MONILIA INFECTION OF THE LUNGS (BRONCHOMONILIASIS)* KANO IKEDA

Monilia infection of the lungs, variously known as bronchomoniliasis, bronchopulmonary moniliasis, etc., represents a chronic and slowly progressive inflammation in which pathogenic monilia is understood to play a cardinal etiologic r61e. The condition was first recognized by Castellani2 in 1905 among the tea workers of Ceylon and, for a time, thought to be a tropical or subtropical disease. Numerous cases have since been reported from various parts of the world. The first case in the United States was recorded in 1915 by Boggs and Pincoff1 in the Bulletin of the Johns Hopkins Hospital. Bronchomonihasis is no longer considered a rare condition, although the diagnosis must be made with extreme caution since the organism is frequently demonstrated in the secretions of the upper air passages of normal individuals and particularly in the sputum of patients suffering from chronic pulmonary disease, notably, tuberculosis. Since the infection seldom terminates fatally and only rarely the cases have come to necropsy and since the investigators are, as a rule, interested more in the clinical aspect of the disease and in the organism as its possible etiologic agent, rather than in the pulmonary lesions produced thereby, reports dealing with the pathologic anatomy of this condition have been few and inadequate.6 CLINICAL SYMPTOMS

On the other hand, the clinical history and symptoms of bronchomoniliasis have been fully recorded in a number of excellent case reports, notably by Castellani2, Joekes and Simpson,8 Johns,7 Stovall,11 Warr,13 and others. * From the Pathological Laboratory of the Charles T. Miller Hospital, Inc., St. Paul, and the Department of Pathology, University of Minnesota, Minneapolis, Minnesota Read before the annual meeting of the American Society of Clinical Pathologists, Kansas City, Mo., May 8th-10th, 1936. Received for publication February 23d, 1937. 376

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Bronchomoniliasis may be recognized clinically in one of three forms, the mild, the intermediate and the severe. In the mild form, the patient merely complains of a slight cough without temperature elevation or the appreciable physical signs of pulmonary disease. The sputum is scanty and mucoid in character, the cough may continue for weeks or months. The usual diagnosis of chronic bronchitis is made after the routine elimination of early pulmonary tuberculosis. Frequent recurrence of the symptoms is a characteristic clinical feature. In the intermediate form, the clinical symptoms and physical signs are more exaggerated. There is a persistent low grade fever; the cough is more troublesome; the sputum is muco-purulent and tenacious and may be abundant. There is frequent recurrence of symptoms. The diagnosis of chronic bronchitis, bronchiectasis, or bronchial asthma is usually made although the possibility of pulmonary tuberculosis is never altogether excluded. In the severe form, two clinical types may be recognized: In the first type, the patient suffering from the mild or intermediate form of this condition may suddenly develop an acute pneumonia involving a wide area of the lung. This may be a typical form of lobar or bronchopneumonia or as a diffuse inflammation of the lung, in which pyogenic microorganisms usually play an etiologic r61e, while, at the same time, the fungus finds a fertile soil for further multiplication. The patient is acutely ill with elevation of the temperature and all evidence of acute pulmonary infection. This, lasting for a week or more, may subside completely or may be followed by an empyema or other complications of acute pneumonia. The second type of the severe form may result from a complication of the preceding type, or may represent a progressive low grade infection of a long standing in which no etiologic agents can be demonstrated save the pathogenic monilia and which offers the utmost difficulty in differential diagnosis. A diagnosis of chronic advanced pulmonary tuberculosis is favored in spite of the repeated absence of tubercle bacilli in the sputum. It runs a chronic course with periods of exacerbation. The patient may run a hectic temperature and complain of night sweats; there is a gradual emaciation and loss of weight and strength, and the patient suffers from attacks of dyspnea and severe paroxysmal cough which is worse during the night. The sputum is usually copious in amount, muco-purulent, tenacious, glairy, and often hemorrhagic. It is described as "curdy," "lumpy" or "gruel-like" by various authors. It may suggest an yeast-like or sweetish odor. Occasionally, the secondary, or co-existing bacterial invaders may greatly alter the character of the sputum. Physical examination elicits signs of patchy consolidation and fibrosis and of bronchiectasis or small cavities, usually limited to the lower fields. In the final stages of the disease a gradual failure of the right heart may develop, which is directly responsible for the death of the patient. This last possibility is not mentioned by other authors.

