Version May 2024
INTRODUCTION — Nontuberculous mycobacteria (NTM) are ubiquitous in the environment, and approximately 200 species have been identified [1]. Solid organ transplant (SOT) recipients have an increased risk for infection with NTM due to depressed cell-mediated immunity. Although NTM infection rates are low compared with other types of infection, their overall incidence of NTM infections is increasing [2]. NTM infections in transplant recipients can cause significant morbidity and mortality, due in part to difficulties in disease recognition, delayed diagnosis, and complex drug interactions [3-5].
This topic reviews NTM infections in solid organ transplant recipients. Tuberculosis (TB) and the evaluation, treatment, and prophylaxis of infection in solid organ transplant recipients, as well as bacterial, viral, and fungal infections in lung transplant recipients, are reviewed separately.
●(See "Tuberculosis in solid organ transplant candidates and recipients".)
●(See "Evaluation for infection before solid organ transplantation".)
●(See "Infection in the solid organ transplant recipient".)
●(See "Prophylaxis of infections in solid organ transplantation".)
●(See "Bacterial infections following lung transplantation".)
●(See "Viral infections following lung transplantation".)
●(See "Prevention of cytomegalovirus infection in lung transplant recipients".)
●(See "Fungal infections following lung transplantation".)
EPIDEMIOLOGY — Most NTM species have been found in soil and water and the majority of infections arise from environmental exposure [6]. Infections were thought not to be transmitted from animal to human or human to human; however, human-to-human spread of Mycobacterium abscessus among patients in cystic fibrosis centers and on a population level has been reported [7-9]. It is not clear whether this transmission occurred through direct person-to-person spread or, more likely, environmental contamination through aerosols and fomites [6].
In regions where tuberculosis is not endemic, NTM infections are more common in SOT recipients than TB [3]. The exact incidence is difficult to determine since reporting is not mandatory. A large single center study of SOT recipients of all organ types reported an incidence of NTM infection (defined as any positive culture for NTM) of 1.5 percent [10]. Lung transplant recipients have the highest rates of infection, ranging from 0.5 to 8.0 percent, followed by heart transplant recipients, ranging from 0.2 to 2.8 percent [6,11]. By contrast, rates of NTM infection in renal transplant recipients range from 0.16 to 0.38 percent; and, in one series of liver transplant recipients, the rate was 0.04 percent [3,6].
The slowly growing mycobacteria Mycobacterium avium and Mycobacterium intracellulare (together known as Mycobacterium avium complex [MAC]) are the most common NTM species to cause infection in the United States and are the most common species isolated after SOT [11,12]. In addition to MAC, there have been approximately 25 species of NTM reported to cause disease in SOT recipients including the slowly growing species Mycobacterium kansasii, Mycobacterium haemophilum, and Mycobacterium marinum, along with the rapidly growing species Mycobacterium fortuitum, Mycobacterium chelonae, and M. abscessus (table 1) [3,5,6]. The predominant NTM organism can differ based on transplanted organ. For example, Mycobacterium abscessus is the most commonly reported species among lung transplant recipients whereas Mycobacterium avian complex and Mycobacterium kansasii are most commonly reported NTM species in heart transplant recipients [13]. (See "Epidemiology of nontuberculous mycobacterial infections".)
SOT recipients have an increased risk for infection with NTM due to depressed cell-mediated immunity. A prior single center study identified lung transplant itself as a risk factor for NTM infection [14]. Among lung transplant patients, risk factors for NTM infection include cystic fibrosis (CF) as underlying diagnosis, use of anti-thymocyte globulin for induction immunosuppression, NTM disease or colonization pre-transplant, and single lung transplant [15,16]. A recent multi-national case control study evaluated risk factors for NTM infection in solid organ transplant recipients of all organ types and found that older age at time of transplant, recent hospital admission within the past 90 days, receipt of antifungals, and receipt of lymphocyte depleting antibodies were associated with increased risk of NTM infection [17].
