Abstract

Mycobacterial infections frequently develop as a consequence of immunosuppression and are often a causative cause of morbidity and mortality. Epidemiology and clinical characteristics of mycobacterial infections after solid organ and stem cell transplantation have been well-described. However, due to the rarity of clinical data, the pertinent aspects of mycobacterial infection after heart transplantation remain to be clarified. A comprehensive literature collection revealed mycobacterial infections after heart transplantation usually developed late after transplantation. Cutaneous and pulmonary infections were the most common with Mycobacteria tuberculosis being the prevailing pathogen. Unlike in solid organ transplant recipients, non-tuberculous mycobacterial infections in heart transplant recipients were sporadic with no prevailing species. Combined drug therapy seemed to be more effective than monotherapy. The overall survival rate was 84.2%.

Mycobacterial infections frequently develop as a consequence of immunosuppression and are often a causative cause of morbidity and mortality.[1] Mycobacterium (M.) tuberculosis in solid organ transplant recipients has a much higher mortality rate than overall population.[2] M. tuberculosis has been reported to represent 6.7% of lung infections in solid organ transplant recipients,[3] while M. abscessus and M. avium complex are the most common pathogens of non-tuberculous mycobacteria (NTM) infections and the lung was the most common infection site.[4] Non-tuberculous mycobacteria infections developed eight months (interquartile range: 2 to 87 months) after solid organ transplant with lung transplant recipients at the highest risk of the infection.[4] In heart transplant recipients, the etiopathogenesis of mycobacterial infections include exacerbation of a silent infection after transplantation as a result of immunosuppression, new infection of the immunosuppressed recipient after transplantation, and direct transmission of infection from the donor. According to the duration of latency, mycobacterial infection can be categorized into early (≤3 months), intermediate (3 to 12 months), and late (≥12 months) presentations.[5] The early presentation can be a consequence of intraoperative infection, whereas late infections may result from post-transplantation immunosuppressive therapy.[5] Epidemiology and clinical characteristics of mycobacterial infections after solid organ or stem cell transplantation have been well-described in the literature.[6,7] However, due to the rarity of clinical data, the pertinent aspects of mycobacterial infections after heart transplantation still remain to be clarified. This study aims to present the clinical characteristics, management and prognosis of the patients with mycobacterial infections after heart transplantation.

Methods

MEDLINE, Highwire Press and Google search engine were searched for publications in the English language between January 2000 and March 2013 on mycobacterial infections after heart transplantation. The major search terms were “Mycobacterium” and “heart transplantation”. “Mycobacterium tuberculosis”, “nontuberculous mycobacteria”, “atypical mycobacterium”, and “M. spp.” were also searched for the completeness of the retrieval. All the articles, titles, and subject headings were screened carefully to find a potential relevance. Mycobacterial infections after heart-lung transplantation were excluded. Data for collection included patients’ demographics, time from heart transplantation to mycobacterial infection, samples for analysis, analysis methods, infection site, mycobacteria, drug therapy, and prognosis.

Results

There were totally 23 articles[5,8-29] including 17 (72.7%) case reports,[8-24] five (22.7%) original articles[5,25-28] and one (4.5%) Letter to the Editor[29] with 39 patients involved. Of these patients, there were 33 males and 4 females with a male-to-female ratio of 8.3:1, while two patients’ sex was unknown. The mean age was 56.4±8.9 (range, 37 to 69; median, 58) years (n=39).

The mean time from heart transplantation to mycobacterial infection was 36.5±28.2 (range, 0 to 96; median, 36) months (n=27). The mean latency was 36.0±23.1 (range, 3 to 67; median, 37) months (n=11) for lung infections[5,9,10,21,24-28] and 36.9±31.9 (range, 0 to 96; median, 47) months (n=16) for non-lung infections[8,11-20,22-26,29] (p=0.9400). A delayed diagnosis of mycobacterial infection was made in nine (23.7%) patients over a mean time of 48.8±49 (range, 3 to 144; median, 36) months from transplantation to diagnosis (n=9). The major infection sites were lung and skin (Figure 1). Sole lung infections were more common than combined infections of lung and other organs and totally five intestinal infections were reported (Figure 1). Mycobacterium was analyzed in 36 patients: 23 (63.9%) patients had one sample,[5,11,12,14,16-18,24-28] six patients (16.7%) had two samples,[9,10,15,19,21,23] five patients (13.9%) had three samples,[8,10,13,22,26] one patient (2.8%) had five samples[20] a nd one patient (2.8%) had eight samples.[29] Of 63 samples, biopsy and sputum were the two most common specimens and the biopsy samples were prevailed by skin and lymph nodes, for investigation of mycobacteria (Figure 2). The biopsied lymph nodes were taken from the mediastinum in three (37.5%), mesenterium in two (25.0%), neck in two (25.0%) and epitrochlea in one patient (12.5%); while the lesions biopsied were those of the duodenum, neck, arm, and jejunum in one (25%) patient each.

