Clinical aspects of
atypical mycobacterial infection
L. M. Kahana,* md, m sc, frcp[c]; H. Richardson,! b sc, mb, bs, md, F. M. COLE,J MB, B CH, MD, MRC PATH Un malade age, souffrant de bronchite Summary: Atypical mycobacterial infections may give rise to various et d'infection pulmonaire causee clinical difficulties. Case reports of par M. kansasii, a ete traite avec six patients three adult patients with succes uniquement par des agents antituberculeux. Nous tentons actuellepulmonary lesions, two children with cervical lymphadenitis and one patient ment un essai de chimiotherapie chez in whom the atypical mycobacterium un cinquieme malade porteur d'une appeared to be present as a commensal cavite pathologique relevant de illustrate these difficulties. M. intracellulare, mais il est probable Determination of the significance of qu'il faudra finir par I'operer. .
.
the organism and differentiation of the condition from tuberculosis and others requires consideration of the clinical picture, the results of skin testing, histologic features and cultural characteristics. Three patients, including the two children, were treated with a combination of surgery and chemotherapy, with satisfactory results. An elderly patient with chronic bronchitis and a pulmonary infection due to M. kansasii was treated successfully with antituberculosis agents alone. Chemotherapy is being tried on a fifth patient with cavitary disease due to M. intracellulare, but is seems likely that an operation will also be required. Resume: Des aspects de I'infection mycobacterienne atypique Les infections mycobacteriennes atypiques peuvent occasionner divers problemes cliniques. Les rapports cliniques de six malades trois .
adultes presentant des lesions pulmonaires, deux enfants souffrant de lymphadenite cervicale et un malade chez lequel la mycobacterie atypique apparaissait comme un commensal illustrent bien ces difficultes. Pour determiner le rdle joue par I'organisme en cause et pour differentier entre la tuberculose et d'autres maladies infectieuses, il faut considerer le tableau clinique, les resultats des tests cutanes, les traits histologiques et les caracteristiques de la culture. Trois malades, dont deux enfants, ont ete traites par une combinaison de la chirurgie et la chimiotherapie, avec des resultats satisfaisants. .
From McMaster University, Hamilton * Assistant professor of medicine, McMaster University and physician in charge, Hamilton region, tuberculosis prevention service, Ontario Ministry of Health fAssociate professor of pathology, McMaster University and director of medical microbiology, McMaster University Medical Centre and Chedoke Hospitals ^Associate professor of pathology, McMaster University and pathologist, St. Joseph's Hospital Reprint requests to: Dr. L. M. Kahana, Provincial Chest Clinic, 74 Hughson St. S, Hamilton, Ont. L8N 2A8
The decline in incidence of tuberculosis has been associated with increasing in¬ terest in mycobacteria other than the mammalian tubercle bacillus (and the leprosy bacillus). These atypical (or
anonymous) mycobacteria present a challenge to the bacteriologist in terms
of classification and identification, and create difficulties for the clinician. Some of the more important organisms are classified in Table I.1,2 For the clinician there are various problems. The physician may have to decide whether a low degree of sensi¬ tivity to tuberculin represents tuber¬ culosis or atypical infection. This is usually simply solved by differential skin testing, tuberculin and one of the atypical antigens being administered to¬ gether; a larger reaction to the latter (difference ^ 5 mm) suggests an aty¬ pical infection.3 Other problems are interpreting the finding of these or¬ ganisms in a sputum culture, recognizing disease due to atypical mycobac¬ teria and treating such conditions. These problems are illustrated by case Table I.Classification* of atypical
mycobacteria Group I. Photochromogens II. Scotochromogens III. Non photochromogens
IV.
Rapid growers
Species M. kansasii M. marinum M. scrofulaceum M. gordonae M.flavescens M. intracellulare M. avium M. xenopi M.fortuitum M. chelonei
?Runyon1
frcp[c]; reports of six patients seen at the Ha¬ milton Provincial Chest Clinic and the St. Joseph's, Hamilton General, Hen¬ derson General and Chedoke hospitals in Hamilton. Skin testing was performed with 5 tuberculin units (TU) of PPD-CT68, a Tween-stabilized tuberculin (Connaught Medical Research Laboratories), and equal strengths of atypical antigens, also Tween-stabilized (Connaught). The atypical antigens were PPD-K (derived from Mycobacterium kansasii), PPDG (from the Gause strain of M. scro¬ fulaceum), PPD-B (from M. intracel¬ lulare) and PPD-F (from M. fortuitum). Testing was performed simulta¬ neously with these antigens, and the transverse diameter (mm) of induration was measured at 48 or 72 hours. Case reports Case 1
A 72-year-old woman without a history of tuberculosis was first seen in 1964 be¬ cause of radiographic signs of inactive pulmonary tuberculosis. She was observed regularly. On reinvestigation in October 1973 she was asymptomatic except for arthritic pains, and results of physical examination were normal. Chest radiography showed patchy nodu¬ lar disease at the right apex, with a calcified primary complex in the right lung. There was minimal left apical disease, un¬ changed since 1964. Results of skin testing with 5 TU of PPD-CT68 were negative. Two of a series of sputum samples induced with heated hypertonic saline were posi¬ tive on smear for acid-fast bacilli. Repeat skin testing with tuberculin and the atypi¬ cal antigens (Table II) was negative except for a small reaction to PPD-B. Treatment with isoniazid, ethambutol and streptomycin was started. By De¬ cember 1973 the two smear-positive speci¬ mens had failed to grow. Culture of one other specimen grew a mycobacterial species, later identified as M. intracellu¬ lare, resistant to all agents except cycloserine; although this organism is po¬ tentially pathogenic, it was considered to be a commensal in an individual with inactive tuberculosis. Chemotherapy was stopped. Follow-up chest radiography
Table II.Cultural identification and results of skin tests Case no. Skin test antigen and induration diameter (mm) Organism PPD-CT68 PPD-K PPD-G PPD-B PPD-F M. intracellulare M. kansasii 15 ND Group III sp. M. intracellulare ND Unclassified No growth 10 negative reaction; ND not done =
=
CMA JOURNAL/FEBRUARY 8, 1975/VOL. 112 321
showed no change, and results of sputum testing remained negative for mycobac¬
teria.
