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OFFICIAL JOURNAL OF THE CALIFORNIA MEDICAL ASSOCIATION

©1954, by the California Medical Association . Volume 81 DECEMBER 1954 Number 6

Pulmonary Mycotic Infections Allergic and Immunologic Factors EDMUND L. KEENEY, M.D., San Diego

* The mechanisms of immunity and allergy, and the immune antibody must be considered at play in every infectious disease, must be as two different and distinct antibodies. comprehended before the pathogenesis of an Skin and serologic tests are important diag- infection can be appreciated. nostic aids in certain pulmonary mycotic infec- Immunity, allergy and serology are con- tions-for example, , blasto- cerned with specific antigen-antibody reactions. , and moniliasis. In immunity the principal concern is with the final disposition of antigen (agglutination, Clinical expressions of allergy may appear in lysis, and phagocytosis). In allergy attention is *coccidioidomycosis, histoplasmosis and moni- focused upon tissue damage resulting from liasis. antigen-antibody union. In serology interest is Pulmonary mycoses are divided into three devoted to the presence of antibody as evalu- groups, that is, the endogenous mycoses ated by certain visible in vitro reactions-pre- (actinomycosis, moniliasis, geotrichosis), the cipitin, agglutination, opsonization and com- endogenous-exogenous mycoses (cryptococco- plement fixation tests. sis, , ) and the exogen- There are two types of allergic reaction- ous mycoses (nocardiosis, coccidioidomycosis, the immediate or anaphylactic type and the de- histoplasmosis, North American ). layed type or the allergic disease of infection. The diagnosis and treatment of the impor- Neither kind takes part in the mechanism of tant mycotic infections that invade lung tissue immunity. At this time the allergic antibody are discussed.

To APPRECIATE the pathogenesis of an infectious certain bacterial and viral infections, there is a pau- disease it is essential to have knowledge concerning city of information of this kind with regard to my- the mechanisms of natural immunity, acquired im- cotic infections, for they have been less carefully munity and allergy pertinent to the infection under scrutinized than the bacterial and viral diseases. consideration. Such data are not available for all In any discussion dealing with immunity and al- infections but it is helpful. to project accessible in- lergic sensitivity it is imperative to understand what formation for the better understanding of the infec- is meant by the terms antigen and antibody. Anti- tious processes that have not as yet been exhaus- gens are substances of protein or polysaccharide tively studied. Although these data are available for nature which, upon injection into an animal body, Presented as part of a Panel on Diseases of the Chest before the stimulate the formation of antibodies. A molecule Section on General Practice at the 83rd Annual Session of the Cali- fornia Medical Association, Los Angeles, May 9-13, 1954. to qualify as an antigen must have a molecular VOL. 81, NO. 6 * DECEMBER 1954 367 weight of 10,000 or more, and possess upon its munity. Although the antibodies responsible for surface a repetition of certain chemical groupings. eliciting serologic reactions are the same antibodies These chemical groupings determine the specificity that neutralize the virulent properties of an offend- of the antigen, and the most important constituent ing microorganism, resistance to infection is not al- of a group is an acid radical. Any one invading ways due to antibody. However, serologic reactions microorganism may be likened to a bag filled with do give clues at times to the nature of the potential an assortment of different antigens. protective activities of antibodies in vivo, and they An antibody is a plasma globulin molecule. Anti- are of course of great value in providing methods bodies, except for their ability to react specifically for diagnosing the existence of an infection. The with antigen, are frequently the same as normal precipitin, the agglutination, and the complement gamma globulin. The concentration and character fixation tests are used with advantage in the diag- of antibodies may be assessed by their physicochem- nosis of certain mycotic lung infections. In not a ical properties; for instance, precipitation by salts, single instance of a fungous infection do these tests analysis in the ultracentrifuge, and analysis in the measure immunity. Tiselius electrophoresis cell. The presence of anti- The concepts of the mechanisms of acquired re- bodies may also be evaluated by a number of sero- sistance (immunity) are fairly simple ones. The logic reactions. There are five major manifestations offending organism is possessed of ability to over- of antibody existence to be noted visibly by sero- come the native resistance of the body, and this act logic reactions: (1) antibodies may precipitate sol- gives the microorganism virulence. The host then uble antigens (precipitin test); (2) antibodies may acquires antibodies which neutralize the virulence cause the aggregation of antigens, if the antigen is properties; hence the microorganism is finally at the in particulate form as part of a bacterial or other mercy of the body's defenses (phagocytic properties cell (the agglutination test); (3) antibody plus the of leukocytes and macrophages). In this scheme we component of normal serum known as complement are concerned with a specific antigen-antibody reac- may cause cells representing antigen to undergo tion, and our attention is directed particularly to- lysis; (4) antibody may bring about a combination ward the final disposition of the antigen. of antigen, such as bacteria and other cells, so as to In all infectious diseases it is not always possible make phagocytosis by leukocytes and macrophages to correlate the presence of antibodies with the im- much more effective (the opsonization test); (5) mune state. Some other mechanism may function antibody combined with almost any antigen will ab- as the harbinger of resistance in place of antibody. sorb complement even though the union be an in- For example, humoral factors other than antibodies visible one (the complement fixation test). may be acquired and give resistance, and alterations There is still a tendency to ascribe the various may take place in the phagocytes which enable them serologic reactions to the activity of a particular to destroy microorganisms more effectively. kind of antibody. It is not uncommon to see state- The study of allergy also deals with specific anti- ments in the literature that "precipitating antibod- gen-antibody reactions. In the mechanism of the ies," "complement fixating antibodies," and "agglu- allergic reaction we are not concerned with what tinating antibodies" are formed during the course happens to the antigen; we are interested in what of an infection. Such statements simply infer that happens to the tissue as a result of the antigen- separate and distinct antibodies are responsible for antibody reaction. each of the serologic reactions. This is not always As one examines the various manifestations of the case. A single antigen in pure state produces only allergy in man one becomes aware of the different one variety of antiboay, and this antibody present types of reactions and the manner in which these in the serum is capable under proper conditions of reactions are induced in an allergic person. Some combining with antigen to produce a variety of sero- forms of allergic reaction (immediate or anaphylac- logic reactions. It is not meant to imply, of course, tic type) may be induced by the entrance of a sim- that only one antibody is produced in the body re- ple antigen into the tissues. Other forms of reaction sponse to invasion by a microorganism; every mi- (delayed type or allergic reaction of infection) are croorganism is a mixture of many antigens. dependent upon the entrance of entire infectious The site of antibody globulin formation in the agents into the body. body probably depends upon the nature of the anti- In the kind of allergy that is established by ordi- gen and the route of entrance into the body. At pres- nary and simple antigens, the subsequent response ent it is believed that three kinds of cells take part to the same antigen takes place immediately. It is in the manufacture of antibody: reticuloendothelial allergy of this type that is present in patients with cells, plasma cells, and lymphocytes. hay fever, , urticaria, eczema, serum disease, There are loose concepts in the minds of many erythema nodosum, erythema multiforme, migrating that the measure of antibody concentration (titer) phlebitis, periarteritis nodosa, rheumatic fever and by serologic tests measures also the degree of im- possibly acute glomerulonephritis. Persons with al-

