Epidemiology, risk factors, and pathogenesis of nontuberculous mycobacterial infections

INTRODUCTION — 

Nontuberculous mycobacteria (NTM) are mycobacterial species other than Mycobacterium tuberculosis and Mycobacterium leprae. NTM are ubiquitous in the environment (table 1) and can also be present on body surfaces or in secretions without causing disease. When they do cause disease, the main associated clinical syndromes are pulmonary diseases, superficial lymphadenitis (especially cervical lymphadenitis) in children, disseminated disease in severely immunocompromised patients, and soft tissue, joint, or bone infection, usually related to direct inoculation [1,2].

The epidemiology (including host risk factors) and pathogenesis of NTM will be reviewed here. Other aspects of NTM are presented separately:

●(See "Overview of nontuberculous mycobacterial infections".)

●(See "Microbiology of nontuberculous mycobacteria".)

●(See "Diagnosis of nontuberculous mycobacterial infections of the lungs".)

●(See "Treatment of Mycobacterium avium complex pulmonary infection in adults".)

●(See "Treatment of lung infection with Mycobacterium kansasii and other less common nontuberculous mycobacteria in adults".)

●(See "Rapidly growing mycobacterial infections: Mycobacteria abscessus, chelonae, and fortuitum".)

●(See "Mycobacterium avium complex (MAC) infections in persons with HIV".)

●(See "Nontuberculous mycobacterial lymphadenitis in children" and "Nontuberculous mycobacterial pulmonary infections in children" and "Disseminated nontuberculous mycobacterial (NTM) infections and NTM bacteremia in children".)

COMMON PATHOGENIC SPECIES — 

NTM most commonly cause pulmonary disease but can also cause extrapulmonary disease, such as infections of the skin and soft tissues, lymph nodes, bones, and joints, as well as disseminated disease. These syndromes are discussed in detail elsewhere. (See "Overview of nontuberculous mycobacterial infections", section on 'Spectrum of clinical syndromes'.)

NTM are generally categorized as slowly growing versus rapidly growing mycobacteria based on the time to colony formation on solid culture media (table 1). In the United States, the most common species causing human disease include:

●M. avium complex (MAC) species (slowly growing)

●M. abscessus subspecies abscessus (rapidly growing)

●M. kansasii (slowly growing)

Less common human pathogens in the United States include the slowly growing species M. marinum, M. xenopi, M. simiae, M. malmoense, and M. ulcerans, as well as the rapidly growing species M. abscessus subspecies massiliense and bolletii, M. fortuitum, and M. chelonae.

However, the prevalence of different species varies by region. As examples, M. xenopi is a more common isolate in some provinces of Canada and in some European countries, M. malmoense is relatively common in Northern Europe, and M. simiae is a more common isolate in some African countries [3].

Among children, other common NTM disease manifestations are cervical lymphadenitis due to MAC (previously M. scrofulaceum) and cutaneous disease due to M. marinum and M. ulcerans [4]. (See "Cervical lymphadenitis in children: Etiology and clinical manifestations", section on 'Nontuberculous mycobacteria infection' and "Soft tissue infections following water exposure" and "Buruli ulcer (Mycobacterium ulcerans infection)".)

TRANSMISSION

Environmental sources — NTM are free-living organisms that are ubiquitous in the environment. They have been recovered from surface water, tap water, soil, domestic and wild animals, milk, and food products [5-8]. Environmental distribution varies slightly among the common pathogenic species:

●M. avium complex (MAC) species – These are readily recovered from natural reservoirs, including soil and water, animals, and food [9].

Environmental MAC isolates usually belong to different serovars than clinical isolates [10]. However, MAC can become aerosolized from water sources, and the more easily aerosolized strains are often phenotypically the same as the strains that cause pulmonary infections [11,12]. Isolates similar or identical to clinical isolates have also been recovered from naturally occurring surface water, hot tubs, and piped hot water systems [10,13-15]. Studies have also demonstrated that NTM are enriched to high levels in many showerhead biofilms, supporting the theory that showers may represent a potential source of MAC infection in humans [16,17].

The frequency of environmental exposure to NTM, particularly MAC, is supported by data from several countries demonstrating delayed cutaneous hypersensitivity responses to MAC antigens in a sizable proportion of children, with rates of reactivity increasing with age [18-20].

However, there are geographic variations in NTM prevalence, as variations in climate and mineral content of soil and water may impact the likelihood of NTM growth in different environments [3]. Specifically, warm and humid environments, coastal wetlands, areas with turbid water with high organic content, and areas with peat-rich, acidic, and water-saturated soil have been associated with a higher prevalence of NTM [21-25]. (See 'Geographic distribution' below.)

There is also variability in exposure in indoor environments. As above, biofilm on indoor plumbing (eg, showerheads, home and institutional automatic ice machines) has been associated with recovery of NTM, especially in homes with infrequent water use resulting in stagnant water [16,17,26-30]. Although the temperature for optimal growth of MAC is not precisely known and likely varies by species (34.5°C [94.1°F] for M. avium and 31.5°C [88.7°F] for M. intracellulare), MAC survives in wide-ranging temperatures, as reflected by their presence in hot and frigid settings. However, the temperature setting of the hot water system may play a role in the risk of NTM exposure through household water sources. In one study, isolation of NTM from plumbing was more likely when the water heater temperature was ≤50°C (≤125°F) compared with ≥55°C (≥130°F) [31]. Another study suggested that NTM was more likely killed at a temperature of 55°C (131°F) compared with 50°C (122°F); killing was even more rapid and sustained at 60°C (140°F) [32]. Accordingly, some have proposed that the advice to lower temperatures in home and institutional hot water systems in the United States during the energy crisis in the 1970s was partly responsible for the increased prevalence of NTM disease over the subsequent decades [13,33]. NTM can also survive in water sources despite chlorination; medium-grown M. avium is 600 to 2300 times more resistant to chlorine than Escherichia coli, and water-grown M. avium is 6000 to 17,000 times more resistant [34].

Among the MAC group, there are also species-specific variations in environmental prevalence. As an example, one study from the United States suggested that M. chimaera (a subspecies of M. intracellulare) and M. avium were more likely to be recovered from household water than M. intracellulare; presumably, soil is a more likely source for M. intracellulare [35].

