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Pulmonary Mycobacterium fortuitum infection in association with achalasia of the oesophagus
Brit.oT. Dis. Chest (z97o) 64, xx2.
Pulmonary Mycobacteriumfortuitum Infection in Association with Achalasia of the Oesophagus Case Report and Review of the Literature R. BANERJEE, RACHEL HALL AND G. R. V. HUGHES The London Hospital, Whitechapel, London E x SEVERAL aetiological mechanisms may be present in pneumonitis complicating achalasia of the cardia (Spencer 1961). In particular the necrosis of pulmonary tissue resulting from aspiration of fatty material (lipoid pneumonia) impairs the local response to infection. Such infection may be caused by organisms which are usually non-pathogenic. Gibson (I953) , in a review of the literature, discussed the bacteriological findings in five patients with achalasia of the cardia and noted the association between achalasia, pulmonary damage and the presence of an unclassified atypical acid-fast bacillus. In retrospect, these organisms would appear to be morphologically similar to the rapidly growing group (group IV) (Runyon 1959; Runyon & Timpe 1954) of atypical mycobacteria, of which Mycobacteriumfortuiturn is the main example. The present paper describes the findings in a patient with a fatal subacute pneumonitis (which had failed to respond to conventional antibiotic therapy) in whom the only organism isolated was Myco. fortuitum. The patient had had long-standing achalasia of the cardia, and had been treated for rheumatoid arthritis with corticotrophin for six months before death.
Case Report The patient, a 54-year-old widow, was well until one year before her death, when she developed polyarthritis. She was first seen at The London Hospital in April I967, four months after the onset of symptoms. At this time she was crippled with rheumatoid arthritis--the usual analgesics having failed to control her symptoms. The latex test for rheumatoid factor was strongly positive, and her E S R remained between 60 and 9 ° m m (Westergren). In particular, at this time, there were no respiratory symptoms, but a chest radiograph showed a diffuse opacity in the left lung (Fig. I). In addition, there was widening of the upper mediastinum, and barium swallow showed achalasia of the cardia (Fig. 2). A trial of gold therapy resulted in a flare up of her joint symptoms. She was (Receivedfor publication,April z969)
PLATE
V
~. i. Initial chest X-ray showing diffuse opacity FIG. 2. Barium swallow showing dilated tortuous oesophagus packed in left lung with food debris
FIG. 3. Chest X-ray now showed dense confluent consolidation throughout the lower two-thirds of both tung fields To face page II~
PLATE
VI
~o
d
b~
_=
d
PLATE
VII
Fro. 6. Opened oesophagus showing gross dilatation of middle and distal portions
FIG. 7. Collections of foamy and pigment-laden macrophages related to fat spaces (× 4 o)
FIc, 8. Giant cells in inflammatory exudate ( x 4 o)
PLATE VIII
FIG. 9. F a t in spaces ( S u d a n i I i ) ( x 4 o )
o. I o. F a t spaces in areas of necrosis with related rim ofneutrophils ( x 4 o)
Fla. I I. Pleomorphic acid alcohol fast rod shaped m y c o b a c t e r l a in bronchial l u m e n ( x 60)
PLATE
IX
Fio, 12. Organisms in fat space ( x 4 o)
Fro. 13. Organisms in infla~mato~ry ¢xudate ( x 4 o)
PLATE
X
FIG. 14. Sections demonstrating pleomorphism of mycobacteria ( x 400)
PULMONARY
MYCOBACTERIUM
FORTUITUM
INFEGTION
II3
started on corticotrophin 4 ° units twice weekly in November 1967, which she continued to receive until her death six months later. In early I968 she began to suffer from difficulty in swallowing food and occasionally coughed following the ingestion of food and liquids. In March 1968 she began to feel generally ill, complaining of weakness and weight loss, and was admitted to hospital. On examination she was pyrexial (39°C) with a respiratory rate of 4o/min and bilateral basal crepitations. She was not cyanosed. There was moderate ankle oedema. The chest radiograph now showed dense peri-hilar shadowing in both lung fields, with underlying fine mottling throughout (Fig. 3)She was never able to cough up sputum, and in view of the radiographic appearances bronchopneumonia was diagnosed and she was given ampicillin 25 ° mg q.d.s, but the physical signs and radiograph appearances showed no improvement after two weeks. The antibiotic was changed to cephaloridine (x g q.d.s.) but again she did not improve. Terminally she went into severe heart failure became shocked and cyanosed and died 48 hours later. Throughout her admission she had had obvious difficulty in swallowing, and was fed on a fluid diet consisting of homogenized pudding, homogenized meat, milk and egg, cereal and milk (groats). She had been taking paraffin emulsion regularly for constipation and this was continued in hospital. During the year Of her illness she had become progressively more anaemic, her haemoglobin falling from xo. 7 g/Ioo ml in April I967 to 8.I g/ioo ml in April I968. The anaemia was hypochromic and microcytic in type and her serum iron, terminally, was 21 mg/ml. She had a persistent leucocytosis with a white cell count rising to 34,ooo/mm3 one month before death. Differential counts showed a persistent neutrophilia, and on one occasion the neutrophils showed a shift to the left.
