Bacteriological and radiographic features of lung infection by opportunist mycobacteria: A review

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BACTERIOLOGICAL AND RADIOGRAPHIC FEATURES OF LUNG INFECTION BY OPPORTUNIST MYCOBACTE~: A REVIEW By P. L. COOK,R. W. RIDDELLand G. SIMON from the Brompton Hospital, London. S. W.3.

SUMMARY Opportunist mycobacterial diseases of the lung are reviewed and the epidemiology of the infections discussed. The course of disease based on radiological changes is described in 27 patients. Seventeen patients (63 per cent) had distinctive radiographic changes; 5 showed very distinstive lesions consisting of groups of 1 cm homogeneous shadows around translucent zones with line shadows radiating from each lesion, while 12 had relatively small but thick-walled cavities. In 10 patients (37 per cent) the appearances were non-specific; 5 had large relatively thin-walled cavities in shrunken upper lobes (an appearance often considered pathognomonic of opportunist mycobacterial disease), and another 5 had shrunken upper lobes with only small cavities or dilated bronchi within them.

RI?SUMI? Les auteurs ttudient les infections pulmonaires a mycobacteries “opportunistes” et discutent l’epidemiologie de ces infections. 11sdecrivent l’evolution de la maladie basee sur les changements radiologiques chez 27 malades. Dix sept malades (63 %) montrent des changements radiologiques nets; 5 ont eu des lesions distinctes consistant en ensembles d’ombres homogenes de 1 cm group& autour de zones translucides avec des lignes d’ombre rayonnant de chaque lesion tandis que 12 ont eu des cavites relativement petites, mais a parois Cpaisses. Pour 10 malades (37 %) l’image radiologique n’ttait pas specifique; 5 ont eu des cavites relativement grandes mais a parois minces, dans des lobes superieurs retract& (une image souvent consideree comme pathognomonique des infections a mycobacteries “opportunistes”) et 5 autres malades ont eu des lobes superieurs retract& presentant seulement de petites cavites ou des dilatations bronchiques.

RESUMEN Se pasan en revista las enfermedades pulmonares oportunistas por micobacterias y se discute le epidemiologla de las infecciones. Se describe el curso de la enfermedad basado en cambios radiologicos en 27 pacientes. Diez y siere pacientes (63 %) presentaron canbios diversos; 5 mostraron lesiones diferentes constituidas por grupos de sombras homogeneas, de 1 cm., alrededor de zonas hiperclaras con sombras lineares irradiando de cada lesion; 12 tenian cavidades relativamente pequefias pero con pared gruesa. En 10 pacientes (37 %) la imagen no era especifica; 5 tenlan grandes cavidades de paredes delgadas ubicadas en lobules superiores retraidos (una

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imagen a menudo condiderada coma patognomonica de la micobacteriosis oporunista); 10s otros 5 tenian lobules retraidos con pequeiias cavidades o bronquios dilatados. ZUSAMMENFASSUNG