368 CALIFORNIA MEDICINE TABLE l.-Endogenous pulmonary mycoses. Geographical Appearing in Sputum Identified by Cultured Disease Distribution Organism Source as Growth on- Actinomycosis World wide Actinomyces Israeli Tonsils, gums "Sulphur granules" Brewer's Thioglycol- late medium, 370 C. Moniliasis World wide Mouth, skin, va- Budding cells, Sabouraud's 300 C. gina, gastrointes- Mycelia tinal tract Geotrichosis World wide Geotrichum sp. (spe- Mouth, gastro- Rectangular and Sabouraud's 300 C. cies not identified) intestinal tract spherical cells

TABLE 2.-Endogenous-exogenous pulmonary mycoses. Geographical Appearing in Sputum Identified by Cultured Disease Distribution Organism Souree as- Growth on- World wide Cryptococcus Soil, skin Budding yeast cells Sabouraud's 300 C. neoformans with wide capsules Aspergillosis World wide fumigatus Soil, grains, Broken fragments of Sabouraud's 30° C. (at times, grasses, respira- mycelium. Small, other species) tory tract round conidia Mucormycosis World wide Mucor corymbifer Soil, skin, Fragments of non- Sabouraud's 300 C. (at times, other respiratory tract septate mycelium species) lergy of this type have humoral antibodies that may it must be generally conceded that inflammation is be transferred by means of their serum to normal helpful to the body in impeding the spread of micro- individuals. Only certain cells of the body become organisms by calling forth rapidly an accumulation sensitized and take part in the allergic reaction; for of phagocytes, it does not necessarily follow that the example, endothelial cells, smooth muscle cells and exaggerated inflammatory reaction of allergy ampli- collagen. These manifestations are regarded as char- fies protection. It has been ably demonstrated that acteristic of the immediate or the anaphylactic type organisms begin to spread before the allergic re- of allergic reaction. action takes place and, furthermore, the organisms In the kind of allergic reaction which is dependent are spread with the rush of fluids that accompany the upon invasion by the entire infectious agent there violent inflammation. Thus the milder inflammation are definite characteristics which separate it from provoked by the antigenic stimulus in nonallergic the immediate type: The reaction of the tissues to tissue is more protective in its localizing attributes antigen is delayed; humoral antibodies are not pres- than the intense inflammatory reaction of allergy. ent; any cell of the body may be destroyed following There is, therefore, no evidence at this time to contact with antigen. This type of allergic reaction, consider the allergic reaction as a part of the mech- spoken of as the delayed type or the allergy of in- anism of immunity in infectious diseases. fection, is responsible for the tissue damage in tuber- With these fundamental thoughts in mind with culosis, coccidioidomycosis, histoplasmosis, blasto- regard to allergy, immunity and serologic reactions, mycosis, , moniliasis and many other one is in a better position to appraise the patho- infectious diseases. The presence of this kind of genesis of infectious diseases. Hence, the signs and allergy is demonstrated by delayed positive reaction symptoms produced by mycotic infections and the to skin test with antigenic materials such as tuber- diagnostic significance of serologic and skin reac- culin, coccidioidin, histoplasmin or blastomyces tions in these diseases can be more fully appreciated. vaccine. The pulmonary mycoses may be divided into What then may be the relationship of allergy to three groups, the endogenous mycoses, the endoge- immunity? The allergic reaction could be of assist- nous-exogenous mycoses and the exogenous my- ance to the body in resisting an invading micro- coses. Actinomycosis, caused by Actinomyces Israeli, organism if the antibody responsible for the allergic moniliasis caused by Candida albicans, and geo- reaction were also the antibody responsible for trichosis caused by species of Geotrichum are consid- resisting the invasion and progress of the micro- ered to be endogenous mycoses (Table 1) . The fungi organism. However, this possibility has never been responsible for these infections may and do live in substantiated. It must be concluded at this time that various regions of the human body without becom- the allergic antibody and the immune antibody are ing parasitic. Actinomyces Israeli may be found in not the same, but are two different antibodies. tonsillar crypts, in dental scum and about carious The allergic reaction, whether immediate or de- teeth. Candida species are inhabitants of the normal layed, might aid resistance to infection if the intense mouth, intestinal tract and , and may be cul- inflammation produced by the allergic reaction could tured from these sites in 35 to 40 per cent of normal restrict the spread of an infectious agent. Although persons. Geotrichum species are frequently isolated

VOL. 81. NO. 6 * DECEMBER 1954 369 TABLE 3.--Exogenous pulmonary mycoses. Geographical Appearing in Sputum Identified by Cultured Disease Distribution Organism Source as Growth on- Nocardiosis World wide Nocardia asteroides Soil Granules. Short and Veal infusion agar long fragments of (1o glucose). mycelium Sabouraud's 30° C. Coccidioido- Southwest U.S.A., immitis Soil "Spherules" Sabouraud's 300 C. mycosis Northern Mexico, Argentina Histoplasmosis Central U.S.A. In Histoplasma Soil Small yeast-like cells Sabouraud's 30° C. other specific capsulatum (cottony). Blood agar areas of world 370 C. (yeast-like) North American Southeast U.S.A., Blastomyces Soil Doubly contoured, Sabouraud's 300 C. Blastomycosis Central U.S.A., dermatitidis granular, budding Blood agar370 C. North America cells (yeast-like)

TABLE 4.-Mycotlc Infections In which allergy and serology In reactions are Important. Serologic Reactio Complement Laboratory Expressions Precipitin Fixation Agglutination of Allergy Skin Tests Test Test Test Disease Organism Clinical Expressions of Allergy with: Positive Positive Positive Coccidioido- Coccidioides In primary phase: Morbilliform Coccidioidin: Yes Yes Not mycosis immitis rash, erythema nodosum, erythema Positive suitable multiforme, arthralgia, phlyctenu- lar conjunctivitis Histoplasmosis Histoplasma In disseminated form: Purpura, Histoplasmin: Not Not Not capsulatum urticaria, erythema Positive evaluated evaluated evaluated North American Blastomyces 0 Blastomycin and blas- Yes Yes Not Blastomycosis dermititidis tomyces vaccine: suitable Positive Moniliasis Candida Asthma, urticaria, eczema Candidin and Candida Yes Not Yes albicans vaccine: Positive evaluated from the mouths and the intestinal tracts of patients histoplasmosis, blastomycosis) occur predominately without disease. The native resistance of the body in certain restricted geographical areas. These three prevents these microorganisms from becoming in- mycotic infections have certain common character- vasive. However, native resistance is flexible and in istics. For example: They occur mostly in the United certain circumstances these same fungi may sur- States; the gross cultural characteristics of two of mount all barriers and proceed to invade, multiply the causative organisms (H. capsulatum, B. derma- and disseminate through the body. In these respects titidis) are similar; the allergic reaction of delayed the endogenous fungi act in a manner similar to type develops during the course of infection; with staphylococci and streptococci. moniliasis, they are the only mycotic infections in There are certain mycotic diseases that may be which a positive reaction to a skin test is a diagnos- endogenous as well as exogenous and these are: tic attribute; two of the mycoses (coccidioidomy- cryptococcosis, aspergillosis and mucormycosis cosis, histoplasmosis), with moniliasis, are the only (Table 2). Cryptococcus neojormans has been iso- mycoses that have clinical manifestations of the lated from apparently normal skin and soil; species allergic reaction of immediate type during the course of Aspergillus are found in the respiratory passages of infection; two of the mycoses (coccidioidomyco- of patients with chronic and asthma and sis, blastomycosis), with moniliasis, are the only my- in soil and on grains and grasses; species of Mucor coses which during the course of infection stimulate have been isolated from the respiratory passages and the production of the immune type of antibody and skin of normal persons and in soil. they are, therefore, the only mycotic infections in The endogenous and the endogenous-exogenous which serologic tests are of diagnostic aid (Table fungi, excepting Actinomyces Israeli and Cryptococ- 4). These similarities are recalled not with the pur- cus neolormans, become more virulent when the pose of relating the organisms or the infections to relationship of the normal flora of the body and their one another but expressly to stimulate a scheme of environment is altered by the prolonged administra- simple thinking about a subject which somehow or tion of the wide spectrum antibiotics. other has been made unnecessarily forbidding. The exogenous fungi (Table 3) survive and mul- The various mycoses in which pulmonary disease tiply in soil or on plant material. Of the four strictly is an important feature will now be discussed indi- exogenous mycoses only one, nocardiosis, is rather vidually. No longer do these infections play an un- evenly distributed throughout the world. The re- important and remote position in medicine and pub- maining fungous infections (coccidioidomycosis, lic health. Mycotic infections occur with sufficient

370 CALIFORNIA MEDICINE frequency to justify consideration of them in the borders of the lobules. By crushing the granule be- differential diagnosis of every difficult and compli- tween two slides and then staining with Gram's cated pulmonary infection, and even, under certain stain, the Gram-positive branched filaments can be circumstances, in supposedly benign and simple res-' demonstrated. These branched filaments make up the piratory diseases. interior of the "sulphur granules." Actinomyces Israeli is difficult to culture. The spu- THE ENDOGENOUS PULMONARY MYCOSES tum should be washed several times with sterile nor- mal saline solution. Suspected granules should be ACTINOMYCOSIS recovered with a bacteriological loop, washed again The term actinomycosis should refer only to in- in sterile normal saline solution, and then placed in fections that are caused by the anaerobes Actino- Brewer's thioglycollate medium and incubated at myces Israeli and Actinomyces bovis. Until the ap- 370 C. Colonies that gradually develop appear as pearances of the studies of Erikson,"' of England, fluffy discrete masses of variable size suspended in and later Thompson,28 of the Mayo Clinic, it was the the media. Mycelia do not project from the surface. opinion of the majority of investigators that human A satisfactory antigenic substance, prepared from and bovine actinomycosis were caused by the same the organism or from the broth in which the organ- anaerobic microorganism, and depending upon the ism has been grown, has never been isolated. There- investigator the organism was referred to either as fore, skin tests and serological tests, which would be Actinomyces bovis or Actinomyces Israeli. How- of doubtful diagnostic value anyway for this infec- ever, since the appearance of the sixth edition of tion, are not performed. "Bergey's Manual of Determinative Bacteriology" Treatment. Treatment for the most part is unsat- in 1948, Actinomyces Israeli has been catalogued as isfactory and consists of indicated surgical drainage, the cause of actinomycosis in human beings, and the administration of to the point Actinomyces bovis as the etiologic microorganism of intolerance, and x-ray therapy. There are numer- of the bovine infection. ous clinical reports in the literature proclaiming the Actinomyces Israeli commonly exists as a sapro- effectiveness of sulfonamides,22 penicillin,19, aureo- phyte in the oral cavity and has never been isolated mycin 7 and chloramphenicol.26 In the majority of from soil or vegetation. In the mouth the organism these reported cases surgical measures, iodides, and is commonly present in and about carious teeth, den- x-ray therapy supported the sulfonamide and anti- tal scum, and the crypts of tonsils. From such posi- biotic therapy, and it is, therefore, impossible to tions, the organisms may be inhaled or aspirated ascribe the entire clinical result to the use of these into the lungs to incite pulmonary infection. latter drugs. It must be concluded that necessary Diagnosis. The primary lesions in pulmonary surgical intervention, adequate x-ray therapy, and actinomycosis are usually bilateral and basal, but intensive iodide administration are essential ad- they may occur unilaterally in any portion of the juncts to antibacterial and antibiotic therapy if lung. In the primary site a granulomatous process is optimal results are to be obtained in the treatment of induced which usually extends to the mediastinum, this serious pulmonary infection. pericardium and heart, and/or to the pleura produc- ing pleural pain and occasionally pleural effusion. MONILIASIS Eventually the organism invades directly through Mycologists have replaced the familiar generic the pleura to the chest wall, giving rise to numerous term Monilia with the name Candida. However, the draining sinuses. Infrequently the pulmonary infec- term maniliasis, because of its common usage in the tion will be the result of a spread from the primary medical literature, has been retained in spite of sug- focus in one or more of the ribs. Rarely in pulmo- gestions that candidosis or candidasis might be more nary actinomycosis is there a spread to the regional appropriate. There are seven important species in lymph nodes, but metastasis by the blood stream to the genus Candida and these are: albicans, tropi- any part of the body may occur. calis, pseudotropicalis, Krusei, parakrusei, stellatoi- The diagnosis is established in the laboratory by dea, and GuiUiermondi. Only one of these species, isolating from the sputum the organism in the form albicans, is commonly pathogenic for man. of characteristic "sulphur granules." These granules Diagnosis. Bronchopulmonary moniliasis is the vary in size and shape and have a radiating lobu- term employed to designate that type of Candida in- lated structure and usually, although not always, are fection of the lungs in which the disease process is yellow in color. They are best observed with a low limited to the bronchial tree. Infection of this type, power microscope lens, but occasionally are large which is not at all uncommon, is manifest clinic- enough to be identified macroscopically or with a ally by the signs and symptoms of ordinary bron- hand lens. The interior of the granule does not stand chitis. The temperature may be normal or only