●M. abscessus – Like MAC, M. abscessus and other rapidly growing mycobacterial species are hardy environmental organisms that are widely distributed in nature. They have been isolated from soil, dust, water, land and aquatic animals, hospital environments (including hospital tap water), and contaminated reagents and pharmaceuticals [9,36,37]. They are able to withstand extreme temperatures (although in the laboratory, optimal growth occurs at 28 to 30°C [82 to 86°F]) and nutritionally poor environments [38].

●M. kansasii – Unlike other NTM, M. kansasii has never been found in soil or natural water supplies but has been recovered consistently from municipal water supplies in cities where M. kansasii is endemic. Studies in Texas show that M. kansasii disease is concentrated in urban areas, supporting a possible association between clinical disease and potable water supplies [39].

Route of acquisition — Infection can occur following inhalation, ingestion, aspiration, and direct inoculation of NTM found in the environment. Human-to-human transmission is thought not to occur, although rare case reports and genotyping association studies suggest the potential in certain populations.

●Inhalation – Most pulmonary infections with NTM are thought to be acquired by inhalation, most likely of aerosols from soil, natural surface water, domestic and institutional hot water systems, and water-associated biofilms. While some studies have not clearly and consistently identified associations between NTM and certain activities that may increase exposure to aerosolized water or soil (eg, showering, use of jacuzzies or saunas, gardening) [40,41], others have found genotypic and/or microbiologic associations between the NTM found in patients’ respiratory samples and their corresponding environment [10,13-15,26,29,42-46]. Furthermore, NTM has been isolated more frequently from shower aerosols in homes of patients with NTM pulmonary disease than in controls [26]. Prolonged exposure to soil has also been identified as a risk factor for MAC infection in the United States [47].

●Ingestion – Ingestion of NTM is thought to be an additional route of infection. Some patients with advanced HIV and disseminated MAC had evidence of a preceding gastrointestinal site of infection (with stool cultures positive for MAC), suggesting that the organism was initially ingested or normally resides in the gastrointestinal tract; however, secondary seeding of the gut is also possible. Among young children, NTM can cause lymphadenitis, with frequent involvement of the cervical lymph nodes. Pathogenesis of cervical lymphadenitis is thought to be initiated by ingestion of material (soil) containing NTM and subsequent spread of the NTM into the draining cervical lymph nodes.

●Aspiration – Aspiration can occur either from swallowing dysfunction or gastroesophageal and laryngopharyngeal reflux. Swallowing dysfunction could feasibly result in aspiration of NTM that have colonized the oral pharynx. Aspiration of viable NTM into the lungs through gastroesophageal or laryngopharyngeal reflux is also plausible, especially if NTM are able survive in the stomach of those treated with antacids. This potential route is supported by studies that report a higher prevalence of gastroesophageal reflux disease (GERD) in those with NTM lung disease compared with controls without NTM infection (26 to 44 percent versus 12 to 28 percent) [48-51].

●Direct inoculation – Exposure to NTM through traumatic or iatrogenic breaks in the skin can result in infections of the skin, soft tissues, joints, and bone as well as dissemination infection. Procedures that inoculate the patient with water contaminated with NTM have been well-documented routes of infection and the sources of various outbreaks. Examples include M. intracellulare subspecies chimaera infections associated with contaminated heater-cooler devices used during cardiac surgery [52,53], M. abscessus infections associated with contaminated water used during pediatric dental procedures [54,55], and NTM infections associated with contaminated footbaths at nail salons [56]. Outbreaks of NTM infection have also been reported following other surgical procedures or medical interventions where there were lapses in infection control [57,58].

●No clear role for person-to-person transmission – A clear role has not been established for NTM in general and for MAC, in particular. However, occasional studies in specific populations have suggested the possibility of direct or indirect person-to-person transmission. When considering this possibility, the type of NTM infection should be taken into account:

•For skin and soft tissue NTM infection, one example of apparent indirect person-to-person transmission was an outbreak of surgical wound infections caused by a novel species of a rapidly growing NTM that occurred among individuals who underwent breast implant insertion; the outbreak was traced to a single surgeon who was colonized with the isolate, presumably through exposure to jacuzzi water [59].

•For isolated NTM pulmonary disease, direct airborne transmission and indirect fomite transmission could plausibly result in person-to-person spread [60-62]. As an example, in a study of 168 separate isolates from 30 patients with cystic fibrosis, whole-genome sequencing demonstrated two clusters of drug-resistant M. massiliense, in which isolates from different patients were highly related to each other, and epidemiological investigation suggested cross-infection between patients within the hospital [62].

However, other analyses have challenged the conclusion that dense clustering of similar NTM strains reflects person-to-person transmission. Some studies have found genetically related pairs or clusters of isolates (with M. abscessus and MAC) that have no epidemiologic link and thus a low likelihood of direct person-to-person transmission [63,64]. Another study suggested that the identification of clusters of related M. abscessus strains could reflect individuals coincidentally acquiring infection with the same strain rather than transmission, since the appearance of the clusters coincided with a slowing of the mutation rate (resulting in less genetic variance) [65]. Because NTM can exist in expectorated respiratory secretions, person-to-person and person-to-fomite-to-person remain possible modes of transmission but are likely uncommon (or rare) modes due to the relatively low virulence of NTM and lower burden of bacteria in NTM pulmonary disease.

FREQUENCY OF DISEASE

Challenges in estimating incidence/prevalence — The precise frequency of disease due to the different species of NTM is unknown. Determining the incidence and prevalence of NTM pulmonary disease is difficult because disease reporting is not mandatory in the United States and many other countries. Additionally, mere isolation of NTM does not necessarily indicate disease, and studies that use the frequency of NTM isolates as a surrogate for disease prevalence may overestimate it.

One option for evaluating NTM pulmonary disease epidemiology has been use of diagnostic codes in databases from large health care delivery systems, managed care providers, and health care insurers. However, there are potential limitations with this approach, which can result in both underdiagnosis (lack of disease recognition by the clinician) and overdiagnosis (inappropriate diagnosis for patients who do not meet diagnostic criteria). The accuracy of diagnostic coding depends on the clinical acumen of the clinician assigning them.