Autopsy Findings An emaciated female with oedema of left leg and sacrum. Changes of advanced rheumatoid arthritis were present. The appearances of both lungs were essentially similar (Figs 4 and 5) with extensive, dense, yellowish-white consolidation of all lobes--sparing only the apices and the medial portions of the anterior basal segments. This process extended to the pleural surfaces in several places, and there were dense pleural adhesions. The free outlines of the areas of consolidation presented a trefoil appearance. These appearances were suggestive of a confluent tuberculous bronchopneumonia. There was moderate enlargement of the heart due to right ventricular hypertrophy. Atheroma of lobar and segmental arteries was present, indicative of pulmonary hypertension. The main right pulmonary artery contained laminated thrombus. There was thrombotic occlusion of the left leg veins. The oesophagus was widely dilated from the pharynx to the cardia (Fig. 6), dilatation being most marked in the distal two-thirds. This area showed several superficial ulcers up to o. 3 cm in diameter. v o L . LXIV o
4
I 14
BANERJEE,
HALL
AND
HUGHES
Microscopy The lungs showed scattered areas of coagulative necrosis of varying size. These contained nuclear debris, and in places associated (or intermingled) foamy macrophages (Fig. 7)- Several Langhans type giant ceils were present but no typical tuberculoid granulomata (Fig. 8), though there was occasional hisfiocyte palisading around areas of necrosis. Situated mainly within the areas of necrosis there were spaces containing lipoid material (Fig. 9). Special stains identified this as cholesterol. These fat spaces were occasionally surrounded by a rim ofneutrophils, the rim varying in width (Fig. IO). There was no fibrosis. Numerous acid-alcohol fast bacilli were present, mainly within small bronchioles (Fig. 11), in fat spaces (Fig. I2), and also scattered throughout the necrotic and inflamed tissue (Fig. 13). They were pleomorphic, showed pseudo-branching and some were beaded. They appeared larger than typical bacilli. While there was frequent bunching or palisading of organisms, the majority were arranged in an irregular and haphazard manner (Fig. 14). The bacilli were also strongly Gram positive. The oesophagus showed achalasia. Sections from an inter-phalangeal joint confirmed the presence of rheumatoid arthritis. As it has been suggested (Gibson 1953) that the presence and nature of the fat in the lungs in some way enhances the pathogenicity of the organism, an analysis was made of the fat content of the diet in the period before death, and this was compared with the fat present in the lungs at autopsy. A series of fat stains were performed on the lung sections--the same stains being carried out on smears from samples of her diet. The results are set out in Table I. While T A B L E I. RESULTS OF F A T STAINS O N F R O Z E N
SECTIONS OF L U N O S S M E A R S F R O M SAMPLES OF DIET
Sudan III
Wile blue sulphate
Sudan black
Fat in lungs
+
+
Homogenized pudding Homogenized meat Ice cream Milk and egg Emulsified paraffin Milk (groats)
+ + . + + +
+ + .
. + . +
.
+ (redpurple) + (red) . + (red) . + (redpurple)
GOMPARED
WITH
Schulze for Cholesterol cholesterol birefringence at 5o°C +
+
+
-
-
-
-
-
. .
cholesterol was present in all the lung sections its absence (equivocal in one case) in smears from examples of diet is difficult to explain, particularly in view of the high cholesterol content of milk (II g/Ioo g in the case of whole milk, and 3 g/xoo g in skimmed milk). In Gibson's case he came to the conclusion that milk had contributed significantly to the pathogenicity of the organism. It may
PULMONARY
MYCOBACTERIUM
FORTUITUM
INFECTION
I
15
be postulated that the cholesterol in the lungs was endogenous in origin, as seen in lipoid pneumonias without bacterial colonization (Spencer I96x).
