Infections Caused by Nontuberculous Mycobacteria Other than Mycobacterium avium Complex


Infections Caused by Nontuberculous Mycobacteria Other than Mycobacterium avium Complex

Barbara A. Brown-Elliott, Richard J. Wallace Jr.


The improvement in mycobacterial culture techniques and the increasing utility of modern molecular techniques for identification of previously unidentified organisms has produced a major resurgence of interest in disease caused by the nontuberculous mycobacteria (NTM). In addition, there has been an increasing appreciation of the defects in lung structure and immune response that predispose to NTM.1 This group of mycobacteria is composed of species other than the Mycobacterium tuberculosis complex (MTBC), which consists of M. tuberculosis, M. africanum, M. bovis, and M. leprae. Previous names for this group of organisms include “atypical mycobacteria” or “mycobacteria other than M. tuberculosis (MOTT).”2 Currently there are more than 150 species of NTM, of which more than half are considered to be pathogens or potential sources of human or animal disease. Approximately 32 of these species have been described since 2009.35 M. avium complex (MAC) is described extensively in Chapter 253. Traditionally, NTM have been categorized into different groups based on characteristic colony morphology, growth rate, and pigmentation (the Runyon system of classification). This system has become less useful as we focus on more rapid molecular systems of diagnostics. However, growth rates and colony pigmentation continue to provide practical means for grouping species of mycobacteria within the laboratory and are thus still used.2

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 now include approximately 10 species within the M. fortuitum group (M. fortuitum, M. peregrinum, M. senegalense,6,7 M. setense,8 and the third biovariant complex including M. septicum,9 M. porcinum,10,11 M. houstonense, M. boenickei, M. brisbanense, and M. neworleansense10). Previously, M. mageritense was considered a member of this group but recent studies show that it is more closely related to M. wolinskyi.12,13 Additionally, there are three validated species within the second group, M. chelonae/abscessus group (M. chelonae, M. salmoniphilum,14 and M. immunogenum,13,15 and three subspecies: M. abscessus subsp. bolletii, M. massiliense, and M. abscessus subsp. abscessus).1618 Currently the taxonomy of M. abscessus and its subspecies is in debate, but for the purposes of this chapter, we refer to them as three subspecies, with M. abscessus representing the former M. abscessus subsp. abscessus (sensu stricto), and M. abscessus subsp. massiliense (for brevity M. massiliense) and subsp. bolletii (for brevity M. bolletii) referring to the former species M. massiliense and M. bolletii, respectively.1619 “M. franklinii,” a not yet validated species, has been the cause of multiple pulmonary and sinus infections.20 M. salmoniphilum has been revived as a fish pathogen but as yet has not been recovered in human samples.14 The M. mucogenicum group includes three species: M. mucogenicum (formerly M. chelonae-like organism) and two newly described species, M. aubagnense and M. phocaicum.6,17 A fourth group of pathogenic organisms within the RGM is the M. smegmatis group.6,21 Isolates within this group include two late pigmenting species: M. smegmatis (formerly M. smegmatis sensu stricto) and M. goodii.21 All of these species, including the newly described species, have been recovered from clinical specimens on multiple occasions.6,13,21

The fifth group, (early) pigmenting RGM, is difficult to identify using conventional (phenotypic) laboratory methods. The pigmented species that have been implicated in clinical disease include M. flavescens, M. neoaurum, M. vaccae, M. phlei, M. canariasense, M. cosmeticum, M. monacense, M. psychrotolerans, the thermophilic species M. thermoresistibile, and two newly described species, M. bacteremicum22 and M. iranicum.23 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.24

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.2,25 The major clinically important established species within this group include MAC, which is discussed in Chapter 253; M. kansasii; M. xenopi; M. simiae complex (M. simiae, M. lentiflavum, M. triplex, and the newly described pigmented species, M. europaeum26); M. szulgai; M. malmoense; and M. scrofulaceum. Additionally, the M. terrae/M. nonchromogenicum complex is now composed of several new clinically significant species, M. arupense,27 M. kumamotonense,2,25 M. hiberniae,25 and two newly described species, M. heraklionense27 and M. longobardum,27 and one pink pigmented species not yet established as pathogenic, M. engbaekii.27 M. asiaticum,28 M. florentinum,5 M. senuense,2 and M. montefiorense,2,25 a pathogen in eels,2,25 were previously described. Newly described nonpigmented species also include human pathogens and potential pathogens, M. kyorinense,29 M. noviomagense,30 M. shinjukuense,31 M. sherrisii,32 M. koreense,3 and M. riyadhense,33 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. stomatepiae34 and M. algericum35 (also related to the M. terrae complex), were described as pathogens in fish and goats, respectively. M. minnesotense, described in early 2013, has not been recovered from clinical samples to date.36 Pigmented newly described species include M. europaeum,26 M. arosiense,25 M. paraseoulense,37 M. shigaense,38 M. mantenii,39 and a newly revived species, M. parafficum.40

Other previously described pigmented organisms in this group include M. nebraskense,2,25 M. parascrofulaceum,25 M. parmense,25 M. saskatchewanense,25 M. seoulense,25 and M. pseudoshottsii (a fish pathogen related to M. shottsii).25