Clinical diagnosis of NTM pulmonary disease is based on three criteria: symptoms, microbiology, and radiographic findings. Although some studies suggest that using the microbiologic criterion alone may be an acceptable proxy for disease for epidemiologic purposes in specific populations, it is unclear whether these are generalizable to larger and more diverse patient populations [66,67]. As an example, in a study of 367 patients who were receiving tumor necrosis factor (TNF)-alpha inhibitor therapy for rheumatoid arthritis and had either a culture positive for NTM or had a diagnostic code for NTM, meeting microbiologic criteria (ie, one positive culture from a bronchoscopic specimen or two sputum cultures positive for the same species) yielded positive predictive values of 78 to 100 percent for fulfilling complete NTM pulmonary disease criteria, depending on the center [67].

Increasing burden of disease — Despite methodologic differences, studies performed mainly in resource-abundant settings show a remarkably consistent trend of increasing NTM disease (particularly pulmonary disease) prevalence, especially in older and female patients. Reasons for this observation are not immediately clear. Some of the increase may be due to better awareness of NTM pulmonary disease, better microbiologic diagnostic tools, increased use of chest computed tomography (CT), and changing coding practices for NTM pulmonary disease. It is also possible there is a true increase in NTM pulmonary disease prevalence due to more extensive environmental NTM exposure or host susceptibility factors, such as increased incidence of bronchiectasis and/or chronic obstructive pulmonary disease (COPD) or use of immunosuppressive agents, including inhaled glucocorticoids [68]. (See 'Host risk factors' below.)

Global trends — The burden of NTM appears to be increasing worldwide [3,69-72]. One comprehensive review of global NTM disease prevalence emphasized that disease burden and frequency of specific isolates were heterogeneous worldwide but concluded that NTM pulmonary disease was increasing in North America, Europe, Asia, and Australia [73]. More specifically, in a systematic review that included 47 studies from 18 countries with culture-based data for at least three years and from at least 200 samples, both respiratory isolation of NTM and the diagnosis of NTM pulmonary disease increased 4 percent per year [3]. Most isolates evaluated were M. avium complex (MAC) or M. abscessus.

NTM pulmonary disease is especially prevalent in parts of Asia [74-76]. One study from Japan analyzed data from health insurance claims for NTM pulmonary disease (identified either through an NTM diagnostic code or a claim for combination antimycobacterial regimens) [74]. The prevalence in 2011 was 29 per 100,000 persons and was higher among females than males in most age groups. Another study using a different method estimated a prevalence of 25 per 100,000 persons in Japan in 2019 [75]. In South Korea, a report found that prevalence of NTM pulmonary disease increased from 6.7 cases to 39.6 cases per 100,000 persons between 2007 and 2016 [76]. Overall prevalence for the study was higher in older adults and in females.

Studies from Europe, North America, and Australia also reflect increasing frequency of NTM disease. In a national registry study from Denmark, the prevalence of NTM pulmonary disease increased from 0.4 to 3.5 and extrapulmonary NTM disease from 0.3 to 1.0 per 100,000 persons between 2000 and 2017 [77]. In Ontario, Canada, prevalence of patients meeting American Thoracic Society microbiologic criteria for NTM pulmonary disease also increased 10 percent per year from 2003 to 2008 [78]. In a study of pulmonary NTM cases in Queensland, Australia, where NTM disease is a notifiable condition, the incidence of cases rose from 2.2 to 3.2 per 100,000 population between 1999 and 2005 [79].

Although fewer data are available from resource-limited settings, the burden of NTM disease appears to be increasing in those countries as well [80]. Although studies from several decades ago indicated a lower rate of disseminated MAC in resource-limited settings compared with resource-abundant settings [81], more recent data suggest that the rates of NTM infection and disease may be more comparable across settings. In a systematic review of 37 studies evaluating approximately 120,000 pulmonary samples in Africa, the prevalence of NTM isolation was 7.5 percent (8980 NTM isolates) [82]. Of the 962 participants with sufficient information to assess for NTM pulmonary disease, 266 (28 percent) met criteria. In a study from Zambia of over 6000 individuals with suspected tuberculosis (because of chest radiograph or symptoms), 15 percent had NTM isolated and 0.2 percent had NTM and M. tuberculosis isolated; the prevalence of symptomatic NTM was estimated at 1477 of 100,000 [83].

United States

Trends in NTM disease — Trends in NTM disease in the United States are similar to those worldwide, with increasing prevalence, particularly among females in older age groups.

One study reviewed annual medical claims with diagnostic codes for NTM disease within a national managed care database that represented a geographically diverse population of approximately 27,000,000 members [69]. From 2008 to 2015, the annual incidence of NTM pulmonary disease increased from 3.1 to 4.7 per 100,000 person-years, and the annual prevalence increased from 6.8 to 11.7 per 100,000 persons. For women, the annual incidence increased from 4.2 to 6.7 per 100,000 person-years, and the annual prevalence increased from 9.6 to 16.8 per 100,000 persons. For individuals aged 65 years and older, the annual incidence increased from 12.7 to 18.4 per 100,000 person-years, and the annual prevalence increased from 30.3 to 47.5 per 100,000 persons. The incidence and prevalence of NTM pulmonary disease increased in most states as well as at the national level.

Consistent with trends of increasing NTM disease, there is also evidence of increasing exposure to NTM, particularly MAC, over time. Skin testing to MAC antigens has been used to estimate the frequency and distribution of exposure to MAC. In a study based on data obtained through the National Health and Nutrition Examination Surveys (NHANES), the prevalence of skin test reactivity to a particular MAC antigen was 11.2 percent during the 1971 to 1972 period and increased to 16.6 percent during 1999 to 2000 [84].

Geographic distribution — The geographic distribution of NTM in the United States is not uniform. In general, the prevalence of NTM isolation and disease is higher in the South, particularly the Southeast, and in Hawaii.

In a nationwide study of over 100,000 respiratory specimens submitted for acid-fast bacilli cultures at a large commercial laboratory, 16 percent were positive for NTM. Of these, 70 percent were MAC, and 13 percent were M. abscessus [85]. The Southeast was the region with the highest prevalence of NTM culture positivity. In another study of Medicare beneficiaries (age 65 years and older), the estimated prevalence of NTM pulmonary disease from 1997 to 2007, as indicated by diagnostic coding, was at least 200 cases per 100,000 in Hawaii, Florida, California, Arizona, Mississippi, and Arizona [86]. Approximately one-third of cases were from the Southeast.

