Postgraduate Medicine

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Atypical Mycobacteria Richard E. Brashear & Lawrence M. Lampton To cite this article: Richard E. Brashear & Lawrence M. Lampton (1975) Atypical Mycobacteria, Postgraduate Medicine, 58:4, 117-121, DOI: 10.1080/00325481.1975.11714173 To link to this article: https://doi.org/10.1080/00325481.1975.11714173

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Atypical mycobacteria are generally innocuous but can cause pulmonary disease that is difficult to differentiate from tuberculosis except on culture. Men over age 40 seem to be particularly susceptible. Sorne organisms cause lymphadenitis in children. Treatment generally involves multiple-drug regi mens and possibly surgery.

Atypical or opportunistic mycobacteria are also called chromogens or anonymous or unclassified mycobacteria. These organisms are biologically distinct from Mycobacterium tuberculosis, M leprae, and M bovis but are structurally similar to the human (M tuberculosis) and bovine (M bovis) bacilli and also are strongly acid-fast. Atypical organisms cao be differentiated from human tubercle bacilli, saprophytic bacteria, and weakly acid-fast Actinomycetes species by differentiallaboratory testing. Enzyme and biochemical studies may be necessary for specifie identification, since various atypical organisms closely resemble each other and M tuberculosis. Less developed countries that do not have extensive laboratories often are not able to identify and characterize atypical organisms correctly. Thus, data on the occurrence and pathogenetic properties of atypical mycobacteria vary, depending in large part on the quantity and quality of microbiologie techniques and methodology available. Man probably cornes into daily contact with ali the divergent forms of atypical mycobacteria, but infections caused by these organisms did not emerge as a health problem until the era of tuberculosis chemotherapy. Sorne investigators feel that as the incidence of typical tuberculosis decreased, atypical mycobacteria began to appear. In countries where the incidence of typical tuberculosis is high, M tuberculosis and M bovis are thought to compete with atypical mycobacteria.1 Sorne authorities question this concept. There is also no substantial evidence that atypical organisms are mutants of typical human M tuberculosis. 2 The atypical organisms are readily recovered from the environment, mainly in soil and in

ln 1953 an organism isolated from two patients at autopsy was noted to produce a yellow pigment on culture.4 The pigment did not develop if the organism was not exposed to light. This was named the yellow bacillus and subsequently also named M kansasii. Later, Runyon 5 categorized the atypical organisms into four groups, as follows. Runyon group 1 were named photochromogens, consisting of M kansasii and M balnei (M balnei was originally M marinum, a skin

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Atypical Mycobacteria A FACTOR TO CONSIDER IN LUNG DISEASE RICHARD E. BRASHEAR, MD LAWRENCE M. LAMPTON, MD Indiana University School of Medicine Indianapolis

water, and milk bas been incriminated as a source.3 Although their virulence is low, these atypical organisms are increasingly being implicated as a source of disease in man. Epidemiologically, the greatest impact of the atypical organisms in the United States is in relation to the tuberculin test. The majority of tuberculin reactions are not caused by M tuberculosis but by latent infections with atypical mycobacteria.2 Classification

RICHARD E. BRASHEAR Dr. Brashear is professor of medicine, Indiana University School of Medicine, Indianapolis.

pathogen). They develop a yeilow, orange, or brick-red color while growing in the light, but little or no color while growing in the clark. Runyon group II were named scotochromogens. These organisms develop a yeilow-orange colony while growing in the clark. When they are exposed to light they develop more color. The main organism is M scrofulaceum. Runyon group III were cailed nonchromogens or nonphotochromogens. They have either no pigment or only faint yeilow or tan pigment, and the pigment is not influenced by light. The typical organism is M intracellulare, which is also referred to as the Battey baciilus. Runyon group IV organisms are the rapid growers, including predominantly M fortuitum but also M smegmatis and other saprophytes. Pigment production is varied. M fortuitum is a pathogen found in man that will develop colonies on culture by the 7th to 14th day of incubation.2·3

with granulomatous lung disease. Of these organisms, 12.8% were M kansasii (Runyon group 1) and 3.3% were M intracellulare (Battey baciilus, Runyon group III). One case involved M fortuitum (Runyon group IV). Pathologie or radiographie examination did not permit differentiation between typical and atypical organisms. Incidence rates may vary in different geographie areas. A five-year study9 in Kansas showed that in only 38.6% of 520 patients did cultures positive for mycobacteria grow typical human M tuberculosis. M kansasii was isolated from 12.3% (64 patients), while other atypical tuberculosis organisms were found in the remaining 49.1%. Only 31 of the 64 patients with M kansasii on culture were found to have lung disease due to this organism, while in the other 33 patients the organism was found to be a saprophyte. Clinical Criteria