Figure 1: Sites of mycobacterial infections.

Figure 2: Samples for mycobacterial analysis.

Microbiology of all analyzed samples showed high sensitivity and histopathology of only biopsy and sputum samples showed high sensitivity for mycobacterial inspections. Polymerase chain reaction (PCR) was also used to determine the species of the mycobacteria (Table 1).

Table 1: Results of mycobacterial analysis of samples

Of the 39 mycobacteria, M. tuberculosis w as t he most common representing 55.3%.[10,18,24-28] Besides, there were three cases (7.9%) of M. leprae,[15,17,19] and two (5.3%) avium complex infections.[11,20] M. spp. (other than M. tuberculosis, M. bovis, M. avium, or M. leprae) of the remaining 12 patients included M. abscessus,[5,14,22] M. genavense,[12,29] M. haemophilum,[13,23] M. xenopi,[9,10] M. kansasii,[8] and M. chelonae,[16] and the species of one atypical mycobacteria was not determined[21] (Figure 3). One patient with M. xenopi i nfection had a co-infection of Pseudomonas aeroginosa.[10]

Figure 3: Mycobacterial pathogens.

Anti-mycobacterial regimens were described in 34 patients: a 2-combined in one (2.9%),[5] a 3-combined in 13 (38.2%),[10,11,13-20,22-26] a 4-combined in 17 (50%),[8-10,12,24-26] a 5 -combinedin one ( 2.9%)[29] and a 6-combined antibiotic regimen in two patients (5.9%),[26] respectively.

The distributions of the anti-mycobacterial agents used in 34 patients showed that the anti-tuberculous agents were the most commonly used (Figure 4). The duration of the anti-mycobacterial agent use was 11.2±4.8 (range, 4 to 21; median, 12) months (n=26). During the treatment, six patients (13.2%) showed antimycobacterial renal toxicity (n=3),[11,14,15,23] cyclosporine intoxication (n=1),[10] or gastrointestinal adverse reactions (n=3),[10,13,15] to seven drugs used in eight patients including cyclosporine (n=2), rifampin (n=1), moxifloxacin (n=1), doxycycline (n=1), clarithromycin (n=1), amikacin (n=1) and aminoglycoside (n=1), leading to discontinuation, reduction, or change of drug. A significant interaction between cyclosporine concentrations and antibiotic treatment was noted in eight (20.5%) patient, in whom a 3-~6-fold of cyclosporine dose was required for maintaining the therapeutic levels during antibiotic therapy.[10,26]

Figure 4: Anti-mycobacterial agents.

Multiple logistic analyses revealed that patient’s sex, age, immunosuppressive agent with cyclosporine, onset time of mycobacterial infection, lung infection, M. spp. i nfection a nd g raft r ejection w ere n ot found to be predictive risk factors for mortality (Chi-square =29, p=0.739).

Interventions were necessary in two patients including pacemaker and atrial lead removal in one patient[22] and ankle aspiration in another.[8]

The mean follow-up was 27.5±35.6 (range, 1 to 120; median, 15) months (n=12). Prognoses of the patients were described in 38 patients: 26 (68.4%) had a complete recovery (one of them was complicated with spinal diskitis and osteomyelitis), five (13.2%) had a significant improvement, one (2.6%) had no progress and six (15.8%) died. The overall survival was 84.2%.