out sharply, but the clubs of the periphery are very slightly elevated, and the health of the patient not refractile and appear as irregular lines marking the seriously affected. Pulmonary roentgenograms re- VOL. 81. NO. 6 * DECEMBER 1954 371 veal slight to moderate peribronchial thickening. culture form on Sabouraud's agar. On Sabouraud's The infection may disappear spontaneously or be- medium the organism grows as a yeast, but when come chronic and thereby mimic the symptoms of stab cultures are made in gelatin or corn meal agar chronic bronchitis of bacterial origin. the mycelial form of the fungus is produced. To Pulmonary moniliasis is the term for infections of make certain that the organism isolated is the patho- the parenchyma of the lungs. While the parenchy- genic species of Candida, it should be tested for mal is not so common as the bronchial infection, it fermentation reactions. C. albicans will form acid is more serious. Pulmonary moniliasis may resemble and gas in glucose, acid and gas in maltose, but miliary with cough, fever, dyspnea, only acid in sucrose media. Recently a technique pain in the chest, hemoptysis and night sweats. was described by Weld29 for the rapid identification There may be signs of pleural thickening. Areas of of C. albicans. consolidation resembling bronchopneumonia may Treatment. Bronchopulmonary moniliasis is best be scattered throughout two or more lobes and, in- treated with potassium iodide by mouth and sodium frequently, there may be lobar consolidation. caprylate by aerosol. The official solution of potas- The diagnosis of bronchopulmonary and pulmo- sium iodide should be given in as large a dose as nary moniliasis is fraught with difficulties. Isolation can be tolerated by the patient. One milliliter of a of the organism, particularly if the patient has re- 10 per cent solution of sodium caprylate (New and ceived antibiotics, is not conclusive. The organism Non-Official Remedies) should be given by aerosol frequently establishes itself in the bronchial mucous several times daily. Best results are obtained if a membranes as a secondary invader. A diagnosis total daily dose of 1 gram is reached. must be made indirectly by excluding all other con- Pulmonary moniliasis is treated in a manner iden- ditions, infections and that might affect tical to that of bronchopulmonary moniliasis. Gen- the bronchial and parenchymal tissue, and by re- tian violet should be given intravenously if the pa- peated demonstration of the organism in the spu- tient is not doing well on iodide and caprylate ther- tum. Actually there are no indisputable criteria for apy. The dosage is 5 mg. per kilogram of body establishing the diagnosis short of the impractical weight and may be repeated daily or every other day procedure of lung biopsy. for three to seven doses. Clinical manifestations of allergic reaction of the It is usually advisable before administering potas- immediate type may develop during the course of a sium iodide to give the patient three to four weeks C. albicans infection. Bronchial asthma was reported of specific desensitization treatment with C. albicans by the author14 to have followed a bronchial infec- vaccine. The prolonged use of a C. albicans vaccine tion. The asthmatic symptoms completely disap- in the management of patients with chronic infec- peared with the alleviation of the infection. The tions is also advisable. author'5 has also observed the development of urti- caria in a patient with cutaneous moniliasis. The GEOTRICHOSIS author'5 likewise has observed in the past year the development of typical allergic eczema in a two- Geotrichosis is a fungous infection due to one or year-old child one month following the administra- more species of Geotrichum. There has never been tion of aureomycin. C. albicaws was isolated from a careful study of the saprophytic and pathogenic the stools. After the organism was eliminated from species of the genus Geotrichum. The organism is the gastrointestinal tract the skin became normal. capable of producing lesions in the mouth, intestinal Eczematoid dermatitis of the face and certain cases tract, bronchi and lungs. of miliaria are thought to be allergic reactions to Diagnosis. Bronchitis is probably the most fre- Candida infections. Vesicular lesions on the hands, quently recognized manifestation of geotrichosis. referred to as moniliids and similar in appearance The symptoms are identical to those of chronic bron- to dermatophytids, are the result of allergic reac- chitis of bacterial origin. The sputum is often gela- tions to infections occurring elsewhere in the body. tinous; the pulse and temperature are rarely ele- Agglutinins and precipitins are occasionally pres- vated; and the general health is good. Medium and ent in the serum of patients with the severe forms of coarse rales are noticeable especially at the lung Candida infections. However, there are agglutinins bases. Diffuse peribronchial thickening is a nonspe- for C. albicans in the serum of many normal persons. cific condition observed in pulmonary x-ray films. Therefore, serologic tests are of doubtful diagnostic Invasion of the parenchyma of the lungs brings importance. Skin tests are of no value because posi- about signs and symptoms suggestive of pulmonary tive reactions occur in a large proportion of patients tuberculosis. The temperature is elevated, the pulse without active infection. accelerated and the leukocyte content of the blood The laboratory diagnosis of moniliasis is estab- increased. The sputum is mucopurulent and may or lished by isolating from the sputum budding cells may not contain blood. The physical findings are not and filaments, and by growing the organism in pure specific, but may lead to suspicion of tuberculosis. 372 CALIFORNIA MEDICINE Pulmonary roentgenograms reveal patches of in- the brain is by way of the blood stream. Crypto- filtration with or without cavity formation. coccosis, however, may rarely remain confined to Microscopic examination of the sputum reveals the lung; there are a few reports in the literature oblong or rectangular cells with rounded ends and attesting this isolation. Of course, it is quite con- large spherical cells which measure from 4 to 10 ceivable thaf pulmonary cryptococcosis might occur microns in diameter. At room temperature on Sabou- without being diagnosed, because few signs or symp- raud's medium the organism grows rapidly and toms accompany pulmonary involvement, and the forms a white to cream colored colony with a dry, organism is rarely looked for in the sputum unless it mealy surface. Microscopically the hyphae are seen has been previously demonstrated in the cerebro- to segment into rectangular arthrospores, which spinal fluid. The majority of cases of cryptococcosis vary in size and roundness of their ends. The rec- of the lungs, therefore, occur in patients who have tangular cells ordinarily germinate by a germ tube coexisting lesions in other tissues, especially the from one corner. This is a very characteristic find- central nervous system. ing in cultures of Geotrichum. It is common, although not unvarying, for pul- Treatment. Bronchial infections usually respond monary cryptococcosis to be accompanied by only rather quickly to iodide by mouth. The official solu- meager local and constitutional signs and symptoms. tion of potassium iodide should be administered in Symptoms when present are those of a cough with the largest dose that can be given with tolerance. some expectoration, and at times with hemoptysis. The pulmonary form of the disease should like- Occasionally pleural pain may appear or a small wise be treated with iodides, but such therapy should effusion be present in the pleural cavity. Rarely does not be instituted until tuberculosis has been ex- the infection cause disease of clinical severity. Phy- cluded in the differential diagnosis. If the infection sical signs, if