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The roentgenogram of the lungs merely may show the usual changes of chronic bronchitis or bronchiectasis. In the severe form, there may be a wide spread shadow indicative of an acute diffuse pneumonia. More frequently, soft, irregular, mottled or feathery shadows with peribronchial thickening and infiltration and intervening areas of emphysema throughout a greater portion of the lungs are described. Cavities may be present occasionally while the pleura may be thickened in chronic severe cases. These constitute a picture often interpreted as chronic pulmonary tuberculosis or chronic mycotic pneumonia. LABOKATOKY DIAGNOSIS

The mere demonstration of the yeast-like organism of the Genus Monilia in the sputum does not constitute the diagnosis of bronchomoniliasis. The sputum must be obtained directly from the lungs, after having taken every precaution to prevent possible contamination from other sources. It is, as a rule, quite tenacious and mucopurulent, and may be blood-tinged or frankly hemorrhagic during the acute stage. It often simulates a typical "asthmatic" sputum in consistency and general appearance. On close inspection, small, whitish granules may be observed which represent minute masses of the organism. The sputum is persistently negative for tubercle bacilli. There may be a predominance of eosinophiles. On stained smears or wet preparations, the yeast-like bodies, budding forms and sometimes branching filaments of the fungus are demonstrated with comparative ease, especially during the active stage of the disease (fig. 1, A). The isolated organism should be subjected to the known methods of identification and its pathogenicity determined through animal inoculations. It is generally agreed among the medical mycologists that M. albicans is the only species of the Genus Monilia which is pathogenic to man and should be regarded as responsible for the development of bronchomoniliasis. It is therefore imperative that the identity of the isolated fungus be established before the significance of the finding is made known. MODE OF INFECTION

Monilia is resistant to drying and may live indefinitely in dust and dry environment. Inhalation of contaminated dust or air probably plays the most important r61e in the transmission of the fungus deep into the respiratory tract. The occurrence of this condition among the tea tasters and the coolies working in the dust of the tea factories in India,3 among the pigeon dealers who handle dried bird food,9 among the pedlers of dried fruit and straws in Egypt,4 all point to inhalation as the most probable means of transmission. Secondly, monilia may exist as saprophyte in the upper air passages. An yeast-like fungus is frequently observed in the secretions of the nose and

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throat and the accessory sinuses. Under favored conditions, the organism may invade the lungs. Likewise, monilial lesions of the skin and mucous membrane elsewhere in the body may be a source of infection.

FIG. 1. A. Monilia albicans in the sputum of a typical clinical case of bronchomoniliasis. B. Gross specimen of the lung, after fixation, showing areas of acute pneumonia in which are noted bronchiectasis, emphysema and fibrosis; from a case of clinically undiagnosed chronic non-specific pneumonitis of several years' duration believed to represent an example of bronchomoniliasis. The transmission from man to man may also be a possibility. More than one member of the same family have been known to be afflicted with this condition. AMERICAN JOURNAL OF CLINICAL PATHOLOGY, VOL. 7, N O . 5

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IKEDA

Since the fungus requires an acid medium for life, there must necessarily be some chemical changes in the otherwise alkaline secretion of the bronchus to favor the continued growth of the organism. This suggests the existence of a pre-existing, primary lesion which must alter the chemical reaction of the tissue before the invasion of monilia can take place. PATHOLOGY

