Early history.Robert Koch’s discovery and laboratory culture of the causative agent of tuberculosis (Mycobacterium tuberculosis), was announced in 1882, and by the end of the century many other varieties of mycobacteria had been described in animals, birds, and also in the environment as non-disease causing organisms.

The earliest report of growth of mycobacteria other than M. tuberculosis – so called nontuberculous mycobacteria (NTM) – dates back to the late 1880s when Alvarez and Tavil described the organism later known as Mycobacterium smegmatis. The first probable description of MAC came with the finding of “tuberculosis” in chickens (avian) that mimicked disease seen in humans, described in England in 1868. By 1890, it was recognized that this avian bacteria (now known as Mycobacterium avium) was distinct in the laboratory from the human variety of M. tuberculosis. Human disease due to MAC was not recognized until almost a half century later. In 1933, human-derived disease causing (pathogenic) strains were reported. Later studies revealed the organisms to be M. avium complex. In 1943, one of the first human cases of MAC was described when a mycobacterial species later identified as Mycobacterium avium was recovered from the sputum of a patient suffering from chronic lung disease with an associated underlying lung illness called silicosis (related to silica inhalation). By 1953 (10 years later), more cases of M. avium like organisms in humans were described by other investigators along with four cases that later were identified as M. intracellulare. At that time, these and other scientists thought that these organisms probably had little or no ability to cause disease (virulence) and that these strains were actually avian tubercle organisms that had lost their ability to cause disease in chickens.

M. intracellulare (the “Battey” bacilllus).

The confusion in the laboratory about the nature of these organisms was increased in 1949 with report of disease the authors thought was caused by a bacteria they called Nocardia intracellularis. (Later studies renamed this organism as M. intracellulare.) In an attempt to reduce the confusion of what was M. avium, one scientist proposed that the strains virulent (i.e., causing disease) for chickens and rabbits be called M. avium and those “avium-like” strains from humans without virulence for chickens and rabbits be called “Battey bacillus”, derived from the Battey State Hospital in Georgia which was one of the first institutions to recognize and treat patients with MAC lung disease. In light of this redefinition of these two species scientists began to work on laboratory testing that would aid in differentiating the two groups (i.e., M. avium and the “Battey bacillus”). The Battey bacillus strains were later renamed M. intracellulare.

The origin of MAC. Speculation was that M. intracellulare strains arose by mutation from M. avium as a result of being in a resistant host or in the environment for long periods of time. However, there was no scientific evidence to support this theory. Both M. avium and M. intracellulare were known to be present in soil and water, and one study demonstrated that M. avium strains remained viable (alive) and virulent in soil for at least 4 years. Subsequent studies have shown that M. avium and M. intracellulare are closely related but represent different species, and can be differentiated from each other in the laboratory only by genetic methods. Hence they are usually referred to as M. avium complex (MAC) or M. avium-intracellulare (MAI). Both species can cause lung disease in patients.

In 1963, clinical investigators pointed out that human disease caused by the so-called “Battey bacilli” looked almost exactly like disease seen with M. tuberculosis. This finding emphasized the need for culture identification to separate the two as tuberculosis due to M. tuberculosis is highly contagious between persons, requires patient isolation, and is a major public health issue while MAC is environmental, not contagious, and of little public health interest. Laboratories were generally still not able to differentiate the two groups of organisms and some scientists thought that these “strange mycobacteria” were host adapted variants of other known species (hence the early term “atypical” tuberculosis). Scientists also pointed out that there were disease causing and non-disease causing bacteria in the two groups.

Serotyping. MAC isolates vary in the lipid composition of their outer coat, and different samples of serum were able to cause some strains to clump together or agglutinate. This typing method for MAC was called “serotyping.” Early studies tried to relate virulence to “serotype” so that certain “serotypes” were virulent to chickens, other animals, and humans. This type of classification has generally become antiquated as molecular methods of typing or grouping MAC have replaced serological methods.

Most M. avium complex isolates were found to be resistant in the laboratory (in vitro) to the antituberculous drugs that were available during those early years. Classic studies showed that of the many single and multiple drug treatments available during the early years, only those containing isoniazid, rifampin, ethambutol, and streptomycin seemed to be effective.

