INTRODUCTION — Nontuberculous mycobacteria (NTM) species are mycobacterial species other than those belonging to the Mycobacterium tuberculosis complex (eg, M. tuberculosis, Mycobacterium bovis, Mycobacterium africanum, and Mycobacterium microti) and Mycobacterium leprae. NTM are generally free-living organisms that are ubiquitous in the environment. Molecular identification techniques, including whole-genome sequencing, have identified approximately 200 NTM species.
An overview of NTM infection in HIV-negative patients, with emphasis on chronic lung infections that account for up to 90 percent of patient encounters due to NTM, will be reviewed here. The epidemiology, microbiology, pathogenesis, diagnosis, and treatment of NTM infection, as well as infection due to rapidly growing mycobacteria and M. ulcerans, are discussed separately. (See "Epidemiology of nontuberculous mycobacterial infections" and "Microbiology of nontuberculous mycobacteria" and "Pathogenesis of nontuberculous mycobacterial infections" and "Diagnosis of nontuberculous mycobacterial infections of the lungs" and "Treatment of Mycobacterium avium complex pulmonary infection in adults" and "Rapidly growing mycobacterial infections: Mycobacteria abscessus, chelonae, and fortuitum" and "Buruli ulcer (Mycobacterium ulcerans infection)".)
NTM infections in patients with HIV and lung transplant candidates and recipients are also reviewed separately. (See "Mycobacterium avium complex (MAC) infections in persons with HIV" and "Overview of nontuberculous mycobacteria (excluding MAC) in patients with HIV" and "Nontuberculous mycobacterial infections in solid organ transplant candidates and recipients".)
SPECTRUM OF CLINICAL SYNDROMES — In broad terms, Nontuberculous mycobacteria (NTM) can cause four clinical syndromes in humans [1,2]:
●Pulmonary disease, especially in older persons with or without underlying lung disease and patients with cystic fibrosis, caused primarily by Mycobacterium avium complex (MAC), Mycobacterium abscessus subsp abscessus, and Mycobacterium kansasii.
Other species that cause lung disease include Mycobacterium xenopi, Mycobacterium malmoense, Mycobacterium szulgai, and Mycobacterium simiae (table 1) . Geography plays a prominent role in the epidemiology of NTM pulmonary disease. M. xenopi is relatively more common in Europe, Great Britain, and Canada, M. simiae is relatively more common in the Southwest United States and Israel, while M. malmoense is relatively more common in Scandinavia and Northern Europe [1,4]. (See "Epidemiology of nontuberculous mycobacterial infections".)
●Superficial lymphadenitis, especially cervical lymphadenitis, in children caused mostly by MAC, Mycobacterium scrofulaceum, and, in Northern Europe, M. malmoense and Mycobacterium haemophilum. (See "Disseminated nontuberculous mycobacterial (NTM) infections and NTM bacteremia in children" and "Nontuberculous mycobacterial lymphadenitis in children".)
●Disseminated disease in severely immunocompromised patients (most commonly caused by MAC and less commonly by the rapidly growing mycobacteria [RGM], eg, M. abscessus, M. fortuitum, and Mycobacterium chelonae). (See "Mycobacterium avium complex (MAC) infections in persons with HIV" and "Rapidly growing mycobacterial infections: Mycobacteria abscessus, chelonae, and fortuitum".)
●Skin and soft tissue infection usually as a consequence of direct inoculation, caused primarily by Mycobacterium marinum and Mycobacterium ulcerans, the RGM, and other NTM species including MAC. RGM infections in this category may be nosocomial, including surgical site infections . (See "Rapidly growing mycobacterial infections: Mycobacteria abscessus, chelonae, and fortuitum".)