Discussion

Although symptoms of post-transplantation mycobacterial infections range from localized lesions of the skin and soft tissue, lungs and lymph nodes to disseminated infections, the most common initial symptoms are cutaneous and pulmonary.[30] In the recipients of solid organ transplant including heart transplant with M. abscessus infection, localizations of infections predominated by skin and lung infections.[5,30] The median interval from transplantation to diagnosis was 24 months (range, 7 days to 276 months).[5]

Ziehl-Neelsen method showed low sensitivity.[31] However, acid-fast bacilli were observed in 75% of the analyzed samples.[5] Respiratory and cutaneous samples were predominant with skin lesions being the major source of the primary symptoms prior to disseminated infection.[5] The present study further conforms these results. Ray et al.[21] reported that the causative mycobacterial species were unable to be identified due to the absence of species-specific PCR. Guitard et al.[29] demonstrated that the duodenal and lymph node biopsied specimens were negative by PCR for 16S rRNA. However, Ziehl-Neelsen staining showed numerous acid-fast bacilli. The results of PCRs were negative for M. tuberculosis and M. avium, but positive for M. spp. One patient had high performance liquid chromatography detected for isolation of mycobacterial series.[13]

In the transplant recipients, M. tuberculosis infection may cause graft dysfunction, being responsible for the increased mortality.[2,32,33] Interactions between antituberculous agents (rifampicin, in particular) and the calcineurin inhibitors (cyclosporine and tacrolimus) may enhance the graft rejection.[2,33,34] Comerci et al.[11] investigated the possibility of hematopoietic donorreceipt chimera as a possible etiology of mycobacterial infection; however, the authors reported negative results. Due to the fact that the limit of detection was only 3%, chimera was unable to be completely excluded in <3% of the donors and >97% of the recipients. The prevailing NTM in solid organ transplant recipients were M. avium complex (32%) and M. kansasii (28%).[2] Nontuberculous mycobacteria infections usually develop in the late stage of solid organ transplantation (range, 86 days to 11.5 years; median, 15 months).[2] In this study, I found that the time interval from heart transplantation to mycobacterial infection were even longer. Proposed risk factors for infection due to NTM in heart transplant recipients were previous heart operation, history of opportunistic infections, and enhanced immunosuppressive management due to the recent acute rejection.[2]

The presence of intestinal disease is rare in heart and solid organ transplant recipients.[2] As monotherapy may cause drug resistance easily,[35] combined drug regimen are recommended, as it was suggested in the present study. Clarithromycin and azithromycin are the most active drugs against M. avium complex. The initial treatment regimen for NTM infection should include a macrolide plus ethambutol and a third drug with either clofazimine, rifabutin, or ciprofloxacin.[36] Reducing immunosuppression therapy may play a role in the management of disease due to NTM infection.[2] The cure rate was 64% and NTM infection-related death was 8%.[2]

The management of tuberculosis in solid organ transplant recipients is challenging due to the side effects of anti-tuberculous drugs and their potential interactions with immunosuppressive agents.[5] Drug interactions may lead to graft rejection[5] and drug toxicity.[37] Interaction between itraconazole or clarithromycin and cyclosporine or pravastatin,[16] rifampin and cyclosporine,[17] and clofazimine and azathioprine[17] have been also studied. The reduced serum concentrations of immunosuppressive agents are presumed to be mediated by cytochrome P450 activation.[37] Therefore, drug therapy needs to be tailored to accommodate the immunosuppressant regimen.[17] Observations showed that cyclosporine A concentration increased between the second and fourth day after clarithromycin treatment was initiated.[38] Long-term rifampin therapy caused an over two fold reduction of dose-calibrated mycophenolic acid exposure, which may be interpreted by concurrent elicitation of visceral uridine diphosphateglucuronosyltransferases and organic anion transporters which suppress mycophenolic acid.[39] Decline of use of rifampine and clofazimine and a modified leprosy regimen consisting of dapsone 100 mg, ethionamide 250 mg and minocycline 100 mg once daily have been proposed to avoid the potential drug interactions.[19]

Furthermore, the present study, for the first time, presents a comprehensive analysis of mycobacterial infections after heart transplantation. The latency from heart transplantation to mycobacterial infection was as long as over three years. Lung and skin were the most prevalent infection sites. Microbiological examination of all samples and histopathological examination of biopsy and sputum specimens showed high sensitivity for mycobacterial analysis. In addition, PCR was helpful in determining the species of the pathogen. M. tuberculosis was the most common with no prevailing M. spp. species. Combined drug therapy seemed to be more effective than monotherapy. The prognosis was similar to those of the solid organ transplant recipients (treatment success rate 85.7% and mortality 19%).[28]

In conclusion, mycobacterial infections were rare and usually developed late after heart transplantation. Cutaneous and pulmonary infections were the most common with M. tuberculosis b eing t he p redominant pathogen. Unlike in solid organ transplant recipients, NTM infections were sporadic in heart transplant recipients with no prevailing species. I suggest that combined drug therapy is more effective than monotherapy in this patient population.