Bacteriology Smears obtained from the fresh!y cut surfaces of the lungs showed acidalcohol fast organisms similar to those previously described in lung sections. Swabs were obtained for culture from the lung and bronchial lumens. A rapidly growing mycobacterium was grown on blood agar aerobically, with colonies appearing in 24 hours and being well formed in 48 hours. These colonies were yellowish-white and in three days were very coarsely lobulated. The organisms were injected intraperitoneally into mice in amounts of 3 mg, 1.5 mg and 0"75 mg. When killed in 4 weeks all showed multiple renal abscesses in which mycobacteria were seen in histological sections. At no time were any other microorganisms isolated. Myco. tuberculosis was not isolated, either in the smear, on culture or six weeks after guinea-pig inoculation. Antibiotic sensitivities were carried out, but growth of the organism was not inhibited by penicillin, streptomycin, tetracycline, novobiocin, erythromycin and cloxicillin. The rapid growth of the organism and its other morphological and staining characteristics placed it in group IV of the anonymous mycobacteria (Runyon's classification).* The intensely Gram positive staining of the organism should be stressed--in contrast to the lack of reaction seen with Myco. tuberculosis.
Discussion For many years it was thought t h a t tuberculosis and leprosy were the only significant diseases caused by mycobacteria. While other acid fast bacilli of the mycobacterium family had long been recognized, they differed in that they were considered non-pathogenic to man (Buhler & Pollack 1953; Curry i965; Adels & Cox 1967). This large group of anonymous mycobacteria (atypical mycobacteria) was consequently designated saprophytes en masse. Runyon (Runyon & Timpe i954; Runyon I959; Hobby et al. I965) devised a classification of these organisms, dividing them into four groups based on pigment production and the rate of growth of colonies. The most commonly isolated anonymous mycobacteria from human sputum and upper respiratory tract belong to group II (Guest et al. x965) but these are rarely described in the pathology of human disease. Where the anonymous mycobacteria are implicated as causal agents, they have usually been reported as belonging to group I (e.g. Myco. kansasii) or II (e.g. Battey bacillus). The rapidly growing group of anonymous mycobacteria (group IV) which includes Myeo. fortuitum are commonly found as contaminants of sputum (Geraci et al. 1968) and gastric washings (Chapman 1967) and are widely distributed in nature--mainly in the soil. They are recognized as being of low virulence (Wagley et al. I965) , but * We are indebted to Dr J. Marks in Cardiff for confirmatoryevidence,based On a method of lipid analysis, that the organism was Myco.fortuitum (Wilson & Miles 1965).
i16
BANERJEE, HALL AND HUGHES
resistant to antibiotic therapy (Geraci et al. 1968). Infection, when it occurs, is thought to be due to reduced resistance in the host or to a very large inoculum (Geraci et al. 1968 ). In the present case both these factors applied. It is doubtful whether corticotrophin therapy contributed significantly as pulmonary disease was evident on the chest radiograph before it was started. A definite association between achalasia of the cardia and lung infection with non-tuberculous acid-fast bacilli has been observed (Commins & Williams i933; Baldwin 1942; Warring & Rilance 1942; Rothstein & Pirkle 1946; Gibson 1953). Belcher (1949) in a review of the pulmonary complications of dysphagia stressed the frequency with which pathological conditions of the oesophagus were associated with abnormalities of the lungs and included two cases of infection by non-tuberculous acid-fast bacilli. The ubiquity of these organisms in nature led Baldwin (1942) to suggest that food was the portal of entry. Gibson then suggested that the presence of fat in the lungs might be essential for infection with anonymous mycobacteria, the organisms being rarely found in normal lung tissues, and quoted Laporte who had, in animal experiments, noted the enhanced pathogenicity of rapidly growing mycobacteria injected in fatty solution. He suggested that fat in addition to damaging pulmonary tissue might physically protect the organisms from the action of enzymes even after their ingestion by macrophages--partly by the favourable effects of a fatty environment on their growth. At the same time the organisms were themselves able to pass freely through this fat. Both Chapman (1967) and Runyon (I959) accept that the presence of a lipoid pneumonitis enhances the probability of paratuberculous disease but state that this is not an invariable prerequisite for infection by rapid growers. That the nature of the damaging agent may vary was confirmed by Guest et al. (i 965) who described group IV infection occurring in association with mineral oil granulomata. (In our case the patient had, in addition, been taking emulsified paraffin for a considerable period before death.) The symptoms and natural history of the disease appear to depend largely on the presence or absence of achalasia. In the cases associated with achalasia, who were all females of varying ages, the major complaints were of dysphagia. As in our case, pulmonary symptoms were infrequent and there was sometimes a fatal outcome (Gibson i953; Guest et al. i965). In the series of cases without achalasia described by Runyon (1959) the patients were mainly males in their fifties who complained of pulmonary symptoms and were treated by resection of the affected lobes (having been unresponsive to antibiotic therapy). The important question of whether Myco.fortuitum was the true pathogen m constituting an opportunist infection--or a passenger organism applies as strongly in our case as in those previously described. Group IV mycobacteria are sometimes found as contaminants of specimens in which Myco. tuberculosis is the pathogen (Hobby et al. 1965). In the present case Myco. tuberculosiswas never isolated nor were other organisms present. The evidence strongly suggests that Myco.fortuitum was the cause of an opportunist infection in this case. The haematological abnormalities associated with Myco. tuberculosis infec-
PULMONARY MYCOBACTERIUM FORTUITUM I N F E C T I O N
117
tion and anonymous mycobacterlal infection (Kilbridge et al. 1967; Brit. med.0% leader 1968) were not observed in the present case. In conclusion, the association of lipoid pneumonia with achalasia of the cardia appears to provide a background highly suited to infection with atypical acid-fast bacteria, a complication to be borne in mind when chest infection in these patients seems resistant to the usual antibiotic therapy. Summary The case of a fifty-four-year-old woman with rheumatoid arthritis and achalasia of the cardia which resulted in a lipoid pneumonia with superadded infection with Mycobacteriumfortuitum is reported. Previous cases are reviewed and possible pathogenic mechanisms are discussed. Attention is drawn to the possibility of this diagnosis in any antibiotic resistant pneumonia complicating achalasia.