Human (clinical) disease. By the 1970s, M. avium and M. intracellulare were considered the most common causes of chronic lung infection worldwide among all the species of NTM. However, at that time, the disease was thought to be more prevalent among men. In fact, a state of the art paper by one of the pioneers in mycobacteriology, Dr. Emanuel Wolinsky, described the average case of M. avium-intracellulare disease as “a 48 year old white man with long standing lung disease, such as chronic obstructive pulmonary disease (COPD) or silicosis who presents with a 3 month history of increasingly productive cough, night sweats, a low-grade fever, and moderate weight loss. The chest x-ray shows fibrosis and thin-walled cavity in the right upper lobe (RUL) and the sputum is positive for AFB on smear. Investigation reveals no family history or obvious source for tuberculosis” (Wolinsky, 1979). An additional statement was made later in the same paper “that cases do occur in women, younger men, and in middle-aged men without apparent lung disease or deficiency of cellular immunity” (Wolinsky, 1979). This was one of the first recognitions of the disease now known as nodular bronchiectasis seen predominantly in women.

Early reports of MAC cavitary lung disease also showed that there was a relationship between MAC and individuals with “dusty occupations” such as coal miners, sandblasters, welders, etc. For example, of 89 cases of pulmonary MAC in England and Wales, almost half occurred in patients with environmental exposure such as in the occupations listed above. Among 83 sandblasters with silicosis in the New Orleans area, 22 had complicated mycobacterial infections with three of those infections associated with MAC.

Lady Windermere’s syndrome. The second major form of MAC lung disease was described in the 1990s, more than 40 years after the description of upper lobe cavitary disease that mimicked tuberculosis. This second form of disease produced small round areas of lung infection called nodules, and occurred in patients (80% older non-smoking women) with underlying bronchiectasis. These findings (nodules and bronchiectasis) were only appreciated with the technical advancements brought by the use of computerized tomography (CT) scans of the lung. For lack of a better term, the phrase Lady Windermere’s syndrome was coined for this disease after the character in Oscar Wilde’s play. The disease is also referred to as “nodular” disease or “nodular bronchiectasis.”

Environmental Studies. In the 1970s, Australian scientists studied garden soils and were able to recover strains of MAC from 36 of 74 samples. Twenty-eight samples contained serotypes associated with human disease. The same scientists also studied 53 strains of MAC recovered from house dust in Australia and found that 12 serotypes of MAC found among the dust strains were also identified in 53% of the sputum isolates. Japanese scientists performed a similar study comparing strains from patients sputum to dust found in their rooms. They found that the strains associated with pulmonary disease usually were different from those of the environmental strains. Another study attempted to relate the infection of pigs and cattle with MAC. The scientists looked at the sputum and gastric specimens of healthy workers in a piggery during an outbreak of MAC disease in the pigs. They found that 8 of 11 workers had MAC unrelated to disease. In Japan, scientists did a similar study and found that infected pigs were not the source of the MAC that infected humans.

Geography. A study of more than 275,000 naval recruits who had lived their entire lives in a single county within one state was made using skin tests, one of which was derived from M. intracellulare(called PPD-B after the “Battey” bacillus). Published in 1979, this study showed most strong skin test reactors to PPD-B to live in the southeastern U.S. (None of these recruits was ill from their MAC.) Other studies described in the 1970s associated the majority of MAC lung disease with the southeastern United States. Other areas in the USA including Wisconsin, Texas, Ohio, Oklahoma, and Missouri also reported multiple cases of MAC. Outside the USA, western Australia, Japan, Germany, Norway, and Israel also reported multiple cases of MAC.

Summary. In summary, MAC consists of two species: M. avium and M. intracellulare, which have been recognized for more than 100 years. These two species exist and probably multiply in a wide variety of natural sources including soil, natural and piped water systems, domestic and wild animals, and birds. Some of the environmental strains are similar to those known to cause human disease and because person-to-person transmission has not been confirmed, it seems reasonable to conclude that humans may become infected from the environment. There is strong genetic evidence that strains of MAC from birds and animals are different from strains that cause disease in humans. Human disease in MAC has now been recognized for more than 50 years, although some forms of disease such as nodular bronchiectasis in older women has been recognized only within the past 10 years.
Special thanks to Dr. George Kubica who provided helpful discussions for this section and many of the references cited here.
More details concerning the history and epidemiology of MAC may be found in the following references.


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