These results mirror studies evaluating exposure to MAC, as reflected by skin test reactivity to MAC antigens. A survey of 275,000 naval recruits who had lived their entire lives in a single county showed skin test reactivity to be most frequent among recruits from the Southeastern and Gulf Coast states (figure 1) [87]. In these areas, more than 70 percent of individuals had been exposed to or infected with MAC or an antigenically similar organism. In another study, reactivity to a MAC antigen was identified in 46 percent of subjects from Southern sites and 33 percent from Northern sites in the United States [88].

Because large-scale testing of skin test reactivity to M. kansasii antigens has not been performed, the geography of M. kansasii is less well-known than that of MAC. Based upon reports of clinical disease, the organism seems to predominate along the Southeastern and Southern coastal states and the Central Plains states [36].

HOST RISK FACTORS — 

Host risk factors may be divided into those that increase susceptibility to disseminated/extrapulmonary visceral disease and those that are associated with isolated NTM pulmonary disease. Each of these two broad categories may also be subdivided into acquired and inherited/genetic disorders that predispose to NTM infections. Some risk factors (eg, anti-tumor necrosis factor [TNF]-alpha agents) may be associated with both disseminated/extrapulmonary visceral disease and isolated pulmonary disease.

Acquired risk factors for isolated NTM pulmonary disease

Structural lung disease — Structural lung disease is a primary risk factor for NTM pulmonary disease. As an example, in a systematic review that included 60 studies evaluating risk factors for NTM pulmonary disease, comorbid respiratory disease was the most strongly associated factor [89]. Specific respiratory diseases included bronchiectasis (odds ratio [OR] 21), history of tuberculosis (OR 13), chronic obstructive pulmonary disease (OR 7), interstitial lung disease (OR 6), and asthma (OR 4). In another review of 231 cases of NTM pulmonary disease in the United States, 73 percent had underlying lung disease [90]. Among patients with chronic airway disease, use of inhaled glucocorticoids is associated with further increased risk of NTM [91]. (See 'Immunomodulating agents' below.)

●Bronchiectasis – This is highly associated with NTM pulmonary disease, particularly the nodular/bronchiectatic form of M. avium complex (MAC) pulmonary disease. This most frequently occurs in nonsmoking females older than 50 years. Such individuals often do not have a known history of lung disease, and the bronchiectasis is identified at the same time as the NTM [92,93].

NTM occurs frequently in individuals with known bronchiectasis. In a study of over 1000 patients who had bronchiectasis but no known NTM and were followed for over five years through a national registry in the United States, the probability of acquiring NTM was 4 percent per year [94].

Multiple possible causes or risk factors may contribute to bronchiectasis, which in turn predisposes the patient to NTM infection. Potential etiologies for bronchiectasis in patients with NTM pulmonary disease include gastroesophageal reflux with chronic aspiration, alpha-1 antitrypsin deficiency, cystic fibrosis [95,96], primary ciliary dyskinesia [97], and connective tissue disorders, such as Marfan syndrome [98], hyper-IgE syndrome [99], and congenital contractural arachnodactyly (CCA) [100]. Some patients with bronchiectasis and MAC pulmonary disease are heterozygous for cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations but do not meet criteria for frank cystic fibrosis [95]. (See 'Hereditary risk factors for NTM pulmonary disease' below.)

While pre-existing bronchiectasis predisposes to secondary NTM infection, NTM can also cause de novo bronchiectasis [101]. Some have suggested that this pattern of disease be considered “primary” NTM pulmonary disease [102]. NTM infection may result in bronchiectasis through at least two distinct mechanisms: (1) chronic granulomatous inflammation leads to mucosal ulceration and atrophy, which weaken and dilate the airway wall, and (2) chronic inflammatory mucous plugging leads to distal airway obstruction and progressive cystic bronchial/bronchiolar dilatation. These processes may further progress to cavitation, as reflected by the “feeding bronchus” sign on computed tomography (CT), characterized by a patent bronchus leading to the cavity [103].

●Chronic obstructive pulmonary disease (COPD) – In reviews of population-based studies of NTM pulmonary disease or respiratory isolation, COPD is a common comorbidity, particularly in studies from the United States and Europe [3]. As an example, in a study from the Veterans Health system in the United States, 68 percent of over 2000 individuals with NTM pulmonary disease also had COPD compared with 38 percent of matched controls without NTM [104]. Specifically, the fibrocavitary form of MAC most commonly occurs in male smokers with chronic pulmonary symptoms due to underlying lung disease.

Immunocompromising conditions

Immunomodulating agents — Use of immunomodulating agents, particularly TNF-alpha inhibitors, has been associated with an increased risk of NTM infection, usually NTM pulmonary disease with the typical findings of nodular bronchiectasis with or without cavitation [105-107].

In a study of older adults with rheumatoid arthritis, individuals who had NTM infection were more likely to be using TNF-alpha inhibitor therapy than those without NTM (OR 2.19) [106]. While robust prospective data are not available, clinical experience suggests that NTM lung disease in the setting of TNF-alpha inhibitor use presents with the typical radiographic patterns (eg, nodular-bronchiectasis with or without cavities; fibrocavitary disease) but that progressive disease is more likely. Patients using TNF-alpha inhibitors also have a higher risk of extrapulmonary infection compared with the general population [107]. (See "Risk of mycobacterial infection associated with biologic agents and JAK inhibitors", section on 'Nontuberculous mycobacterial disease'.)

In studies of patients with rheumatoid arthritis, use of leflunomide and systemic glucocorticoids were also associated with NTM [106]. Risk with other immunomodulating agents are not well studied.

Inhaled glucocorticoids have also been associated with pulmonary NTM disease. In a systematic review of four studies among patients with chronic lung disease, there was an increased likelihood of NTM pulmonary disease in those who used inhaled glucocorticoids (OR 3.9) [91].

Transplant receipt — Individuals who have undergone solid organ or hematopoietic stem cell transplant (HSCT) are at risk for NTM disease mainly because of their immunosuppressive regimens.

Among solid organ transplant recipients, the risk is generally highest among lung transplant recipients and has been associated with older age at transplant, increased intensity of immunosuppression (eg, use of anti-lymphocyte antibodies for treatment of acute rejection), and pre-transplant colonization or disease [108-110]. The epidemiology of NTM in solid organ transplant recipients is discussed in detail elsewhere. (See "Nontuberculous mycobacterial infections in solid organ transplant candidates and recipients", section on 'Epidemiology'.)

