Ann Thorac Surg 2005;80:719-721
© 2005 The Society of Thoracic Surgeons
Case report
Successful Management of Two Heart Transplant Recipients With Mycobacterial Pulmonary Infections
Torsten Bossert, MD
*
,
Hartmuth B. Bittner, PhD,
Markus Richter, MD,
Axel Rahmel, MD,
Markus Barten, MD,
Jan F. Gummert, PhD,
Friedrich W. Mohr, PhD
Department of Cardiac Surgery, University of Leipzig Heart Center, Leipzig, Germany
Accepted for publication January 22, 2004.
* Address reprint requests to Dr Bossert, Department of Cardiac Surgery, University of Leipzig, Heart Center GmbH, Strümpellstr 39, 04289 Leipzig, Germany (Email: tbossert11{at}aol.com).
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Abstract
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We report two cases of pulmonary tuberculosis in heart transplant recipients: a 46-year-old man with pulmonary tuberculosis due to Mycobacterium tuberculosis and a 64-year-old man with nontuberculous mycobacterial infection with pulmonary infiltrates due to Mycobacterium xenopi. The time intervals from transplantation to diagnosis were 3 and 4 years, respectively. The patient with tuberculosis underwent standard treatment with isoniazid, rifampin, ethambutol, and pyrazinamide. The patient with the nontuberculous mycobacterial infection received treatment with clarithromycin and ciprofloxacin for 18 months in addition to rifampin for the first 3 months. Both patients responded well to treatment. No recurrences were observed during follow-up. The interactions between antibiotic treatment and cyclosporine therapy should be observed closely in organ transplant recipients, requiring frequent level determinations and dosing changes.
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Introduction
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Mycobacterioses are opportunistic infections commonly seen among patients on long-term immunosuppressive therapy, with associated mortality rates ranging from 25% to 40% [1]. Nontuberculous mycobacteriosis (NTM) after heart transplantation is rare, with fewer than 30 cases reported in the literature. Nontuberculous mycobacteriosis species like Mycobacterium xenopi have recently been described as a cause of pulmonary disease in patients infected with human immunodeficiency virus. Nevertheless M. xenopi infection was originally thought to be an infrequent and relatively benign disease. Mycobacterium xenopi is still relatively uncommon in the United States [2], but is a common cause of NTM pulmonary disease in Western Europe [3]. The results of antibiotic therapy of NTM remain unpredictable, with occasional nonresponders or relapses after cessation of treatment. Antibiotic therapy continues to be controversial [4].
In our consecutive series of 165 orthotopic heart (n = 158), lung (n = 4), and heart-lung (n = 3) transplant recipients between March 1995 and March 2003, two cases of pulmonary tuberculosis occurred: a 46-year-old man had pulmonary tuberculosis due to M. tuberculosis, and a 64-year-old man who presented with pulmonary infiltrates was found to have M. xenopi NTM infection. Pretransplant history was free of tuberculosis in both patients, and tuberculin skin testing has not been performed. Donor transmission was unknown. Both patients received intraoperatively 500 mg prednisolone and anti-T cell antibodies, followed by a standard regimen consisting of cyclosporine, azathioprine, and prednisone. Cyclosporine levels were maintained between 200 and 250 ng/mL. The intervals between transplantation and mycobacterial diagnosis were 3 and 4 years, respectively. No rejection episodes occurred during that time.
Both patients presented with nonproductive cough and fever, but no dyspnea. Chest radiographs and computed tomography revealed new focal infiltrates (Fig 1) compared with numerous previous radiographs. In both cases, acid-fast bacilli were found in sputum cultures and in cultured samples from bronchial washings and transbronchial biopsies obtained in the affected areas. The sputum cultures of the patient with M. xenopi also showed Pseudomonas aeroginosa. No extrapulmonary manifestations occurred. In the case of NTM, the diagnostic criteria of NTM lung disease of the American Thoracic Society were fulfilled.
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Fig 1. Computed tomography scan showing noncharac teristic infiltrates due to Mycobacterium xenopi, but no adenopathy.
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The patient with pulmonary tuberculosis underwent standard treatment with isoniazid 300 mg, rifampin 600 mg, ethambutol 15 mg/kg, and pyrazinamide 20 mg/kg for 3 months, followed by isoniazid and rifampin for a total treatment time of 1 year.
The patient with NTM also received a combined antibiotic treatment consisting of clarithromycin 500 mg twice a day, ciprofloxacin 500 mg twice a day for 18 months, and rifampin 600 mg for 3 months. Owing to a gastrointestinal adverse reaction (nausea), rifampin was stopped by the local medical doctor, and 5 days later the patient had to be admitted to the hospital owing to acute cyclosporine intoxication. Maximum blood level of cyclosporine reached 972 ng/mL.