Acknowledgements We are most grateful to Professor C. F. Barwell and the Department of Bacteriology, The London Hospital, to Professor I. Doniach and to Dr N. L. Rushy for their help and advice and to Dr W. S. Tegner:for permission to publish this case.
References ADELS, B. R. & Cox, P. J. N. (1967) Mycobacterium battey infection resembling tuberculosis. Brit, reed. or., 3, 157. BALDWIN,E. R. (1942) Non-pathogenic acid-fast bacilli. Amer. Rev. Tuberc., XLV, 756. BELCHER,J. R. (i949) The pulmonary complications of dysphagia. Thorax, IV, 44. BUHLER, V. B. & POLLACK,A. (1953) Human infection with atypical acid-fast organisms. Amer. 07. din. Path., 23, 363. CHAPMAN,J. S. (1967) Atypical mycobacterial infections. Pathogenesis, clinical manifestations and treatment. Med. Glin. N. Amer., 5 x, 5o3. CUMMINS, S. L. & WILLIAMS,E. M. (I933) An acid-fast bacillus other than Koch's bacillus cultured from sputum. Tubercle, XV, 49. CURRY, F.J. (I965) Atypical acid-fast mycobacteria. New Engl. 07. Med., 272, 415 • GERACI,J. E., ANDERSON,M. W. & KARLSON,A. G. (1968) Endocarditis due to a rapidly growing chromogenic mycobacterium. Mayo Clin. Proe., 43, 124. GIBSON,J. B. (I953) Infection of the lungs by 'saprophytic' mycobacteria in achalasia of the cardia, with report of a fatal case showing lipoid pneumonia due to milk. 07. Path. Bact., 65, 239. GUEST,J. L., Jr., AREAN,V. M. & BRENNER,H. A. (1965) Group IV atypical mycobacterium infection occurring in association with mineral oil granuloma of lungs. Amer. Rev. resp. Dis., 95, 656. HOBBY, G. L., REDMOND, W. B., RUNYON, E. H., SCHAEFER, W. B., WAYNE, L. G. & WIGHELHAUSEN, R. S. (I965) A study on pulmonary disease associated with mycobacteria other than Mycobacterium tuberculosis: Identification and characterisation of the mycobacteria. Amer. Rev. resp. Dis., 95, 954. KILBRIDGE, T. M., GONELLA,J. W. & BOLAN,J. T. (1967) Pancytopenia and death. Disseminated anonymous mycobacterial infection. Arch. intern. Med., I2o, 38. ROTHSTEIN, E. & PIRKLE, H. B. (1946) Pulmonary disease secondary to cardiospasm with acid-fast bacilli in the sputum. Dis. Chest, x2, 232.
ii8
BANERJEE~ HALL AND HUGHES
RUNYON, E. H. (1959) Anonymous mycobacteria in human disease. Med. Clin. aM. Amer., 43, 273. RuNYo~, E. H. & TIMPE, A. (1954) The relationship of'atypical' acid-fast bacteria to human disease. 07. Lab. din. Med., 44, 2o2. SPENCER, H. (I961) Pathologyof the Lung, xst edn. Oxford: Pergamon; p. 385 . WAGLEY, P. F., KRESS, M. B. & BEACHAM,E. G. (I965) Some clinical observations on anonymous myeobacteria. Bull. 07ohnsHopk. Hosp., xx7, 2o7. WARX~I~G, F. C., Jr. & RILA~CE, A. B. (I942) Chronic infurative pneumonia resulting from cardiospasm. A case with non-chromogenie acid-fast bacilli in the sputum. 07. Lab. Clin. Med., XXVIII, x59I. WILSON, G. S. & MILES, A. A. (x965) Principles of Bacteriology and Immunity, 5th edn, vol. i. London: Arnold. p. 568. L~.ADINO ARTICLE (X968) Anonymous mycobacteriosis. Brit. med. 07, 2, 3o8.
