Mycobacterium avium Complex

Reservoir and Route of Acquisition

MAC is composed of environmental organisms thought to be acquired by inhalation, microaspiration, or ingestion. Perhaps due to the low virulence described later, person-to-person spread has not been observed. Environmental sites harboring MAC are diverse; they include water, soil, and animals. MAC has been found to colonize natural water sources as well as indoor water systems, pools, and hot tubs. Although specific sites from which individuals acquire MAC are only rarely identified, exposure to recirculating water systems has been described as a specific source of acquisition in human disease, especially in persons with HIV or acquired immunodeficiency syndrome (AIDS). However, only a minority of cases can be traced to this source, and this type of connection between exposure and disease has been less clearly documented in the HIV-negative population, suggesting that other environmental reservoirs are important. Aerosols of natural fresh and salt water as well as dirt particles may contain MAC, and these have been proposed as vehicles leading to transmission of MAC respiratory disease, although aerosolized fluids were not associated with the acquisition of MAC in a case-control study, and other studies have shown a less clear connection between what is in household water and the lungs. Cutaneous MAC infection has been described to occur specifically in relation to hot tub/Jacuzzi use. Aerosols from heater-cooler units of heart-lung machines have been specifically documented to transmit M. chimaera during open heart surgery, causing a notable global outbreak of these infections, including cases of disseminated disease. There is also a strong and growing association between MAC pulmonary disease and gastric reflux disease, and an association with microaspiration, suggesting that this may be the proximate route of entry in many individuals. Overall, the ubiquitous presence of MAC in nature makes it difficult to ascertain where an individual patient acquired his or her disease, and except in specific situations this makes avoidance strategies or investigations to identify a source of limited utility.

Pulmonary Disease

MAC pulmonary disease is seen worldwide, although for a variety of reasons prevalence is higher in developed countries, likely in part due to increased life span. In the United States and Canada, regional studies have shown an overall disease prevalence of 5 to 19 per 100,000 persons, with prevalence rates potentially as high as 20 to 45 per 100,000 persons in the elderly. Incidence of disease seems to be increasing in many countries, including the United States, Canada, the United Kingdom, and Denmark, and shows substantial geographic variability within countries. ^a

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Few countries have a national database to accurately evaluate the true occurrence of MAC, although in Denmark where there is complete capture of pulmonary mycobacterial cultures in a national database, the incidence of NTM lung disease (of which 57% are MAC) in 2008 was 1.08 per 100,000 persons. The average age of patients with MAC pulmonary disease in the United States is greater than 60 years, and most patients above this age are women. However, younger persons with cystic fibrosis (CF) are at significantly increased risk for MAC pulmonary disease, and a causal role has been proposed for this organism in the pulmonary tissue destruction in CF. Some specific risk factor(s) for MAC pulmonary disease are present in most cases; these include airway diseases (e.g., bronchiectasis), damage from prior pulmonary infections, structural lung diseases (e.g., chronic obstructive pulmonary disease), and processes that affect the immune systems, such as the use of corticosteroids and other immunosuppressive agents. Chronic bronchiectasis is a particularly interesting entity in this regard because it is strongly associated with MAC, but it is still unclear if it is the result of the disease or a predisposition to the disease, as is discussed further later. These factors, even taken together, do not explain the overall increase in cases of MAC over the past decade.

Extrapulmonary Disease

The most well-known form of extrapulmonary MAC, disseminated MAC (dMAC), was extremely rare before 1980. The heightened susceptibility of patients with HIV/AIDS to this process led to a marked increase, and in 1994 an estimated 37,000 cases of dMAC were seen in patients with AIDS, making this the most common clinical manifestation of MAC at that time. With the introduction of effective ART and the increase in ART access, the number of patients with AIDS has declined and with it the number with dMAC. The greatest risk for MAC in patients with HIV is with the severe depression of the CD4 ⁺ cell count, with dMAC rarely seen in patients with greater than 100 CD4 ⁺ cells/mm ³ and the median CD4 ⁺ cell count among patients with dMAC and AIDS around 10 cells/mm ³ . However, there is a spectrum of risk for dMAC that increases as the CD4 ⁺ count declines, and the prior occurrence of another opportunistic condition increases the risk for dMAC at any given CD4 ⁺ cell level, as does a detectable HIV viral load. Children with AIDS have a risk for MAC similar to that of adults, and rates of dMAC have also fallen dramatically in this age group as HIV treatment has improved.

dMAC can also be seen in patients with disease states or medications that cause a mycobacterial-specific immune defect, such as anti–tumor necrosis factor-α (anti–TNF-α) inhibitors, corticosteroids, interferon-γ (INF-γ) pathway defects, GATA2 mutations, or primary immunodeficiency diseases, such as interferon-γ receptor 1 (IFNγR1) or interleukin-12 receptor β-1 (IL-12Rβ1) deficiency ( Table 251.1 ). While disseminated disease due to innate immunodeficiencies is rare, disseminated disease due to iatrogenic immunosuppression is growing with increasing use of corticosteroids, inhibitors of TNF-α, chemotherapeutic agents, and organ transplants. The combination of anti–TNF-α agents and steroids seems to confer the most MAC-specific (and mycobacterial disease–specific in general) risk for disease dissemination in comparison to their risk of triggering dissemination of other infections, although pulmonary MAC infection is still the most common entity with anti–TNF-α use.

