Intestinal Involvement by Nontuberculous Mycobacteria After Heart Transplantation

The prevalence of disease due to nontuberculous mycobacteria (NTM) in the United States is 1.8 cases per 100,000 population [1]. In the general population, 5%–10% of mycobacteria causing infections are NTM, whereas in transplant recipients NTM cause 25%–40% of all mycobacterial infections [2]. We describe a case of infection with Mycobacterium avium/Mycobacterium intracellulare in a heart transplant recipient and review the literature on disease due to NTM [3–12]. A 56-year-old man underwent orthotopic heart transplantation in June 1990 for ischemic cardiomyopathy. In November 1992, he was admitted to the hospital because of fever (temperature, 39°C) during treatment with cyclosporine, azathioprine, and deflazacort. Physical examination disclosed a small epitrochlear node and a tender periumbilical mass. His erythrocyte sedimentation rate was 92 mm/h. Blood cultures and serological tests for Brucella, Salmonella, Yersinia, cytomegalovirus, and HIV were negative. Ziehl-Neelsen staining of urine and sputum samples were negative, as were cultures of these samples on Löwenstein-Jensen medium. Purified protein derivative skin testing was also negative. A CT scan of the chest and abdomen revealed enlarged retroperitoneal and mesenteric lymph nodes. Biopsy of the epitrochlear node revealed granulomas with scarce acid-fast bacilli, and culture of the node on Lowënstein-Jensen medium was negative. Laparotomy showed mesenteric and retroperitoneal lymphadenopathies. Histopathologic examination of the nodes demonstrated non-caseat-ing granulomatous adenitis, whereas Ziehl-Neelsen staining of the nodes and culture of the nodes on Löwenstein-Jensen medium were negative. Azathioprine therapy was discontinued, and the cyclosporine dose was reduced. Subsequently, the fever subsided, the erythrocyte sedimentation rate normalized, and lymphadenopathies regressed. The patient remained asymptomatic until December 1993, when he presented because of abdominal pain and a 5-kg weight loss. Gastrointestinal examination revealed a distorted duodenum with duodenal and jejunal mucosal thickening. An abdominal CT scan revealed mesenteric lymph node enlargement and a 5 × 2.5-cm abdominal mass in contact with jejunal loops. Oral panendoscopy showed erythematous duodenal lesions, and biopsy of the lesions revealed non-caseat-ing granulomas with acid-fast bacilli. The patient underwent laparotomy that disclosed mesenteric lymph nodes and jejunal wall thickening. The lymph nodes were biopsied, and a 6-cm-long segment of jejunum was resected. Histological study of a lymph node and the intestinal wall showed granulomas with acid-fast bacilli, and cultures of the specimens on Löwenstein-Jensen medium yielded M. avium/M. intracellulare. Antimycobacterial treatment with clarithromycin (1 g every 12 h), ethambutol (15 mg/kg/d), and ciprofloxacin (750 mg every 12 h) was started. Six months later, the patient showed clinical and radiological improvement and declined further treatment. Five years later, the patient had no evidence of disease. In our heart transplantation program, the prevalence of disease due to NTM is 0.24% (1 case per 410 transplantations); NTM account for 25% of all mycobacteria causing disease. The prevalence of disease due to NTM after cyclosporine-based immunosuppression (0.24%–1%) is lower than that before cyclosporine therapy (5%–5.5%) [3, 8]. We found 24 previously reported cases of disease due to NTM in heart transplant recipients in the literature; these cases and ours are summarized in table 1 [3–12]. Infection due to NTM appears in the late post-transplantation period (median, 15 months; range, 86 days to 11.5 years). The prevailing types of NTM in the 25 cases were M. avium complex (32%) and Mycobacterium kansasii (28%). Proposed risk factors for infection due to NTM in heart transplant recipients are open heart surgery before transplantation, previous opportunistic infections [3, 4, 9, 11], and increased immunosuppression for acute rejection in the previous 6 months [3, 5, 6, 11]. Disseminated forms of infection due to NTM accounted for 13 (52%) of the 25 cases; subcutaneous tissue was involved in 10 of these 13. The lung was the most frequent site of localized disease (7/12 cases). Although disseminated forms of disease due to NTM predominate in immunocompromised patients, most of the cases in the general population are pulmonary [1]. The presence of intestinal disease in our patient is noteworthy. Although intestinal involvement is common in HIV-infected patients, it is unprecedented in heart transplant recipients and is rather exceptional after solid organ transplantation; only 2 other cases (1 in a liver transplant recipient and 1 in a renal allograft recipient) have been reported [11, 13]. Granulomas, which were observed in 11 cases, are not a uniform finding in immunosuppressed patients [11]. Cyclosporine has been demonstrated to reduce the granulomatous response induced by mycobacterial antigens in experimental animals [14]. Treatment of infections due to NTM is complicated, because of the hydrophobic and intracellular nature of these organisms. Most (18) of the patients received treatment with a combination of antibiotics. Monotherapy may be responsible for the development of drug resistance [4]; treatment relies on the use of multiple drugs. Clarithromycin and azithromycin are the drugs most active against M. avium complex. The initial treatment regimen for infection due to NTM should include a macrolide plus ethambutol and a third drug (clofazimine, rifabutin, or ciprofloxacin). Currently, it is advised that immunosuppressed patients with infection due to NTM receive treatment for at least 2 years [3]. Reducing immunosuppression therapy may play a role in the management of disease due to NTM, as evidenced by reversal of disease in our patient and in an additional patient [3]. Outcome was favorable in most cases (cure rate, 64%). Seven patients (28%) had a chronic course, 5 of whom did not receive appropriate treatment. Death was directly related to infection with NTM in 2 patients (8%). Summary of data on cases of infection due to nontuberculous mycobacteria in heart transplant recipients.