Pulmonary Mycobacteriumfortuitum Infection in Association with Achalasia of the Oesophagus Case Report and Review of the Literature R. BANERJEE, RACHEL HALL AND G. R. V. HUGHES The London Hospital, Whitechapel, London E x SEVERAL aetiological mechanisms may be present in pneumonitis complicating achalasia of the cardia (Spencer 1961). In particular the necrosis of pulmonary tissue resulting from aspiration of fatty material (lipoid pneumonia) impairs the local response to infection. Such infection may be caused by organisms which are usually non-pathogenic. Gibson (I953) , in a review of the literature, discussed the bacteriological findings in five patients with achalasia of the cardia and noted the association between achalasia, pulmonary damage and the presence of an unclassified atypical acid-fast bacillus. In retrospect, these organisms would appear to be morphologically similar to the rapidly growing group (group IV) (Runyon 1959; Runyon & Timpe 1954) of atypical mycobacteria, of which Mycobacteriumfortuiturn is the main example. The present paper describes the findings in a patient with a fatal subacute pneumonitis (which had failed to respond to conventional antibiotic therapy) in whom the only organism isolated was Myco. fortuitum. The patient had had long-standing achalasia of the cardia, and had been treated for rheumatoid arthritis with corticotrophin for six months before death.
Case Report The patient, a 54-year-old widow, was well until one year before her death, when she developed polyarthritis. She was first seen at The London Hospital in April I967, four months after the onset of symptoms. At this time she was crippled with rheumatoid arthritis--the usual analgesics having failed to control her symptoms. The latex test for rheumatoid factor was strongly positive, and her E S R remained between 60 and 9 ° m m (Westergren). In particular, at this time, there were no respiratory symptoms, but a chest radiograph showed a diffuse opacity in the left lung (Fig. I). In addition, there was widening of the upper mediastinum, and barium swallow showed achalasia of the cardia (Fig. 2). A trial of gold therapy resulted in a flare up of her joint symptoms. She was (Receivedfor publication,April z969)
PLATE
V
~. i. Initial chest X-ray showing diffuse opacity FIG. 2. Barium swallow showing dilated tortuous oesophagus packed in left lung with food debris
FIG. 3. Chest X-ray now showed dense confluent consolidation throughout the lower two-thirds of both tung fields To face page II~
PLATE
VI
~o
d
b~
_=
d
PLATE
VII
Fro. 6. Opened oesophagus showing gross dilatation of middle and distal portions
FIG. 7. Collections of foamy and pigment-laden macrophages related to fat spaces (× 4 o)
FIc, 8. Giant cells in inflammatory exudate ( x 4 o)
PLATE VIII
FIG. 9. F a t in spaces ( S u d a n i I i ) ( x 4 o )
o. I o. F a t spaces in areas of necrosis with related rim ofneutrophils ( x 4 o)
Fla. I I. Pleomorphic acid alcohol fast rod shaped m y c o b a c t e r l a in bronchial l u m e n ( x 60)
PLATE
IX
Fio, 12. Organisms in fat space ( x 4 o)
Fro. 13. Organisms in infla~mato~ry ¢xudate ( x 4 o)
PLATE
X
FIG. 14. Sections demonstrating pleomorphism of mycobacteria ( x 400)
PULMONARY
MYCOBACTERIUM
FORTUITUM
INFEGTION
II3
started on corticotrophin 4 ° units twice weekly in November 1967, which she continued to receive until her death six months later. In early I968 she began to suffer from difficulty in swallowing food and occasionally coughed following the ingestion of food and liquids. In March 1968 she began to feel generally ill, complaining of weakness and weight loss, and was admitted to hospital. On examination she was pyrexial (39°C) with a respiratory rate of 4o/min and bilateral basal crepitations. She was not cyanosed. There was moderate ankle oedema. The chest radiograph now showed dense peri-hilar shadowing in both lung fields, with underlying fine mottling throughout (Fig. 3)She was never able to cough up sputum, and in view of the radiographic appearances bronchopneumonia was diagnosed and she was given ampicillin 25 ° mg q.d.s, but the physical signs and radiograph appearances showed no improvement after two weeks. The antibiotic was changed to cephaloridine (x g q.d.s.) but again she did not improve. Terminally she went into severe heart failure became shocked and cyanosed and died 48 hours later. Throughout her admission she had had obvious difficulty in swallowing, and was fed on a fluid diet consisting of homogenized pudding, homogenized meat, milk and egg, cereal and milk (groats). She had been taking paraffin emulsion regularly for constipation and this was continued in hospital. During the year Of her illness she had become progressively more anaemic, her haemoglobin falling from xo. 7 g/Ioo ml in April I967 to 8.I g/ioo ml in April I968. The anaemia was hypochromic and microcytic in type and her serum iron, terminally, was 21 mg/ml. She had a persistent leucocytosis with a white cell count rising to 34,ooo/mm3 one month before death. Differential counts showed a persistent neutrophilia, and on one occasion the neutrophils showed a shift to the left.
