar MS, Araj G, Abouna GM. Is tuberculosis a contraindication for renal transplantation? Transplant Proc 1989;21:2036-8.  Back to cited text no. 7
    
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Lattes R, Radisic M, Rial M, Argento J, Casadei D. Tuberculosis in renal transplant recipients. Transpl Infect Dis 1999;1:98-104.  Back to cited text no. 8
    
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Qunibi WY, al-Sibai MB, Taher S, et al. Mycobacterial infection after renal transplantationreport of 14 cases and review of the literature. Q J Med 1990;77:1039-60.  Back to cited text no. 10
    
11.
Higgins RM, Cahn AP, Porter D, et al. Mycobacterial infections after renal transplantation. Q J Med 1991;78:145-53.  Back to cited text no. 11
    
12.
Ghafari A, Makhdoomi K, Ahmadpoor P, Afshari AT, Fallah MM, Rezaee K. Tuberculosis in Iranian kidney transplant recipients: A singlecenter experience. Transplant Proc 2007;39:1008-11.  Back to cited text no. 12
    
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Mojahedi MJ, Feizzadeh B, Aghdam B, Hekmat R. The prevalence of tuberculosis in recipients of renal transplantation. Saudi J Kidney Dis Transpl 2011;22:1266-8.  Back to cited text no. 13
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Yildiz A, Sever MS, Turkmen A, et al. Tuberculosis after renal transplantation: Experience of one Turkish centre. Nephrol Dial Transplant 1998;13:1872-5.  Back to cited text no. 14
    
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Riska H, Kuhlback B. Tuberculosis and kidney transplantation. Acta Med Scand 1979;205:637-40.  Back to cited text no. 15
    
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Singh N, Paterson DL. Mycobacterium tuberculosis infection in solid-organ transplant recipients: Impact and implications for management. Clin Infect Dis 1998;27:1266-77.  Back to cited text no. 16
    
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Narita M, Stambaugh JJ, Hollender ES, Jones D, Pitchenik AE, Ashkin D. Use of rifabutin with protease inhibitors for human immunodeficiency virus-infected patients with tuberculosis. Clin Infect Dis 2000;30:779-83.  Back to cited text no. 17
    
18.
Weiner M, Benator D, Burman W, et al. Association between acquired rifamycin resistance and the pharmacokinetics of rifabutin and isoniazid among patients with HIV and tuberculosis. Clin Infect Dis 2005;40:1481-91.  Back to cited text no. 18
    
19.
Centers for Disease Control and Prevention (CDC). Severe isoniazid-associated hepatitisNew York, 1991-1993. MMWR Morb Mortal Wkly Rep 1993;42:545-7.  Back to cited text no. 19
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Correspondence Address:
Dr. Payam Tabarsi
Clinical Tuberculosis and Epidemiology Research Center, National Research Institute of Tuberculosis and Lung Disease, Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran
Iran
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DOI: 10.4103/1319-2442.148710

PMID: 25579709

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