Outbreaks related to environmental or nosocomial exposure have been described in SOT recipients. A report of a biphasic outbreak of M. abscessus in 126 patients included 70 SOT recipients and was associated with a contaminated water source at a tertiary care hospital [18]. An outbreak of Mycobacterium chimaera infection associated with contaminated Sorin 3T heater cooler devices used in cardiopulmonary bypass has affected patients with ventricular assist devices, but no infections in heart or lung transplant patients were reported [19].
In SOT recipients, the median onset of NTM infection is usually a year or more after transplantation [6,11,17,20,21]. A large retrospective study of all lung and heart-lung transplant recipients at a single center in Australia over a 12-year period was performed to better define the epidemiology of NTM infection in this population [11]. The following findings were noted:
●Of 261 transplants, 23 cases of mycobacterial disease were detected (9 percent), only two of which were caused by TB. One of the patients with TB was co-infected with MAC.
●The most common site of infection was the lungs (19 cases [83 percent]).
●Thirteen cases (57 percent) were caused by MAC. Other NTM species that caused disease were M. haemophilum (five cases), M. abscessus (three cases), M. kansasii (one case), and M. asiaticum (one case).
●The median time to diagnosis of NTM infection following transplantation was 450 days (range 50 to 3272 days); this is much later than the median time to onset of TB. (See "Tuberculosis in solid organ transplant candidates and recipients", section on 'Timing following transplantation'.)
●Although no deaths were attributed to mycobacterial infection, many patients with MAC experienced a decline in pulmonary function that persisted despite treatment of the infection. Thus, infection with MAC should be considered in the differential diagnosis of chronic allograft dysfunction. (See 'Outcomes' below.)
A retrospective study of all solid organ transplant recipients at a United States center over a 7.5-year period found 34 cases of NTM infection [14]. These included 6 single lung, 13 bilateral lung, 8 heart, 4 liver, and 2 kidney transplant recipients, as well as 1 pancreas-kidney transplant recipient. Twenty-four of the 34 patients were male, median age was 55 years, and median time of occurrence was 8 months post-transplant. M. abscessus and MAC were the most common pathogens, and lung was the most frequent site of infection.
CLINICAL FINDINGS — The clinical presentation of NTM disease depends upon the infecting species, the site(s) of involvement, and whether the infection is localized or disseminated.
Pleuropulmonary disease is the most common manifestation of NTM infection after transplantation, and lung transplant recipients are most commonly affected [11]. Patients with NTM involving the lungs usually present with respiratory signs and symptoms such as chronic cough, sputum production, and, occasionally, hemoptysis. Disease can be fibrocavitary, nodular/bronchiectatic, or a combination of both [3,6,11]. Patients may present with radiographic abnormalities such as pulmonary nodules or tree-in-bud opacities on chest computed tomography. In a small case-control study, larger opacities (>2 cm) and cavitary nodules were more common in immunocompromised patients than in immunocompetent patients [22]. M. avium complex (MAC), M. kansasii, M. abscessus, and Mycobacterium xenopi are the most common causes of pulmonary disease [3,6,11]. M. kansasii, in particular, can cause aggressive disease in lung transplant recipients and often mimics reactivated pulmonary tuberculosis (TB), including cavitary infiltrates with an upper-lobe predilection [12]. (See "Overview of nontuberculous mycobacterial infections".)
Cutaneous, musculoskeletal (including tenosynovitis and septic arthritis), and disseminated infections are the next most common presentations, and the most common presentations among non-lung solid organ transplant recipients [6,13,23]. Disseminated infection caused by MAC and other NTM typically presents with constitutional symptoms (weight loss, fever, night sweats); although notably, in the SOT population with disseminated disease, these symptoms are frequently absent [6,20]. In a systematic review of renal transplant patients with NTM, disseminated disease was the most common manifestation, affecting 40 percent of patients [24]. M. abscessus, M. chelonae, and M. kansasii are the NTM species most frequently associated with disseminated infections in solid organ transplant recipients [5,6]. Interestingly, MAC infection in organ transplant recipients can primarily involve the allograft. There are case reports of MAC causing acute interstitial nephritis in renal transplant recipients and hepatic infection in liver transplant recipients [25,26]. (See "Overview of nontuberculous mycobacterial infections".)