Case 2 A 65-year-old
man
who had been
a
heavy smoker, with a long history of chronic cough and exertional dyspnea, was first seen in September 1972. Over the preceding 3 weeks he had complained of increased cough with scanty mucoid sputum, chills, night sweats and weight loss of almost 7 kg. Cyanosis, clubbing of the fingers, limited chest expansion and diminished breath sounds were noted. Chest radiography showed a patchy infiltrate in the right upper lobe. A tuber¬ culin skin test gave a negative result. Several sputum specimens were positive on smear, and later on culture, for acidfast bacilli (M. kansasii) that were sensi¬ tive only to rifampin, cycloserine and ethionamide. Results of further skin test¬ ing for tuberculin and the atypical anti¬ gens
were
again negative (Table II).
Serial radiographs revealed progressive atelectasis in the right upper lobe but bronchoscopy revealed no abnormalities. Treatment with rifampin and ethambutol, with ethionamide at first and later cy¬ closerine, was followed by conversion of results of sputum testing to negative, but collapse of the right upper lobe persisted. Case 3 A 32-year-old steel worker, a heavy smoker, was seen in September 1973 be¬ cause of a radiographically visible cavitary lesion. Fatigue and left axillary pain dated from December 1972; brief attacks of tachycardia and shortness of breath were other symptoms. Physical findings were normal. The chest radiograph and tomograms showed an oval nodule with central rarefaction at the apex of the right lung. Results of skin testing on two occasions with PPD-CT68 were negative, as were results of testing with histoplasmin; there was, however, a 15-mm response to PPDK and a smaller reaction to PPD-B (Table II). Four induced sputums were negative on smear, and later on culture, for acidfast organisms. Bronchoscopy revealed no abnormali¬ ties. In November 1973 the apical segment of the right upper lobe was resected; treat¬ ment then consisted of rifampin, etham¬ butol and streptomycin. A caseous cystic nodule showed the classic microscopic features of tuberculosis (Fig. 1). ZiehlNeelsen staining of the tissue showed large numbers of a short, stubby, acid-fast bacil¬ lus. This was identified as a member of RunyonV group III (Table I) but there were some anomalous features, particu¬ larly sensitivity of the organism to various primary and secondary drugs, including
September
1973 because of an abnormal survey chest radiograph. He had no symp¬ toms but had had diabetes for 10 years; despite treatment with 36 units of pro-
tamine zinc insulin daily the diabetes was frequently out of control. He had had pleurisy with effusion at the age of 11 years and a duodenal ulcer, treated medically, in 1966. Physical examination re¬ vealed no abnormalities. The chest radiograph showed two small cavities in the left upper lobe. Skin testing with 5 TU of PPD-CT68 gave a 13-mm reaction. Three of five sputum specimens were positive on smear for acid-fast ba¬ cilli; one contained numerous organisms. Treatment with isoniazid, ethambutol
and streptomycin was promptly started. Tuberculin skin testing of his wife and children gave negative results. Sputum cul¬ tures grew M. intracellulare, resistant to all agents except cycloserine and ethion¬ amide. Chemotherapy was changed to isoniazid, ethambutol and rifampin. His sputum has been negative since No¬ vember 1973, although little radiographic change is evident. Subsequent skin testing was negative for tuberculin, PPD-K and PPD-F, but positive for PPD-G and PPDB (Table II).
Case 5 A 4-year-old boy was seen in January 1973 because of an enlarged cervical lymph node and a questionably positive tuberculin test. He had been well until 3 weeks before, when a discharge from the left eye developed; a swelling on the left side of the neck was noted 10 days later. The conjunctiva of the left eye was red and secretion was observed. The preauricular node was not palpable but there was an enlarged node (diameter, 2 cm) below the angle of the left mandible. Skin testing gave a 15-mm reaction to PPD-G, a small response to PPD-B and negative reactions to the other antigens, including
tuberculin (Table II). The chest radiograph was normal. Cloxacillin therapy (started by his pe¬ diatrician) was continued. After 10 days there was discolouration of the skin over¬ lying the left submandibular node and a smaller node was palpable on the right side. In hospital, results of testing with a "monospot" test for infectious mononucleosis, a Sabin-Feldman dye test for toxoplasmosis, and a cat-scratch skin test were all negative. An ophthalmologist ex¬ pressed purulent material from the nasolacrimal duct, which appeared to be blocked. The left submandibular node was ex¬ cised; its basic architecture was replaced by granulomas with a dimorphous his¬ tologic appearance (Fig. 2), and minimal necrosis, but collections of polymorphonuclears surrounded by epithelioid cells, and both Langhans' and foreign-body giant cells were seen. Culture of the node re¬ vealed a slowly growing organism, coloured pale yellow in the dark, that was resistant to all agents. Dr. Ernest Runyon (at the tuberculosis research unit of the South African Medical Research Council) believed that it did not conform exactly to any group II or III species but had characteristics similar to those of M. scro-
fulaceum.
The child was then treated with isonia¬ zid and ethambutol (dosage of both, 15 mg/kg daily). Despite the resistance of the organism, the response was satisfac¬ tory. The discharge from the eye stopped, the incisional site healed and the right submandibular node decreased in size. Tonsillectomy was performed after 6 months, while the child was still receiving
chemotherapeutic agents; pathologie ex¬ only reactive hyperplasia. v amination revealed
Case 6
A
4-year-old girl had
a
history of
streptomycin, rifampin, cycloserine and
ethionamide.