MYCOBACTERIUM AVIUM COMPLEX — The term M. avium complex (MAC) encompasses multiple species including M. avium, Mycobacterium intracellulare, Mycobacterium chimaera, Mycobacterium colombiense, Mycobacterium arosiense, Mycobacterium marseillense, Mycobacterium timonense, Mycobacterium bouchedurhonense, Mycobacterium vulneris, and Mycobacterium yongonense. These organisms are genetically similar and generally not differentiated in the clinical microbiology laboratory. Among nontuberculous mycobacteria (NTM), MAC (specifically M. avium and M. intracellulare) is the most common cause of pulmonary disease worldwide. (See "Microbiology of nontuberculous mycobacteria".)
It is generally felt that these organisms are acquired from the environment. Mounting evidence suggests that municipal water sources may be an important source for MAC lung infections [6-8]. Unlike M. tuberculosis, there are no convincing data demonstrating human-to-human or animal-to-human transmission of MAC. (See "Epidemiology of nontuberculous mycobacterial infections".)
Clinical manifestations — The symptoms and signs of MAC lung disease are variable, not specific, and are influenced by whether the patient has pre-existing symptomatic lung disease. They include cough (productive or dry), fatigue, malaise, weakness, dyspnea, chest discomfort, and occasionally hemoptysis. Fever and weight loss occur less frequently than in patients with typical tuberculosis. Examination of the lungs is often normal but, since these infections frequently coexist with underlying lung disease such as chronic obstructive pulmonary disease (COPD) or bronchiectasis , physical findings of the latter diseases may predominate.
Two major clinical presentations have been described:
●Disease in those with known underlying lung disease – This occurs primarily in White, middle-aged or older men with a history of smoking and underlying chronic obstructive pulmonary disease. The disease resembles typical tuberculosis clinically and radiographically, with cough, weight loss, upper lobe infiltrates, and cavities [10,11]. Symptoms are generally less severe than those associated with tuberculosis. Additionally, due to the relatively indolent nature of MAC lung disease, lung destruction may be quite extensive at the time of diagnosis with very large cavities on chest radiograph.
Another presentation is seen in patients in whom MAC develops in areas of prior bronchiectasis, such as patients with prior tuberculosis. Older adults are also affected, but there is no association with male sex or smoking-related pulmonary disease. Most commonly, patients with prior treated tuberculosis develop symptoms, such as cough, sputum production, fatigue and weight loss, and a new infiltrate in the previously affected lung zone suggesting a relapse of tuberculosis. This pattern is also seen with other types of bronchiectasis including cystic fibrosis [11,12].
●Disease in those without previously suspected or diagnosed lung disease – This occurs predominantly in nonsmoking women over age 50 who have abnormal chest radiography consistent with bronchiectasis [9,13]. Such patients usually experience many years of progressive respiratory symptoms and recurrent respiratory infections due to unrecognized underlying bronchiectasis. For many clinicians, this is the most commonly encountered form of MAC lung disease. The typical presenting symptoms are persistent cough with variable sputum production, sometimes with weight loss but usually without fever. In one report, the mean duration of cough was 25 weeks before the diagnosis was made , but some patients are symptomatic for many years prior to diagnosis. Previously thought to represent a relatively benign process, the serious nature of this disease has become increasingly evident. Patients with persistently positive sputum cultures for MAC experience worsening radiographic appearance, accelerated decline in pulmonary function testing, and increased mortality [9,14,15].
Radiographically, this form of MAC lung disease is invariably associated with multiple small nodules and cylindrical bronchiectasis (often in the mid-lung fields) and is referred to as nodular/bronchiectatic MAC lung disease . A syndrome of right middle lobe or lingular infiltrates, sometimes called the Lady Windermere syndrome, has been noted in older women without predisposing lung disease, volume loss, adenopathy, or cavitation .
Shedding of MAC into the respiratory secretions in these patients is less consistent than in the fibrocavitary form of the disease. Sputa may be intermittently positive and/or positive with low numbers of organisms.
