Free Publication in 2019
Joanna K. Nelson, Aruna Subramanian
Received: November 30, 2018; Published: February 01, 2019; doi:10.21926/obm.transplant.1901047
Nontuberculous mycobacteria (NTM) are ubiquitous in the environment and have been isolated from soil and water from both natural and treated sources. With increased awareness and improvement in microbiologic techniques and detection, an explosion in the number of identified species has occurred over recent years, with now greater than 150 species described. Despite the breadth of species in this group, the majority of infections are caused by a relatively small number of species, most commonly Mycobacterium avian complex (MAC), M.kansasii, M. marinum, M.haeophilum, M.xenopi and the rapid growing mycobacteria (RGM) including M.abscessus, M. chelonae and M. fortuitum . A total of approximately 25 NTM species have been previously reported to cause NTM disease in solid organ transplant (SOT) recipients . Most infections occur as a result from exposure to the environment. There exists regional variation in species and consequently regional variation in predominant pathogens. Outbreaks related to environmental or nosocomial exposure have been described. A recent nosocomial outbreak of 126 patients with M. abscessus, which included 70 SOT recipients, was associated with a contaminated water source . An outbreak of M. chimaera infection has affected patients requiring cardiopulmonary bypass utilizing Sorin 3T heater cooler devices, but no infections in heart or lung transplant recipients have been reported to date . Although the vast majority of NTM infections are secondary to environmental exposure, there is now also report of possible person to person transmission involving M.abscessus in cohort of cystic fibrosis patients .
NTM infections across the general population are on the rise . Incidence of disease in the SOT population is difficult to definitively determine. NTM infections are not communicable and although reporting of extra-pulmonary infection is mandated in at least one state, Oregon, this has not been required on a national level. A large single center study of SOT recipients of all organ types noted an incidence of NTM infection, defined as any positive culture for NTM, of 1.5% . Incidence of NTM infection varies based on transplanted organ, with the highest being in lung transplant patients. Prior reports suggest incidence of 0.04% in liver transplant patients, 0.16-0.38% in kidney transplant patients, 0.24-2.8% in heart transplant recipients, and 0.46-8% in lung transplant patients .
SOT patients are at increased risk of NTM infections due to impairments in cellular immunity from immunosuppression. Lung transplant itself is a risk factor for NTM infection . This may be related to multiple factors unique to this patient population: structural lung disease which is a known risk factor for NTM infection, direct exposure of allograft to the environment, a relatively high net state of immunosuppression in these patients, and the unique state of airway injury associated with chronic rejection manifesting as bronchiolitis obliterans. Among the lung transplant population, 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 .
Late presentation of NTM disease after SOT is common, with median onset ranging from 10-20 months post-transplant across different organ types . NTM infections can have protean manifestations in the SOT population. Presentations can vary based on type of organ transplanted. Fever and constitutional symptoms can be absent due to underlying immunosuppression. Disseminated disease is common, and the most commonly isolated organisms in this setting include M abscessus and M. chelonae [2,11]. In a recent systematic review of renal transplant patients with NTM, disseminated disease was the most common manifestation, affecting 40% of patients . Cutaneous disease, either localized or disseminated, is the most commonly reported manifestation of NTM in heart transplant recipients . Skin lesions present as erythematous or violaceous subcutaneous nodules which often progress to form abscesses or ulcerations. Osteoarticular disease presenting as tenosynovitis or arthritis is also possible. RGM species (M.abscessus, M.chelonae, M. fortuitum) are the most common cause for NTM soft tissue and joint infections in SOT recipients . Pleuropulmonary disease is the most commonly reported manifestation of NTM in lung transplant patients and also a significant cause of disease in heart transplant recipients . Symptoms include cough, often productive of sputum, and dyspnea. The most common organisms to cause pulmonary disease include MAC, M.kansasii, M.abscessus and M.xenopi .
NTM infection post-transplant is relatively rare; as such, it is crucial to maintain a high index of suspicion so timely diagnosis can be made and appropriate treatment started. If NTM disease is suspected, tissue or fluid sample of affected area (i.e. bronchial lavage or skin biopsy) should be submitted to the lab for histopathology, fluorochrome staining and mycobacterial culture. Culture should be performed in both liquid media and solid media. 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 (Table 1). For example, M. haemophilum requires media supplementation for growth, and M. marinum and M. haemophilum grow at temperatures lower than the standard incubation temperatures. Furthermore, the required incubation period varies depending on species. RGM typically grow within 7 days, whereas slow growers take longer, up to 8-12 weeks for M. genavense . Given this slow growth, awaiting identification and susceptibilities can delay treatment decisions. More advanced molecular techniques such as DNA probes, PCR, and high-performance liquid chromatography are used to rapidly identify some NTM species once growing on media .