Among HSCT recipients, the risk of NTM is higher than in the general population, although the rate varies by study [108,111,112]. In one study of over 1000 allogeneic HSCT recipients in Canada who were followed between 2001 and 2013, the five-year risk of NTM disease was 2.8 percent, estimated to be approximately 65 times the risk in the general population [111]. The vast majority had NTM pulmonary disease (93 percent) and were diagnosed within two years of transplant (83 percent). Independent risk factors included severe graft versus host disease and cytomegalovirus (CMV) viremia.

Low body fat and sarcopenia — Individuals with lower body fat are predisposed to NTM pulmonary disease [95,113-117]. Furthermore, low body fat may be associated with worse outcomes. In a retrospective study of 377 patients with MAC pulmonary disease, more fat in the muscles (myosteatosis) and less fat in the subcutaneous tissues on imaging were associated with a higher risk of death [118].

A proposed mechanism for the association between low body fat and NTM pulmonary disease is the deficiency of leptin, a fat-derived satiety hormone. Leptin is known to skew undifferentiated T cells toward the T_H1, interferon-gamma-producing phenotype [119]. Patients with NTM pulmonary disease have reduced serum leptin levels [120] and are less likely to have the direct relationship between serum leptin concentration and total body fat typically observed in the general population [113]. Leptin-deficient mice are also more susceptible to M. abscessus experimental pulmonary infection [121].

Decreased body fat is also associated with increased adiponectin, which increases immunosuppressive cytokines [122,123]. NTM patients have higher adiponectin levels than patients without NTM [120].

Post-menopausal status — Among patients with NTM pulmonary disease who do not have an obvious risk factor, a disproportionate number (60 to 85 percent of cases) are post-menopausal women [92,95,113,114,124-133]. Even in a study of familiar clusters of NTM pulmonary disease, in which the patterns of transmission suggested dominant and recessive modes of inheritance, the majority of affected individuals were women [125].

The eponym “Lady Windermere syndrome” originates from the hypothesis that women are at greater risk for NTM pulmonary disease because they are less inclined to expectorate forcefully (ie, they suppress cough) and thus do not clear respiratory pathogens effectively [93]. However, this belief is unsubstantiated, and the eponym has evolved to refer to a particular body type associated with NTM pulmonary disease. (See 'Asthenic body habitus and potential connective tissue disease' below.)

Declining estrogen levels may be a more plausible reason for increased susceptibility to NTM pulmonary disease among post-menopausal women [114]. Estrogen induces endothelial nitric oxide synthase (eNOS) and production of NO (which has anti-mycobacterial activity), augments macrophage activity, and improves ciliary function in progesterone-treated airway epithelial cells [129,134]. Oophorectomized mice are more susceptible to MAC pulmonary disease than mice with intact ovaries, and exogenous 17-beta-estradiol administration protects against NTM infection in those oophorectomized mice through enhanced NO production [135].

In addition to aging, reduced body fat may also contribute to decreased estrogen levels since reduced leptin levels results in sequential reduction in follicle-stimulating hormone/luteinizing hormone and estrogen levels.

Other factors — Other clinical features that have been associated with NTM pulmonary disease include:

●Gastro-esophageal reflux disease (GERD) [48,49,51]

●Rheumatoid arthritis [136,137]

●Lung cancer [138]

Hereditary risk factors for NTM pulmonary disease

Cystic fibrosis — NTM strains are commonly isolated from sputum in patients with cystic fibrosis. In a study of more than 16,000 persons with cystic fibrosis, 20 percent had a pathogenic NTM species isolated at least once over a five-year period [139]. Most (61 percent) had MAC and 39 percent had M. abscessus complex isolated. Patients with either MAC or M. abscessus complex were significantly more likely to have been diagnosed with cystic fibrosis at an older age, have a lower body mass index, and have fewer years of chronic macrolide therapy. The incidence appeared to increase over time. (See "Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection", section on 'Nontuberculous mycobacteria'.)

Asthenic body habitus and potential connective tissue disease — Some patients without clear risk factors for NTM pulmonary disease have similar clinical characteristics and body types, including life-long slender body habitus, greater than average height, scoliosis, pectus excavatum, mitral valve prolapse, and joint hypermobility [95,113,114,120,124,128,140-143]. The eponym “Lady Windermere syndrome,” first used to posit that cough suppression contributed to the pathogenesis of NTM pulmonary disease, has evolved to describe women with these physical features, but this morphotype has also been described in men with NTM pulmonary disease [144]. The frequency of this morphotype in patients with NTM pulmonary disease supports the possibility of an underlying syndrome, perhaps a connective tissue disorder, that predisposes to NTM [95,113,114,120,124,128,140].

There is a potential genetic basis behind the morphotype. The physical features are also seen with Marfan syndrome and related connective tissue disorders like Loeys-Dietz syndrome and Shprintzen-Goldberg syndrome [140]. Marfan syndrome is caused by a mutation in the fibrillin-1 gene, which encodes a connective tissue protein. A mutation in this gene was also identified in one of several patients with NTM pulmonary disease who underwent whole-exome sequencing [145]. NTM pulmonary disease has also been reported in a patient with congenital contractural arachnodactyly (CCA), a genetic disorder that is due to a mutation in the fibrillin-2 gene and shares many clinical features with Marfan syndrome [100].

Marfan syndrome is associated with bronchiectasis as well as increased tissue levels of the immunosuppressive cytokine transforming growth factor-beta (TGF-beta), increased levels of which are also seen in patients with NTM pulmonary disease or experimental NTM infections [146-150]. Thus, it is plausible that the asthenic morphotype, with its predisposition to NTM pulmonary disease, represents a forme fruste of Marfan syndrome [151]. Additionally, an enlarged dural sac diameter, which occurs in patients with Marfan syndrome, Loeys-Dietz syndrome, and Shprintzen-Goldberg syndrome, has also been identified in patients with idiopathic bronchiectasis, among whom it has been associated with NTM pulmonary disease and long fingers [152].