In a series of selected patients with this form of MAC lung disease, it was noted that they tend to be taller and leaner than control subjects and have increased likelihood of pectus excavatum, scoliosis, and mitral valve prolapse [17,18]. These patients are also more likely to have cystic fibrosis transmembrane conductance regulator mutations in the absence of recognized immune defects . There were no consistent or severe immune defects such as cell-mediated immune dysfunction or cytokine pathway abnormalities identified in these patients. The pathophysiologic consequences of the morphologic abnormalities and their potential contribution(s) to the predisposition for MAC infection are not yet known. While there is no clear single genetic mutation to explain this association, it has been suggested that several genetic variants predispose to MAC lung disease [19,20]. (See "Pathogenesis of nontuberculous mycobacterial infections", section on 'Nodular/bronchiectatic disease'.)
Two other less common forms of MAC lung disease have been described:
●Solitary pulmonary nodules – One report noted an unexpectedly high frequency (78 of 244 patients) of MAC pulmonary infections presenting as solitary pulmonary nodules, which resembled lung cancer . Solitary pulmonary nodules caused by MAC were observed in 11 patients in South Korea in a retrospective study .
●Hypersensitivity pneumonitis – MAC exposure in immunocompetent hosts without underlying lung disease has been linked to the development of hypersensitivity pneumonitis, particularly following hot tub use [22-25]. The resulting hypersensitivity reaction ("hot tub lung") generally responds to avoidance of the offending environment, and the role of antibiotic therapy appears limited. (See "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Epidemiology, causes, and pathogenesis", section on 'Ventilation and water-related contamination'.)
Diagnostic criteria — Diagnostic criteria for nontuberculous mycobacterial pulmonary infections include compatible symptoms, imaging studies consistent with pulmonary disease, and recurrent isolation (from at least two specimens) of mycobacteria from sputum or isolation of mycobacteria from at least one bronchial wash in a symptomatic patient (table 2) [2,26]. (See "Diagnosis of nontuberculous mycobacterial infections of the lungs".)
Disseminated disease — Disseminated MAC disease may complicate MAC pulmonary disease through local multiplication and entry into the bloodstream with seeding of other organs and tissues. The disease primarily occurs in severely immunocompromised patients, such as those with advanced HIV infection, hematologic malignancy, or a history of immunosuppressive therapy including therapy with tumor necrosis alpha inhibitors [27-29]. (See "Epidemiology of nontuberculous mycobacterial infections", section on 'Disseminated disease'.)
Disseminated disease following exposure to contaminated equipment used in cardiac surgery has also been described. (See 'M. chimaera associated with cardiac surgery' below.)
Clinical symptoms and signs — Clinically, disseminated MAC manifests as intermittent or persistent fever (>80 percent), night sweats (>35 percent), weight loss (>25 percent), with additional symptoms including fatigue, malaise, and anorexia . Organ-specific symptoms and signs reflect the major sites of involvement including anemia and neutropenia from bone marrow involvement; adenopathy or hepatosplenomegaly from lymphoreticular involvement; diarrhea, abdominal pain, hepatomegaly, and elevations of liver enzymes from involvement of the gastrointestinal tract; and cough and lung infiltrates from pulmonary involvement.
Diagnosis — The diagnosis is most readily established by culture of blood for mycobacteria. It is important to note that mycobacterial blood cultures are collected in special media, different from the media used in standard bacterial blood cultures, and must be specifically requested. Mycobacterial cultures must be specifically requested so that the cultures are not discarded before there has been time to detect mycobacterial growth. Although mycobacterial growth can sometimes be detected as early as a few days after obtaining the culture, in general, mycobacterial cultures cannot be confidently deemed negative until six weeks have passed without growth.
Specimens from bone marrow, or fluid or tissue from suspected sites of involvement should also be submitted for culture and histopathology. Noncaseating granulomas on pathology are supportive of mycobacterial involvement. Bacillary forms may be visible on acid-fast staining, but their absence does not rule out the possibility of infection.
Although molecular testing has been used for epidemiological investigation, such techniques are generally not clinically available.
Management — Limited data are available to guide management of disseminated MAC in patients without HIV infection. Medical therapy typically consists of several antimycobacterial agents for at least several months. Correction of immunosuppression is also essential for an optimal response to therapy. Patients with disseminated disease may also require adjunctive surgical intervention (eg, valve replacement, joint replacement, or debridement of infected bone) for clinical cure.