Declaration of conflicting interests
The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

Funding
The authors received no financial support for the research and/or authorship of this article.

References

1) Escalante P. Mycobacterial infections in solid organ transplantation. Curr Opin Organ Transpl 2007;12:585-90.

2) Muñoz RM, Alonso-Pulpón L, Yebra M, Segovia J, Gallego JC, Daza RM. Intestinal involvement by nontuberculous mycobacteria after heart transplantation. Clin Infect Dis 2000;30:603-5.

3) Eyüboğlu FÖ, Küpeli E, Bozbaş SS, Ozen ZE, Akkurt ES, Aydoğan C, et al. Evaluation of pulmonary infections in solid organ transplant patients: 12 years of experience. Transplant Proc 2013;45:3458-61.

4) Longworth SA, Vinnard C, Lee I, Sims KD, Barton TD, Blumberg EA. Risk factors for nontuberculous mycobacterial infections in solid organ transplant recipients: a case-control study. Transpl Infect Dis 2014;16:76-83.

5) Morales P, Gil A, Santos M. Mycobacterium abscessus infection in transplant recipients. Transplant Proc 2010;42:3058-60.

6) Doucette K, Fishman JA. Nontuberculous mycobacterial infection in hematopoietic stem cell and solid organ transplant recipients. Clin Infect Dis 2004;38:1428-39.

7) Jacobs S, George A, Papanicolaou GA, Lacouture ME, Tan BH, Jakubowski AA, et al. Disseminated Mycobacterium marinum infection in a hematopoietic stem cell transplant recipient. Transpl Infect Dis 2012;14:410-4.

8) Baker JF, Stonecypher M. Coexistence of oligo-articular gout and Mycobacterium kansasii joint and bursal infection in a patient with an orthotopic heart transplant. Clin Exp Rheumatol 2009;27:843-5.

9) Bishburg E, Zucker MJ, Baran DA, Arroyo LH. Mycobacterium xenopi infection after heart transplantation: an unreported pathogen. Transplant Proc 2004;36:2834-6.

10) Bossert T, Bittner HB, Richter M, Rahmel A, Barten M, Gummert JF, et al. Successful management of two heart transplant recipients with mycobacterial pulmonary infections. Ann Thorac Surg 2005;80:719-21.

11) Comerci GD Jr, Williams TM, Kellie S. Immune tolerance after total lymphoid irradiation for heart transplantation: immunosuppressant-free survival for 8 years. J Heart Lung Transplant 2009;28:743-5.

12) de Lastours V, Guillemain R, Mainardi JL, Aubert A, Chevalier P, Lefort A, et al. Early diagnosis of disseminated Mycobacterium genavense infection. Emerg Infect Dis 2008;14:346-7.

13) Fairhurst RM, Kubak BM, Pegues DA, Moriguchi JD, Han KF, Haley JC, et al. Mycobacterium haemophilum infections in heart transplant recipients: case report and review of the literature. Am J Transplant 2002;2:476-9.

14) Freudenberger RS, Simafranca SM. Cutaneous infection with rapidly-growing mycobacterial infection following heart transplant: a case report and review of the literature. Transplant Proc 2006;38:1526-9.

15) Gasink LB, Seymour C, Blumberg EA, Goldberg LR, Fishman NO. An uncommon presentation of an uncommon disease: leprosy in a heart transplant recipient. J Heart Lung Transplant 2006;25:854-6.

16) Kim JE, Sung H, Kim MN, Won CH, Chang SE, Lee MW, et al. Synchronous infection with Mycobacterium chelonae and Paecilomyces in a heart transplant patient. Transpl Infect Dis 2011;13:80-3.

17) Launius BK, Brown PA, Cush E, Mancini MC. A case study in Hansen's disease acquired after heart transplant. Crit Care Nurs Q 2004;27:87-91.

18) Le Meur A, Arvieux C, Guggenbuhl P, Cormier M, Jolivet- Gougeon A. Tenosynovitis of the wrist due to resistant Mycobacterium tuberculosis in a heart transplant patient. J Clin Microbiol 2005;43:988-90.

19) Modi K, Mancini M, Joyce MP. Lepromatous leprosy in a heart transplant recipient. Am J Transplant 2003;3:1600-3.