Other genetic causes — Other genetic causes of isolated NTM pulmonary disease include [153]:

●Primary ciliary dyskinesia (predisposing to bronchiectasis due to defect in mucociliary clearance)

●Alpha-1-antitrypsin deficiency (predisposing to emphysema and bronchiectasis due to unchecked elastase activity)

●Williams-Campbell syndrome (predisposing to bronchiectasis and bronchomalacia due to bronchial cartilage defect)

●Mounier-Kuhn syndrome (predisposing to tracheobronchomegaly and bronchiectasis due to atrophy or absence of longitudinal elastic fibers of the large airways)

Multigenic predisposition — Emerging evidence suggests that NTM pulmonary disease is a multigenic disease, in which combinations of variants across gene categories, plus environmental exposures, increase susceptibility to infection. The identification of familial clusters of NTM pulmonary disease more strongly supports the concept that at least some patients have hereditary predispositions to disease [125,146,154].

In a study of 69 patients with NTM pulmonary disease and 18 unaffected family members, whole-exome sequencing identified more low-frequency, protein-affecting genetic variants in immune, cystic fibrosis transmembrane regulator (CFTR), cilia, and connective tissue categories among the patients than among controls [154]. Susceptibility to NTM pulmonary disease in these patients may thus be related to bronchiectasis formation resulting from multi-gene abnormalities, although the exact pathways for disease development are still unknown.

Another gene that has been associated with NTM pulmonary disease is the TTK protein kinase gene on chromosome 6q14.1, which encodes a protein kinase essential for mitotic check points and the DNA damage response [155].

Risk factors for disseminated or extrapulmonary infections — Acquired or inherited causes of immunodeficiency are the main risk factors for disseminated NTM disease. (See 'Disseminated disease' below.)

HIV — Advanced immunosuppression from untreated HIV is a primary risk factor for disseminated NTM infection. HIV infection is also associated with M. kansasii infection.

●Disseminated NTM – Disseminated MAC had previously been common among patients with advanced HIV infection (CD4 cell counts below 50 cells/microL) in resource-rich settings, but the incidence declined dramatically with widespread use of antiretroviral therapy (ART). Disseminated MAC is also uncommon among patients with advanced HIV in settings where tuberculosis (TB) is endemic despite the presence of MAC in the environment as well as positive skin testing indicating MAC exposure in those regions [81,156,157]. These observations suggest the potential for cross-protective immunity from childhood Bacillus Calmette-Guerin (BCG) and/or latent TB. The epidemiology of disseminated MAC in patients with HIV is discussed in detail elsewhere. (See "Mycobacterium avium complex (MAC) infections in persons with HIV", section on 'Epidemiology'.)

●M. kansasii – HIV has been associated with M. kansasii infection, both pulmonary and disseminated disease. In a population-based laboratory surveillance study from California in the mid-1990s, 270 cases of M. kansasii infection were identified, of which 187 (69 percent) were in people with HIV infection [158]. The estimated incidence was 115 and 647 per 100,000 people among those with HIV and advanced HIV infection, respectively, compared with 0.75 per 100,000 people among those without HIV. The risk of significant M. kansasii disease once the organism is isolated also appears higher among patients with HIV than without [159]. (See "Overview of nontuberculous mycobacteria (excluding MAC) in patients with HIV", section on 'Mycobacterium kansasii'.)

Deficits in IFN-gamma/IL-12 pathways — Consistent with the importance of the interferon (IFN)-gamma and interleukin (IL)-12 pathway in the host response to NTM infection, inherited and acquired deficits in this pathway have been associated with susceptibility to NTM disease (see 'Host response' below). When such deficits are due to a genetic cause, they are grouped together as Mendelian Susceptibility to Mycobacterial Diseases. Other predisposing deficits may be caused by antibodies against IFN-gamma or other cytokines in the pathway. Many of these immune deficits are especially associated with disseminated infection. (See "Mendelian susceptibility to mycobacterial diseases: An overview", section on 'Presentation and clinical features'.)

Genetic studies of individuals with severe infection caused by NTM or M. bovis following vaccination with BCG identified patients who were unable to produce or respond to IFN-gamma due to mutations in genes that encode major proteins in the IFN-gamma-IL-12 axis [160].

Similarly, the anti-IFN-gamma antibody syndrome has been associated with disseminated NTM infections, as well as other types of bacterial and viral infections [161-165]. In this syndrome, which has been described most commonly among Asian adults but can also occur in other populations, neutralizing auto-antibodies impair the ability of IFN-gamma to induce TNF, human leukocyte antigen (HLA) class II, and IL-12 expression by macrophages.

Additionally, suppressed levels of IFN-gamma and IL-10 have been found in the stimulated whole blood of patients with NTM pulmonary disease [113,166].

Specific defects in these cytokine pathways are discussed in further detail elsewhere. (See "Mendelian susceptibility to mycobacterial diseases: Specific defects" and "Mendelian susceptibility to mycobacterial diseases: An overview", section on 'Differential diagnosis'.)

MonoMAC syndrome (GATA2 deficiency) — The MonoMAC syndrome is a life-threatening, autosomal dominant and pre-cancerous disorder characterized by disseminated NTM infection and opportunistic infections with other pathogens. Clinical disease occurs within a wide age range (3 to 80 years) but often presents in adulthood. Other features include monocytopenia, B and NK cell lymphopenia, and decreased dendritic cell numbers.

MonoMAC is due to a mutation of GATA2, a transcription factor that belongs to a GATA family of transcription activators and is involved in myeloid and erythroid development. This syndrome is discussed in detail elsewhere. (See "Mendelian susceptibility to mycobacterial diseases: Specific defects", section on 'GATA2 deficiency (MonoMAC syndrome)'.)

PROTECTIVE FACTORS — 

Few patient characteristics that are protective of infection with NTM have been described. Epidemiologic studies from Sweden and Finland have shown that childhood immunization with Bacillus Calmette-Guerin (BCG) vaccine is associated with a reduced risk of childhood cervical lymphadenitis due to NTM [167,168].

PATHOGENESIS

Pulmonary disease — The pathogenesis of pulmonary disease due to NTM is poorly understood. Early comparative studies with tuberculosis (TB) established that the granulomatous lesions caused by different species of mycobacteria were indistinguishable to trained pathologists [169,170]. Therefore, it is presumed that there are substantial similarities to the pathogenesis of TB. Most of the understanding of the pathogenesis of NTM pulmonary disease comes from studies of M. avium complex (MAC).