Chemotherapy has been maintained. His subsequent course has been uneventful. Further skin testing has given negative responses to tuberculin and all of the atypical antigens. Case 4 A 41-year-old
man was
first
seen
in
r
.iliJt
FIG. 1.Case 3. Tuberculous granulation tissue in lung. Lymphocytes, cells and giant cell on left; caseous tissue on right (xl80).
322 CMA JOURNAL/FEBRUARY 8, 1975/VOL. 112
epithelioid
a
lump
on
the right side of the neck for Discussion
lump had suddenly in¬ creased in size after a fail a few days before admission, and fever had been noted. Two discrete nodes were detected at the angle of the right mandible. The erythrocyte sedimentation rate was 50 mm/hr and the leukocyte count was 12000/mm3 with 47% neutrophils, 31% lymphocytes, 6% monocytes, 6% eosinophils and 10% bands. The tuberculin skin test result was reported as positive and that of the cat-scratch skin test negative. The chest radiograph was normal. She was discharged on isoniazid, 10 mg/kg daily, and referred to the chest clinic. A large confluent mass of nodes was found in the right submandibular region. Differential skin testing resulted in a 254 to 5 weeks. The
mm response to PPD-B, a 20-mm reaction to PPD-G and smaller responses to the other antigens; reaction to PPD-F was
negative (Table II). The dosage of isonia¬ zid was increased to 15 mg/kg daily and ethambutol in the same dosage was added. Two weeks later the nodes were fluctuant and the overlying skin was reddened. The area was explored surgically approximately 1 month after initiation of chemotherapy. The nodes revealed extensive granulomatous inflammation with necrosis and neutrophil collections surrounded by epi¬ thelioid cells and giant cells (Fig. 3). No organisms were seen on Ziehl-Neelsen staining, and culture proved negative. Chemotherapy was maintained after operation and healing was satisfactory.
FIG. 2.Case 5. Dimorphous appearance of lymph node tissue. Giant cell in centre is
(x250).
adjacent to polymorphonuclears
Atypical mycobacteria are frequently
found in sputum and other specimens and form a significant proportion of all mycobacterial isolates. Thus, for 1973, of 321 positive mycobacterial cultures reported by the regional mycobacteriology laboratory at Chedoke Hospital 72 (22.4%) were identified as atypical organisms. Most often these are nonpathogenic and their identity and lack of significance are readily ap¬
parent; occasionally they present
not
inconsiderable problems in both diag¬ nosis and management. The range of difficulties is indicated in the present case
reports.
The clinician has not only to de¬ termine whether the organism is pro¬ ducing disease but also to distinguish the condition from tuberculosis and other diseases. This may require con¬ sideration of the clinical picture, the response to differential skin testing, histologic features and the results of
bacteriologic study.
Manifestations of atypical mycobac¬ terial infection may include cutaneous or skeletal lesions, and disseminated disease has been reported.4"6 More usual, however, is either a pulmonary infiltrate resembling tuberculosis or cervical adenitis. In the case of a lung lesion
the clinical picture is of limited dif¬ ferential value. There may be a back¬ ground of pre-existing pulmonary dis¬ ease such as chronic bronchitis (as in case 2), bronchiectasis or pneumoconiosis.7 A lack of symptoms, particularly in cases of cavitary disease (as in cases 3 and 4), may be of some significance. Finally, the radiologic picture may be unusual, as Chapman and Corpe8 have noted; the complete atelectasis seen in case 2 is perhaps an example of this. In contrast, atypical cervical adenitis is a more distinctive clinical entity.9 It occurs in the pre-school-age child, but is rare in those less than 1 year of age. The affected nodes are usually located in the submandibular region, whereas in tuberculosis the nodes at the base of the neck are more likely to be involved. This difference reflects the location of the primary focus, which is generally in the lung in cases of tuberculosis, but is probably in the tonsil or mouth in cases of atypical infection. Eating of dirt has been suggested as a cause.10 An additional point of difference from tuberculosis is a greater tendency fois atypical nodes to break down. Finally, in atypical cervical adenitis there is no family source of tuberculosis and the chest radiograph is normal. Most of these features characterized cases 5 and 6, with lymphadenitis.