20) Muñoz P, Rodríguez C, Bouza E. Mycobacterium tuberculosis infection in recipients of solid organ transplants. Clin Infect Dis 2005;40:581-7.

21) Ray R, Chakravorty S, Tyagi JS, Airan B, Talwar KK, Venugopal P, et al. Fatal atypical mycobacterial infection in a cardiac transplant recipient. Indian Heart J 2001;53:100-3.

22) Richey LE, Bahadorani J, Mushatt D. Endovascular Mycobacterium abscessus infection in a heart transplant recipient: a case report and review of the literature. Transpl Infect Dis 2013;15:208-13.

23) Sagi L, Leshem E, Barzilai A, Baum S, Har-Zahav Y, Rahav G. Mycobacterium haemophilum infection presenting as bilateral cellulitis and annular lesion in a heart transplant recipient. Isr Med Assoc J 2010;12:57-8.

24) Weile J, Eickmeyer H, Dreier J, Liebke M, Fuchs U, Wittke JW, et al. First case of Mycobacterium tuberculosis transmission by heart transplantation from donor to recipient. Int J Med Microbiol 2013;303:449-51.

25) Chou NK, Liu LT, Ko WJ, Hsu RB, Chen YS, Yu HY, et al. Various clinical presentations of tuberculosis in heart transplant recipients. Transplant Proc 2004;36:2396-8.

26) Hsu MS, Wang JL, Ko WJ, Lee PH, Chou NK, Wang SS, et al. Clinical features and outcome of tuberculosis in solid organ transplant recipients. Am J Med Sci 2007;334:106-10.

27) Bodro M, Sabé N, Santín M, Cruzado JM, Lladó L, González-Costello J, et al. Clinical features and outcomes of tuberculosis in solid organ transplant recipients. Transplant Proc 2012;44:2686-9.

28) García-Goez JF, Linares L, Benito N, Cervera C, Cofán F, Ricart MJ, et al. Tuberculosis in solid organ transplant recipients at a tertiary hospital in the last 20 years in Barcelona, Spain. Transplant Proc 2009;41:2268-70.

29) Guitard J, Edouard S, Lepidi H, Segonds C, Grare M, Ranty- Quintyn ML, et al. Identification of cause of posttransplant cachexia by PCR. Emerg Infect Dis 2012;18:1386-8.

30) Garrison AP, Morris MI, Doblecki Lewis S, Smith L, Cleary TJ, Procop GW, et al. Mycobacterium abscessus infection in solid organ transplant recipients: report of three cases and review of the literature. Transpl Infect Dis 2009;11:541-8.

31) Barrón H, Monteghirfo M, Rivera N. Diagnóstico molecular de Mycobacterium tuberculosis en biopsias pleurales embebidas en parafina. Ana Fac Med (Perú) 2006;67:11-8.

32) Singh N, Paterson DL. Mycobacterium tuberculosis infection in solid-organ transplant recipients: impact and implications for management. Clin Infect Dis 1998;27:1266-77.

33) Aguado JM, Torre-Cisneros J, Fortún J, Benito N, Meije Y, Doblas A, 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;48:1276-84.

34) Holty JE, Sista RR. Mycobacterium tuberculosis infection in transplant recipients: early diagnosis and treatment of resistant tuberculosis. Curr Opin Organ Transplant 2009;14:613-8.

35) Tuder RM, Renya GS, Bensch K. Mycobacterial coronary arteritis in a heart transplant recipient. Hum Pathol 1986;17:1072-4.

36) Novick RJ, Moreno-Cabral CE, Stinson EB, Oyer PE, Starnes VA, Hunt SA, et al. Nontuberculous mycobacterial infections in heart transplant recipients: a seventeen-year experience. J Heart Transplant 1990;9:357-63.

37) Spicer ST, Liddle C, Chapman JR, Barclay P, Nankivell BJ, Thomas P, et al. The mechanism of cyclosporine toxicity induced by clarithromycin. Br J Clin Pharmacol 1997;43:194-6.

38) Sádaba B, López de Ocáriz A, Azanza JR, Quiroga J, Cienfuegos JA. Concurrent clarithromycin and cyclosporin A treatment. J Antimicrob Chemother 1998;42:393-5.

39) Kuypers DR, Verleden G, Naesens M, Vanrenterghem Y. Drug interaction between mycophenolate mofetil and rifampin: possible induction of uridine diphosphateglucuronosyltransferase. Clin Pharmacol Ther 2005;78:81-8.