Infections Caused by Nontuberculous Mycobacteria Other Than Mycobacterium avium Complex

Rapidly Growing Mycobacteria

The group of organisms called rapidly growing mycobacteria (RGM) includes nonpigmented and pigmented species that produce mature growth on media plates within 7 days. There are currently six groups or complexes of RGM based on pigmentation and genetic relatedness. Nonpigmented pathogenic species within the M. fortuitum group now include approximately 10 species: M. fortuitum, M. peregrinum, M. senegalense, M. setense, and former members of the third biovariant complex, including M. septicum, M. porcinum, M. houstonense, M. boenickei, M. brisbanense, and M. neworleansense. A newly described, closely related species, M. aquaticum, has been recovered from hemodialysis water but not yet considered pathogenic. In addition, there are six validated species within the second group, the M. chelonae-abscessus group ( M. chelonae, M. saopaulense [a pathogen described in humans and fish], M. salmoniphilum, M. franklinii [multiple pulmonary and sinus infections], M. immunogenum, and the recently emended three subspecies of M. abscessus: M. abscessus subsp. bolletii, M. abscessus subsp. massiliense, and M. abscessus subsp. abscessus , previously designated as M. bolletii, M. massiliense, and M. abscessus, respectively). M. salmoniphilum has been revived as a fish pathogen but as yet has not been recovered in human samples. The M. mucogenicum group includes three species: M. mucogenicum (formerly M. chelonae –like organism) and two newer-described species, M. aubagnense and M. phocaicum . A fourth group of pathogenic organisms within the RGM is the M. smegmatis group. Isolates within this group include two late-pigmenting species: M. smegmatis (formerly M. smegmatis [sensu stricto]) and M. goodii . All of these species, including the newly described species, have been recovered from clinical specimens on multiple occasions.

The fifth group, (early) pigmenting RGM, contains several species that have been implicated in clinical disease, including M. flavescens, M. neoaurum, M. vaccae, M. phlei, M. canariasense, M. cosmeticum, M. monacense, M. psychrotolerans, the thermophilic species M. thermoresistibile, M. bacteremicum, and M. iranicum. Recent additions include M. celeriflavum , M. hippocampi (a marine pathogen), and M. anyangense (a cattle pathogen). M. mageritense (formerly in the M. fortuitum group) and M. wolinskyi (formerly in the M. smegmatis group) have been suggested to comprise a sixth group of nonpigmented species, which are genetically closely related to each other.

Slowly Growing Mycobacteria

This group includes species of mycobacteria that require more than 7 days to reach mature growth. Some species may also require nutritional supplementation of routine mycobacterial media. The major clinically important established species within this group include the MAC, which is discussed in Chapter 251 ; M. kansasii; M. xenopi; M. simiae complex ( M. simiae, M. lentiflavum , M. triplex, and the newly described pigmented species, M. europaeum ); M. szulgai; M. malmoense; and M. scrofulaceum. In addition, the M. terrae–M. nonchromogenicum complex is now composed of several clinically significant species associated with tenosynovitis, including M. arupense ; M. kumamotonense ; M. hiberniae ; M. heraklionense ; M. longobardum ; and most recently, M. virginiense , and one pink pigmented species, M. engbaekii, that, like M. nonchromogenicum, has not yet been established as pathogenic. M. asiaticum, M. florentinum, M. senuense, and M. montefiorense, a pathogen in eels, were previously described. Recently described nonpigmented species also include human pathogens and potential pathogens: M. kyorinense ; M. noviomagense ; M. shinjukuense ; M. sherrisii ; M. koreense ; and M. riyadhense, a species related to M. malmoense and M. szulgai, which was originally identified as MTBC due to a false-positive commercial line probe. Two other species, M. stomatepiae and M. angelicum, genetically related to M. szulgai, have been reported in fish. M. algericum, genetically related to the M. terrae complex, was described as a pathogen in goats. M. minnesotense, described in early 2013, has not been recovered from clinical samples to date. M. paraterrae, M. paragordonae, and M. parakoreense have rarely been described in patients and still have uncertain clinical significance. Pigmented newly described species include M. europaeum, M. paraseoulense, M. shigaense, and M. parafficum . M. persicum , a pigmented species described in 2017 and related to M. kansasii, has been reported in pulmonary samples from four unrelated patients in Iran.