Various tests differentiate the atypical organisms from human tubercle baciili. The niacin test is the most reliable and inexpensive for a clear-cut differentiation of M tuberculosis from ail other mycobacterial strains. 2 The typical tuberculosis organism is niacin-positive, but a few other mycobacteria also produce niacin. These cause no problem, however, since other basic tests can easily differentiate them from M tuberculosis. 6 ·; Atypical organisms are not unusual; in a study 8 at Veterans Administration Hospital, New Orleans, atypical organisms were found in 16.1 % of ail sputum specimens containing acid-fast organisms from a total of 328 patients

ln the majority of instances, mycobacteria other than human M tuberculosis isolated from sputum or gastric specimens seem to lack pathologie significance. Since atypical mycobacteria are widely distributed in nature, a single isolation from a gastric washing or from sputum does not necessarily indicate the presence of related disease. However, repeated and consistent isolation of an atypical organism should be considered significant. One set of criteria for the diagnosis of atypical mycobacterial disease consists of (1) isolation of atypical organisms from individuals with clinical or radiographie evidence of lung disease or both, (2) isolation of organisms on two or more occasions with the finding of multiple colonies per culture, and (3) no known isolation of typical M tuberculosis or other known pathogens. 10 A somewhat different set consists of ( 1) radiographie changes compatible with mycobacterial disease, with the absence of an alternative disease, (2) clinical evidence to suggest mycobacterial disease, (3) multiple isolations of the appropriate atypical mycobacteria, and (4) absence of typical M tuberculosis.U Clinicaily, atypical infections in the United States are more frequent in white males over age 40. Pulmonary and extrapulmonary lesions

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Differentiation and Prevalence

LAWRENCE M. LAMPTON

that are evident radiographicaily and the macroscopic and microscopie characteristics are the same as chose produced by typical tuberculosis. The only reliable way to differentiate atypical infection from typical tuberculosis is by isolating and identifying the organism in the laboratory.2 For pulmonary disease caused by Runyon group I mycobacteria (photochromogens), essentiaily M kansasii, the ratio of men to women is about 3: 1. Such pulmonary disease seems to occur only in adules, with most patients between ages 40 and 60. Middle-aged to elderly white males with emphysema and chronic bronchitis seem particularly susceptible. Lymphadenitis is seen in children; otherwise, extrapulmonary disease is rare. Symptoms are similar to those in tuberculosis-hemoptysis may occur but night sweats are uncommon. 3 · 9 Provided the dose of antigen is the same, the skin test reactions to PPD-S (M tuberculosis) and PPD-Y (M kansasii) may be equal. 2 Runyon group II mycobacteria (scotochromogens) usually involve lymph nodes and rarely produce pulmonary disease. The cervical nodes are usuaily involved unilateraily in young children; they may break clown and sinuses may form. Chest radiographs are normal. The portal of entry is probably the mouth. 3 Arnong Runyon group III mycobacteria (nonchromogens, Battey baciilus), M intracellulare pulmonary disease most commonly affects men living in the rural southeastern United States. The disease is often associated with emphysema and chronic bronchitis and has a predilection for persons in lower socioeconomic groups. Indolent and insidious in its development, the chronic disease produces persistent, productive cough, with weakness, shortness of breath, and weight loss as frequent complaints. Hemoptysis, chest pain, and fever may be noted. Cervical adenitis in young children is sometimes due co M intracellt~lare, and lymph node excision may give good results. 3 Runyon group IV mycobacteria (M fortuitttm) are widespread in nature and are frequently cultured from sputum specimens from healthy people as weil as from those recovering from pulmonary tuberculosis. M fortuitum may produce lung lesions as weil as lesions of bone or

Most atypical organisms are resistant to most of the primary antituberculosis drugs. The organisms almost always show in vitro resistance to streptomycin, isoniazid, and para-aminosalicyclic acid (PAS) and also to many second-line drugs. Sensitivity tests are a much less reliable guide for selection of therapy in atypical infections than in typical tuberculosis. Treatment of atypical infections must take into account the high incidence of therapeutic failure and the comparatively insignificant risk of direct spread of infection. Chemotherapy of atypical infections has been mainly empirical, and the regimens employed are diverse; current regimens are the result of graduai evolution. From 1962 to 1970 at National Jewish Hospital at Denver, 109 patients with atypical infections producing disease were treated. Ali 53 patients with Runyon group I (M kansasii) infection did weil on a variety of regimens. 13 The currently recommended regi-

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Dr. Lampton is assistant professer of medicine, Indiana University School of Medicine.