present, are those of bronchitis or of does not respond to iodide therapy an autogenous consolidation. Pulmonary roentgenograms are help- vaccine should be prepared and immunization car- ful and important in making a diagnosis. In roent- ried out. Also in the event that iodides are ineffec- gen appearance the lesions may suggest a tumor, a tive, neomycin should be administered. Neomycin pyogenic abscess or a hydatid cyst. In addition to has proven effective in the treatment of Geotrichum these shadows there may be linear markings with septicemia,' and urinary tract infections.10 It must surrounding woolly shadows, which suggest in turn be emphasized that neomycin is a toxic antibiotic the findings common in pulmonary moniliasis. which causes deafness as well as renal damage if The only exacting proof of pulmonary crypto- administered for more than a short time. coccosis is the finding of the organism in the spu- tum. Fortunately the Ziehl-Neelsen stain is excellent ENDOGENOUS AND EXOGENOUS PULMONARY MYCOSES for detecting C. neoformans as well as the tubercle bacillus. An India ink preparation of sputum shows CRYPTOCOCCOSIS up the capsules of the organism brilliantly and thus The organism responsible for cryptococcosis in aids in their identification. Pulmonary cryptococ- man was named Torula histolytica by Stoddard and cosis must be differentiated from other chronic lung Cutler27 in 1916, and thereafter the disease became diseases such as tuberculosis, unresolved pneumonia, known as torulosis. There are now grounds for be- pyogenic abscess, bronchitis, bronchiectasis, fibro- lieving that the organism is not a true Torula but sis, primary and secondary carcinoma, Boeck's sar- instead a Cryptococcus. The correct name of the coid, hydatid cyst and other mycotic infections. fungus is , and of the dis- On Sabouraud's media at 300 C. the organism ease it produces, cryptococcosis. However, reports grows slowly. At first the growth is moist, smooth, of many cases of this infection will be found indexed and cream colored. As the culture ages the color under torulosis. changes to yellow and then to brown. A portion of Diagnosis. Clinical manifestations stem from the the culture examined microscopically and in an central nervous system, the respiratory system, the India ink preparation reveals best the wide typical lymphatic system, the skin, the mucous membranes capsules. This capsule takes on a reddish color when and the bones and joints. Ordinarily a combination the cells are stained by Gram's technique. of these tissues, rather than just one, is invaded by The antibody response in cryptococcosis is poor C. neoformans, but the evidence of the involvement and consequently precipitin, agglutination and com- of other tissues is usually submerged by the more plement fixation tests are of no importance in the serious signs of central nervous system disease. diagnosis. With regard to the diagnostic significance Pulmonary involvement is, in frequency, second of skin tests very little work has been done. The only to that of the meninges and brain. It is gener- poor antibody response which accompanies this in- ally considered that the primary lesion in crypto- fection is undoubtedly partially responsible for the coccosis occurs in the lungs and that metastasis to poor prognosis. VOL. 81. NO. 6 * DECEMBER 1954 373 Treatment. There is no specific method of treat- green. Microscopic preparations should be made by ment, but this does not imply that a hopeless attitude placing a small portion of the aerial growth in lacto- be assumed. In dealing with a case of cryptococcosis phenol cotton blue and covering with a cover slip. chemotherapeutic tests on mice with all promising The characteristic swollen conidiophore bearing the drugs should be performed. There is always the pos- sterigmata and then the chains of conidia, which sibility that the specific strain of C. neoformans iso- may have been partially broken in making the prepa- lated will be susceptible to one of the sulfonamides, ration, can be identified. to one of the antibiotics, to actidione, or to some Nothing is known concerning the antibody re- other drug not yet discovered or synthesized. sponse in humans to infection; consequently, sero- Immunization with a vaccine of C. neoformans logic tests remain unevaluated. Positive skin reac- should be tried and continued during the entire tions to extracts of Aspergillus species, of the imme- course of the disease. If possible a weakly encapsu- diate whealing type, occur in patients with bronchial lated strain of the organism should be employed in asthma, but the significance of reaction of the de- the vaccine, since there is evidence that vaccines layed type and its value in the diagnosis of asper- prepared from the weakly encapsulated strains are gillosis is unappraised. more immunogenic than vaccines prepared from the Treatment. The official solution of potassium strongly encapsulated ones.18 iodide should be given orally in the largest doses Pulmonary lesions that are isolated and not part that can be tolerated. Prognosis is favorable if the of a generalized infection may heal. However, since infection is limited to the bronchi, but very poor if the infection is very likely to disseminate, early there is extensive involvement of the parenchyma excision of the circumscribed lesion is advisable.2 of the lung with/or without abscess formation. Cryptococcus neolormans thrives in an acid me- dium, and it does not survive temperatures of 1050 MUCORMYCOSIS for seven days or of 107° F. for six days. Accord- The genus of Mucor, along with Rhizopus, be- ingly, alkalinization and hyperthermia have been longs to the family Mucoraceae. of this fam- suggested as possible methods of treatment. Attempts ily are frequently referred to as the bread molds thus. far with alkalinization have met with failure and they are found abundantly in soil, manure and and hyperpyrexia has not been adequately tried. on fruits and starchy foodstuffs. Human infections from species of Mucor are rare. Of the many species ASPERGILLOSIS of this genus only a few, notably M. corymbifer, are Species of Aspergillus are widely distributed in pathogenic. nature and, for the most part, may be considered Diagnosis. In most of the reported cases of human as saprophytes. Occasionally some species become infection due to the Mucors only a single organ or parasitic and produce inflammatory granulomatous system is ordinarily involved. Infection of the lungs lesions in the skin, the external auditory canal, the is most common, yet there is no clue from the signs paranasal sinuses, the orbit, the bronchi, the lungs or symptoms offered by the infection that might lead and, infrequently, in the bones and meninges. one to suspect infection from Mucor. As in asper- The disease aspergillosis, which is caused for the gillosis the findings may suggest pulmonary tuber- most part by Aspergillus fumigatus, is world wide culosis or other mycotic infections. in distribution and occurs in persons exposed often The diagnosis of mucormycosis is fraught with to massive doses of the spores; for example, farmers difficulties. Even growth of the fungus on culture of exposed to dust from threshers; fur cleaners employ- the sputum is not unimpeachable evidence of pri- ing rye flour as a grease remover; and, in France, mary infection. The conidia of Mucor are airborne the squab feeders who take grain into their mouths and may become laboratory contaminants, and they to moisten it and, coincidently, inhale spores. may reside as saprophytes in the respiratory pass- Diagnosis. Primary pulmonary infection is rare ages and on the skin. Characteristic fragments of and diagnosis is ordinarily made at autopsy. The mycelium must be repeatedly demonstrated in spu- clinical symptoms and signs may be those of pulmo- tum or from the region where infection is suspected. nary tuberculosis, or other mycotic infections