The clinical spectrum of disease caused by the rapidly growing mycobacteria (M. fortuitum, M. chelonae, and M. abscessus) varies depending upon the species. M. fortuitum and the slow-growing M. marinum tend to cause localized skin infections, which disseminate infrequently. These may present as papules or nodules (frequently with purple discoloration). M. marinum infection is commonly known as fish-tank granuloma and usually occurs after exposure to aquariums or marine environments [27]. Skin infection with the rapidly growing mycobacteria may result in recurrent abscesses or chronic draining sinuses. (See "Rapidly growing mycobacterial infections: Mycobacteria abscessus, chelonae, and fortuitum" and "Epidemiology of nontuberculous mycobacterial infections".)
M. abscessus tends to be particularly virulent and can cause pulmonary, cutaneous, surgical site or prosthetic device infection, and/or disseminated disease. Several cases of fatal post-transplant M. abscessus infection involving the lungs and/or pleural space have been reported in lung transplant recipients [7,28-34]; severe cases have also been reported in renal, heart, and multivisceral transplant recipients [35,36]. A retrospective study of patients with cystic fibrosis found that colonization with M. abscessus prior to transplantation strongly predicted invasive disease as compared with isolation of other NTM species (odds ratio 7.45, 95% CI 2.9-16.9); this association was not observed for other NTM species [32].
In an international survey of lung transplant centers, M. abscessus infections were identified in 17 of 5200 patients (0.33 percent) [31]. Eleven of 16 patients (73 percent) who were treated had a radiographic or microbiologic response to therapy, and two died from the infection. Two patients had late recurrence of infection at a distant site following cessation of therapy.
DIAGNOSIS — Because of the rarity and protean manifestations of NTM infection in the SOT population, it is crucial to maintain a high index of suspicion so timely diagnosis can be made and appropriate treatment started. NTM should be considered in solid organ transplant recipients with pulmonary complaints, especially lung transplant recipients. Staining and culture for acid-fast bacilli (AFB) should be performed on all bronchoscopy specimens. In addition, mycobacterial infections should be considered in transplant recipients with atypical skin lesions or soft tissue infections, including surgical site infections. Skin biopsy should be performed in all patients with suspicious lesions and should be sent for AFB staining and culture as well as histopathology.
Some NTM species require specialized media, temperatures, or longer duration of incubation for growth; an awareness of this and potentially alerting the microbiology lab of suspicions can be paramount in making the appropriate diagnosis (see "Microbiology of nontuberculous mycobacteria"). Nucleic acid probes are available for identification of some NTM (ie, M. avium complex and M. kansasii); molecular methods can be used for the species/subspecies identification of rapidly growing mycobacteria (RGM). Sequence-based identification, often with the 16S rRNA gene as target, or matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF MS) are being increasingly utilized as methods to more rapidly identify organisms [6]. In RGM, identification of an inducible macrolide-resistance gene (erm gene) is important in guiding treatment decisions. (See "Diagnosis of nontuberculous mycobacterial infections of the lungs" and "Rapidly growing mycobacterial infections: Mycobacteria abscessus, chelonae, and fortuitum".)
Because NTM can be found as environmental or laboratory contaminants and can transiently colonize the lungs, a positive culture from a non-sterile site such as from bronchoalveolar lavage (BAL) fluid does not necessarily indicate infection. In a cohort study of 237 lung transplant recipients, NTM were isolated from 53 patients (22.4 percent), but only 6 patients required treatment (2 met criteria for pulmonary disease and 4 had surgical site infections) [37]. Although the incidence rate of NTM isolation was 9.0 per 100 person-years, that of NTM disease was only 1.1 per 100 person-years [37]. The burden of organisms recovered, the specific NTM species involved, and clinical and radiographic signs and symptoms should be considered when defining the approach to treatment [23]. For example, since M. abscessus is particularly virulent, the isolation of this species from a post-transplant sputum culture should warrant an aggressive evaluation and careful consideration of treatment.