Other previously described pigmented organisms in this group include M. nebraskense, M. parascrofulaceum, M. parmense, M. saskatchewanense, M. seoulense, and M. pseudoshottsii (a fish pathogen related to M. shottsii ).

In Africa and Australia M. ulcerans continues to be a major pathogen. Cultivation of this species is difficult because it requires up to several months to grow, so molecular detection and identification are currently more optimal than culture techniques. Other organisms that require special nutritional supplements include M. haemophilum, which requires hemin for growth (hence its name), and M. genavense, which requires mycobactin J and prolonged incubation in broth culture. Most of these slowly growing mycobacteria grow best at 35° to 37°C, with the exception of M. haemophilum, which prefers lower temperatures (28°–30°C), and M. xenopi, which usually grows well at 42° to 45°C.

Intermediately Growing Mycobacteria

This group of organisms includes M. marinum, M. gordonae, and M. intermedium , and a newly described cattle pathogen, M. bourgelatti , related to the latter species, may also belong to this group but has not yet been described in humans. These organisms are pigmented and require 7 to 10 days to reach mature growth. M. marinum grows optimally at 28° to 30°C, whereas M. gordonae prefers 35° to 37°C. M. intermedium, an NTM of uncertain clinical significance has an optimal temperature between 31° and 37°C .

Nontuberculous Mycobacteria and the Environment

Most NTM species are readily recovered from the environment. Isolates have been recovered from samples of soil, water, animals, plant material, and birds. A few fastidious species that are known to cause disease, such as M. haemophilum and M. ulcerans, have rarely been recovered from the environment. Although an association with an environmental source may be present, a direct link to the environment has not been proven except for health care–associated disease and pseudooutbreaks. Recently, the possibility of person-to-person spread of a strain of M. abscessus subsp . massiliense has been reported among patients in a US cystic fibrosis center. Isolates that genetically match the strain have been seen in geographic areas outside the United States, including the United Kingdom and South America. Community drinking water systems are considered the major reservoirs for most common human NTM pathogens and thus are of increasing public health interest. Slowly growing NTM species, other than MAC, isolated from household tap water include M. gordonae, M. kansasii, M. xenopi, M. simiae, M. arupense, and the newly described M. aquaticum.

Among the RGM, M. mucogenicum and the closely related M. phocaicum are common tap water isolates. Other RGM species from tap water include M. porcinum, M. immunogenum, and M. chelonae. Recent studies of household water have shown that biofilms, which are the filmy layers at the solid and liquid interface, are recognized as a source of growth and possibly a mode of transmission for mycobacteria. Moreover, biofilms may serve to render mycobacteria less susceptible to disinfectants and antimicrobial therapy. Biofilms appear to be present in almost all collection and piping systems, so mycobacteria may often be recovered from these sites. The persistence of pathogenic NTM in water and biofilms has important implications in the epidemiology of infections related to water.

Nontuberculous Mycobacteria and Clinical Disease

NTM produce six major clinical disease syndromes ( Table 252.1 ), which are reviewed in the following sections.

Geography of Common Nontuberculous Mycobacteria Species

Chronic pulmonary disease in a human immunodeficiency virus (HIV)-negative host is the most common localized clinical disease caused by NTM. In the United States MAC, followed by M. kansasii, is the most frequently recognized pathogen. In Canada, some parts of the United Kingdom, and Europe, M. xenopi ranks third, whereas M. malmoense is second after MAC in Scandinavia and northern Europe. In southeast England M. xenopi and M. kansasii, known to be present in local water supplies, are both more common than MAC. A recent study in Ontario, Canada showed that M. xenopi was the second most frequently isolated NTM after MAC. The study also revealed that patients with M. xenopi disease have higher rates of pulmonary cavitation than MAC and are often associated with chronic obstructive pulmonary disease (COPD) and significant mortality rates. In the United States the third most common cause of NTM pulmonary disease is M. abscessus complex, which produces 80% of pulmonary infections caused by RGM. (This study antedated recognition of the subspecies bolletii and massiliense. ) Intriguingly, the proportion of M. abscessus subsp. massiliense varies geographically. Reports from Korea and Japan have indicated, inexplicably, that the ratio of M. abscessus to all NTM is much higher in South Korea than in other Asian countries, including Japan. Reports from the National Institutes of Health in the United States show M. abscessus subsp. massiliense in 28% of 40 patients with lung disease due to NTM, 21% of 39 isolates in the Netherlands, 22% of 50 patients with cystic fibrosis in France, and 55% of 150 patients and 26% of 102 patients in South Korea and Japan, respectively. Bronchiectasis was found to be significantly more frequent in M. abscessus subsp. abscessus than in M. abscessus subsp. massiliense. Recently, M. abscessus subsp. massiliense has been increasingly recognized in respiratory samples of patients, including patients with cystic fibrosis. Studies in Korea and Japan and, more recently, the United States (for in vitro MIC studies) have emphasized major differences in macrolide susceptibility patterns and clinical response rates between M. abscessus subsp. abscessus, of which approximately 80% are resistant to macrolides, and M. massiliense, which are usually macrolide susceptible; thus patients with M. abscessus subsp. massiliense respond favorably to clinical treatment with macrolides, unlike M. abscessus subsp. abscessus.