FIG. 3.Case 6. Intermingling of granulomatous and pyogenic components in lymph node tissue. Centrally there is a polymorphonuclear collection, and below and to left a Langhans' cell (xlOO). CMA JOURNAL/FEBRUARY 8, 1975/VOL. 112 323
Skin testing with tuberculin and antigens derived from the atypical organisms can be of .considerable diagnostic assistance, for it is possible to distinguish atypical and tuberculous infection. The skin reaction may also facilitate making a decision about the significance of a culture reported to be positive for one of the atypical organisms; a negative skin test may indicate that the organism is only incidentally present.11 However, as these case reports indicate, there are limitations to the usefulness of skin tests. The aged person with tuberculosis is not infrequently tuberculin-negative,12 and, judging by case 2, the same would appear to be true of patients with atypical infection. A disappointing lack of precision to the skin tests was also evident and it was not possible to use the test results to pinpoint the particular atypical group or species. The explanation of this is the fact that the atypical antigens used are but a few of the representatives of a larger group. Antigens to the atypical organism in an individual case may not be included, but, because of cross-reactivity, a positive skin test to another antigen is recorded.3 Strong antigens will increase the tendency to cross-reactions, and it is known that the Tween-stabilized skin testing materials used in this study, PPD-CT68 and the atypical antigens, are at least twice the strength of unstabilized PPD-S, the international standard.13 When bioequivalent antigens become available skin testing may yield greater accuracy. Reid and Wolinsky,14 reviewing the histopathologic findings in atypical disease in lymph nodes, noted that a picture entirely characteristic of tuberculosis was the most frequent finding. Not infrequent, however, was a dimorphous pattern in which a central suppurative zone containing polymorphonuclears was surrounded by a granulomatous reaction, with histiocytes, epithelioid cells and giant cells, but no caseation. In both our cases of lymphadenitis a similar picture was seen, although, as Reid and Wolinsky
have emphasized, it is not a particularly specific one and can occur in catscratch disease and in tuberculosis. The increased tendency of nodes to break down and discharge may be due to the pyogenic element. The gross and microscopic features of pulmonary lesions are, on the other hand, similar in most respects to those of tuberculosis.15 This was the case in the only patient with pulmonary infection in this group from whom a tissue specimen was obtained. A presumptive diagnosis of atypical infection can be made on the basis of clinical features, the results of skin testing and the pathologic picture, as in case 6. Generally, however, bacteriologic identification is essential and this requires the use of various tests.2 Growth rate and pigment production are the basis of the Runyon classification.1 The niacin test is of particular importance since M. tuberculosis is niacin-positive but atypical mycobacteria are niacin-negative. (M. bovis is also niacin-negative but it is a rare organism at present.) Sensitivity testing may also be helpful in that the discovery of primary resistance to multiple agents should suggest an atypical organism. Although it is evident from cases 3 and 5 that it may not be possible to classify precisely all strains, species identification can be helpful in determining whether an organism is of clinical significance. Thus, although some species such as M. kansasii are commonly pathogens, others such as M. gordonae are always saprophytes and can be ignored. The circumstances of isolation are perhaps of equal importance, and the discovery of an organism in tissue, for example, means more than does its finding in sputum or urine. More attention should be paid to repeat cultures of an atypical mycobacterium than to a single positive specimen, even when this is a pathogen.'1 For atypical mycobacterioses it may be possible to select a regimen of chemotherapy to which the organisms are sensitive and which produces a success-
ful result. This is more likely to be the case in infections with M. kansasii, particularly since the introduction of rifampin.16 More frequent is either resistance to most of the drugs or limitation of choice to more toxic agents. There may be a discrepancy between the results of sensitivity testing and the clinical response, and this is more characteristic of atypical infections than of tuberculosis.17 Nevertheless, the most effective approach to treatment appears to be a combination of surgery and chemotherapy.18 When an operation is impossible and when there is multiple resistance, as is frequently the case in M. intracellulare infections, the use of four or five drugs has been suggested.17 However, the risk of toxicity, the lowgrade nature of the illness and the lack of infectiousness may lead one to manage these patients without specific therapy. We wish to thank Dr. N. L. Jones for his helpful comments, Drs. E. G. Beatty and J. T. Groves for preparing the photomicrographs, and Mrs. Jeanette Long for typing the manuscript. References 1. RUNYON EH: Anonymous mycobacteria in pulmonary disease. Med Clin North Am 43: 273, 1959 2. KUBICA GP: Differential identification of mycobacteria. VII. Key features for identitication of clinically significant mycobac-
teria. Am Rev Resp Dis 107: 9, 1973 3. EDWARDS PQ: Interpretation and significance of the tuberculin test in typical and atypical mycobacterial infections, in Rational Therapy and Control oj Tuberculosis, edited by JOHNSON JE in, Gainesville FL, U of Ela Pr, 1970, p 43 4. MULLOHAN GS, ROMEIt MS: Public health significance of swimming pool gsd'nuloma. Am J Public Health 51: 883, 1961 5. LINCOLN EM, GILBERT LA: Disease in children due to mycobacteria other than Mycobacterium tuberculosis. Am Rev Resp Dis 105: 683, 1972 6. SArro H, TASAKA H, SHosHABuRo 0, et al: Disseminated Mycobacterium intracellulare infection. Am Rev Resp Dis 109: 572, 1974 7. B.ms JH: A study of pulmonary disease associated with mycobacteria other than Mycobacterium tuberculosis: clinical characteris-
8. 9. 10. 11.
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ON THE
ANNUAL MEETING IN CALGARY IN THE NEXT ISSUE OF CMAJ 324 CMA JOURNAL/FEBRUARY 8, 1975/VOL. 112
tics. XX. A report of the Veterans Administration-Armed Forces cooperative study on tbe chemotherapy of tuberculosis. Am Rev Resp Dis 96: 1151, 1967 CHAPMAN JS, Coiu'a RF: Infection caused by "unclassified" mycobacteria, in Clinical Tuberculosis, edited by PFUETZE KH, RADNER DB, Springfield IL, CC Thomas, 1966, p 359 BLACK BG, CHAPMAN JS: Cervical adenitis in children due to human and unclassified mycobacteria. Pediatrics 331: 887, 1964 Hsu KHK: Nontuberculous mycobacterial inIection in children. A preliminary clinical and epidemiologic study. J Pediatrics 60: 705, 1962 MARKS J: The opportunist mycobacteria, in
Recent Advances in Respiratory Tuberculosis,
edited by HEAF F, Ruse. NL, sixth ed, London, Churchill, 1968, p 205 12. WOODRUFF CE, CHAPMAN PT: Tuberculin sensitivity in elderly patients. Am Rev Resp Dis 104: 261, 1971 13. LAND! 5, HELD HR, TsENO MC: Disparity of potency between stabilized and nonstabilized dilute tuberculin solutions. Ibid, p 385
14. RaID JD, WOLINsEY E: Histopathology of lymphadenitis caused by atypical mycobactens. Am Rev Resp Dis 99: 8, 1969 15. CHAPMAN JS: Atypical mycobacterial infection, in Rational Therapy and Control of Tuberculosis, op cit 16. RYNEARsON TK, SHRONTS JS, WOLINSKY E: Rifampin: in vitro effect on atypical mycobacteria. Am Rev Resp Dis 104: 272, 1971 17. FIsCHER DA, SCHAEFER WB, LESTER W: Infections with atypical mycobacteria. Five years' experience at the National Jewish Hospital. Am Rev Resp Dis 98: 29, 1968 18. GOLDMAN KP: Treatment of unclassified mycobacterial infection of the lungs. Thorax 23: 94, 1968
atypical mycobacterial infection
L. M. Kahana,* md, m sc, frcp[c]; H. Richardson,! b sc, mb, bs, md, F. M. COLE,J MB, B CH, MD, MRC PATH Un malade age, souffrant de bronchite Summary: Atypical mycobacterial infections may give rise to various et d'infection pulmonaire causee clinical difficulties. Case reports of par M. kansasii, a ete traite avec six patients three adult patients with succes uniquement par des agents antituberculeux. Nous tentons actuellepulmonary lesions, two children with cervical lymphadenitis and one patient ment un essai de chimiotherapie chez in whom the atypical mycobacterium un cinquieme malade porteur d'une appeared to be present as a commensal cavite pathologique relevant de illustrate these difficulties. M. intracellulare, mais il est probable Determination of the significance of qu'il faudra finir par I'operer. .