endocardium, but the latter are exceedingly rare. In one instance, this organism was cultured from the sputum of 56 patients with pulmonary disease. There was no clinical or radiographie evidence of disease progression whether or not patients were given antituberculosis drugs. It was concluded chat ( 1) the organism was innocuous and chat repeated isolations of M fortuitum did not warrant its incrimination as a cause of the disease and (2) prolonged chemotherapy with multiple drugs was not indicated in patients with sputum positive for M fortflitum, since chemotherapy did not alter the benign course and did not eradicate organisms from the sputum. 12 Therapy

men is isoniazid, rifampin, and streptomycin. The combination of ethambutol, ethionamide, and viomycin could be used for treatment failure.3 Untreated M kansasii infection is a slowly progressive disease. 14 In vitro drug susceptibility studies can show a degree of resistance for M kansasii that would suggest failure if the same drugs were to be used against typical human tubercle bacilli with the same degree of resistance. However, patients with M kansasii infection improve clinically despite results of in vitro drug resistance studies that would indicate the contrary. Runyon group II organisms have significant drug resistance, and drug therapy probably is not effective. Surgical removal of the lymph nades is indicated, followed by multiple-drug treatment.3 In Runyon group III (M intracellulare, Battey bacillus) infections, more drugs have gradually been added until the use of four to six drugs is currendy recommended. Drug programs have included four to six of the following drugs: isoniazid, rifampin, ethambutol, pyrazinamide, cycloserine, and capreomycin sulfate.3 One report15 described 45 patients with pulmonary disease from M intracellulare,- the most common associated disease was chronic obstructive lung disease. AU patients were given isoniazid, with many also receiving PAS, streptomycin, and other antituberculosis drugs. Adjunctive surgical treatment was used in 19 patients. At five years, the cumulative rate of relapse was 19.6% and 20% of the patients had died of active disease. ln earlier studies, treatment with isoniazid, PAS, and streptomycin showed a 25% to 50% success rate. This rate has been improved by using a four- to six-drug treatment program. 16 - 19 The general opinion is that a success rate of 70% to 90% can be achieved when multiple-drug treatment (usually five drugs) is combined with lung resection.11· 20 In infections with M intracellulare, use of multiple drugs is often beneficiai despite the organism's in vitro resistance to many drugs. Resection to remove localized lesions is desirable in Runyon group III disease when the extent of disease does not preclude surgery. The hazard of bronchopleural fistula and emphysema is less in patients with culture-positive

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Runyon group III disease than in those with culture-positive Runyon group 1 or M tuberculosis infection. If possible, resection should be postponed until chemotherapy has converted the cultures to negative; totallobectomy is preferable to segmentai resection or collapse therapy. Younger patients with Runyon group III infections whose sputum cultures are still positive after four to six months may particularly benefit from surgery. ln general, when the response to chemotherapy is not good, resection should be considered.3 Runyon group IV organisms in general show absolute resistance to all available drugs and chemotherapy is seldom successful. Subcutaneous abscesses are best treated by incision and drainage. 3 A recent review 21 of atypical mycobacterial disease in children found only 13 culture-proved cases of pulmonary involvement. The most frequent form of infection was involvement of superficial lymph nades with Runyon groups II and III. There was little evidence of mycobacterial disease elsewhere in the children with lymphadenitis. The treatment of choice was excision of diseased nades after a trial of chemotherapy. Skin Tests

There are separate skin tests for typical tuberculosis and for atypical organisms-PPD-S for M tuberculosis, PPD-Y for M kansasii (Runyon group 1), PPD-G for Gause strain of scotochromogen (Runyon group Il), PPD-B for M intracellulare (Battey bacillus, Runyon group III), PPD-A for avian tuberculosis (Runyon group III), and PPD-F for M fortuitum (Runyon group IV). These antigens, except PPD-S, are not readily available. ln one study,22 a skin test reaction to intermediate-strength PPD-S with induration of 5 mm or more was related to contact with tuberculosis and was noted in 11 % of those with no known contact, 20% of those with intermediate contact, and 41 % with close contact. When second-strength PPD-S was used, 34% of the persans who had not reacted to the intermediate-strength PPD-S skin test showed reactivity that was independent of the degree of contact with tuberculosis. The reactions to second-

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strength PPD-S were probably due to an infection with mycobacteria other than M tuberculosis. In the United States, most reactions to tuberculin tests are probably caused by mycobacteria other than the usual variety of human tubercle bacilli. There is no clear-cut difference in skin test reactions to PPD-Y (M kansasii) and PPD-S (M tuberculosis), since there is a close antigenic relationship between the two organisms. If the PPD atypical antigens (any or ali) produce reactions smaller than that for intermediate-strength PPD-S, it is unlikely that the reactions are caused by atypical organisms. If the reactions to PPD atypical antigens are significantly larger than' the reaction to intermediatestrength PPD-S, it is probable they are caused by atypical infection.

Conclusion

In essence, atypical mycobacteria are probably accidentai pathogens in man. Infection is probably transient in most individuals, and it is not clear why clinical disease develops in sorne individuals and not in others. Atypical disease is often associated with poor host defenses and is particularly likely to occur in the presence of bronchitis. With the exception of M kansasii, these atypical organisms are resistant to antituberculous agents. However, multiple-drug regimens are successful in sorne patients, and surgery probably bas a role in selected patients. Address reprint requests to Richard E. Brashear, MD, Department of Medicine, Indiana University Medical Center, 1100 W Michigan St, Indianapolis, IN 46202.

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