Nontuberculous Mycobacteria Species Associated Infrequently With Pulmonary Disease

Among the newly described RGM, pulmonary infection has been reported with M. iranicum (from Italy, Iran, and Turkey), the newly validated species M. franklinii , and M. celeriflavum . Less commonly, M. fortuitum, M. goodii, M. abscessus, and M. smegmatis have been associated with lipoid pneumonia and achalasia. Patients with achalasia exhibit a bilateral subacute to acute alveolar disease with high fevers, striking leucocytosis count higher than 20,000/µL, cough, and mucus production; acute illness is common. The histopathology shows a combination of lipoid disease and acute/granulomatous infection. Other NTM that are infrequently associated with pulmonary disease include M. szulgai, M. simiae, M. celatum, M. lentiflavum, M. asiaticum, M. heckeshornense, M. florentinum, M. arupense, M. kumamotense, M. nebraskense, and rarely, M. gordonae, M. saskatchewanense, M. senuense, and M. seoulense . Recently described species M. kyorinense, M. noviomagense, M. paraseoulense, M. europaeum, (recently validated, but not recently described), M. shinjukuense, M. koreense, M. sherrisii, and the aforementioned new species in the M. terrae complex have also been associated with pulmonary disease. Some isolates originally described as M. nonchromogenicum and thought to be pathogenic have recently been identified as M. heraklionense. Rarely, isolates of M. persicum, M. parakoreense, M. paraense, and M. talmoniae have also been recovered from pulmonary samples.

Pulmonary Syndromes Associated With Nontuberculous Mycobacteria Other Than Mycobacterium avium Complex

Clinical disease with M. kansasii produces upper lobe fibrocavitary disease and nodular disease similar to MAC in the same setting. The M. abscessus complex also produces nodular disease in the setting of bronchiectasis. Pulmonary NTM disease is rare in children, except for those with cystic fibrosis. M. abscessus subsp. abscessus and M. abscessus subsp. massiliense have been increasingly recovered from respiratory samples collected from patients with cystic fibrosis. The majority of patients with the M. abscessus complex are younger and have more severe disease. Patients with cystic fibrosis also have bronchiectasis in addition to chronic recurrent airway and parenchymal infections that may predispose them to NTM infections.

Clinical Presentation of Nontuberculous Mycobacterial Lung Disease

Because the signs and symptoms of NTM lung disease are often variable and nonspecific, disease with NTM is difficult to diagnose without positive respiratory cultures ( Table 252.2 ). Patients often present with chronic cough, a “throat clearing” with or without sputum production, and fatigue. Less frequently, complaints of malaise, dyspnea, fever, hemoptysis, and weight loss may also be present. Clinical studies should include microbiologic cultures for acid-fast bacilli (AFB) and routine chest radiographs. High-resolution chest computed tomography (CT) is essential in patients suspected of having nodular bronchiectasis. Recovery of NTM from a single sputum sample is not proof of NTM disease, especially when the AFB smear is negative and NTM are present in low numbers. The American Thoracic Society statement on the diagnosis and treatment of NTM has revised the diagnostic criteria to determine lung disease caused by NTM ( Table 252.3 ). For NTM disease due to organisms other than MAC, these criteria may need to be adjusted because inadequate data are available to evaluate these criteria. Expert consultation should be obtained when NTM that are infrequently encountered are recovered.

Treatment of Mycobacterium avium Complex Lung Disease

This issue is discussed separately in Chapter 251 .