that Treatment. A specific form of therapy has never involve the lungs. There is no clinical characteristic been developed. It is necessary to adapt procedures that might lead one to suspect the disease process that have been applied to other mycotic infections. resulting from invasion by Aspergilli. Direct microscopic examination of sputum re- THE EXOGENOUS PULMONARY MYCOSES veals broken fragments of hyphae with many small, round, dark green conidia. On Sabouraud's agar at NOCARDIOSIS 30° C. the organism grows rapidly, appearing first The term nocardiosis defines infections in man as a white, cottony growth. As the conidia are pro- produced by one or several of the species of actino- duced the color of the colony turns to green or dark mycetes included in the genus Nocardia. The actino- 374 CALIFORNIA MEDICINE mycete in this genus which is of interest to the clini- States. The light, minute arthrospores which are cian is Nocardia asteroides. This organism is com- readily adapted to widespread dissemination, gain mon in the soil and it is reasonable to assume that entrance into the human body through the respira- pulmonary infection is initiated by the inhalation tory tract, or more infrequently into the skin fol- of contaminated dust particles. The disease is un- lowing trauma. Rodents and other animals in the common but world-wide in distribution. endemic areas may act as reservoirs for the fungus. Diagnosis. In the lung the organism produces Diagnosis. The symptoms of primary coccidi- bronchopneumonia of a caseating type that may be oidomycosis are indistinguishable from those of followed by cavity formation. The clinical picture, many acute, mild respiratory infections. Actually the therefore, is frequently confused with that of pulmo- great majority of primary infections are entirely nary tuberculosis. There is a tendency for the organ- asymptomatic. When symptoms do occur there may isms to disseminate via the blood stream with the be gradations of expression. The incubation period eventual formation of abscesses in many of the or- varies from one to three weeks. There is usually fever, gans, particularly the brain. Death is frequently which ranges from 990 to 1010 F. Pain in the chest caused by brain abscess. Often the lesions in the lungs is one of the most typical and suggestive symptoms are not observed until postmortem examination. of the disease. Headache, backache, night sweats, Nocardia asteroides undergoes fragmentation in anorexia and sore throat are common symptoms. the sputum and, being acid-fast, the fragments re- Quite often a morbilliform rash will appear one to semble tubercle bacilli. However, the long branched two days after the onset of infection. Eight to 14 filaments eventually can be found by careful search. days following the onset of illness, allergic reactions The organism grows readily on culture media, but such as erythema nodosum, erythema multiforme, more slowly than bacteria; consequently isolation arthralgia and phlyctenular conjunctivitis may oc- from sputum by plating is difficult. Pure cultures cur. Usually no abnormality is noted upon examina- can be obtained by inoculating guinea pigs with tion of the lungs. However, in one out of five patients sputum. The animals die after four to nine days and some change in the quality of the breath sounds may at autopsy miliary white nodules are observed over be noted. Roentgenograms of the lungs may or may the omentum and the peritoneal surfaces. not reveal the following: Thin-walled cavitation usu- There is no evidence that antibodies are formed ally present in the middle or lower lobes, but rarely as a result of infection. Serologic tests, therefore, are above the clavicle; soft infiltrations; enlarged hilar not employed as a diagnostic aid. Asteroidin, which nodes; and fan-shaped densities radiating out from is a broth filtrate of Nocardia asteroides, has been the hilar nodes. If the lung changes present in the employed as a skin testing substance in the experi- primary form persist for six or more weeks, the mental infection of guinea pigs and rabbits. Its use progressive form of the disease should be suspected. as a diagnostic aid in human infections has not been With the progression of the infection the infiltra- evaluated. tions increase in size; there is enlargement of the Treatment. The specific measures of treatment mediastinal nodes; cavities, formerly present. en- are similar to those for actinomycosis produced by large; cough is pronounced; and the sputum which Actinomyces Israeli. There is one notable exception. was scanty becomes more profuse and is occasion- Penicillin is not particularly effective in nocardi- ally tinged with blood. Approximately 0.1 to 1.0 osis. Sulfadiazine, alone or combined with sulfa- per cent of the primary cases develop into the pro- merazine, and aureomycin are the drugs of choice. gressive form of the disease. COCCIDIOIDOMYCOSIS Laboratory studies are helpful in making a diag- Coccidioidomycosis is a name originated by Dick- nosis. There is frequently accompanied son8' 9of Stanford University for the disease pro- by eosinophilia. The sedimentation rate is elevated duced by the fungus . The or- and ordinarily there is positive reaction to the coc- ganism produces an acute, usually mild and benign cidioidin skin test. Should a positive reaction to skin respiratory infection, which is classified as the pri- test occur in a patient with a normal sedimentation mary type of coccidioidomycosis. Infrequently, the rate it is unlikely that the current illness is due to infection becomes chronic and disseminates to al- Coccidioides immitis. During the recovery phase of most any organ, producing therein granulomatous the primary infection the lymphocytes rise to 50 per lesions, which progress to such an extent that death cent or more of the total white blood cell count and occurs in 50 per cent of such cases. This chronic the sedimentation rate gradually declines. The pre- form of the disease is spoken of as progressive or cipitin and complement fixation tests are usually disseminated coccidioidomycosis. positive, but they may be negative in mild infections. The fungus is present in the dust and soil of the Titers of the precipitin and complement fixation arid and semi-arid regions of southwestern United tests are high in the progressive form of the disease.

VOL. 81. NO. 6 * DECEMBER 1954 375 Coccidioides immitis grows on Sabouraud's agar nosed where suspicion is alerted and sound mycolo- as a white, cottony which pigments with age. gic methods are used. Old cultures contain myriad large, thick-walled Diagnosis. There are two types of benign pulmo- arthrospores (chlamydospores). When these spores nary infection, asymptomatic and symptomatic. are injected into animals they enlarge and become In the asymptomatic lorm the diagnosis is made spherical. These large spherical cells, referred to as in retrospect after observing areas of calcification in "spherules," give rise to endospores by cleavage of the pulmonary roentgenograms of patients with posi- their cytoplasm. It is the "spherule" that is found tive reaction to histoplasmin skin tests. Although in the sputum of the patient infected with Coccidi- the patients may have positive reaction to tuberculin oides immitis. It is usually taught that the "spher- skin tests it is now generally agreed that pulmonary ules" are not contagious. However, investigations calcification occurs twice as frequently in associa- recently reported by Rosenthal23' 24 indicated that tion with histoplasmin sensitivity as with tubercu- it is well to be suspicious of the old dogma that coc- lin sensitivity. The pulmonary lesions preceding the cidioidomycosis is never contagious. areas of calcification are infiltrative and difficult to Treatment. There is no specific form of therapy differentiate from similar lesions occurring in pul- for coccidioidomycosis and it can only be hoped