Early pulmonary lesions of bronchomoniliasis have not been described and probably can not be distinguished from those caused by any other form of inflammation. It is possible that a primary bacterial or allergic inflammation of the bronchi or the pulmonary parenchyma may, first, prepare the "soil" for the invasion and growth of monilia which, once planted firmly in the tissue, continues to live a tenacious, semi-saprophytic existence and to mildly stimulate chronic irritation and a resulting low grade inflammation. This conception is supported by the findings in a case of chronic bronchial asthma in whom not only was disclosed the infestation of Monilia in the polypoid mucosa from the antrum which had been removed at operation during life but also within the walls of the bronchi and in the regional lymph nodes at necropsy, several months later. This may be considered the pathologic basis of bronchomoniliasis in the early stage.6 The continued low grade inflammation of the bronchial wall adds susceptibility to a recurrent acute infection including probably small localized areas of pneumonia which undoubtedly favors the more rapid growth of the fungus. This results in the formation of small abscesses or pseudotubercles in the involved areas such as described by Mendelson10 who was the only observer to report the small tubercles which "in reality are mycotic tumors which stand out as very prominent masses," in the lungs of individuals who were afflicted with this condition but who died from other causes. These "mycotic tumors," which are easily reproduced in experimental animals, probably undergo resolution in the majority of cases, leading, as in animals, to complete recovery. Others may break down to form true abscesses which may coalesce to form larger ones. These abscesses may be the basis of the advanced form of bronchomoniliasis or may eventually heal and be replaced by fibrous scar. Only a partial healing is usually the rule and a long continued suppurative and proliferative pneumonitis results in which the major pathologic lesions include the scattered areas of fibrosis, bronchiectasis and abscess formation with intervening and adjacent zones of atelectasis and emphysema (fig. 1, B). In other instances, a chronic pneumonia of unknown origin may become infested with pathogenic monilia which by "adding insult to injury," completes a clinico-pathologic picture of bronchomoniliasis. Overwhelming infestation of monilia in chronic specific lesions such as advanced pulmonary tuberculosis, may actually bring about complete annihilation of the primary etiologic agent, thereby transforming it to true bronchomoniliasis—a speculation which may well be within the realm of possibility.

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Microscopically, as in gross appearance, there are no lesions specific for this condition. More conspicuous are the non-specific granulomatous lesions in which equally active are fibroblastic proliferation and cellular exudation, the

FIG. 2. A. A granulomatous area showing a rich infiltration of plasma cells in which are seen a few distorted air spaces. A section of the lung, shown in figure 1, B. B. Nests of yeast-like cells along the perivascular space bordering on an area of chronic exudative pneumonia shown in A. (Gram-Weigert stain.) infiltrates being usually entirely of plasma cells, less frequently of polymorphonuclears or of mixed cellular elements (fig. 2, A). Other changes include the peribronchial and perivascular round cell infiltration, proliferative endarteritis

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and the proliferative reaction of the alveolar epithelium, all denoting a long continued, low grade inflammation. Distinct abscesses or bronchiectatic

B FIG. 3. A. An area of acute hemorrhagic pneumonia produced by intrapulmonary injection of 1 cc. of a saline suspension of Monilia culture, showing diffuse extravasation and edema and rapid growth of the organism which penetrates mto the lumen of the vessels. Animal killed 2 days after injection. B. A high power view of a partly thrombosed capillary in a pneumonic area, showing apparent penetration of a mycelium through the wall. cavities lined with a heavy zone of infiltrates are frequently encountered. There are also areas predominantly productive in type with spreading interstitial fibrosis which obliterates alveoli and causes atelectasis and emphysema of the

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adjacent parenchyma. The macrophages are conspicuous in the neighboring, less active areas while foreign body giant cells may be occasionally observed. The presence of monilia—the nests of yeast-like bodies and mycelia—cannot be demonstrated by the routine H and E stain which accounts for the universal failure to make the pathological diagnosis of this condition. The GramWeigert stain brings out the fungus very distinctly and should be employed in every case presenting obscure chronic suppurative lesions of the lungs. The

FIG. 4. A. A section of a lung of a rabbit killed 5 days after intratracheal injection of the organism in suspension. Note several white mycotic "tumors" along the main pulmonary artery. B. A pleural surface of a lung of a rabbit killed 5 days after intrapulmonary injection of the organism in suspension. Note several white mycotic nodules over the surface. yeast-like bodies are scattered through the lesions particularly in the walls of the abscess and perivascular spaces (fig. 2, B). They are doubtless taken up by the lymphatics as a pseudo-foreign body. Mycelia are encountered less frequently. The regional lymph nodes are invariably infested with the fungus. With the finding of histo-pathologic characteristics already enumerated and in the absence of other specific etiologic agents in the lesion and in the light of the positive clinical and laboratory findings, a pathologic diagnosis of bronchomoniliasis may be reasonably made.