Lungenerkrankungen durch atypische Mykobakterien werden erortert ; die Epidemiologie der Infektionen wird diskutiert. Beschrieben wird an Hand der Rontgenbefunde der Krankheitsverlauf bei 27 Patienten. Siebzehn (63 %) Patienten hatten charakteristische Veranderungen im Riintgenbild. Bei ftinf lagen homogene Verschattungen von 1 cm Durchmesser vor, von denen zarte Schatten in die umgebenden vermehrt strahlendurchlassigen Zonen ausgingen. Zwolf hatten verhaltnismafiig kleine aber dickwandige Kavernen. Bei zehn (37%) Patienten waren die Veranderungen unspezifisch: ftinf hatten groBe relativ diinnwandige Kavernen in geschrumpften Oberlappen (dies wird oft als pathognomonisch fur Infektionendurch atypische Mykobakterien angesehen), bei den anderen ftinf lag ebenfalls ein geschrumpfter Oberlappen vor aber nur mit kleinen Kavernen oder Bronchiektasien. Introduction In any large group of patients suffering from pulmonary mycobacterial disease, a small proportion will be found in whom the infection is not due to Mycobacterium tuberculosis or to M. bovis but to one of the opportunist mycobacteria. These organisms began to be recognised soon after Koch’s discovery of M. tuberculosis almost a hundred years ago, and much of what has happened in recent years has been a re-appraisal of their significance in human disease. Although strongly acid-fast and for all practical purposes structurally similar to human and bovine bacilli these organisms are, nevertheless, biologically distinct. By laboratory tests they can be differentiated from tubercle bacilli, from saprophytic mycobacteria and from weakly acid-fast actinomycetes such as Nocardia asteroides. The opportunist mycobacteria have also been known as the ‘chromogens’ or as ‘atypical’, ‘anonymous’ or ‘unclassified’ mycobacteria * . Their classification was tentative (American Thoracic Society, 1963; Runyon and McDermott, 1965), the most widely used being based initially on colonial and pigment-forming characteristics as suggested by Runyon (1959). Many species are now well described and the most important pathogens are shown arranged in their original Runyon groups in Table I. Since the culture and cell morphology of M. tuberculosis may be modified by anti-tuberculosis drugs (Chapman, 1962; Marks and Trollope, 1960), and because some opportunist organisms so closely resemble tubercle bacilli as well as each other, biochemical, enzymal, serological and mycobacteriophage-susceptibility patterns may be necessary to identify them. They often produce more catalase than M. tuberculosis and practically never produce niacin or peroxidase. The addition of the sodium salt of p-nitro-benzoic acid to Lowenstein-Jensen medium inhibits the growth of M. tuberculosis and M. bovis but not that of the opportunist organisms. Unlike tubercle bacilli, apart from isoniazid-resistant strains, these organisms produce only local disease in guineapigs inoculated experimentally. The importance of the opportunist mycobacteria in human disease was not generally recognised until the last decade. Various names such as ‘mycobacteriosis’ or ‘pseudotuberculosis’ have been suggested but have not received general acceptance. Epidemiology and Natural History

Opportunist mycobacteria occur in the environment so their isolation from a patient is more often than not irrelevant. They are regarded as possibly significant pathogens when recovered directly from infected tissue or pleural fluid, or repeatedly from the sputum of patients with radio* In this review, for want of a better name, they are called ‘opportunist’ mycobacteria on the assumption that they tend to produce opportunist infections more readily than do M. tuberculosis or M. bovk

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TABLE I.-THE Group

Runyon

Runyon

I

II

Runyon III

Mycobacterium Species M. kansasii’

M. xenopi”

Water; river estuaries and costal areas. Possibly sea birds.

M. fortuitum’*

___Skin pathogens only

Water not soil; rarely isolated from animals. South to North Central USA; Europe. Soil and water; probabl! common “contaminant’ World-wide.

M. avium’

M. marinum’**(a (M. bahei)

Organs Affected in Humans

Probable Habitat and Distribution

M. scrofulacer4m2

M. intraceNulare4

IV

SIMON

OPPORTUNISTMYCOBACTERIA

(Battey bacillus)

Runyon

AND

Soil; especially W. Australia and S.E. United States. Soil especially rural; wild and domestic birds, pigs and cattle.

Lungs; especially middle-aged males.

I-

Cervical lymph nodes especially children ; rarely lungs, bursae, skin.

Lungs.

I Lungs and lymph nodes.

Soil; very common contaminant. Water ; swimming pools fish, insects. _

Skin.

M. ulcerans4**(b) M. borstelense4*(c

1 2 s p * **

Photochromogenic Scotochromogenic Slowly and weakly chromogenic Non-chromogenic Growth within 7 days at 25°C No growth at 37°C.

(a) Runyon Group I (b) Runyon Group III (c) Runyon Group IV

graphic evidence of tuberculosis-like pulmonary lesions. Particular attention is paid to the isolation of these organisms when no other cause for disease can be established and if M. tuberculosis or M. bovis have not been isolated (Bates, 1967; Beck and Stanford, 1968; Heitzmann, Bornhurst and Russell, 1968). The single isolation of an opportunist strain is relatively common. Warring (1968) found this to be the case in 5 to 6 per cent of a group of patients considered to have pulmonary tuberculosis, though in only O-9 per cent were the organisms regarded as of significance. The incidence of disease caused by these bacteria varies in different parts of the world and also in different localities in individual countries. Expressed as a percentage of total admissions of ‘tuberculosis’ patients, figures of from 1 per cent to 20 per cent for these infections have been recorded in different world