For patients with macrolide-susceptible disease, a multidrug regimen similar to that used for pulmonary MAC disease (ie, a macrolide plus ethambutol plus a rifamycin) is generally used. Patients with extensive, severe, or life-threatening disease should also receive a parenteral aminoglycoside, such as amikacin, during the initial 8 to 12 weeks of therapy, although even longer periods of parenteral therapy may be required.
If the isolate is macrolide-resistant, therapy consists of ethambutol plus a rifamycin, preferably rifabutin, plus a parenteral aminoglycoside. The addition of another antimycobacterial agent, such as clofazimine, may also be of some value, although there are few data supporting its use in this setting. The fluoroquinolones have no demonstrated activity or value in this setting.
Oral agents are administered daily. Parenteral aminoglycosides (eg, amikacin) are administered three to five times weekly. (See "Treatment of Mycobacterium avium complex pulmonary infection in adults", section on 'Regimen selection'.)
The optimal duration of treatment has not been established, but treatment is usually administered for at least six months. The precise duration depends on the underlying cause or predisposition for the disseminated MAC infection. As an example, for patients with easily remediable sources of MAC dissemination (ie, without a sequestered site of infection), six months of therapy may be adequate. In contrast, for patients with MAC infections in areas where antibiotic penetration is suboptimal, such as bone or joints, 12 months of therapy is likely necessary for cure. Similarly, for those patients with underlying immunosuppression, the duration of therapy depends on the severity and reversibility of the immune deficits. For patients with reversible or temporary immunosuppression, treatment duration is similar to that for patients with HIV and disseminated MAC who recover immune function (ie, at least 12 months of treatment with at least six months of immune reconstitution). For patients with persistent and severe immunosuppression, the adequate duration of therapy is not established, and may be open ended. (See "Mycobacterium avium complex (MAC) infections in persons with HIV", section on 'Duration of MAC therapy'.)
One difficult aspect of treating extra-pulmonary MAC infection is the lack of diagnostic tools to measure treatment outcome. Whereas sputum AFB cultures and chest radiographic studies are relatively easy to obtain and follow to evaluate a patient's response to therapy for pulmonary MAC disease, obtaining sequential cultures may be essentially impossible for many extra-pulmonary sites. The reliability of sequential imaging for sites such as bone and joints is also not established. (See "Treatment of osteomyelitis due to nontuberculous mycobacteria in adults", section on 'Monitoring during therapy'.)
M. chimaera associated with cardiac surgery — Mycobacterium chimaera is a MAC species that has generally been thought to have relatively low virulence, at least as a pulmonary pathogen. Two prolonged outbreaks of M. chimaera prosthetic valve infections and associated disseminated infection, in which the source was determined through epidemiologic and molecular analysis to be the heater-cooler unit used for cardiac bypass procedures, were first described in 2015 in Europe and the United States [30,31], and subsequent clusters have been reported elsewhere [32,33]. Molecular testing further suggested that the source of contamination of the implicated heater-cooler devices (Stockert 3T) was the manufacturing facility itself . In the United States, the Food and Drug Administration and Centers for Disease Control and Prevention have made several recommendations to try to lower the risk of additional infections [35,36]. These include removing from service any Stockert 3T heater-cooler device that has tested positive for M. chimaera or that has been associated with known M. chimaera infections, replacing accessories and connectors that were used with such devices, and refraining from using any 3T heater-cooler device manufactured before September 2014 except in emergent situations when no other device is available. These infections can also be avoided by physically removing heater-cooler devices from the operating room. Testing of devices to identify contamination is not recommended because of technical challenges and a high rate of false-negative tests.