monary tuberculosis. The diagnosis is established that by exercising careful nonspecific measures pro- by culturing Histoplasma capsukatum from the spu- gression and dissemination of the infection can be tum, which is not always easily accomplished. In the prevented. A patient with primary coccidioidomy- event that tubercle bacilli cannot be cultured or cosis must be kept at absolute bed rest until: (1) the demonstrated by direct microscopic technique, histo- physical symptoms of the infection have disappeared, plasmosis may be suspected. This is especially true (2) there is evidence from roentgen examination of if the reaction to a histoplasmin skin test is strongly the lungs that the lesion has either disappeared or is positive and the tuberculin test is negative or only regressing, (3) the sedimentation rate has returned mildly positive. to normal, (4) the precipitin and complement fixa- In the symptomatic jorm of histoplasmosis the tion tests are disappearing or absent. clinical course of the disease and the roentgenologic Most of the patients with the progressive form of findings offer a relatively uniform picture. The incu- the disease die in two to twelve months, but some bation period is from five to 18 days. The onset of may recover spontaneously. If patient is extremely symptoms is rather sudden, with generalized ma- sensitive to coccidioidin, that is has a large skin laise, weakness, vague pain in the chest, nonproduc- reaction to a 1:1,000 or 1:10,000 dilution, desensiti- tive cough and fever (temperature 1020 to 1050 F.). zation with this antigen should be given a trial: There are a few positive physical findings. During the early course of the disease pulmonary roent- HISTOPLASMOSIS genograms reveal the lung fields to be clear, but later The disease histoplasmosis was first discovered disseminated and bilateral lesions varying from fine in the Panama Canal Zone by Darling5 -in 1906. or mottled granular infiltrations to soft miliary nod- Darling believed the causative organism was a proto- ules are observed. Cavitation rarely occurs. The zoan and gave it the name Histopklsma capsulatum. lesions tend to calcify in from three to five years De Monbreun6 eventually established that the etio- after-the onset of the acute illness. Even after the logic organism in histoplasmosis is a fungus. He acute phase of the illness has disappeared the symp- suggested that a relatively mild and nonfatal form toms of shortness of breath, cough and fatigue often of the disease, similar in nature to the primary and persist for months or even years. nonfatal form of coccidioidomycosis might exist.7 There is some evidence that the symptomatic form Palmer20 and Christie and Peterson,3 together, were may occur in epidemic proportions. Fairly large principally responsible for the discovery and recog- groups of persons have developed pneumonitis fol- nition of histoplasmosis of the common benign pul- lowing exposure to the dust of pigeon manure and monary type. There are surprisingly few instances subsequently has been iso- of progressive histoplasmosis in view of the many lated from the dust.'2 13 Such epidemics simply cases of primary pulmonary infection. It is tempt- serve to exemplify that histoplasmosis may occur in ing to speculate that the form of the organism that epidemic proportions if exposure to dust from soil is inhaled is less virulent than the form that enters contaminated with the organism takes place. the body through the skin, mucous membranes, and The fungus in its parasitic phase is a small yeast- gastrointestinal tract. The organism has been iso- like organism ranging in diameter from 2 to 3 lated from the soil and the disease recognized in microns. These yeast-like bodies invade the mono- diversified regions of the United States. It is now nuclear cells in enormous numbers. In the sputum the belief that histoplasmosis can exist in any age the yeast-like bodies are extracellular. Cultures taken group, in widespread localities, and can be diag- from the sputum must be placed on both blood agar 376 CALIFORNIA MEDICINE and Sabouraud's media. On Sabouraud's agar at project into the lung fields with irregular outlines. 300 C. the organism produces a white, cottony The finding of such a hilar mass may quite nat- growth. Spores ranging in size from 10 to 25 mi- urally provoke a diagnosis of bronchogenic carci- crons are produced and from these spores rise noma. As the infection progresses the mediastinum finger-like projections 5 microns in length. The becomes invaded and there is eventually involve- growth on blood agar at 370 C. is yeast-like. The ment of the pericardium and the heart. The infection gross cultural characteristics of Histoplsma capsu- may disseminate from the lungs by way of the blood. latum and Blastomyces dermatitidis are similar. The diagnosis is established by demonstrating the Histoplasmin is a cultural filtrate and contains organism in the sputum, wherein the fungus occurs extracellular antigenic fractions of Histoplasma cap- only as a round or oval yeast-like cell which repro- sulatwn produced by growing the organism in a duces by budding. The cells are easier to demon- synthetic liquid medium. Skin tests are usually con- strate if the sputum is first treated with 20 per cent ducted with 1:1,000 and 1:100 dilutions of this sodium hydroxide. The finding of doubly contoured broth filtrate. A negative skin reaction to 0.1 ml. budding cells with granular contents, which in size of the 1:100 dilution rules out the presence, in the are slightly smaller than leukocytes, makes the diag- past or at the time of testing, of histoplasmosis. nosis certain. Cultures should be made on both Sa- Diagnostic and prognostic attributes of the precipi- bouraud's and blood agar media. On Sabouraud's tin and complement fixation tests in human histo- media at 300 C. the colonies first appear smooth plasmosis have not as yet been authenticated. and grayish, but they soon become wrinkled, and Treatment. In the pulmonary form of the dis- eventually a white cottony type of growth develops. ease the prognosis is ordinarily good with only non- Cultures on blood agar incubated at 370 C. do not specific supportive measures of treatment. Only one develop filamentous growth but remain yeast-like in drug, ethyl vanillate, of the many different therapeu- appearance. tic agents tested, has proven to be effective in the A blastomyces vaccine or a broth filtrate (blasto- management of the disseminated form of the dis- mycin) prepared in synthetic media from the grow- ease. The original article by Christie4 and co-work- ing fungus is used for skin testing. Cross reactions ers should be carefully read before treatment with between blastomyces vaccine or blastomycin and this drug is given to a patient. histoplasmin and coccidioidin are common. This is undoubtedly due to an antigenic fraction common NORTH AMERICAN BLASTOMYCOSIS to Blastomyces dermatitidis, Histoplasma capsu- North American blastomycosis is a relatively latum and Coccidioides immitis. Therefore, regard- common fungous disease characterized by the for- less of which mycotic infection is suspected, skin mation of granulomatous lesions in the skin, lungs tests with blastomyces vaccine or blastomycin, histo- and bones. It is caused by the fungus Blastomyces plasmin and coccidioidin should always be made. dermatitidis. Only those patients very sensitive to coccidioidin Blastomyces dermatitidis is derived from soil and (positive reaction to 1:10,000 dilution) give cross infections develop, for the most part, in persons reactions with blastomyces vaccine or blastomycin whose occupations take them into the fields and the and histoplasmin. Cross reactions between blasto- forests where contact with the natural source of myces vaccine or blastomycin and histoplasmin are the saprophytic form of the fungus occurs. Although very common. However, patients with blastomycosis