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zones. In Goldman’s (1968) series from the Brompton Hospital the proportion was 1:77. Mycobacterium kansusii is the commonest opportunist organism in most regions and the most important in Europe, but in some zones other species predominate. An example is M. intracellulare which was predominant in the South Eastern United States (Warring, 1968) and also in Western Australia (Edwards, 1970), whilst M. xenopi was most common in the British series of Beck and Stanford (1968). In the Veterans Administration-Armed Forces study of 391 patients by Hobby and others (1967) it was impossible to draw conclusions concerning the prevalence, incidence and geographic distribution of opportunist mycobacterial infections in the United States. The reservoirs of infection are uncertain but are probably soil and water (Kubica and others, 1961; Wolinsky and Rynearson, 1968; Lester, 1966) (see Table 1). Rats and mice have been suggested as possible hosts by Chapman, Bernard and Speight, 1965) and pigs and cattle by Mallman and others (1965). Wolinsky (1960) stated that renal infections are very common in animals. Edwards and Palmer (1959) reported the isolation of opportunist mycobacteria from the pharynx and gastric washings of healthy human subjects, and some have been found in raw milk (Chapman, Bernard and Speight, 1965). Acquisition

of Infection

Opportunist pulmonary mycobacterial disease is acquired, as in tuberculosis and the mycoses, by inhalation of infected air-borne particles, and as a result interesting zonal distributions in resident populations of skin-test positive reactors to homologous antigens have been reported. A high incidence of suchreactors to Battey (44. intracellulure) PPD has been reported in the S. E. United States of America where most cases of infection by the homologous organism occur (Edwards, Edwards and Palmer, 1959). Since M. kunsasii is much more closely related to tubercle bacilli antigenically than other opportunist mycobacteria, skin-testing with M. kansasii PPD presents difficulties. The great majority of reactors to intermediate strength mammalian-type PPD and ‘Tine’ test antigen in the S. E. United States appear to be due to latent infections with opportunist mycobacteria rather than to tubercle bacilli (Fogan, 1970). Patients suffering from opportunist infections often have negative skin-test responses to mammalian-type PPD or less strongly positive reactions to this antigen compared with the homologous mycobacterial PPD. Results may be complicated, however, since multiple mycobacterial infections must be common and the duration of colonisation of tissues by individual mycobacterial strains variable. Acquisition by person to person transmission, as occurs in tuberculosis, appears to be extremely rare. Chapman (1962) gives two examples of possible familial transmission between children and adults, and Beck, Keeping and Zorab (1963) describe the isolation of M. xenopi from a man and his wife. It is recognised that there can be a higher rate of skin test reactions to M. kunsasii PPD among contacts of patients infected with this organism than among normal controls, but communicability of infection has not been proved. Pm-Existing

Diseases

These mycobacterial infections show similar social and racial distributions to those in tuberculosis. An association with alcoholism, diabetes, steroid therapy and peptic ulceration has been noted but is less obvious than in tuberculosis. Among the pre-existing lung diseases with which these types of infection become associated are emphysema, pneumonconiosis, silicosis and aspiration pneumonia and dysphagic pneumonitis; miners, metal workers and welders appear especially susceptible. Pre-existing tuberculosis affords no protection, indeed opportunist mycobacteria, like fungi, may become secondary invaders of chronic tuberculous lesions. Co-existent infections with fungi, such as Histoplasma capsdatum, are also known (Fields and others, 1969). Course of Disease

The mode of presentation is variable. Disease generally begins in the lower respiratory tract but G