Although the risk is low, providers of patients who have undergone cardiac surgery should be aware of the possibility of M. chimaera infection if they develop signs and symptoms compatible with disseminated mycobacterial disease (eg, persistent fever, night sweats, weight loss). The majority of the patients described in the outbreaks presented with prosthetic valve endocarditis accompanied by other signs of disseminated disease including ocular emboli, bony involvement (eg, vertebral osteomyelitis), splenomegaly, pancytopenia, hepatitis, and renal impairment [30,31,33,37]. Other cases have involved surgical site infection. Patients presented months to years following the surgical procedure. Patients who have a presentation compatible with disseminated M. chimaera infection should have several mycobacterial blood cultures; depending on the clinical presentation, specimens from other sites should also be collected for microbiological and pathological testing . (See 'Clinical symptoms and signs' above and 'Diagnosis' above.)
Treatment of the prosthetic valve and disseminated M. chimaera infections requires combined medical and surgical approaches. M. chimaera appears to be similar to other MAC species with regard to antibiotic responses and should be treated with the same macrolide-based regimens as other MAC species such as M. avium and M. intracellulare. However, similar to other MAC species, treatment success is not guaranteed with macrolide-based therapy. (See 'Management' above.)
This outbreak is unusual from many perspectives but especially with regards to the causative organism, which had traditionally been thought of as having low virulence. There is also no precedent for a similar outbreak of nosocomial mycobacterial prosthetic valve endocarditis. The reason that this pathogen has manifest now with this clinical presentation is unknown. Nevertheless, the relatively rapid identification of an unusual pathogen as the cause of a nosocomial outbreak and the identification of the environmental source of the infecting organism is a testament to the utility of molecular epidemiologic techniques for mycobacteria .
MYCOBACTERIUM KANSASII — Unlike other NTM, M. kansasii has never been found in soil or natural water supplies but has been recovered consistently from tap water in cities where M. kansasii is endemic. Thus, there appears to be an association between clinical disease and potable water supplies. (See "Epidemiology of nontuberculous mycobacterial infections", section on 'Mycobacterium kansasii'.)
Clinical features — M. kansasii usually presents as lung disease that is nearly identical to tuberculosis, although fever may be less common . In older studies, cavitation occurred in 85 to 95 percent of cases, being bilateral in 20 percent [10,40,41]. In some cases, the cavities tended to have thinner walls and less surrounding parenchymal infiltration than in tuberculosis [10,41].
A survey of 56 adults with M. kansasii pulmonary infection in Israel diagnosed in the time period 1999 to 2004 noted the following findings :
●The most common clinical presentations were chest pain (82 percent), cough (84 percent), hemoptysis (38 percent), fever, and night sweats (39 percent).
●Cavitation occurred in 54 percent.
The explanation for the difference in prevalence of cavitation in the studies is unclear, although patients in older studies may have had more advanced disease prior to diagnosis.
Disseminated infection is a rare complication that occurs in immunocompromised hosts such as those with HIV infection. (See "Overview of nontuberculous mycobacteria (excluding MAC) in patients with HIV", section on 'Mycobacterium kansasii'.)
Diagnosis — The same diagnostic criteria apply to the diagnosis of pulmonary infection with M. kansasii as to MAC infection. (See "Diagnosis of nontuberculous mycobacterial infections of the lungs".)
RAPIDLY GROWING MYCOBACTERIA — Rapidly growing mycobacteria (RGM) include three clinically relevant species: M. abscessus (including three subspecies: abscessus, massiliense, and bolletii), M. fortuitum, and M. chelonae (table 1). The RGM are environmental organisms found worldwide that usually grow in culture in less than one week following initial isolation, and may sometimes grow on standard microbiologic media (rather than requiring special mycobacterial media). Pulmonary disease due to rapidly growing mycobacteria (RGM) is predominantly due to M. abscessus subsp abscessus and subsp massiliense and, less commonly, subsp bolletii. M. fortuitum and M. chelonae are rarely associated with lung disease. This is discussed in detail separately. (See "Rapidly growing mycobacterial infections: Mycobacteria abscessus, chelonae, and fortuitum", section on 'Pulmonary infection'.)