the greatest incidence of the cases is in the south- give larger reactions to blastomyces vaccine or blas- eastern states and in the Mississippi River Valley tomycin than to histoplasmin, and the reverse is true area, isolated cases have been reported from nearly of patients with histoplasmosis. every section of the United States as well as from The complement fixation test is positive during regions in eastern and western Canada. an active infection and the titer rises as the infection Diagnosis. The pulmonary form of the disease is progresses. The titer of the test also declines as the often followed by dissemination. The symptoms of patient improves, and disappears with recovery. pulmonary blastomycosis are insidious and are usu- Treatment. Pulmonary and systemic blastomy- ally those of an ordinary subacute respiratory infec- cosis are not often favorably improved by x-ray tion. There is usually a nonproductive cough, dis- therapy. Patients who are in good general condition comfort in the chest, low grade fever and slight dys- with sera containing antibodies that fix complement, pnea. With progress of the infection the shortness usually respond to iodide therapy. Iodides should of breath becomes more annoying, the temperature be given to the point of maximal tolerance and main- climbs, and there is loss of weight and strength. tained at the largest daily dose that can be adminis- Roentgenograms of the lungs frequently disclose tered without symptoms of iodism. Because im- enlargement of the mediastinal lymph nodes. Dense provement is very gradual, iodide therapy must be masses are frequently observed near the hilum and continued over a period of one to three years. Pa- VOL. 81. NO. 6 * DECEMBER 1954 377 tients with positive reaction to skin tests with blasto- 9. Dickson, E. C., and Gifford, M. A.: Coccidioides infec- myces vaccine or blastomycin, with or without posi- tion (coccidioidomycosis), Arch. Int. Med., 62:853, 1938. tive complement fixation tests, usually do not re- 10. Duncan, G. G., Clancy, C. F., Wolgamot, J. R., and Beidleman, B.: Neomycin: results of clinical use in ten spond to iodide therapy and the disease causes death cases, J.A.M.A., 145:75, 1951. quickly. However, if these patients are desensitized 11. Erikson, D.: Pathogenic anaerobic organisms of the with blastomyces vaccine and then treated with Actinomyces group, Med. Research Council, Special Report iodides they ordinarily improve as rapidly as the Series No. 240, London, His Majesty's Stationery Office, patients who are not allergic. Patients without posi- 1940. tive complement fixation tests and with negative skin 12. Feldman, H. A., and Sabin, A. B.: Pneumonitis of tests should receive treatment with blastomyces vac- unknown etiology in group of men exposed to pigeon ex- cine until there is a positive complement fixation creta, J. Clin. Invest., 27:533, 1948. 13. Furcolow, M. L., and Larsh, H. W.: Direct isolation test. Thereafter, iodide therapy should be given. of Histoplasma capsulatum from soil: probable etiological Certain diamidines exert an in vitro fungistatic relationship to Camp Gruber pneumonitis, Proc. Soc. Exp. effect on Blastomyces dermatitidis,25 and several Biol. and Med., 80:246, 1952. patients with blastomycosis have been treated with 14. Keeney, E. L.: Candida asthma, Ann. Int. Med., 34: some success with stilbamidine.21 26 This drug, 0.05 223, 1951. gm. to 100 ml. of 5 per cent glucose solution, is 15. Keeney, E. L.: Practical Medical Mycology. Charles given by slow intravenous drip the first day. If this C. Thomas, Springfield, Ill. To be published. dose is well tolerated, then 0.1 or 0.15 gm. is admin- 16. Littman, M. L., Paul, J. S., and Fusillo, M. H.: Treat- ment of pulmonary actinomycosis with chloramphenicol istered in a similar fashion every day for 10 to 14 (chloromycetin): report of a case, J.A.M.A., 148:608, 1952. days. This course may be repeated if advisable after 17. McVay, L. V., Jr., and Sprunt, D. H.: A long-term a two-week period during which the drug is not evaluation of aureomycin in the treatment of actinomycosis, given. The amount of stilbamidine necessary for Ann. Int. Med., 38:955,-1953. cure is not known, but probably a total dosage of 3 18. Neill, J. M., Abrahams, I., and Kapros, C. E.: A com- to 6 gm. given in two or three courses is enough. parison of the immunogenicity of weakly encapsulated and In a high percentage of patients a neuropathic of strongly encapsulated strains of Cryptococcus neoformans condition involving the trigeminal nerve appears (Torula histolytica), J. Bact., 59:263, 1950. 19. Nichols, D. R., and Herrell, W. E.: Penicillin in the two to five months after treatment with stilbamidine. treatment of actinomycosis, J. Lab. and Clin. Med., 33:521, The sensation to touch is lost but sensations to pain, 1948. temperature and pressure remain intact. The sen- 20. Palmer, C. E.: Nontuberculous pulmonary calcifica- sory changes may persist indefinitely. tion and sensitivity to histoplasmin, Pub. Health Rep., 60: Although stilbamidine is the first drug of choice 513, 1945. in the treatment today of all cases of pulmonary 21. Pariser, H., Levy, E. D., and Rawson, A. J.: Treat- blastomycosis, regardless of the immunologic and ment of blastomycosis with stilbamidine, J.A.M.A., 152: allergic status of the patient, physicians must be ever 129, 1953. 22. Poulton, E. P.: Discussion of treatment of bacterial mindful that its use represents a new form of treat- diseases with substances related to sulphanilamide, Proc. ment and, therefore, its dangers and limitations have Roy. Soc. Med., 31:149, 1937. not at this time been entirely evaluated. 23. Rosenthal, S. R., and Routien, J. B.: Contagiousness 1540 Sixth Avenue, San Diego 1. of coccidioidomycosis: an experimental study, Arch. Int. Med., 80:343, 1947. 1. Bendove, R. A., and Ashe, B. I.: Geotrichum septi- 24. Rosenthal, S. R., and Elmore, F. H.: Studies on the cemia, Arch. Int. Med., 89:107, 1952. contagiousness of coccidioidomycosis. II. The fate of spher- 2. Berk, M., and Gerstl, B.: Torulosis (cryptococcosis) ules in sputum, exposed out of doors. III. Infection in producing a solitary pulmonary lesion: report of a four-year guinea pigs by contact with diseased animals, Am. Rev. cure with lobectomy, J.A.M.A., 149:1310, 1952. Tuberc., 61:95, 1950. 3. Christie, A., and Peterson, J. C.: Pulmonary calcifica- 25. Schoenbach, E. B., and Greenspan, E. M.: Pharma- tion in negative reactors to tuberculin, Am. J. Pub. Health, cology, mode of action and therapeutic potentialities of stil- 35:1131, 1945. bamidine, pentamidine, propamidine and other aromatic 4. Christie, A., Middleton, J. G., Peterson, J. C., and diamidines, Medicine, 27:327, 1948. McVickar, D. L.: Treatment of disseminated histoplasmosis 26. Schoenbach, E. B., Miller, J. M., and Long, P. H.: with ethyl vanillate, Pediatrics, 7:7, 1951. Treatment of systemic blastomycosis with stilbamidine, 5. Darling, S. T.: A protozoan general infection producing Ann. Int. Med., 37:31, 1952. pseudotubercles in the lungs and focal necrosis in the liver, 27. Stoddard, J. L., and Cutler, E. C.: Torula infection in spleen and lymph nodes, J.A.M.A., 46:1283, 1906. man. Studies from the Rockefeller Institute for Med. Re- 6. De Monbreun, W. A.: The cultivation and cultural search, Reprints, 1:25, 1916. characteristics of Darling's Histoplasma capsulatum, Am. J. 28. Thompson, L.: Isolation and comparison of Actino- Trop. Med., 14:93, 1934. myces from human and bovine infections, Proc. Staff Meet. 7. De Monbreun, W. A.: The dog as a natural host for Mayo Clin., 25:81, 1950. Histoplasma capsulatum, Am. J. Trop. Med., 19:565, 1939. 29. Weld, J. T.: Candida albicans. Rapid identification in 8. Dickinson, E. C.: Coccidioides infection, Arch. Int. pure cultures with carbon-dioxide on modified eosin-methy- Med., 59:1029, 1937. lene blue medium, Arch. Dermat. and Syph., 66:691, 1952. 378 CALIFORNIA MEDICINE