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sometimes in cervical lymph nodes or the gut. In a scrofula-like syndrome, occurring particularly In children, the bacteria presumably gain access through tonsils or adenoids. In primary cutaneous disease, M. marinum (M. halnei). M. ulcerans and M. horsrclense produce indolent granulomata when introduced into the skin through trauma. Infection of the lungs may be symptom-free and detected only in routine chest radiographs; often there is an exacerbation of existing symptoms of chronic lung disease. The symptoms associated with the disease do not differ materially from those of pulmonary tuberculosis. Bronchogenic and haematogenous spread of opportunist mycobacteria were once considered rare, but are now recognised more frequently. Schonell and others (1968) describe miliary lung lesions; bone marrow, spleen, liver, lymph nodes and meninges may similarly become involved sometimes with corresponding radiographic changes (Heitzmann, Bornhurst and Russell, 1968). Spread of this kind is usuaily fatal and most common in children less than 2 years of age. As in fungal infections, dissemination occurs more frequently in cases of Hodgkin’s disease and lymphosarcoma (Kilbridge, Gonnella and Bolan, 1967) and, as in disseminated tuberculosis (Oswald, 1963), a relationship has been noted with severe anaemia, neutropenia, granulocytic hyperplasia, myeloproliferative diseases and myeloid leukaemia. Previous irradiation therapy or treatment with immunosuppressive drugs may similarly predispose to mycobacterial invasion. Treatment Illness tends to be long and fluctuating and therapy difficult because, apart from M. xenopi, the opportunist mycobacteria are resistant to most anti-tuberculosis drugs. The strains almost always show in vitro resistance to streptomycin, isoniazid and PAS. Selkon and Mitchison (1959) reported that of 55 patients infected by primary drug-resistant mycobacteria, 7 (13 per cent) were infected by opportunists. There is also in vitro resistance to some of the ‘second-line’ anti-tuberculosis drugs. In clinical practice, treatment with both ‘first-line’ and ‘second-line’ drugs is most effective when disease is caused by M. xenopi. Therapy is often successful in M. kansasii infections using drugs for treating tuberculosis (Fischer, Lester and Schaefer, 1968). M. scrqfulaceum and M. intracellzhre diseases are particularly recalcitrant and M. ,fortuitum infections are unresponsive to therapy. Laboratory tests for drug sensitivity are less certain to be reliable guides to therapy than is the case for tuberculosis. There is often considerable strain difference in drug susceptibility of these organisms particularly so for M. intracellulare. Patients suffering from opportunist mycobacterial infection need to be treated differently from those with tuberculosis because of the frequency of therapeutic failure and the insignificant risk of direct spread of infection. Their long-term prognosis is probably worse than was at one time supposed. Pathology The histopathology of opportunist mycobacterial infections is usually described as within the range of tissue changes caused by M. tuberculosis, but Kent and Lester (1959) reported a higher incidence of sub-mucosal or ulcerative endobronchial lesions and more fibrosis. Acid-fast bacilli present in lesions are sometimes morphologically unlike tubercle bacilli (Snijder, 1965) but, as with general histological, appearances variations are usually too small to be of diagnostic value. The Present Series The radiographic appearances were studied in 27 cases from the records of the Brompton Hospital. In all, opportunist mycobacteria were repeatedly isolated and neither M. tuberculosis nor M. bovis were cultured. The cases included most of those used in the therapeutic study reported by Goldman (1968). In 16 the lesions appeared to be caused by M. kansasii, in 2 M. scrofuluceum, in 3 M. intra-

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cellulare and in 2 M. fortuitum In the remaining 4 the strains were not classified. They were niacin and peroxidase negative and resistant to many drugs; but the early cultures were no longer available for conformation of the species. Seven patients had histories of respiratory disability, usually ventilatory obstruction, and 1 of these had fibrosing alveolitis. Two other patients had had pulmonary tuberculosis but both had been sputum negative for many years before the opportunist mycobacteria were isolated. Two patients developed caseous bronchopneumonia but none had general dissemination. The limited effect of chemotherapy in many of the patients has been previously described (Goldman, 1968), Five of the 27 patients died, but in all of them there were other contributory factors. Resection was done in 9. In some other patients resection was not possible and one patient refused surgical treatment. One patient died post-operatively from haemorrhage and a broncho-pleural fistula. A high incidence of such complication has been mentioned by various authors (Harrison and others, 1959; Corpe and Liang, 1960). Pathological material was available from 7 patients who had a resection and from 1 necropsy. The original reports and subsequent ones on specimens re-examined failed to show any characteristic histological features. Giant cell systems in the bronchial mucosa after prolonged chemotherapy were reminiscent of those seen in tuberculous lesions before the introduction of effective chemotherapy. Radiology

There is disagreement over the specificity of the radiographic changes which follow pulmonary infection by opportunist mycobacteria. Chapman (1962) stated that in up to 50 per cent of patients the appearance becomes sufficiently characteristic to suggest the diagnosis but is by no means pathognomonic. The changes have been enumerated by Bonte and others (1960) and by Heitzmann, Bornhurst and Russell (1968). Their comparisons with tuberculosis may be summarised as follows: (1) Cavities have thinner walls and show little surrounding exudate (2) Nodular shadows of granulomata occur less frequently (3) Spread to other parts of the lung is less frequent and less extensive (4) Fibrotic reaction is less marked and hilar retraction not so common or so severe (5) Pleural reaction in relation to the cavitary disease may occur but is less at the base. Seibert and Tabrisky (1969) generally agreed with these findings but described cavities as being ‘well demarcated and large for the amount of disease present with little surrounding infiltration’ rather than thin-walled. If the patients with silicosis are excluded from their series, about one-third TABLE H-CLASSIFICATION OF RADIOCRAPHKAPPEARANCES IN 27 PATIENTS