Diagnosis of NTM disease is fairly straightforward when NTM is isolated from a sterile site. However, diagnosis of disease is more challenging when NTM is isolated from a non-sterile site, such as sputum or bronchoaveolar lavage fluid. In the lung transplant population a positive culture is not always indicative of disease. Colonization of the airway by NTM is common in lung transplant patients, comprising 75-89% of cases with positive culture in two single center studies. Only 11-25% of lung transplant patients with positive cultures had disease that required treatment [9,14]. Similarly, another small single center study found the same percentage of pulmonary colonization amongst all organ types (75%) . Joint American Thoracic Society (ATS) and Infectious Disease Society of America (IDSA) guidelines suggest that the following criteria are required to diagnose pulmonary NTM disease: positive cultures from at least two separate expectorated sputum samples or one BAL specimen, clinical symptoms associated with NTM disease, and characteristic radiographic findings of NTM pulmonary disease such as bronchonodular or fibrocavitary changes . Although there are limited data for applying these criteria to the immunocompromised patient, it is reasonable to use them as a framework for diagnosis of NTM disease in SOT patients. It needs to be recognized, however, that following these guidelines too strictly may miss cases of invasive disease in this population. There are circumstances, particularly in the setting of potentially virulent organisms, such as M.abscessus in the setting of lung transplant where treatment may be warranted even in the absence of fulfilling all ATS criteria for disease. In any instance, burden of infection, radiographic changes and clinical symptoms should be taken into account for treatment decisions and treatment often individualized.
Table 1 NTM with special growth requirements.
Any clinically significant NTM isolate should be identified to the species level because, with the exception of MAC, this portends important information regarding prognosis and treatment. Furthermore, in certain cases, sub-speciation can be critical to optimal management. For example, M. abscessus complex is made up of subspecies abscessus, bolletii, and massiliense. Isolation of these various subspecies imparts important prognostic and treatment information since M.a.massiliense, which tends to be macrolide susceptible, portends a better prognosis than the other two subspecies . In M. abscessus complex, a surrogate to this sub-speciation is molecular testing for the presence of a functional erm(41) gene. This gene is typically functional in M. abscessus subspecies abscessus and bolletii, but not in massiliense. The erm(41) gene confers inducible resistance to macrolides, such that the initial macrolide testing may appear susceptible but if incubated over a longer time period the organism will display macrolide resistance.
An additional challenge in diagnosis of NTM infection in SOT is the number of new species being discovered. It is inevitable that we isolate some of these new species in our SOT population and will be met with the challenge to determine the clinical significance of a positive culture and derive an effective treatment regimen for newly described organisms.
These infections are often difficult to treat. Disease cure rates in the literature range from 32-44%, although a greater number do have some clinical improvement without complete resolution of infection on NTM therapy . Outcomes in transplant patients with NTM disease are highly variable: depending on the extent of infection, susceptibility of the organism and level of immunosuppression of the host [9,11,12]. Early infection (within the first year post-transplant) has been associated with decreased survival in SOT patients, although NTM infection itself was listed as a cause of death in a minority . Immunomodulatory effects of the infection, rejection, or development of secondary nosocomial infections are all thought to contribute to this mortality. Interestingly, there is no significant difference in survival between patients infected with M.abscessus or other non-M.abscessus NTM infections . In lung transplant patients specifically, one study suggests increase in mortality associated with NTM isolation, although cause of death was more commonly related to a non-NTM infection . Other studies in the lung transplant population did not show any increased mortality associated with NTM isolation, but one did suggest trend towards increased incidence of bronchiolitis obliterans syndrome (BOS) [14,17].
Detailed specific drug regimens targeting individual NTM is outside the scope of this review; however, Table 2 provides recommended initial empiric regimens for the most commonly isolated organisms. Empiric regimens may differ based on site of infection. A key principle in the treatment of NTM infections is that a multi-drug regimen for prolonged period is required for cure and to avoid development of antimicrobial resistance. It is also important to recognize that there is discordance between in vitro drug susceptibilities and clinical response. For MAC, clinical response correlates only to macrolide in vitro susceptibility but other drug susceptibilities do not reliably predict clinical outcome. For many NTM species, laboratory determined susceptibility breakpoints have not been confirmed to be clinical meaningful. Therefore, it is necessary to approach interpretation of this data with an appreciation of the limitations. It is also worth noting the possibility of inducible macrolide resistance in RGM. A functional erm gene confers inducible macrolide resistance, and can be found in M. fortuitum and M. abscessus subspecies abscessus and bolletii. If present, these organisms can be resistant to macrolides even when they appear susceptible in the laboratory. To evaluate for inducible resistance, isolates either need to be held for two weeks to evaluate for phenotypic evidence or molecular diagnostics utilized to evaluate for presence of a functional erm gene.