.
the organism and differentiation of the condition from tuberculosis and others requires consideration of the clinical picture, the results of skin testing, histologic features and cultural characteristics. Three patients, including the two children, were treated with a combination of surgery and chemotherapy, with satisfactory results. An elderly patient with chronic bronchitis and a pulmonary infection due to M. kansasii was treated successfully with antituberculosis agents alone. Chemotherapy is being tried on a fifth patient with cavitary disease due to M. intracellulare, but is seems likely that an operation will also be required. Resume: Des aspects de I'infection mycobacterienne atypique Les infections mycobacteriennes atypiques peuvent occasionner divers problemes cliniques. Les rapports cliniques de six malades trois .
adultes presentant des lesions pulmonaires, deux enfants souffrant de lymphadenite cervicale et un malade chez lequel la mycobacterie atypique apparaissait comme un commensal illustrent bien ces difficultes. Pour determiner le rdle joue par I'organisme en cause et pour differentier entre la tuberculose et d'autres maladies infectieuses, il faut considerer le tableau clinique, les resultats des tests cutanes, les traits histologiques et les caracteristiques de la culture. Trois malades, dont deux enfants, ont ete traites par une combinaison de la chirurgie et la chimiotherapie, avec des resultats satisfaisants. .
From McMaster University, Hamilton * Assistant professor of medicine, McMaster University and physician in charge, Hamilton region, tuberculosis prevention service, Ontario Ministry of Health fAssociate professor of pathology, McMaster University and director of medical microbiology, McMaster University Medical Centre and Chedoke Hospitals ^Associate professor of pathology, McMaster University and pathologist, St. Joseph's Hospital Reprint requests to: Dr. L. M. Kahana, Provincial Chest Clinic, 74 Hughson St. S, Hamilton, Ont. L8N 2A8
The decline in incidence of tuberculosis has been associated with increasing in¬ terest in mycobacteria other than the mammalian tubercle bacillus (and the leprosy bacillus). These atypical (or
anonymous) mycobacteria present a challenge to the bacteriologist in terms
of classification and identification, and create difficulties for the clinician. Some of the more important organisms are classified in Table I.1,2 For the clinician there are various problems. The physician may have to decide whether a low degree of sensi¬ tivity to tuberculin represents tuber¬ culosis or atypical infection. This is usually simply solved by differential skin testing, tuberculin and one of the atypical antigens being administered to¬ gether; a larger reaction to the latter (difference ^ 5 mm) suggests an aty¬ pical infection.3 Other problems are interpreting the finding of these or¬ ganisms in a sputum culture, recognizing disease due to atypical mycobac¬ teria and treating such conditions. These problems are illustrated by case Table I.Classification* of atypical
mycobacteria Group I. Photochromogens II. Scotochromogens III. Non photochromogens
IV.
Rapid growers
Species M. kansasii M. marinum M. scrofulaceum M. gordonae M.flavescens M. intracellulare M. avium M. xenopi M.fortuitum M. chelonei
?Runyon1
frcp[c]; reports of six patients seen at the Ha¬ milton Provincial Chest Clinic and the St. Joseph's, Hamilton General, Hen¬ derson General and Chedoke hospitals in Hamilton. Skin testing was performed with 5 tuberculin units (TU) of PPD-CT68, a Tween-stabilized tuberculin (Connaught Medical Research Laboratories), and equal strengths of atypical antigens, also Tween-stabilized (Connaught). The atypical antigens were PPD-K (derived from Mycobacterium kansasii), PPDG (from the Gause strain of M. scro¬ fulaceum), PPD-B (from M. intracel¬ lulare) and PPD-F (from M. fortuitum). Testing was performed simulta¬ neously with these antigens, and the transverse diameter (mm) of induration was measured at 48 or 72 hours. Case reports Case 1
A 72-year-old woman without a history of tuberculosis was first seen in 1964 be¬ cause of radiographic signs of inactive pulmonary tuberculosis. She was observed regularly. On reinvestigation in October 1973 she was asymptomatic except for arthritic pains, and results of physical examination were normal. Chest radiography showed patchy nodu¬ lar disease at the right apex, with a calcified primary complex in the right lung. There was minimal left apical disease, un¬ changed since 1964. Results of skin testing with 5 TU of PPD-CT68 were negative. Two of a series of sputum samples induced with heated hypertonic saline were posi¬ tive on smear for acid-fast bacilli. Repeat skin testing with tuberculin and the atypi¬ cal antigens (Table II) was negative except for a small reaction to PPD-B. Treatment with isoniazid, ethambutol and streptomycin was started. By De¬ cember 1973 the two smear-positive speci¬ mens had failed to grow. Culture of one other specimen grew a mycobacterial species, later identified as M. intracellu¬ lare, resistant to all agents except cycloserine; although this organism is po¬ tentially pathogenic, it was considered to be a commensal in an individual with inactive tuberculosis. Chemotherapy was stopped. Follow-up chest radiography
Table II.Cultural identification and results of skin tests Case no. Skin test antigen and induration diameter (mm) Organism PPD-CT68 PPD-K PPD-G PPD-B PPD-F M. intracellulare M. kansasii 15 ND Group III sp. M. intracellulare ND Unclassified No growth 10 negative reaction; ND not done =
=
CMA JOURNAL/FEBRUARY 8, 1975/VOL. 112 321
showed no change, and results of sputum testing remained negative for mycobac¬
teria.