Group A (5 cases)

Group B ( I2 cases)

Group C (5 cases) --- _____ Group D (5 cases)

A group of opacities roughly one centimetre in diameter, around a central transradiant area, with peripheral line shadows (e.g. Figs 1 and 2) A thick-walled ring shadow i.e. a definite cavity. (i) Central cavitation - 6 cases (e.g. Fig 3) (ii) Eccentric cavitation - 6 cases (e.g. Fig 4) -_____ Large cavities in a shrunken upper lobe (e.g. Fig 5)

-_

--

____

__~_

Small cavities or dilated bronchi in a shrunken upper lobe (e.g. Fig 6)

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showed features regarded as distinctive; hilar elevation and retraction were ‘quite common’. The remaining patients showed appearances indistinguishable from those of tuberculosis or fungus infection, and no differences were obvious between disease due to various opportunist mycobacteria. To discover whether there are, in fact, radiographic appearances distinct from those of pulmonary tuberculosis will require larger and more carefully controlled investigations than have so far been possible. In the present case studies the radiographic appearances were somewhat at variance with these reports and are summarised in Table II. Patients in Group A have distinctive radiographs not

Frti. 1 Male (C.B.) aged 48--M. kansasii (sputum) 1cm. opacities left upper zone grouped round a central transradiant area of uninvolved lung. No cavity. Line thadows radiating out towards the pleura.

FIG. 2 Male (H.M.) aged 44 --M. kansasii (sputum) Shadows left upper zone similar to Fig. 1. Transradiant area not a cavity, wall incomplete laterally.

previously described and are characterised by opacities roughly 1 cm in diameter grouped round central transradiant areas (probably unaffected normal lung tissue rather than a cavity). From the homogenous shadows, several line shadows radiate towards the periphery (Figs. 1 and 2), an appearance very rarely seen in tuberculosis. In 1000 consecutive cases of pulmonary tuberculosis with M. tuberculosis in the sputum (500 British, 500 Hong Kong) no shadows were seen with these characteristics. Group B patients show a relatively small but comparatively thick-walled cavity which may be central (Fig. 3) or eccentric (Fig. 4). The appearances would raise suspicion of a neoplasm rather than tuberculosis. In Group C, patients have larger cavities all in shrunken upper lobes, an example being shown in Fig. 5. Group D consists of those patients with upper lobe shrinkage but with slight cavitation or only tubular shadows indicating bronchiectasis (Fig. 6), an appearance seen also in.tuberculosis, allergic aspergillosis (McCarthy and Simon, 1970) and ‘bird fanciers’ lung (Hargreaves, Simon and McCarthy, 1971). Thus, the apparently more specific changes (Groups A and B) were seen in 17 patients (63 per cent) while the less distinctive upper lobe shrinkage (Groups C and D), with or without gross cavitation, was seen in 10 patients (37 per cent). Twelve of 16 patients infected with M. kunsasii had group A or B changes, compared with only 5 of 11 infected with other organisms (the difference is not significant) (Table III).

OPPORTUNIST

FIG. 3 kansasii (sputum) Male (C.Ba) aged 5&M. Thick walled central cavity left upper zone.

FIG. 5 Male (L.D.) aged 62-M kansasii (sputum) Large cavity in shrunken upper lobe.

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239

FIG. 4 Male (E.D.) aged 24-M. scrofulaceun~ (sputum) Eccentric cavity in opaque area left upper zone.

FIG. 6 Female (L.T.) aged 36-M. forlrrifum (sputum) Shrunken left upper lobe with patchy clouding in it and tubular shadows (of bronchiectasis).

The disease, as in pulmonary tuberculosis predominantly involved the upper lobes. Radiographically it followed a fluctuating course. In 7 the appearances remained unchanged, but 4 of them had a resection and were followed for an average period of only 1 year. In 11 patients there was deterioration; 4 died. In only 1 of the 11 patients did the sputum become negative on culture. Of the 9 in whom there was radiographic improvement 5 became sputum negative; but in the remaining 4 the sputum remained positive.

240

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