Interactions between NTM therapy and immunosuppressive medications complicate the treatment of this disease (Table 3). Azithromycin is the preferred macrolide for treatment of NTM over clarithromycin since it is a less potent inhibitor of cytochrome P450 (CYP450) and thus, has less of an impact on calcineurin inhibitor (CNI) levels. Rifampin is a potent inducer of CYP3A4 resulting in decreased CNI and sirolimus levels which can lead to organ rejection. Rifabutin has less of this effect, and is thus the preferred rifamycin in SOT recipients. Close monitoring of drug levels, medication side effects, and allograft function during treatment for NTM infection is critical. Careful consideration should be given to the appropriateness of intermittent or three times a week therapy in this population given the potential for fluctuating levels of immunosuppression if thrice weekly antibiotics are administered and also the potential absorption issues associated with complications of lung transplantation.
Table 2 Initial Antibiotic regimens for treatment of common NTM infections*.
Table 3 Interactions between antibiotics used to treat NTM and immunosuppressive agents.
Whenever possible, a reduction in the intensity of immunosuppression should be employed as part of the treatment of NTM infection. However, similar to Mycobacterium tuberculosis in SOT patients, paradoxical Immune Reconstitution Inflammatory Syndrome (IRIS) has been described in a kidney patient with M. kansasii infection . Therefore, a worsening in clinical status after initial improvement with appropriate antibiotic therapy and reduction in immunosuppression with the absence of positive culture results should prompt consideration of IRIS. In the case described by Lemoine et al, an increase in immunosuppression led to favorable response.
Optimal duration of therapy in this patient population is not clear. Guidelines recommend 12 months of therapy from date of culture clearance for pulmonary disease and at least 4-6 months for soft tissue disease or bone disease respectively. Ongoing disease surveillance with follow up imaging and microbiologic testing whenever possible can be helpful in determining duration of therapy. In the setting of pulmonary disease, ATS/IDSA guidelines suggest monthly sputum samples for monitoring of infection, with the first negative sputum counting as day zero for the length of treatment . Due to underlying immunosuppression, the duration of therapy may need to be longer in SOT patients than what is suggested in guidelines. It is reasonable to consider these recommended durations as the minimum in this patient population . Relapse is possible after completion of therapy so patients should have ongoing clinical and possibly microbiologic monitoring.
A specific challenge is the management of transplant candidates who are colonized or infected with NTM organisms pre-transplant. This occurs most commonly in the lung transplant population as many of these transplant candidates have structural lung disease, such as CF or chronic obstructive pulmonary disease (COPD), which is a risk factor for presence of NTM. NTM infection incidence in the CF population is as high as 20% . The transplant candidacy of patients infected with M.abscessus has been controversial. The presence of M.abscessus pre-transplant is associated with post-operative thoracic cavity infection including mediastinal and sternal wound infections [20,21]. Patients with a positive culture pre-transplant are more likely to develop post-transplant disease [22,23]. Despite the increase in post-operative morbidity, survival has not been significantly altered in single center studies [10,23,24]. As such, International Society of Heart and Lung Transplantation (ISHLT) guidelines suggest that M.abscessus is not an absolute contraindication to transplantation unless there is progressive disease despite therapy or when therapy is tolerated poorly . In general, lung transplant candidates with M.abscessus infection should be started on therapy as soon as transplant is being considered with the goal to lessen burden of infection and assess tolerability of an effective anti-mycobacterial regimen [21,22,24]. If a patient is transplanted with positive AFB cultures for M.abscessus, experts recommend chest cavity irrigation with an anti-mycobacterial agent and close attention to surgical technique to avoid contamination. Post-operative management should include close monitoring of surgical wounds and pleural space, monitoring of BAL specimens for NTM, and continuation of peri-operative anti-mycobacterial antibiotics . The significance of colonization with other NTM including MAC pre-lung transplant is also unclear. Practices vary from no treatment with monitoring to pre-transplant and/or peri-transplant anti-mycobacterial therapy. The American Society of Transplantation recommends that lung transplant candidates colonized or infected with MAC should be treated with multi-drug therapy prior to transplant .
Both authors participated in critical review of the literature, writing of this manuscript and approval of final version.
There was no funding for this review.
The authors have declared that no competing interests exist.