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.25,28,41 Other organisms that require special nutritional supplements include M. haemophilum, which requires hemin for growth (hence its name), and M. genavense,25,28 which requires mycobactin J and prolonged incubation in broth culture. Most of these slowly growing mycobacteria grow best at 35° C to 37° C, with the exception of M. haemophilum, which prefers lower temperatures (28° C to 30° C), and M. xenopi, which grows well at 42° C.25,28,42

Intermediately Growing Mycobacteria

This group of organisms includes M. marinum and M. gordonae. 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.25

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.2,25 A few species that are known to cause disease, such as M. haemophilum and M. ulcerans, have rarely been recovered from the environment.25,41 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 pseudo-outbreak, and no evidence of person-to-person spread has been reported, presumably due to the lower virulence of environmental species.25 Tap water is considered the major reservoir for most common human NTM pathogens and thus is of increasing public health interest. Species from tap water include M. gordonae, M. kansasii, M. xenopi, M. simiae, and MAC.

Among the RGM, M. mucogenicum is a common tap water isolate.2,7,25 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.2,43 Moreover, biofilms may serve to render mycobacteria less susceptible to disinfectants and antimicrobial therapy.2,43 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.2,43

Nontuberculous Mycobacteria and Clinical Disease

NTM produce six major clinical disease syndromes (Table 254-1), which are reviewed in the following sections.

TABLE 254-1

Major Clinical Syndromes Associated with Nontuberculous Mycobacterial Infection

Chronic nodular disease (adults with bronchiectasis; cystic fibrosis) MAC (M. intracellulare, and M. avium), M. kansasii, M. abscessus M. xenopi, M. malmoense, M. szulgai, M. smegmatis, M. celatum, M. simiae, M. goodii, M. asiaticum, M. heckeshornense, M. branderi, M. lentiflavum, M. triplex, M. fortuitum, M. arupense, M. abscessus subsp. bolletii, M. phocaicum, M. aubagnense, M. florentinum, M. abscessus subsp. massiliense, M. nebraskense, M. saskatchewanense, M. seoulense, M. senuense, M. paraseoulense, M. europaeum, M. sherrisii, M. kyorinense, M. noviomagense, M. mantenii, M. shinjukuense, M. koreense, M. heraklionense, M. parascrofulaceum, M. arosiense
Cervical or other lymphadenitis (especially children) MAC M. scrofulaceum, M. malmoense (northern Europe), M. abscessus, M. fortuitum, M. lentiflavum, M. tusciae, M. palustre, M. interjectum, M. elephantis, M. heidelbergense, M. parmense, M. bohemicum, M. haemophilum, M. europaeum, M. florentinum, M. triplex, M. asiaticum, M. kansasii, M. heckeshornense
Skin and soft tissue disease M. fortuitum group, M. chelonae, M. abscessus, M. marinum, M. ulcerans (Australia, tropical countries only) M. kansasii, M. haemophilum, M. porcinum,
M. smegmatis, M. genavense, M. lacus,
M. novocastrense, M. houstonense, M. goodii,
M. immunogenum, M. mageritense,
M. abscessus subsp. massiliense, M. arupense,
M. monacense, M. bohemicum, M. branderi,
M. shigaense, M. szulgai, M. asiaticum,
M. xenopi, M. kumamotense, M. setense,
M. montefiorense (eels), M. pseudoshottsii (fish),
M. shottsii (fish)
Skeletal (bone, joint, tendon) infection M. marinum, MAC, M. kansasii, M. fortuitum group, M. abscessus, M. chelonae M. haemophilum, M. scrofulaceum,
M. heckeshornense, M. smegmatis,
M. terrae/chromogenicum complex, M. wolinskyi,
M. goodii, M. arupense, M. xenopi, M. triplex,
M. lacus, M. arosiense
Disseminated infection
M. genavense, M. haemophilum, M. xenopi
HIV-seropositive host M. avium, M. kansasii, M. marinum, M. simiae, M. intracellulare,
M. scrofulaceum, M. fortuitum, M. conspicuum,
M. celatum, M. lentiflavum, M. triplex,
M. colombiense, M. sherrisii, M. heckeshornense,
HIV-seronegative host M. abscessus, M. chelonae M. marinum, M. kansasii, M. haemophilum,
M. chimaera, M. conspicuum, M. shottsii (fish),
M. pseudoshottsii (fish)
Catheter-related infections M. fortuitum, M. abscessus, M. chelonae M. mucogenicum, M. immunogenum,
M. mageritense, M. septicum,
M. porcinum, M. bacteremicum,
M. brumae
Hypersensitivity pneumonitis Metal workers
Hot tub
M. immunogenum
M. avium

Too little information is available for selected pathogens such as M. xenopi, M. malmoense, M. szulgai, M. celatum, and M. asiaticum and the newly described species.

HIV, human immunodeficiency virus; MAC, Mycobacterium avium complex.