Autopsy Findings An emaciated female with oedema of left leg and sacrum. Changes of advanced rheumatoid arthritis were present. The appearances of both lungs were essentially similar (Figs 4 and 5) with extensive, dense, yellowish-white consolidation of all lobes--sparing only the apices and the medial portions of the anterior basal segments. This process extended to the pleural surfaces in several places, and there were dense pleural adhesions. The free outlines of the areas of consolidation presented a trefoil appearance. These appearances were suggestive of a confluent tuberculous bronchopneumonia. There was moderate enlargement of the heart due to right ventricular hypertrophy. Atheroma of lobar and segmental arteries was present, indicative of pulmonary hypertension. The main right pulmonary artery contained laminated thrombus. There was thrombotic occlusion of the left leg veins. The oesophagus was widely dilated from the pharynx to the cardia (Fig. 6), dilatation being most marked in the distal two-thirds. This area showed several superficial ulcers up to o. 3 cm in diameter. v o L . LXIV o
4
I 14
BANERJEE,
HALL
AND
HUGHES
Microscopy The lungs showed scattered areas of coagulative necrosis of varying size. These contained nuclear debris, and in places associated (or intermingled) foamy macrophages (Fig. 7)- Several Langhans type giant ceils were present but no typical tuberculoid granulomata (Fig. 8), though there was occasional hisfiocyte palisading around areas of necrosis. Situated mainly within the areas of necrosis there were spaces containing lipoid material (Fig. 9). Special stains identified this as cholesterol. These fat spaces were occasionally surrounded by a rim ofneutrophils, the rim varying in width (Fig. IO). There was no fibrosis. Numerous acid-alcohol fast bacilli were present, mainly within small bronchioles (Fig. 11), in fat spaces (Fig. I2), and also scattered throughout the necrotic and inflamed tissue (Fig. 13). They were pleomorphic, showed pseudo-branching and some were beaded. They appeared larger than typical bacilli. While there was frequent bunching or palisading of organisms, the majority were arranged in an irregular and haphazard manner (Fig. 14). The bacilli were also strongly Gram positive. The oesophagus showed achalasia. Sections from an inter-phalangeal joint confirmed the presence of rheumatoid arthritis. As it has been suggested (Gibson 1953) that the presence and nature of the fat in the lungs in some way enhances the pathogenicity of the organism, an analysis was made of the fat content of the diet in the period before death, and this was compared with the fat present in the lungs at autopsy. A series of fat stains were performed on the lung sections--the same stains being carried out on smears from samples of her diet. The results are set out in Table I. While T A B L E I. RESULTS OF F A T STAINS O N F R O Z E N
SECTIONS OF L U N O S S M E A R S F R O M SAMPLES OF DIET
Sudan III
Wile blue sulphate
Sudan black
Fat in lungs
+
+
Homogenized pudding Homogenized meat Ice cream Milk and egg Emulsified paraffin Milk (groats)
+ + . + + +
+ + .
. + . +
.
+ (redpurple) + (red) . + (red) . + (redpurple)
GOMPARED
WITH
Schulze for Cholesterol cholesterol birefringence at 5o°C +
+
+
-
-
-
-
-
. .
cholesterol was present in all the lung sections its absence (equivocal in one case) in smears from examples of diet is difficult to explain, particularly in view of the high cholesterol content of milk (II g/Ioo g in the case of whole milk, and 3 g/xoo g in skimmed milk). In Gibson's case he came to the conclusion that milk had contributed significantly to the pathogenicity of the organism. It may
PULMONARY
MYCOBACTERIUM
FORTUITUM
INFECTION
I
15
be postulated that the cholesterol in the lungs was endogenous in origin, as seen in lipoid pneumonias without bacterial colonization (Spencer I96x).