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KANO IKEDA SUMMARY OP ANIMAL EXPERIMENT

The pulmonary lesions were reproduced in animals (rabbits and guinea pigs) experimentally by means of the intravenous, intratracheal and intra-

FIG. 5. A. A nest of mycelia in a mycotic "tumor" or abscess obtained by intrapulmonary injection of the organism. B. A small caseous abscess showing a beginning of calcium deposit in the lung of a rabbit killed 72 days after intrapulmonary injection of the organism. pulmonary injections of the organism. Saline suspensions of the growth from a young culture of M. albicans isolated from the sputum of a typical clinical case of the disease were used according to the technic suggested by Stovall.12

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The most striking result of the injection, in the majority of instances of rabbits was a rapidly developing miliary cortical abscess of the kidneys with a resulting uremia and death within a week. In these animals, miliary focal abscesses or "tubercles," often microscopic, were also observed in the liver, spleen and meninges. Few animals, on the other hand, developed the characteristic nodular lesions in the lungs. However, in the majority of instances where the intravenous or intratracheal injection was employed the pulmonary lesions were quite insignificant. Small isolated nodules were commonly observed, microscopically, in which the yeast-like bodies were apparently in the process of disintegration. The typical tumor-like nodules were produced in the lungs only in a small number of rabbits treated intravenously and intratracheally. These nodules, as a rule, developed along the main bronchovascular trees as several small, white, discrete, dry masses, well circumscribed and from 2 to 4 mm. in average diameter. They represented, microscopically, a mass of leukocytes and yeast-like bodies mixed with scattered mycelial filaments (fig. 4, A). The pulmonary lesions were best and most easily reproduced by the intrapulmonary inoculation of the suspension. The direct trauma to the pulmonary parenchyma and the resulting extravasation and serous exudation apparently furnished an ideal medium for rapid growth of the organism thus introduced. This resulted in the development of an acute hemorrhagic pneumonia, with the wide spread dissemination of the monilial filaments which invaded the vessels and caused the formation of thrombi (fig. 3, A and B). With the subsidence of acute inflammation, mycotic tumors developed at the site of pneumonia and along the over-lying pleura (fig. 4, B). These nodules, white, firm and well circumscribed, might coalesce and often break down to form an abscess. Microscopically, the abscess was filled with soft, cheesy material, pus cells and a few scattered collections of monilial bodies and filaments, the latter often in palisade arrangement along the borders of the mass (fig. 5, A). A zone of active fibroblastic and capillary proliferation surrounded the abscess. In later stage, these abscesses underwent calcification and a few became transformed into calcified tubercles (fig. 5, B). A striking observation was the extreme pleomorphism of this fungus in the experimental lesion. This ranged from a small coccal or a long bacillary form to a club-shaped mycelium or a long, sometimes branching, filamentous thread, with various intermediary forms, which, in many instances, can not be morphologically identified as monilia. DISCUSSION

The question of whether bronchomoniliasis constitutes a primary disease entity can not readily be answered. Certainly, the clinical diagnosis of this condition through the mere demonstration of pathogenic monilia in the sputum seems unjustified.