Host response — Since MAC pulmonary disease is uncommon relative to the high prevalence of skin test reactivity to MAC in young adulthood [171], the normal host immune response is presumably effective at containing or eliminating the organism. It is uncertain if NTM infection leads to latent infection that later causes reactivation disease or if most NTM pulmonary disease is the result of primary infection.

●Cellular immune response – If inhaled, MAC encounters alveolar macrophages and is phagocytosed through the action of various receptors. These include nonopsonic receptors like C-type lectin receptors (eg, Dectin-1, macrophage C-type lectin [MCL], and mannose receptors), scavenger receptors, and Toll-like receptors, as well as opsonic receptors like complement receptors, FcgR1 (receptor for the Fc portion of IgG), and integrin receptors [172,173]. Extracellular matrix proteins and glycoproteins act as a bridge between mycobacterial components (eg, lipids, lipoproteins, glycoproteins) and integrin receptors. Bound mycobacteria are taken up in primary phagosomes that fuse with lysosomes in the phagocyte’s cytoplasm and attempt to destroy its contents through various mechanisms [174,175].

Macrophages also process mycobacterial antigens and present them on their surface in conjunction with major histocompatibility complex (MHC) class I and class II molecules to T lymphocytes. This results in tremendous expansion of T lymphocyte clones that specifically recognize those antigens. T helper (CD4) lymphocytes recruited to the site of mycobacterial infection secrete interleukin (IL)-2 and interferon (IFN)-gamma that activate macrophages to induce intracellular destruction of the mycobacteria and enhance cytotoxic lymphocyte activity [176].

Natural killer (NK) cells are key components of the innate immune response for these pathogens. NK cells are lymphocytes that destroy certain neoplastic or infected cells, targeting cells with a paucity of MHC class I surface molecules [177].

These dynamic cellular events are mirrored histopathologically by the formation of granulomas, which reflect infected foci surrounded by mononuclear inflammatory cells and epithelioid macrophages. One caveat to studies that demonstrate cellular infiltration at active sites of NTM infection is that they do not inform whether those cell types are protective, contribute to tissue injury, or both. Ultimately, the release of cytolytic enzymes and other cytotoxic proteins may result in the necrosis and encapsulating fibrosis of both infected and adjacent tissues [178].

Neutrophils have traditionally been viewed as relatively unimportant in defense against mycobacteria. For example, in one study, it was found that human neutrophils released less superoxide anion in response to M. abscessus than to Staphylococcus aureus [179]. Mycobacteria may exploit a neutrophil-rich setting to promote its survival.

●Role of cytokines – Macrophages elaborate cytokines and chemokines, the latter of which recruit lymphocytes and other macrophages to the site of the infection. This results in complex interactions between these cell types to enhance killing of NTM. IL-12, tumor necrosis factor (TNF), and IFN-gamma are especially important in the antimycobacterial immune response.

Binding of IL-12 results in the transcription of IL-12 responsive genes, particularly IFN-gamma. IFN-gamma, in turn, influences IFN-gamma responsive genes like IL-12, MHC genes, and TNF [180,181]. IL-12, TNF, and IFN-gamma also stimulate and enhance the mycobactericidal activity of T lymphocytes, NK cells, and macrophages [177,182-186]. This positive feedback loop between IFN-gamma and IL-12 is pivotal in the immune response to mycobacteria. Defects in any of the genes for the cytokines and their receptors may negatively affect the production of IFN-gamma and/or IL-12 and, consequently, enhance susceptibility to mycobacterial disease [187]. These defects fall under the rubric of Mendelian Susceptibility to Mycobacterial Diseases because the mutated genes are inherited as autosomal dominant or recessive traits. (See 'Deficits in IFN-gamma/IL-12 pathways' above and "Mendelian susceptibility to mycobacterial diseases: An overview".)

In contrast, IL-4 and IL-10 down-modulate the inflammatory response, especially the effect of TNF, and are therefore permissive factors for proliferation of intracellular mycobacteria [188-190]. Additionally, transforming growth factor beta (TGF-beta), which can suppress IFN-gamma, is elevated following ex vivo stimulation of blood with live M. intracellulare [150].

Evasion of host immune response — Mycobacteria have evolved mechanisms to protect themselves from the host immune response. Biofilm formation and NTM-mediated inhibition of inflammatory cytokine production are mechanisms that can subvert host immunity and promote colonization and subsequent invasion of the bronchial epithelium [191].

●Biofilm formation – Glycopeptidolipids (GPL) are cell wall components produced by NTM but not M. tuberculosis. The composition and concentration of GPL vary between NTM species and can impact colony morphology. As an example, M. abscessus-containing nonspecific GPL (nsGPL) appear as smooth colonies on solid media, while those lacking nsGPL appear as rough colonies. GPLs of M. abscessus with the smooth morphotype facilitate formation of biofilms. Both the GPLs and the biofilm matrix prevent innate immune cells from recognizing and interacting with M. abscessus [192]; thus, these smooth variants can survive in the airways and are relatively noninvasive [193]. The more virulent, rough morphotype does not form biofilm and emerges later, sometimes several years after the initial infection [193]. In contrast to the smooth variants, rough variants of M. abscessus stimulate the human macrophage innate immune response and are associated with more severe and persistent pulmonary disease [192,194]. Thus, loss of GPL may enhance virulence of M. abscessus. The triggers for M. abscessus morphotype switching in vivo remain unknown; however, based on whole-genome analysis, switching between forms is likely an infrequent occurrence [195].

M. avium also display smooth and rough variants due to the presence or absence of serovar-specific GPL on their cell wall, respectively. Unlike M. abscessus, the transition between forms is irreversible and caused by the loss of genes involved in GPL biosynthesis [196]. Isolates with smooth-opaque colony morphology are less pathogenic than those with smooth-transparent colony morphology. MAC of the smooth-opaque colony types elicits greater production of inflammatory cytokines, while smooth-transparent colony types tend to be relatively silent immunologically, causing little production of cytokines and less vigorous host responses [197,198]. While the absence of nsGPL from M. abscessus facilitates intracellular survival, M. avium serovar-specific GPL (ssGPL) is required for intracellular survival and impacts cytokine responses, suggesting that serovar oligosaccharides contribute to species-specific pathogenesis.