Specific criteria exist for establishing the diagnosis of NTM pulmonary disease, as outlined in the table (table 2); these criteria are discussed in detail separately. (See "Diagnosis of nontuberculous mycobacterial infections of the lungs", section on 'Diagnostic criteria'.)
There are limited data for applying these criteria to SOT patients, but it is reasonable to use them as a framework for diagnosis of NTM pulmonary disease in this population.
TREATMENT — For solid organ transplant recipients with disease caused by NTM, recommendations for initial management are similar to those for the general population and involve combination therapy with multiple antimycobacterial agents [12]. There have been no randomized trials of treatment of NTM in solid organ transplant recipients, and data regarding response to therapy among transplant recipients are limited to case series and case reports [11,20,25-33,35,38-42]. (See "Treatment of Mycobacterium avium complex pulmonary infection in adults" and "Rapidly growing mycobacterial infections: Mycobacteria abscessus, chelonae, and fortuitum".)
The following issues regarding management in solid organ transplant recipients should be noted:
●Interactions between antimycobacterial agents and both calcineurin inhibitors and rapamycin (sirolimus) exist and must be taken into account when choosing a regimen [3]:
•The rifamycins, particularly rifampin (also known as rifampicin), reduce serum concentrations of tacrolimus, cyclosporine, rapamycin (sirolimus), and everolimus via induction of cytochrome p450 isoenzyme CYP3A4, and their use has been associated with the development of rejection. (See "Tuberculosis in solid organ transplant candidates and recipients", section on 'Management of active tuberculosis'.)
•Certain macrolides, such as clarithromycin, can lead to increased serum concentrations of the calcineurin inhibitors and rapamycin via cytochrome p450 inhibition [43,44]. Azithromycin is less likely to cause this effect, although calcineurin inhibitor and rapamycin levels should be monitored closely in all patients receiving any macrolide [3].
●Although there are no specific recommendations regarding the duration of antimycobacterial therapy in solid organ transplant recipients, such patients often require a longer course than immunocompetent hosts in order to prevent relapse [3]. For example, in immunocompetent hosts with M. avium complex pulmonary infection, 12 months of therapy following negative sputum cultures is recommended, but this should be the minimum treatment duration among solid organ transplant recipients. In patients in whom immunosuppression cannot be reduced or in whom there is a high burden of disease, prolonged therapy may be necessary. For soft tissue or bone disease due to NTM, at least four to six months of therapy are recommended [12,45]. (See "Treatment of Mycobacterium avium complex pulmonary infection in adults".)
●Ongoing disease surveillance with follow up imaging and microbiologic testing whenever possible can be helpful in determining duration of therapy. In addition, relapse or reinfection can occur after completion of therapy so patients should have ongoing clinical and microbiologic monitoring where possible.
●Intermittent or thrice weekly oral antibiotic regimens, such as those recommended to treat nodular bronchiectatic pulmonary MAC infection in the general population, should be avoided in the SOT population due to the potential for fluctuating levels of immunosuppression with thrice weekly antibiotics and also the potential absorption issues associated with complications of lung transplantation specifically.
●The intensity of the immunosuppressive regimen should be reduced whenever possible [3,6]. Immune reconstitution inflammatory syndrome, typically characterized by an unexplained worsening after initial improvement, can occur when immunosuppressive regimens are reduced [46]. (See "Immune reconstitution inflammatory syndrome".)
