Several terms—nontuberculous mycobacteria (NTM), atypical mycobacteria, mycobacteria other than tuberculosis, and environmental mycobacteria—all refer to mycobacteria other than Mycobacterium tuberculosis, its close relatives (M. bovis, M. caprae, M. africanum, M. pinnipedii, M. canetti), and M. leprae. The number of identified species of NTM is growing and will continue to do so because of the use of DNA sequence typing for speciation. The number of known species currently exceeds 150. NTM are highly adaptable and can inhabit hostile environments, including industrial solvents.
NTM are ubiquitous in soil and water. Specific organisms have recurring niches, such as M. simiae in certain aquifers, M. fortuitum in pedicure baths, and M. immunogenum in metalworking fluids. Most NTM cause disease in humans only rarely unless some aspect of host defense is impaired, as in bronchiectasis, or breached, as by inoculation (e.g., liposuction, trauma). There are no known instances of human-to-human transmission of NTM. Because infections due to NTM are rarely reported to health agencies and because their identification is sometimes problematic, reliable data on incidence and prevalence are lacking. Disseminated disease denotes significant immune dysfunction (e.g., advanced HIV infection), whereas pulmonary disease, which is much more common, is highly associated with pulmonary epithelial defects but not with systemic immunodeficiency.
In the United States, the incidence and prevalence of pulmonary infection with NTM, mostly in association with bronchiectasis (Chap. 258), have for many years been several-fold higher than the corresponding figures for tuberculosis, and rates of the former are increasing among the elderly. Among patients with cystic fibrosis, who often have bronchiectasis, rates of clinical infection with NTM range from 3% to 15%, with even higher rates among older patients. Although NTM may be recovered from the sputa of many individuals, it is critical to differentiate active disease from commensal harboring of the organisms. A scheme to help with the proper diagnosis of pulmonary infection caused by NTM has been developed by the American Thoracic Society and is widely used. The bulk of nontuberculous mycobacterial disease in North America is due to M. kansasii, organisms of the M. avium complex (MAC), and M. abscessus.
In Europe, Asia, and Australia, the distribution of NTM in clinical specimens is roughly similar to that in North America, with MAC species and rapidly growing organisms such as M. abscessus encountered frequently. M. xenopi and M. malmoense are especially prominent in northern Europe. M. ulcerans causes the distinct clinical entity Buruli ulcer, which occurs throughout tropical zones, especially in western Africa. M. marinum is a common cause of cutaneous and tendon infections in coastal regions and among individuals exposed to fish tanks or swimming pools.
The true international epidemiology of infections due to NTM is hard to determine since the isolation of these organisms often is not reported and speciation often is not performed. The increasing ease of identification and speciation of these organisms should have a major impact on the description of their international epidemiology in the next few years.
Because exposure to NTM is essentially universal and disease is rare, it can be assumed that normal host defenses against these organisms must be strong and that otherwise healthy individuals in whom significant disease develops are highly likely to have specific susceptibility factors that permit NTM to become established, multiply, and cause disease. At the advent of HIV infection, CD4+ T lymphocytes were recognized as key effector cells against NTM; the development of disseminated MAC disease was highly correlated with a decline in CD4+ T lymphocyte numbers. Such a decrease has also been implicated in disseminated MAC infection in patients with idiopathic CD4+ T lymphocytopenia. Potent inhibitors of tumor necrosis factor α (TNF-α), such as infliximab, adalimumab, certolizumab, and etanercept, can neutralize this critical cytokine. The occasional result is severe mycobacterial or fungal infection; these associations indicate that TNF-α is a crucial element in mycobacterial control. However, in cases without the above risk factors, much of the genetic basis of susceptibility to disseminated infection with NTM is accounted for by specific mutations in the interferon γ (IFN-γ)/interleukin 12 (IL-12) synthesis and response pathways.
Mycobacteria are typically phagocytosed by macrophages, which respond with the production of IL-12, a heterodimer composed of IL-12p35 and IL-12p40 moieties that together make up IL-12p70. IL-12 activates T lymphocytes and natural killer cells through binding to its receptor (composed of IL-12Rβ1 and IL-12Rβ2/IL-23R), with consequent phosphorylation of STAT4. IL-12 stimulation of STAT4 leads to secretion of IFN-γ, which activates neutrophils and macrophages to produce reactive oxidants, increase expression of the major histocompatibility complex and Fc receptors, and concentrate certain antibiotics intracellularly. Signaling by IFN-γ through its receptor (composed of IFN-γR1 and IFN-γR2) leads to phosphorylation of STAT1, which in turn regulates IFN-γ-responsive genes, such as those coding for IL-12 and TNF-α. TNF-α signals through its own receptor via a downstream complex containing the nuclear factor κB (NFκB) essential modulator (NEMO). Therefore, the positive feedback loop between IFN-γ and IL-12/IL-23 drives the immune response to mycobacteria and other intracellular infections. These genes are known to be the critical ones in the pathway of mycobacterial control: specific Mendelian mutations have been identified in IFN-γR1, IFN-γR2, STAT1, IL-12A, IL-12Rβ1, and NEMO (Fig. 167-1). Despite the identification of genes associated with disseminated disease, only ∼50% of cases of disseminated nontuberculous mycobacterial infections that are not associated with HIV infection have a genetic diagnosis; the implication is that more mycobacterial susceptibility genes and pathways remain to be identified.
Cytokine interactions of infected macrophages (Mφ) with T and natural killer (NK) lymphocytes. Infection of macrophages by mycobacteria (AFB) leads to the release of heterodimeric interleukin 12 (IL-12). IL-12 acts on its receptor complex, with consequent STAT4 activation and production of ...
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