Bacteriology Smears obtained from the fresh!y cut surfaces of the lungs showed acidalcohol fast organisms similar to those previously described in lung sections. Swabs were obtained for culture from the lung and bronchial lumens. A rapidly growing mycobacterium was grown on blood agar aerobically, with colonies appearing in 24 hours and being well formed in 48 hours. These colonies were yellowish-white and in three days were very coarsely lobulated. The organisms were injected intraperitoneally into mice in amounts of 3 mg, 1.5 mg and 0"75 mg. When killed in 4 weeks all showed multiple renal abscesses in which mycobacteria were seen in histological sections. At no time were any other microorganisms isolated. Myco. tuberculosis was not isolated, either in the smear, on culture or six weeks after guinea-pig inoculation. Antibiotic sensitivities were carried out, but growth of the organism was not inhibited by penicillin, streptomycin, tetracycline, novobiocin, erythromycin and cloxicillin. The rapid growth of the organism and its other morphological and staining characteristics placed it in group IV of the anonymous mycobacteria (Runyon's classification).* The intensely Gram positive staining of the organism should be stressed--in contrast to the lack of reaction seen with Myco. tuberculosis.
Discussion For many years it was thought t h a t tuberculosis and leprosy were the only significant diseases caused by mycobacteria. While other acid fast bacilli of the mycobacterium family had long been recognized, they differed in that they were considered non-pathogenic to man (Buhler & Pollack 1953; Curry i965; Adels & Cox 1967). This large group of anonymous mycobacteria (atypical mycobacteria) was consequently designated saprophytes en masse. Runyon (Runyon & Timpe i954; Runyon I959; Hobby et al. I965) devised a classification of these organisms, dividing them into four groups based on pigment production and the rate of growth of colonies. The most commonly isolated anonymous mycobacteria from human sputum and upper respiratory tract belong to group II (Guest et al. x965) but these are rarely described in the pathology of human disease. Where the anonymous mycobacteria are implicated as causal agents, they have usually been reported as belonging to group I (e.g. Myco. kansasii) or II (e.g. Battey bacillus). The rapidly growing group of anonymous mycobacteria (group IV) which includes Myeo. fortuitum are commonly found as contaminants of sputum (Geraci et al. 1968) and gastric washings (Chapman 1967) and are widely distributed in nature--mainly in the soil. They are recognized as being of low virulence (Wagley et al. I965) , but * We are indebted to Dr J. Marks in Cardiff for confirmatoryevidence,based On a method of lipid analysis, that the organism was Myco.fortuitum (Wilson & Miles 1965).
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BANERJEE, HALL AND HUGHES
resistant to antibiotic therapy (Geraci et al. 1968). Infection, when it occurs, is thought to be due to reduced resistance in the host or to a very large inoculum (Geraci et al. 1968 ). In the present case both these factors applied. It is doubtful whether corticotrophin therapy contributed significantly as pulmonary disease was evident on the chest radiograph before it was started. A definite association between achalasia of the cardia and lung infection with non-tuberculous acid-fast bacilli has been observed (Commins & Williams i933; Baldwin 1942; Warring & Rilance 1942; Rothstein & Pirkle 1946; Gibson 1953). Belcher (1949) in a review of the pulmonary complications of dysphagia stressed the frequency with which pathological conditions of the oesophagus were associated with abnormalities of the lungs and included two cases of infection by non-tuberculous acid-fast bacilli. The ubiquity of these organisms in nature led Baldwin (1942) to suggest that food was the portal of entry. Gibson then suggested that the presence of fat in the lungs might be essential for infection with anonymous mycobacteria, the organisms being rarely found in normal lung tissues, and quoted Laporte who had, in animal experiments, noted the enhanced pathogenicity of rapidly growing mycobacteria injected in fatty solution. He suggested that fat in addition to damaging pulmonary tissue might physically protect the organisms from the action of enzymes even after their ingestion by macrophages--partly by the favourable effects of a fatty environment on their growth. At the same time the organisms were themselves able to pass freely through this fat. Both Chapman (1967) and Runyon (I959) accept that the presence of a lipoid pneumonitis enhances the probability of paratuberculous disease but state that this is not an invariable prerequisite for infection by rapid growers. That the nature of the damaging agent may vary was confirmed by Guest et al. (i 965) who described group IV infection occurring in association with mineral oil granulomata. (In our case the patient had, in addition, been taking emulsified paraffin for a considerable period before death.) The symptoms and natural history of the disease appear to depend largely on the presence or absence of achalasia. In the cases associated with achalasia, who were all females of varying ages, the major complaints were of dysphagia. As in our case, pulmonary symptoms were infrequent and there was sometimes a fatal outcome (Gibson i953; Guest et al. i965). In the series of cases without achalasia described by Runyon (1959) the patients were mainly males in their fifties who complained of pulmonary symptoms and were treated by resection of the affected lobes (having been unresponsive to antibiotic therapy). The important question of whether Myco.fortuitum was the true pathogen m constituting an opportunist infection--or a passenger organism applies as strongly in our case as in those previously described. Group IV mycobacteria are sometimes found as contaminants of specimens in which Myco. tuberculosis is the pathogen (Hobby et al. 1965). In the present case Myco. tuberculosiswas never isolated nor were other organisms present. The evidence strongly suggests that Myco.fortuitum was the cause of an opportunist infection in this case. The haematological abnormalities associated with Myco. tuberculosis infec-
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tion and anonymous mycobacterlal infection (Kilbridge et al. 1967; Brit. med.0% leader 1968) were not observed in the present case. In conclusion, the association of lipoid pneumonia with achalasia of the cardia appears to provide a background highly suited to infection with atypical acid-fast bacteria, a complication to be borne in mind when chest infection in these patients seems resistant to the usual antibiotic therapy. Summary The case of a fifty-four-year-old woman with rheumatoid arthritis and achalasia of the cardia which resulted in a lipoid pneumonia with superadded infection with Mycobacteriumfortuitum is reported. Previous cases are reviewed and possible pathogenic mechanisms are discussed. Attention is drawn to the possibility of this diagnosis in any antibiotic resistant pneumonia complicating achalasia.