Biofilm formation also mediates environmental persistence of NTM. NTM organized in biofilms are difficult to eradicate with common decontamination practices and are resistant to standard disinfectants. Microbial pathogens found in biofilms in vivo are also very resistant to high concentrations of antimicrobial drugs [199]. This resistance may be due to virulence enhancement in biofilms via multiple mechanisms. In one study, three rapidly growing mycobacteria (M. smegmatis, M. fortuitum, and M. chelonae) were able to assemble biofilms on surfaces, and this was associated with the ability to spread on solid media [200].

●Survival within macrophages – Another important way that NTM evade host immune mechanisms is by surviving and replicating within macrophages. Experimental evidence indicates that M. avium ingested by macrophages are able to survive and replicate within nonacidic phagosomes [201-203]. Immune-evasion mechanisms by which NTM are able to survive within macrophages include [191,204-209]:

•Inhibition of phagosome-lysosome fusion

•Shift in metabolism to a more anaerobic intracellular environment

•Induction of NTM-related genes that enhance replication

•Deletions and rearrangements of porin genes (mmpA and mmpB) in M. abscessus that normally channel small molecules such as some antibiotics and reactive nitrogen intermediates

•Direct inhibition of host macrophage function and lymphocyte proliferation

•Possibly, induction of macrophage apoptosis by downregulation of the Bcl-2 gene product that normally inhibits apoptosis

Components of the mycobacterial cell wall can also scavenge reactive oxygen intermediates, block acidification of the phagocytic vacuoles, and suppress the synthesis of cytokines [210-212].

Disseminated disease — Disseminated or extrapulmonary visceral NTM disease occurs primarily with MAC and primarily in severely immunocompromised patients. Such underlying immunodeficiency may be broadly divided into acquired or inherited forms, as discussed elsewhere. (See 'Risk factors for disseminated or extrapulmonary infections' above.)

●Acquired disorders include untreated advanced HIV; use of potent immunosuppressive therapy for inflammatory diseases, cancer, or organ transplantation; and acquired autoantibodies to IFN-gamma [153]. One caveat is that there is likely a genetic component to development of anti-IFN-gamma antibodies, as this syndrome appears to be more common in Asian people and in those with HLA DRB16:02 or DRB05:02 [164].

●Inherited disorders associated with disseminated NTM infections are varied. One of the best-analyzed groups are individuals with genetic defects in the IL-12 and IFN-gamma pathways (Mendelian Susceptibility to Mycobacterial Diseases). Specific examples of such defects include mutations of IL-12, IL-12 receptor-1, IFN-gamma receptor, and Stat1-alpha (a downstream transcriptional activator induced by IFN-gamma) [213,214].

In patients with either acquired or inherited immunodeficiency, the pathogenetic model proposes that mycobacteria from the environment infect a mucosal surface (lung or gut), multiply locally, and eventually enter the bloodstream and disseminate, seeding other organs and tissues [215-217]. At first, bacteremia from these localized infections may be infrequent and intermittent. As metastatic foci of infection progress, bacteremia becomes more constant and heavier, and tissue involvement increases. In patients with disseminated MAC who were followed with serial blood cultures through death and postmortem examination, the tissue burden of organisms and the number of tissues involved increased in direct proportion to the time after the initial positive blood cultures and to the fraction of blood cultures that were positive [217].

In contrast to the well-formed lung granulomas that are characteristic of pulmonary NTM disease, patients with disseminated NTM disease associated with immunodeficiency have poorly formed granulomatous inflammation [218]. In one study, heme oxygenase-1 (HO-1) was important for monocyte chemoattractant protein-1 (MCP-1) trafficking, which is necessary for granuloma formation and containment of mycobacterial infection [219].

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".)

SUMMARY AND RECOMMENDATIONS

●Environmental distribution – Nontuberculous mycobacteria (NTM) are free-living organisms (table 1) that are ubiquitous in the environment globally. They have been recovered from surface water, tap water, soil, domestic and wild animals, milk, and food products. (See 'Environmental sources' above.)

●Transmission – Infection can occur following inhalation, ingestion, aspiration, and direct inoculation of MAC found in the environment (eg, water and soil). Human-to-human transmission is thought not to occur, although rare case reports suggest the potential in certain populations. (See 'Route of acquisition' above.)

●Burden of disease – Although precise estimates of incidence and prevalence of NTM disease are difficult to determine, the burden of NTM disease, particularly pulmonary disease, appears to be increasing worldwide. In the United States, the prevalence of NTM exposure and disease is highest in the South, particularly the Southeast, and in Hawaii. (See 'Frequency of disease' above.)

●Acquired risk factors for isolated NTM pulmonary disease – Bronchiectasis and other forms of structural lung disease are the primary risk factor for NTM pulmonary disease. Other acquired risk factors include use of immunosuppressive agents (eg, tumor necrosis factor [TNF]-alpha inhibitors, inhaled glucocorticoids, agents used in transplant recipients), low body fat, and post-menopausal state. (See 'Acquired risk factors for isolated NTM pulmonary disease' above.)

●Hereditary risk factors for isolated NTM pulmonary disease – Genetic conditions that predispose to NTM include cystic fibrosis, primary ciliary dyskinesia, and alpha-1-antitrypsin deficiency. Many patients with NTM pulmonary disease have a characteristic body type (tall, slender, pectus excavatum, scoliosis) that suggests the possibility of an underlying syndrome, such as a connective tissue disorder like Marfan syndrome, that increases risk of infection. (See 'Hereditary risk factors for NTM pulmonary disease' above.)

●Risk factors for disseminated/extrapulmonary disease – Acquired or inherited causes of immunodeficiency, particularly advanced HIV and defects in the interferon (IFN)-gamma/interleukin (IL)-12 signaling pathway, are the main risk factors for disseminated NTM disease. (See 'Risk factors for disseminated or extrapulmonary infections' above.)

●Pathogenesis – The host immune response depends on a complex interaction between macrophages and a robust cellular response, mediated by IL-12, TNF, and IFN-gamma signaling. NTM evade the host response through various mechanisms, including biofilm formation and survival within macrophages. (See 'Pathogenesis' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges David E Griffith, MD, who contributed to earlier versions of this topic review.