●Susceptibility testing of NTM can be particularly helpful in managing infections with NTM in solid organ transplant recipients given the potential for drug interactions and toxicities, although the ability of in vitro susceptibility testing to predict treatment outcomes varies depending on NTM species [3,4,6]. Susceptibility testing should be performed routinely; the agents that should be included in susceptibility testing vary depending upon which species is isolated. In addition to determining the optimal initial regimens, such testing is important for tailoring therapy to an oral regimen once control of the infection has been achieved. It is important to have susceptibility testing done in a laboratory with expertise in evaluating NTM species. (See "Microbiology of nontuberculous mycobacteria" and "Rapidly growing mycobacterial infections: Mycobacteria abscessus, chelonae, and fortuitum", section on 'Susceptibility testing' and "Treatment of Mycobacterium avium complex pulmonary infection in adults", section on 'Antimicrobial susceptibility testing'.)
●Surgical resection of localized skin lesions can be used as an adjunct to medical therapy in the setting of abscess formation, to debulk areas with a large burden of disease, and/or in patients who have not responded to antimycobacterial therapy [4,21]. Surgical source control and/or removal of infected prosthetic devices is especially important for surgical site infections.
OUTCOMES — The outcomes of NTM infections among solid organ transplant recipients have not been well established given the low rates of infection. These infections are often difficult to treat. Reported cure rates range from 32 to 44 percent, although a greater percentage have some clinical improvement with NTM therapy [3]. Outcomes in SOTs are highly variable and depend on the extent of infection, susceptibility of the organism and level of immunosuppression of the host [3,15,24].
A cohort study of 33 solid organ transplant recipients with NTM infections at a single United States center found a significant association between early NTM infection and three-year post-transplant mortality. Interestingly, patients with M. abscessus infections did not have increased mortality compared with those with other NTM infections. Also of interest was that NTM colonization was listed as a cause of death in a minority of patients, suggesting that other factors impact mortality more directly [47]. Immunomodulatory effects of the infection, rejection, or development of secondary nosocomial infections were all thought to contribute to mortality in this cohort.
Reports of outcomes of NTM infection in lung transplant patients are mixed. In a retrospective study that included 13 lung transplant recipients with M. avium complex (MAC) pulmonary infection, none died from MAC [11]. However, among eight patients who were treated with antimycobacterial therapy for more than two months, most had no improvement in graft function following therapy.
A retrospective review of 201 lung transplant recipients found nine with post-transplant NTM disease and 27 with NTM colonization. NTM colonization was a risk factor for NTM disease (hazard ratio [HR] 8.39, 95% CI 2.08-33.85) and presence of either colonization or disease significantly increased the risk of death after lung transplant even when controlling for factors such as bronchiolitis obliterans syndrome (adjusted HR 2.18, 95% CI 1.26-3.76) [15]. Notably, cause of death was more commonly related to a non-NTM infection. A recently published meta-analysis found that NTM disease, but not colonization, was associated with increased mortality (HR 2.69, 95% CI 1.70-4.26) and chronic lung allograft dysfunction (CLAD) (HR 2.11, 95% CI 1.03-4.35) [16].
As described above, M. abscessus can be particularly aggressive in lung transplant recipients, sometimes leading to relapse even after long courses of antimicrobial therapy or death [28]. (See 'Clinical findings' above.)
PREVENTION — The possible efficacy of prophylaxis in transplant candidates or recipients colonized with NTM species has not been established. There is wide variation in the management of solid organ transplant candidates known to be colonized with NTM species, ranging from no therapy to pre- and/or peri-transplant prophylaxis [3].
In lung transplant candidates who are colonized or infected with M. avium complex (MAC), multidrug MAC therapy should be considered prior to lung transplantation to reduce overall burden of disease [6]. The optimal duration of antibiotic therapy prior to transplant or in post-transplant period is unknown. The duration of therapy both prior to and following transplantation must be individualized. Our practice is to start patients on antibiotics prior to transplant at least at the time of listing and likely prior. Duration of therapy post-transplant is driven by intra-operative cultures at the time of transplant and early recipient BAL cultures. If these remain negative, we generally treat for 6 to 12 weeks post-transplant. (See "Treatment of Mycobacterium avium complex pulmonary infection in adults", section on 'Initial treatment'.)