Pulmonary Disease

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.28 In the United States, MAC, followed by M. kansasii, is the most frequently recognized pathogen.28 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.2,28 In southeast England, M. xenopi and M. kansasii (known to be present in local water supplies) are both more common than MAC.2 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.28 (This study antedated recognition of M. bolletii and M. massiliense.) Intriguingly, the proportion of M. abscessus subsp. massiliense varies geographically. Reports from Korea and Japan have indicated that the ratio of M. abscessus to all NTM is much higher in South Korea than in other countries, including Japan.44,45 Recent reports state show that M. massiliense was reported from the National Institutes of Health (NIH) in the United States in 28% of 40 patients, 21% of 39 isolates in the Netherlands, 22% of 50 patients with cystic fibrosis in France, 55% of 150 patients, and 26% of 102 patients in South Korea and Japan, respectively.45 Bronchiectasis was found to be significantly more frequent in M. abscessus than in M. massiliense.45 Recently, M. massiliense has been increasingly recognized in respiratory samples of patients, including patients with cystic fibrosis.28,4648 Studies in Korea and Japan have emphasized major differences in macrolide susceptibility patterns and clinical response rates between M. abscessus, of which approximately 80% are resistant to macrolides, and M. massiliense, which are usually macrolide susceptible; thus, patients with M. massiliense respond favorably to clinical treatment with macrolides, unlike M. abscessus.44,45

Nontuberculous Mycobacteria Species Associated Infrequently with Pulmonary Disease

Among the newly described RGM, pulmonary infection has been reported with M. iranicum23 and the not yet validated species, “M. franklinii.20 Less commonly, M. fortuitum, M. goodii, M. abscessus, and M. smegmatis have been associated with lipoid pneumonia7,21 and achalasia.7,21 Patients with achalasia exhibit a bilateral subacute to acute alveolar disease with high fevers, striking leucocytosis above 20,000, cough, and mucus production; acute illness is common. The histopathology shows a combination of lipoid disease and acute/granulomatous infection.28 Other NTM that infrequently cause pulmonary disease include M. szulgai,25,28 M. simiae,25,28 M. celatum,25,28 M. lentiflavum,25,28 M. asiaticum,25,28 M. heckeshornense,25,28 M. florentinum,5 M. arupense,25,28 M. kumamotense,2 M. nebraskense,25,28 and rarely, M. gordonae,25,28 M. saskatchewanense,5,25 M. senuense,25 and M. seoulense.25 Newly described species M. kyorinense,29 M. noviomagense,30 M. paraseoulense,37 M. europaeum,26 M. sherrisii,32 M. shinjukuense,31 M. koreense,3 M. arosiense4,25 (previously mistaken for M. intracellulare due to a false-positive commercial identification probe), and the aforementioned new species in the M. terrae complex25,27 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.27

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. M. abscessus group also produces nodular disease in the setting of bronchiectasis. Pulmonary NTM disease is rare in children, except for those with cystic fibrosis.28,46 M. abscessus and M. massiliense have been increasingly recovered from respiratory samples collected from patients with cystic fibrosis. The majority of patients with the M. abscessus group are younger and have more severe disease.46 Patients with cystic fibrosis also have bronchiectasis in addition to chronic recurrent airway and parenchymal infections which may predispose them to NTM infections.46

Clinical Nontuberculous Mycobacteria 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 254-2).28 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 and routine chest radiographs. High-resolution chest computed tomography 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 acid-fast bacillus smear is negative and NTM are present in low numbers.28,49 The American Thoracic Society statement on the diagnosis and treatment of NTM28 has recently revised the diagnostic criteria to determine lung disease caused by NTM (Table 254-3 and see Chapter 253).28 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.28

TABLE 254-2

Clinical Settings for Nontuberculous Mycobacterial Lung Disease

Upper lobe cavitary Male smokers, often abusing alcohol, usually early 50s MAC, M. kansasii
Right middle lobe, lingular nodular bronchiectasis Female nonsmokers, usually older than 60 yr MAC, M. abscessus, M. abscessus subsp. massiliense (M. kansasii)
Localized alveolar, cavitary disease Prior granulomatous disease (usually tuberculosis) with bronchiectasis M. abscessus, MAC
Reticulonodular or alveolar bilateral lower lobe disease Achalasia, chronic vomiting secondary to gastrointestinal disease, exogenous lipoid pneumonia (mineral oil aspirations, etc.) M. fortuitum (M. abscessus, MAC, M. smegmatis, M. goodii)
Reticulonodular disease Adolescents with cystic fibrosis, HIV-positive hosts, may be prior bronchiectasis secondary to Pneumocystis pneumonia or other cause MAC, M. abscessus subsp. abscessus, M. abscessus subsp. massiliense
Hypersensitivity pneumonitis Metal workers
Indoor hot tub
M. immunogenum
M. avium

* Too little information is available for selected pathogens such as M. xenopi, M. malmoense, M. szulgai, M. celatum, and M. asiaticum and the newly described species.

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Jul 1, 2017 | Posted by in INFECTIOUS DISEASE | Comments Off on Infections Caused by Nontuberculous Mycobacteria Other than Mycobacterium avium Complex

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