Reducing the cyclosporine serum levels proved to be challenging at the start of rifampin administration, and the patients were hospitalized for 3 weeks undergoing daily serum level testing. We observed a significant interaction between cyclosporine concentrations and antibiotic treament. A threefold dose of cyclosporine was necessary to obtain therapeutic levels during the course of antibiotic therapy, while the step-by-step decrease of antibiotic medications led to rebounding cyclosporine levels. Both patients responded well to treatment. Follow-up examinations revealed improved clinical and radiologic signs. Because of the presence of three multilocular cavities, resection was not an option in the case of M. xenopi infection. No further toxicities were observed during antibiotic therapy. Clinical and laboratory screening was routinely performed to prevent drug toxicity. The patients underwent frequent opthalmologic examinations. There were no allograft rejections during the treatment period, based on endomyocardial biopsy performed every 3 months. No recurrence of tuberculosis and NTM occurred during the follow-up period of 25 and 31 months, respectively.
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Comment
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The prevalence of mycobacterial infections in solid organ recipients is estimated to be close to 15%, with a mortality rate ranging from 25% to 40% [1, 5]. Singh and colleagues [1] reviewed the literature in 1998 and identified 511 cases of TB in solid organ transplant recipients: only 17 cases (3.3%) occurred in heart transplant recipients. In a German single-center experience, the prevalence of tuberculosis and NTM in heart transplant recipients is higher compared with the general population of Germany [6]. In lung transplant recipients, the incidence of tuberculosis is generally higher compared with heart transplant recipients and ranges from 2% to 6.5% [1, 5]. Singh and colleagues [1] determined that most tuberculosis infections (64%) occur within the first 12 months of transplantation, with a median time of 9 months. Since our patients were diagnosed 3 and 4 years after transplantation, new infection and not a reactivation of dormant tuberculosis can be assumed. Our data confirm the presence of ongoing infection risks in patients on low-dose maintenance immunosuppression therapy. Most tuberculosis infections in transplant recipients still represent reactivation of old dormant disease, with an overall mortality of 29% [1].
Drug treatment of NTM and tuberculosis in solid organ transplant recipients continues to be difficult. We recommend closely observing drug levels and being aware of possible drug interactions. Rifampin decreases cyclosporine serum levels owing to the higher activity of the P-450 cytochrome. In addition, accelerated metabolism of immunosuppressive drugs caused by rifampin may trigger allograft rejection [7]. Recently, the first case of primary tuberculosis caused by multidrug-resistant M. tuberculosis in a heart transplant recipient was described [8]. Because of the toxicity of antibiotic procedure, the American Thoracic Society recommends special monitoring during therapy.
Mycobacterium xenopi is significantly less susceptible than other mycobacteria to first-line antituberculous drugs, and in general, the clinical response to antituberculous therapy is poor, even though in vitro testing demonstrates good sensitivity. Drug treatment for NTM needs empiric therapy, with drug susceptibility testing required only for clarithromycin. In the first randomized trial concerning treatment for pulmonary disease due to M. xenopi, the results of susceptibility tests do not correlate well with the patient’s response to chemotherapy. In some cases of NTM, for example, in the presence of localized nodular or cavitary disease, pulmonary resection continues to be an important adjunct to chemotherapy [3].
In conclusion, for patients with tuberculosis and NTM, a carefully selected long-term antibiotic regimen without reducing immunosuppression is the treatment of choice. We recommend early and aggressive treatment to achieve clinical improvement and prevent subsequent dissemination in transplant recipients. The substantial time interval between transplantation and the onset of symptoms indicates the continous risk of tuberculosis infection in immunosuppressed patients. Management of tuberculosis and NTM infection in solid organ transplant recipients is complex and requires a high degree of awareness and clinical expertise.
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References
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- Singh N, Paterson DL. Mycobacterium tuberculosis infection in solid-organ transplant recipientsimpact and implications for management. Clin Infect Dis 1998;27:1266-1277.[Medline]
- Donnabella V, Salazar-Schicchi J, Bonk S, Hanna B, Rom WN. Increasing incidence of Mycobacterium xenopi at Bellevue hospitalan emerging pathogen or a product of improved laboratory methods?. Chest 2000;118:1365-1370.[Abstract/Free Full Text]
- American Thoracic Society Diagnosis and treatment of disease caused by nontuberculous mycobacteria Am J Respir Crit Care Med 1997;156:S1-S25.
- Banks J, Hunter AM, Campbell IA, Jenkins PA, Smith AP. Pulmonary infection with Mycobacterium xenopireview of treatment and response. Thorax 1984;39:376-382.[Abstract/Free Full Text]
- Kesten S, Chaparro C. Mycobacterial infections in lung transplant recipients Chest 1999;115:741-745.[Abstract/Free Full Text]
- Korner MM, Hirata N, Tenderich G, et al. Tuberculosis in heart transplant recipients Chest 1997;111:365-369.[Abstract/Free Full Text]
- Paterson DL, Singh N. Interactions between tacrolimus and antimicrobial agents Clin Infect Dis 1997;25:1430-1440.[Medline]
- Di Perri G, Luzzati R, Forni A, et al. Fatal primary multidrug-resistant tuberculosis in a heart transplant recipient Transpl Int 1998;11:305-307.[Medline]
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Abstract
Introduction