Although less well known than disseminated disease, MAC lymphadenitis is a more common clinical entity in older studies and one that is likely underdiagnosed because many cases of lymphadenitis are not cultured, fail to grow an organism, or never come to medical attention. Before 1980, most nontuberculous lymphadenitis in the United States was due to Mycobacterium scrofulaceum, but more recently, MAC has been the cause. MAC cervical adenitis is largely a disease of children younger than age 3 years on the basis of reports from Europe, North America, and Australia. A report from children in the Netherlands estimated the incidence of MAC lymphadenitis at 51 cases per 100,000. MAC lymphadenitis is also seen in HIV-infected persons, particularly as “unmasking IRIS” a manifestation of the immune reconstitution inflammatory syndrome (IRIS).

MAC skin and soft tissue infection or deeper tendon/joint/bone infection are relatively uncommon entities for which good epidemiologic data are lacking, and are usually related to direct inoculation after puncture wounds, trauma, or surgical incisions. Due to MAC presence in the water and soil, and the association with puncture/trauma, this form commonly involves the hands, and when it does, has a predilection for causing tenosynovitis.

The epidemiology of the relatively newly recognized MAC subspecies, M. chimaera, warrants mention here. Although it is generally considered a minimally pathogenic environmental organism, it is now identified as a cause of intravascular infection, primarily as postoperative infections of prosthetic material stemming from a global outbreak, identified in Germany, in which the source of infection was heater-cooler units used in cardiac surgery. The long incubation time from exposure to disease made diagnosis difficult, with many of the cases diagnosed 1 to 4 years after initial surgery. Although the individual risk of infection after such surgery is low, thousands of patients in Europe and the United States were exposed to the contaminated Stöckert 3T heater-cooler devices, prompting a massive effort to locate and treat infected patients. Decontamination of the heater-cooler devices has proven difficult, and it is not completely clear if the outbreak is resolved.

Organisms

Like other mycobacteria, MAC organisms are aerobic, non–spore-forming, nonmotile bacilli. Their cell walls include mycolic acid–containing, long-chain glycolipids, glycopeptidolipids, or both that protect the facultative intracellular organisms from lysosomal attack and give the organisms their “acid-fast” staining characteristic. MAC are classified as “slow-growing” nontuberculous organisms, generally taking 10 to 35 days to grow on solid media and producing smooth-transparent, smooth-opaque, and rough colony variants that are usually light tan in color, although there are variations of uncertain significance. MAC can be cultured on solid or liquid media, with liquid media more sensitive and yielding growth more quickly but not allowing quantification of load. Glycolipid typing has divided MAC into 28 serovars: 1 through 6, 8 through 11, and 21 are M. avium, and 7, 12 through 20, and 25 are M. intracellulare. There is considerable diversity in the strains of MAC that infect patients, with multiple strains sometimes present in the same patient. Advances in molecular genetics have increased the number of subspecies, but the clinical relevance is poorly understood. Distinguishing between MAC species and subspecies is done by using polymerase chain reaction with DNA sequencing, hybridization with specific DNA probes, or matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry, although depending on the strength of the library there can be some errors seen with MALDI-TOF mass spectrometry. The identification of M. chimaera is relevant in that it does add a prediction of lower virulence for this organism than for MAI in pulmonary infection. It is less clear whether there is a relevant difference between M. avium and M. intracellulare, and since the subspecies cannot be differentiated from each other by traditional biochemical tests, most laboratories group them together as MAI.

Virulence

All members of the MAC complex are relatively low-virulence organisms, with M. chimaera the least virulent. Supporting the lower virulence, patients who actually develop true M. chimaera pulmonary disease are more likely to be immunosuppressed, have cancer, have received a transplant, or have high inoculum exposure due to infected cardiac surgery equipment. There seems to be a difference in virulence between MAC serovars because serovars 1, 4, and 8 are uncommon in the environment but cause most cases of disseminated disease in persons with AIDS. Possible virulence factors include adherence to intestinal epithelial cells, production of catalase, failure to acidify vesicles, and inhibition of phagosome-lysosome fusion. MAC has the ability to change colony types in vivo, and this seems related to virulence because clinical isolates from disseminated disease are usually the smooth-transparent colony type, rather than the domed or opaque type. Colonies that are smooth and transparent are more likely to replicate in vivo, induce cytokines, and cause more infection in animal models and usually have decreased in vitro susceptibility to antimycobacterial agents. There may also be synergy with the HIV virus itself, because isolates from humans with MAC disease can increase cell lysis and stimulate HIV replication in vitro relative to the abilities of animal MAC isolates. It is unclear whether there is a meaningful pathogenicity difference between M. avium and M. intracellulare, although the largest study in this regard, reviewing 590 patients in South Korea with MAC lung disease, showed statistically more symptomatic, radiographically advanced, and sputum smear–positive disease in the M. intracellulare group, as well as less optimal response to treatment. However, it is worth noting that this group was also older and had lower body mass index values, suggesting a sicker host.

Pathogenesis

MAC infection starts from primary acquisition of the organism by inhalation/aspiration, ingestion, or direct inoculation. There are specific characteristics of pathogenesis to consider depending on the site of infection.

Host Immunity