Acknowledgements We are most grateful to Professor C. F. Barwell and the Department of Bacteriology, The London Hospital, to Professor I. Doniach and to Dr N. L. Rushy for their help and advice and to Dr W. S. Tegner:for permission to publish this case.
References ADELS, B. R. & Cox, P. J. N. (1967) Mycobacterium battey infection resembling tuberculosis. Brit, reed. or., 3, 157. BALDWIN,E. R. (1942) Non-pathogenic acid-fast bacilli. Amer. Rev. Tuberc., XLV, 756. BELCHER,J. R. (i949) The pulmonary complications of dysphagia. Thorax, IV, 44. BUHLER, V. B. & POLLACK,A. (1953) Human infection with atypical acid-fast organisms. Amer. 07. din. Path., 23, 363. CHAPMAN,J. S. (1967) Atypical mycobacterial infections. Pathogenesis, clinical manifestations and treatment. Med. Glin. N. Amer., 5 x, 5o3. CUMMINS, S. L. & WILLIAMS,E. M. (I933) An acid-fast bacillus other than Koch's bacillus cultured from sputum. Tubercle, XV, 49. CURRY, F.J. (I965) Atypical acid-fast mycobacteria. New Engl. 07. Med., 272, 415 • GERACI,J. E., ANDERSON,M. W. & KARLSON,A. G. (1968) Endocarditis due to a rapidly growing chromogenic mycobacterium. Mayo Clin. Proe., 43, 124. GIBSON,J. B. (I953) Infection of the lungs by 'saprophytic' mycobacteria in achalasia of the cardia, with report of a fatal case showing lipoid pneumonia due to milk. 07. Path. Bact., 65, 239. GUEST,J. L., Jr., AREAN,V. M. & BRENNER,H. A. (1965) Group IV atypical mycobacterium infection occurring in association with mineral oil granuloma of lungs. Amer. Rev. resp. Dis., 95, 656. HOBBY, G. L., REDMOND, W. B., RUNYON, E. H., SCHAEFER, W. B., WAYNE, L. G. & WIGHELHAUSEN, R. S. (I965) A study on pulmonary disease associated with mycobacteria other than Mycobacterium tuberculosis: Identification and characterisation of the mycobacteria. Amer. Rev. resp. Dis., 95, 954. KILBRIDGE, T. M., GONELLA,J. W. & BOLAN,J. T. (1967) Pancytopenia and death. Disseminated anonymous mycobacterial infection. Arch. intern. Med., I2o, 38. ROTHSTEIN, E. & PIRKLE, H. B. (1946) Pulmonary disease secondary to cardiospasm with acid-fast bacilli in the sputum. Dis. Chest, x2, 232.
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RUNYON, E. H. (1959) Anonymous mycobacteria in human disease. Med. Clin. aM. Amer., 43, 273. RuNYo~, E. H. & TIMPE, A. (1954) The relationship of'atypical' acid-fast bacteria to human disease. 07. Lab. din. Med., 44, 2o2. SPENCER, H. (I961) Pathologyof the Lung, xst edn. Oxford: Pergamon; p. 385 . WAGLEY, P. F., KRESS, M. B. & BEACHAM,E. G. (I965) Some clinical observations on anonymous myeobacteria. Bull. 07ohnsHopk. Hosp., xx7, 2o7. WARX~I~G, F. C., Jr. & RILA~CE, A. B. (I942) Chronic infurative pneumonia resulting from cardiospasm. A case with non-chromogenie acid-fast bacilli in the sputum. 07. Lab. Clin. Med., XXVIII, x59I. WILSON, G. S. & MILES, A. A. (x965) Principles of Bacteriology and Immunity, 5th edn, vol. i. London: Arnold. p. 568. L~.ADINO ARTICLE (X968) Anonymous mycobacteriosis. Brit. med. 07, 2, 3o8.