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Evidence at hand appears to indicate that monilia is probably a secondary invader in a primary lesion already in existence and that it contributes largely to the continued and progressive activity of that lesion. There are, however, several pertinent observations which may be advanced in favor of the opinion that the fungus may, in a limited sense, at least, act as an etiologic agent: (1) The therapeutic effect of iodides is almost specific. A marked symptomatic improvement, often with complete clinical cure, has been reported. (2) A systemic dissemination of pathogenic monilia appears a possibility as is evidenced by the recovery of this organism from the urine in cases of bronchomoniliasis and by the demonstration of the yeast-like bodies in the regional lymph nodes and in the spleen. (3) No other definite etiologic agents are demonstrated in the pulmonary lesions at necropsy. (4) The condition is undoubtedly consistently overlooked in our routine necropsies, due chiefly to the failure to carry out certain technical details to demonstrate the organism in culture as well as in the lesion. The H and E. stain does not bring out the organism in the tissue. (5) The human lesions can be duplicated in the laboratory animals to which the organism is highly pathogenic. (6) Finally, mention should be made of that unexplored field of allergy, tissue sensitivity or susceptibility which appears to play an important role in the pathogenesis of this condition as was suggested by the experiment of Kurotchkin and Lim. 8 The sequence of events leading up to the development of this condition may be described as follows: The fungus gaining its entrance in the lower air passages begins to multiply in the inflammatory exudate in the presence of bronchitis, bronchiectasis or pneumonia; may penetrate the wall of the bronchus or reaching the alveoli, invade the pneumonic area, to prevent resolution and to continue to multiply, producing a low grade suppurative inflammation; this may continue indefinitely, perhaps for many years, in a vicious circle and predisposes the involved areas to periodic attacks of pneumonia which sooner or later develops into a chronic lesion with areas of fibrosis and suppuration. It would thus appear that a pre-existing, primary lesion in the lung is

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essential to initiate the infestation by the fungus. The question of whether specific organisms, such as Tubercle Bacillus, may not be exterminated by the overwhelming presence of monilia and its metabolic products is an interesting speculation. Certain mycotic infections of the lungs have long been recognized as entities. Blastomycosis and actinomycosis are the common examples. Their known pathogenicity to man and their ability to readily produce local lesions and to cause a systemic invasion and visceral involvement and eventual death have established them as definite clinico-pathologic entities. Monilia, on the other hand, is comparatively less pathogenic to man and often leads a tenacious, saprophytic existence in him. However, given a primary lesion in the lung with attendant bio-chemical changes in the tissue which afford a favorable medium for its unrestrained growth, coupled with the inherent or acquired susceptibility of the host, the fungus may become distinctly pathogenic in the lung of that particular individual and produce a chronic suppurative inflammation known clinically as bronchomoniliasis. CONCLUSIONS

The pathological anatomy of bronchomoniliasis in man and in experimental animals is described and its pathogenesis postulated. Bronchomoniliasis may be recognized as a pathologic entity. REFERENCES (1) BOGGS, T. R., AND PINCOFF, M. C.: A case of pulmonary moniliasis in the United States. Bull. Johns Hopkins Hospital 26: 407-410. 1915. (2) CASTELLANI, A.: Fungi and Fungous Diseases. Chicago, American Medical Association, 1927, pp. 121. (3) CASTELLANI, A.: Note on the importance of hyphomycetes and other fungi in tropical pathology. British Med. J. 2: 1208-1212. (Nov. 2) 1912. (4) GROSSI AND BALOG.

Cited by Warr (13).

(5) IKEDA, KANO: Bronchopulmonary moniliasis, its relation to obscure chronic pulmonary infection. • Arch. Path. 22: 62-81. 1936.

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(6) JOEKES, T., AND SIMPSON, R. H.: Bronchomoniliasis. Lancet 2:108-111. (July 21) 1923. (7) JOHNS, F . M.: Five cases of pneumonia in which Monilia pulmonaris were demonstrated. New Orleans M . and S. J. 77: 8-11. 1924. (8) KUEOTCHKIN, T. J., AND LIM, C. E.: Experimental bronchomoniliasis in sensitized rabbits. Proc. Soc. Exp. Biol, and Med. 31: 332-334. 1933. (9) MANTNEE, H.: Cited by Warr (13). (10) MENDELSON, R. W.: Tropical bronchopulmonary mycosis. J. A. M. A. 77: 110-112. (July 10) 1921. (11) STOVALL, W. D., AND GEEELEY, H. P.: Bronchomycosis; report of 18

cases of primary infection in lung. (Nov. 3) 1928.

J. A. M. A. 91: 1345-1351.

(12) STOVALL, W. D., AND PESSIN, S. B.: Classification and pathogenicity of

certain monilias. Am. Jour. Clin. Path. 3 : 347-365. 1933. (13) WAEB, OTIS S.: Bronchomoniliasis: Clinical and pathological study with report of illustrative cases. Ann. Int. Med. 6: 307-332. 1931.