As noted above, disseminated NTM disease usually occurs in the immunosuppressed host. Perhaps surprisingly, M. abscessus is not an important pathogen in patients with HIV. However, in 2000, a previously unrecognized clinical entity of disseminated infection following lymphadenitis was reported in a group of 19 patients from northeast Thailand without HIV . A follow-up report from this region in 2007 described 129 patients with chronic lymphadenitis and subsequent progressive involvement of other organs (eg, skin and soft tissue, lung, bone and joint, liver); 99 of 129 cases involved RGM . Almost half of the patients also had other opportunistic infections, consistent with an underlying T-cell defect. In a subsequent study that included patients in Thailand and Taiwan who did not have HIV but had disseminated NTM (with both slow and rapidly growing species) or other opportunistic infections, the majority had neutralizing anti-interferon gamma autoantibodies . There are only rare patients with a similar syndrome reported in the United States or Western Europe. Evaluation for neutralizing anti-interferon gamma autoantibodies should be performed in patients with disseminated NTM disease and no apparent predisposing risk factor.
RGM occasionally cause skin and soft tissue infections. This is discussed in detail separately. (See "Rapidly growing mycobacterial infections: Mycobacteria abscessus, chelonae, and fortuitum", section on 'Skin and soft tissue infection'.)
OTHER NONTUBERCULOUS MYCOBACTERIA — Other pathogens including M. xenopi, M. simiae, M. szulgai, and M. malmoense can also cause chronic lung disease (table 1) [3,46]. The clinical manifestations and diagnostic criteria for infection are as discussed above for MAC. (See 'Mycobacterium avium complex' 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".)
●Nontuberculous mycobacteria (NTM) species are mycobacterial species other than those belonging to the Mycobacterium tuberculosis complex and Mycobacterium leprae. NTM are generally free-living organisms that are ubiquitous in the environment. (See 'Introduction' above.)
●Pulmonary disease, especially in older persons with or without underlying lung disease, is caused primarily by Mycobacterium avium complex (MAC), Mycobacterium abscessus subsp abscessus, and Mycobacterium kansasii. (See 'Introduction' above.)
●Among NTM, MAC is the most common cause of pulmonary disease worldwide. (See 'Mycobacterium avium complex' above.)
●The symptoms and signs of MAC lung disease are variable and not specific, but include cough (productive or dry), fatigue, malaise, weakness, dyspnea, chest discomfort, and occasionally hemoptysis. (See 'Clinical manifestations' above.)
●Two major clinical presentations of MAC pulmonary disease include:
•Cavitary disease in patients with underlying lung disease who are primarily White, middle-aged or older men, smokers with underlying chronic obstructive lung disease or in patients in whom MAC develops in areas of prior bronchiectasis.
•Nodular/bronchiectatic disease in patients without previously diagnosed lung disease, including nonsmoking women over age 50 who invariably have bronchiectasis on chest radiography. In retrospect, these patients almost invariably have chronic respiratory symptoms, primarily cough, and recurrent respiratory infections. The presence of bronchiectasis is an important NTM lung disease predisposition regardless of the etiology, such as cystic fibrosis and pulmonary ciliary dyskinesia. (See 'Clinical manifestations' above.)
●The American Thoracic Society and Infectious Disease Society of America's diagnostic criteria for nontuberculous mycobacterial pulmonary infections include both imaging studies consistent with pulmonary disease and recurrent isolation of mycobacteria from sputum or isolated from at least one bronchial wash in a symptomatic patient. (See "Diagnosis of nontuberculous mycobacterial infections of the lungs".)
●Unlike other NTM, M. kansasii has never been found in soil or natural water supplies, but has been recovered consistently from tap water in cities where M. kansasii is endemic. (See 'Mycobacterium kansasii' above.)
●M. kansasii usually presents as lung disease that is nearly identical to tuberculosis. (See 'Clinical features' above.)
●Pulmonary disease due to rapidly growing mycobacteria (RGM) is predominantly due to Mycobacterium abscessus (80 percent of cases) and Mycobacterium fortuitum (15 percent of cases). (See 'Rapidly growing mycobacteria' above.)
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