Case 2 A 65-year-old
man
who had been
a
heavy smoker, with a long history of chronic cough and exertional dyspnea, was first seen in September 1972. Over the preceding 3 weeks he had complained of increased cough with scanty mucoid sputum, chills, night sweats and weight loss of almost 7 kg. Cyanosis, clubbing of the fingers, limited chest expansion and diminished breath sounds were noted. Chest radiography showed a patchy infiltrate in the right upper lobe. A tuber¬ culin skin test gave a negative result. Several sputum specimens were positive on smear, and later on culture, for acidfast bacilli (M. kansasii) that were sensi¬ tive only to rifampin, cycloserine and ethionamide. Results of further skin test¬ ing for tuberculin and the atypical anti¬ gens
were
again negative (Table II).
Serial radiographs revealed progressive atelectasis in the right upper lobe but bronchoscopy revealed no abnormalities. Treatment with rifampin and ethambutol, with ethionamide at first and later cy¬ closerine, was followed by conversion of results of sputum testing to negative, but collapse of the right upper lobe persisted. Case 3 A 32-year-old steel worker, a heavy smoker, was seen in September 1973 be¬ cause of a radiographically visible cavitary lesion. Fatigue and left axillary pain dated from December 1972; brief attacks of tachycardia and shortness of breath were other symptoms. Physical findings were normal. The chest radiograph and tomograms showed an oval nodule with central rarefaction at the apex of the right lung. Results of skin testing on two occasions with PPD-CT68 were negative, as were results of testing with histoplasmin; there was, however, a 15-mm response to PPDK and a smaller reaction to PPD-B (Table II). Four induced sputums were negative on smear, and later on culture, for acidfast organisms. Bronchoscopy revealed no abnormali¬ ties. In November 1973 the apical segment of the right upper lobe was resected; treat¬ ment then consisted of rifampin, etham¬ butol and streptomycin. A caseous cystic nodule showed the classic microscopic features of tuberculosis (Fig. 1). ZiehlNeelsen staining of the tissue showed large numbers of a short, stubby, acid-fast bacil¬ lus. This was identified as a member of RunyonV group III (Table I) but there were some anomalous features, particu¬ larly sensitivity of the organism to various primary and secondary drugs, including
September
1973 because of an abnormal survey chest radiograph. He had no symp¬ toms but had had diabetes for 10 years; despite treatment with 36 units of pro-
tamine zinc insulin daily the diabetes was frequently out of control. He had had pleurisy with effusion at the age of 11 years and a duodenal ulcer, treated medically, in 1966. Physical examination re¬ vealed no abnormalities. The chest radiograph showed two small cavities in the left upper lobe. Skin testing with 5 TU of PPD-CT68 gave a 13-mm reaction. Three of five sputum specimens were positive on smear for acid-fast ba¬ cilli; one contained numerous organisms. Treatment with isoniazid, ethambutol
and streptomycin was promptly started. Tuberculin skin testing of his wife and children gave negative results. Sputum cul¬ tures grew M. intracellulare, resistant to all agents except cycloserine and ethion¬ amide. Chemotherapy was changed to isoniazid, ethambutol and rifampin. His sputum has been negative since No¬ vember 1973, although little radiographic change is evident. Subsequent skin testing was negative for tuberculin, PPD-K and PPD-F, but positive for PPD-G and PPDB (Table II).
Case 5 A 4-year-old boy was seen in January 1973 because of an enlarged cervical lymph node and a questionably positive tuberculin test. He had been well until 3 weeks before, when a discharge from the left eye developed; a swelling on the left side of the neck was noted 10 days later. The conjunctiva of the left eye was red and secretion was observed. The preauricular node was not palpable but there was an enlarged node (diameter, 2 cm) below the angle of the left mandible. Skin testing gave a 15-mm reaction to PPD-G, a small response to PPD-B and negative reactions to the other antigens, including
tuberculin (Table II). The chest radiograph was normal. Cloxacillin therapy (started by his pe¬ diatrician) was continued. After 10 days there was discolouration of the skin over¬ lying the left submandibular node and a smaller node was palpable on the right side. In hospital, results of testing with a "monospot" test for infectious mononucleosis, a Sabin-Feldman dye test for toxoplasmosis, and a cat-scratch skin test were all negative. An ophthalmologist ex¬ pressed purulent material from the nasolacrimal duct, which appeared to be blocked. The left submandibular node was ex¬ cised; its basic architecture was replaced by granulomas with a dimorphous his¬ tologic appearance (Fig. 2), and minimal necrosis, but collections of polymorphonuclears surrounded by epithelioid cells, and both Langhans' and foreign-body giant cells were seen. Culture of the node re¬ vealed a slowly growing organism, coloured pale yellow in the dark, that was resistant to all agents. Dr. Ernest Runyon (at the tuberculosis research unit of the South African Medical Research Council) believed that it did not conform exactly to any group II or III species but had characteristics similar to those of M. scro-
fulaceum.
The child was then treated with isonia¬ zid and ethambutol (dosage of both, 15 mg/kg daily). Despite the resistance of the organism, the response was satisfac¬ tory. The discharge from the eye stopped, the incisional site healed and the right submandibular node decreased in size. Tonsillectomy was performed after 6 months, while the child was still receiving
chemotherapeutic agents; pathologie ex¬ only reactive hyperplasia. v amination revealed
Case 6
A
4-year-old girl had
a
history of
streptomycin, rifampin, cycloserine and
ethionamide.