Although successful treatment has been achieved in some lung transplant recipients with M. abscessus infection, lung transplantation in individuals known to be colonized, particularly those with cystic fibrosis, remains controversial. This is especially true for infections caused by M. abscessus subspecies abscessus, which is particularly virulent (see 'Clinical findings' above). The presence of M. abscessus on cultures pretransplant is associated with increased postoperative morbidity, including thoracic cavity infections and sternal wound infections [31-33,48], although survival has not been significantly altered in single-center studies [33,48-50]. If transplant is considered in a patient colonized or infected with Mycobacterium abscessus, it is important to prove that the patient is able to tolerate an effective multi-drug regimen and to demonstrate positive response to treatment prior to transplant. (See 'Clinical findings' above.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Nontuberculous mycobacteria" and "Society guideline links: Infections in solid organ transplant recipients".)
SUMMARY AND RECOMMENDATIONS
●Mycobacterium species – Mycobacterium avium and Mycobacterium intracellulare (together known as Mycobacterium avium complex [MAC]) are the most common nontuberculous mycobacterial (NTM) species isolated after solid organ transplantation and typically involve the lungs. (See 'Epidemiology' above.)
●Clinical presentation – The clinical presentation of NTM disease depends on the infecting species, the site(s) of involvement, and whether the infection is localized or disseminated. Pleuropulmonary disease is the most common manifestation of NTM infection among solid organ transplant recipients, occurring in over 50 percent of cases. (See 'Clinical findings' above.)
●When to suspect the diagnosis – NTM should be considered in solid organ transplant recipients with pulmonary complaints. Staining and culture for acid-fast bacilli should be performed on all bronchoscopy specimens. In addition, mycobacterial infections should be considered in solid organ transplant recipients with atypical skin lesions or soft tissue infections. (See 'Diagnosis' above.)
●Diagnostic criteria – Specific criteria exist for establishing the diagnosis of NTM pulmonary disease as outlined in the table (table 2). (See "Diagnosis of nontuberculous mycobacterial infections of the lungs", section on 'Diagnostic criteria'.)
●Treatment regimens – For solid organ transplant recipients with disease caused by nontuberculous mycobacteria, we suggest similar initial antimycobacterial regimens to those used in immunocompetent hosts (Grade 2C). (See 'Treatment' above.)
●Other aspects of treatment – The following issues regarding management in solid organ transplant recipients should be noted:
•Drug interactions – Interactions between antimycobacterial agents and calcineurin inhibitors exist and must be taken into account when choosing a regimen. The most significant interaction is between the rifamycins and both the calcineurin inhibitors and rapamycin. Certain macrolides, such as clarithromycin, also interact significantly with both the calcineurin inhibitors and rapamycin.
•Duration of therapy – Solid organ transplant recipients often require a longer course than immunocompetent hosts in order to prevent relapse.
•Adjusting immunosuppression – The intensity of the immunosuppressive regimen should be reduced whenever possible. Immune reconstitution inflammatory response syndrome can occur when immunosuppressive regimens are reduced.
•Susceptibility testing – Susceptibility testing can be particularly helpful in managing NTM infections in solid organ transplant recipients given the potential for drug interactions and toxicities. The agents that should be included in susceptibility testing vary depending upon which species is isolated.
•Adjunctive surgery – Surgical resection of localized skin lesions can be used as an adjunct to medical therapy in the setting of abscess formation, to debulk areas with a large burden of disease, and/or in patients who have not responded to antimycobacterial therapy. (See 'Treatment' above.)
●MAC in lung transplant candidates – For lung transplant candidates who are colonized or infected with M. avium complex, we suggest multidrug MAC therapy prior to and following lung transplantation (Grade 2C). (See 'Prevention' above.)
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