Chemotherapy has been maintained. His subsequent course has been uneventful. Further skin testing has given negative responses to tuberculin and all of the atypical antigens. Case 4 A 41-year-old
man was
first
seen
in
r
.iliJt
FIG. 1.Case 3. Tuberculous granulation tissue in lung. Lymphocytes, cells and giant cell on left; caseous tissue on right (xl80).
322 CMA JOURNAL/FEBRUARY 8, 1975/VOL. 112
epithelioid
a
lump
on
the right side of the neck for Discussion
lump had suddenly in¬ creased in size after a fail a few days before admission, and fever had been noted. Two discrete nodes were detected at the angle of the right mandible. The erythrocyte sedimentation rate was 50 mm/hr and the leukocyte count was 12000/mm3 with 47% neutrophils, 31% lymphocytes, 6% monocytes, 6% eosinophils and 10% bands. The tuberculin skin test result was reported as positive and that of the cat-scratch skin test negative. The chest radiograph was normal. She was discharged on isoniazid, 10 mg/kg daily, and referred to the chest clinic. A large confluent mass of nodes was found in the right submandibular region. Differential skin testing resulted in a 254 to 5 weeks. The
mm response to PPD-B, a 20-mm reaction to PPD-G and smaller responses to the other antigens; reaction to PPD-F was
negative (Table II). The dosage of isonia¬ zid was increased to 15 mg/kg daily and ethambutol in the same dosage was added. Two weeks later the nodes were fluctuant and the overlying skin was reddened. The area was explored surgically approximately 1 month after initiation of chemotherapy. The nodes revealed extensive granulomatous inflammation with necrosis and neutrophil collections surrounded by epi¬ thelioid cells and giant cells (Fig. 3). No organisms were seen on Ziehl-Neelsen staining, and culture proved negative. Chemotherapy was maintained after operation and healing was satisfactory.
FIG. 2.Case 5. Dimorphous appearance of lymph node tissue. Giant cell in centre is
(x250).
adjacent to polymorphonuclears
Atypical mycobacteria are frequently
found in sputum and other specimens and form a significant proportion of all mycobacterial isolates. Thus, for 1973, of 321 positive mycobacterial cultures reported by the regional mycobacteriology laboratory at Chedoke Hospital 72 (22.4%) were identified as atypical organisms. Most often these are nonpathogenic and their identity and lack of significance are readily ap¬
parent; occasionally they present
not
inconsiderable problems in both diag¬ nosis and management. The range of difficulties is indicated in the present case
reports.
The clinician has not only to de¬ termine whether the organism is pro¬ ducing disease but also to distinguish the condition from tuberculosis and other diseases. This may require con¬ sideration of the clinical picture, the response to differential skin testing, histologic features and the results of
bacteriologic study.
Manifestations of atypical mycobac¬ terial infection may include cutaneous or skeletal lesions, and disseminated disease has been reported.4"6 More usual, however, is either a pulmonary infiltrate resembling tuberculosis or cervical adenitis. In the case of a lung lesion
the clinical picture is of limited dif¬ ferential value. There may be a back¬ ground of pre-existing pulmonary dis¬ ease such as chronic bronchitis (as in case 2), bronchiectasis or pneumoconiosis.7 A lack of symptoms, particularly in cases of cavitary disease (as in cases 3 and 4), may be of some significance. Finally, the radiologic picture may be unusual, as Chapman and Corpe8 have noted; the complete atelectasis seen in case 2 is perhaps an example of this. In contrast, atypical cervical adenitis is a more distinctive clinical entity.9 It occurs in the pre-school-age child, but is rare in those less than 1 year of age. The affected nodes are usually located in the submandibular region, whereas in tuberculosis the nodes at the base of the neck are more likely to be involved. This difference reflects the location of the primary focus, which is generally in the lung in cases of tuberculosis, but is probably in the tonsil or mouth in cases of atypical infection. Eating of dirt has been suggested as a cause.10 An additional point of difference from tuberculosis is a greater tendency fois atypical nodes to break down. Finally, in atypical cervical adenitis there is no family source of tuberculosis and the chest radiograph is normal. Most of these features characterized cases 5 and 6, with lymphadenitis.
FIG. 3.Case 6. Intermingling of granulomatous and pyogenic components in lymph node tissue. Centrally there is a polymorphonuclear collection, and below and to left a Langhans' cell (xlOO). CMA JOURNAL/FEBRUARY 8, 1975/VOL. 112 323
Skin testing with tuberculin and antigens derived from the atypical organisms can be of .considerable diagnostic assistance, for it is possible to distinguish atypical and tuberculous infection. The skin reaction may also facilitate making a decision about the significance of a culture reported to be positive for one of the atypical organisms; a negative skin test may indicate that the organism is only incidentally present.11 However, as these case reports indicate, there are limitations to the usefulness of skin tests. The aged person with tuberculosis is not infrequently tuberculin-negative,12 and, judging by case 2, the same would appear to be true of patients with atypical infection. A disappointing lack of precision to the skin tests was also evident and it was not possible to use the test results to pinpoint the particular atypical group or species. The explanation of this is the fact that the atypical antigens used are but a few of the representatives of a larger group. Antigens to the atypical organism in an individual case may not be included, but, because of cross-reactivity, a positive skin test to another antigen is recorded.3 Strong antigens will increase the tendency to cross-reactions, and it is known that the Tween-stabilized skin testing materials used in this study, PPD-CT68 and the atypical antigens, are at least twice the strength of unstabilized PPD-S, the international standard.13 When bioequivalent antigens become available skin testing may yield greater accuracy. Reid and Wolinsky,14 reviewing the histopathologic findings in atypical disease in lymph nodes, noted that a picture entirely characteristic of tuberculosis was the most frequent finding. Not infrequent, however, was a dimorphous pattern in which a central suppurative zone containing polymorphonuclears was surrounded by a granulomatous reaction, with histiocytes, epithelioid cells and giant cells, but no caseation. In both our cases of lymphadenitis a similar picture was seen, although, as Reid and Wolinsky
have emphasized, it is not a particularly specific one and can occur in catscratch disease and in tuberculosis. The increased tendency of nodes to break down and discharge may be due to the pyogenic element. The gross and microscopic features of pulmonary lesions are, on the other hand, similar in most respects to those of tuberculosis.15 This was the case in the only patient with pulmonary infection in this group from whom a tissue specimen was obtained. A presumptive diagnosis of atypical infection can be made on the basis of clinical features, the results of skin testing and the pathologic picture, as in case 6. Generally, however, bacteriologic identification is essential and this requires the use of various tests.2 Growth rate and pigment production are the basis of the Runyon classification.1 The niacin test is of particular importance since M. tuberculosis is niacin-positive but atypical mycobacteria are niacin-negative. (M. bovis is also niacin-negative but it is a rare organism at present.) Sensitivity testing may also be helpful in that the discovery of primary resistance to multiple agents should suggest an atypical organism. Although it is evident from cases 3 and 5 that it may not be possible to classify precisely all strains, species identification can be helpful in determining whether an organism is of clinical significance. Thus, although some species such as M. kansasii are commonly pathogens, others such as M. gordonae are always saprophytes and can be ignored. The circumstances of isolation are perhaps of equal importance, and the discovery of an organism in tissue, for example, means more than does its finding in sputum or urine. More attention should be paid to repeat cultures of an atypical mycobacterium than to a single positive specimen, even when this is a pathogen.'1 For atypical mycobacterioses it may be possible to select a regimen of chemotherapy to which the organisms are sensitive and which produces a success-
ful result. This is more likely to be the case in infections with M. kansasii, particularly since the introduction of rifampin.16 More frequent is either resistance to most of the drugs or limitation of choice to more toxic agents. There may be a discrepancy between the results of sensitivity testing and the clinical response, and this is more characteristic of atypical infections than of tuberculosis.17 Nevertheless, the most effective approach to treatment appears to be a combination of surgery and chemotherapy.18 When an operation is impossible and when there is multiple resistance, as is frequently the case in M. intracellulare infections, the use of four or five drugs has been suggested.17 However, the risk of toxicity, the lowgrade nature of the illness and the lack of infectiousness may lead one to manage these patients without specific therapy. We wish to thank Dr. N. L. Jones for his helpful comments, Drs. E. G. Beatty and J. T. Groves for preparing the photomicrographs, and Mrs. Jeanette Long for typing the manuscript. References 1. RUNYON EH: Anonymous mycobacteria in pulmonary disease. Med Clin North Am 43: 273, 1959 2. KUBICA GP: Differential identification of mycobacteria. VII. Key features for identitication of clinically significant mycobac-
teria. Am Rev Resp Dis 107: 9, 1973 3. EDWARDS PQ: Interpretation and significance of the tuberculin test in typical and atypical mycobacterial infections, in Rational Therapy and Control oj Tuberculosis, edited by JOHNSON JE in, Gainesville FL, U of Ela Pr, 1970, p 43 4. MULLOHAN GS, ROMEIt MS: Public health significance of swimming pool gsd'nuloma. Am J Public Health 51: 883, 1961 5. LINCOLN EM, GILBERT LA: Disease in children due to mycobacteria other than Mycobacterium tuberculosis. Am Rev Resp Dis 105: 683, 1972 6. SArro H, TASAKA H, SHosHABuRo 0, et al: Disseminated Mycobacterium intracellulare infection. Am Rev Resp Dis 109: 572, 1974 7. B.ms JH: A study of pulmonary disease associated with mycobacteria other than Mycobacterium tuberculosis: clinical characteris-
8. 9. 10. 11.
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tics. XX. A report of the Veterans Administration-Armed Forces cooperative study on tbe chemotherapy of tuberculosis. Am Rev Resp Dis 96: 1151, 1967 CHAPMAN JS, Coiu'a RF: Infection caused by "unclassified" mycobacteria, in Clinical Tuberculosis, edited by PFUETZE KH, RADNER DB, Springfield IL, CC Thomas, 1966, p 359 BLACK BG, CHAPMAN JS: Cervical adenitis in children due to human and unclassified mycobacteria. Pediatrics 331: 887, 1964 Hsu KHK: Nontuberculous mycobacterial inIection in children. A preliminary clinical and epidemiologic study. J Pediatrics 60: 705, 1962 MARKS J: The opportunist mycobacteria, in
Recent Advances in Respiratory Tuberculosis,
edited by HEAF F, Ruse. NL, sixth ed, London, Churchill, 1968, p 205 12. WOODRUFF CE, CHAPMAN PT: Tuberculin sensitivity in elderly patients. Am Rev Resp Dis 104: 261, 1971 13. LAND! 5, HELD HR, TsENO MC: Disparity of potency between stabilized and nonstabilized dilute tuberculin solutions. Ibid, p 385
14. RaID JD, WOLINsEY E: Histopathology of lymphadenitis caused by atypical mycobactens. Am Rev Resp Dis 99: 8, 1969 15. CHAPMAN JS: Atypical mycobacterial infection, in Rational Therapy and Control of Tuberculosis, op cit 16. RYNEARsON TK, SHRONTS JS, WOLINSKY E: Rifampin: in vitro effect on atypical mycobacteria. Am Rev Resp Dis 104: 272, 1971 17. FIsCHER DA, SCHAEFER WB, LESTER W: Infections with atypical mycobacteria. Five years' experience at the National Jewish Hospital. Am Rev Resp Dis 98: 29, 1968 18. GOLDMAN KP: Treatment of unclassified mycobacterial infection of the lungs. Thorax 23: 94, 1968
