R E S I D U A L P U L M O N A R Y L E S I O N S OF F U N G A L O R I G I N IN S O U T H E R N C A L I F O R N I A by M. STRAUB 1), M. D., B. G. FISHKIN, M. D. & J. SCHWARZ,M.D.

(7.VIII.1962) The existence of areas of high incidence of histoplasmosis in the "Mississippi Valley", and of coccidioidomycosis in the 'Southwest" of the United States has been established b y immunological surveys, clinical cases and to lesser degree b y anatomical studies

(4,7,s,9).

The cross reactions that occur in serologic and skin test evaluation of fungal diseases are presumed to be of a heterologous nature (3,7). Specific anatomical findings to support this contention are not extensive. Consequently, an anatomical study of residual pulmonary lesions of fungal origin was undertaken at the Veterans Administration Hospital in Los Angeles which is located in a geographic area where the native population has a high incidence of positive skin sensitivity to coccidioidin. Furthermore, the hospital draws patients from all over the nation who have resided in this region for a variable period of time. MATERIAL AND METHODS

Lungs of consecutive autopsy cases were x-rayed and carefully dissected b y one of us (M.S.) in the same manner as reported previously (8, 9). Fifty-three lungs were examined of patients who had not died of a pulmonary granulomatous disease, and all calcified or otherwise focalized lesions were examined microscopically. The Gridley (5) and Grocott (6) stains were used routinely for demonstration and identification of fungi; in one case the mucicarmine method of MAYER was applied in an attempt to demonstrate cryptococci. Serial sections were used when indicated and proved helpful in diagnosis. An analysis of all fungal skin tests performed in the dermatology clinic from March 31, 1961 through September 15, 1961 was made. From the Department of Pathology, Veterans Administration Hospital, Los Angeles, California and University of California at Los Angeles, and the Clinical Laboratories, Jewish Hospital, Cincinnati, Ohio. This study was supported in part by Grant E-576 of the N.I.H. x) deceased,

56

M. STRAUBa.o. RESULTS

Calcified foci were found in 39 of the 53 cases; the relatively small number with calcification represents a minimal figure due to the difficulties encountered especially in patients with concurrent pulmonary disease (carcinoma, fibrosis, etc.). Of the 39 cases with calcification, 20 proved to be caused b y H. capsulatum, 6 b y C. immitis and 13 times the causative organisms could not be established. One focus had organisms identified as Cryptococcus neo/O~lY~nS.

The rather high incidence (13) of calcified foci without demonstration of the causative organism eloquently bespeaks the need of new methods of detection for acid fast bacilli in particular (1). The spherules of coccidioidomycosis were frequently found in the periphery of the foci and a ring of anthracotic pigment was commonly seen to form the outer rim of the granuloma. It gave the impression that the granulomas had grown in centrifugal fashion, pushing the pigment towards the periphery. The histoplasmic lesion in contrast showed organisms only in the central part and actually the diagnosis often was missed initially if this central part of the focus was not examined. Anthracotic pigment is not at all prominent in histoplasmic lesions. Of the 6 cases showing sequelae of coccidioidomycosis, only one (2040, a 45 year old white man) had been born in California (Bakersfield). The other 5 hailed from New York, Florida, Mississippi 1), Minnesota and Idaho.

TABLE I

Skin Reactions in Los Angeles Veterans Hospital in Unselected Patients A trending the Dermatology Clinic Total Tested Coccidioidin Histoplasmin Reaction in both antigens

341 297

Positive 61 80 36

% 17.8 26.9

Of the twenty cases with sequelae of histoplasmosis, only 4 came from the core of the endemic area (Tennessee, Missouri, Mississippi and Arkansas), 9 from the "outskirts" of the endemic area (3 from Pennsylvania, 2 from Iowa, 1 each from Illinois, Nebraska, Michigan and West Virginia and the remainder from areas not ordinarily associated with prevalence of the disease, 2 from Colorado, and 1 each from New York, California, Oklahoma, and Austria). 1) This patient had both a histoplasmic and a coccidioidomycotic primary complex.

R E S I D U A L PULMONARY L]~SIONS OF F U N G A L ORIGIN

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DISCUSSION

The findings, while limited in number, acquire importance because of the demonstration of organisms in the lesions. This takes the uncertainty out of the game, a factor which is often argued about in reference to skill test results and which also is present in clinical diagnosis unless confirmed in the laboratory. PALMER (9) has concluded from the results of a large number of young people who were tested in the Southwest with coccidioidin and histoplasmin that their positive reaction to histoplasmin represents a cross reaction to coccidioidin. The present study seems to indicate that even in residents of the Southwest, histoplasmic infection is of appreciable occurrence. Obviously our material is from an older age group, and the place of birth clearly indicated the migratory character of the population, but it seems certain that a large percentage of any given population in the U.S. has traveled extensively within the U.S. and prolonged residence is not a prerequisite for infection with the fungi under discussion. The present data obtained at necropsy indicate that skin reactions to histoplasmin cannot be attributed unmistakably even in the southwestern part of the country to cross reactions but very often represent homologous reactions. Furthermore, the data reiterate the high incidence of primary - - often asymptomatic infection with Histoplasma capsulatum. In contrast, residence of variable duration in the Southwest produced coccidioidomycotic calcifications only in a smaI1 number (11~o). Two explanations come to mind; either coccidioidomycosis occurs in prime targets commonly (Kern County, California; Phoenix, Tucson, Arizona) but outside these areas with less frequency, or else it is conceivable (but unlikely) that primary infection with C. immitis does not necessarily produce.necrosis and subsequent calcification - - but restitutio ad integrum. There are gross and microscopic differences in the appearance of primary foci according to the causative organism. The primary focus in tuberculosis is more often small than large. As a rule, a single such focus is present. The corresponding lesion in histoplasmosis is large and the appearance is a composite (mosaic) of numerous discrete whitish (chalky) calcifications. Multiple primary foci are common. The primary focus of coccidioidomycosis can be either small or large and the calcification is far less prominent and dense than in the two other diseases. Seldom is there more than one primary focus. The lymph nodes, draining the primary focus in human tuberculosis and histoplasmosis, are prominent and often represent several times the volume of the pulmonary focus. The healed lymph nodes in histoplasmosis can be very large and sometimes form an agglommeration of individual calcific foci which measures several centimeters in diameter. In coccidioidomycosis, lymph node involvement is not always demonstrable during or after primary

58

M. STRAUB a.o.

infection and seems to represent already a step towards dissemination. A dissociation in the state of activity between pulmonary and lymph node lesion was found only in coccidioidomycosis whereas in tuberculosis and histoplasmosis, the gross and microscopic behavior of the lymph nodes closely parallels the primary focus. Microscopically the primary focus in histoplasmosis and tuberculosis is quite similar. They are both the result of expanding caseous pneumonia leading to encapsulation in the overwhelming majority of cases. A fibrohyaline capsule - - m o r e often than n o t with an osseous rim is found in the healed focus. Liquefaction necrosis is the rule in the histoplasmic primary focus. In coccidioidomycosis, b y contrast, the capsule is the result of healing of a granulomatous productive perifocal inflammation. CONCLUSIONS AND SUMMARY

1. In 53 consecutive unselected autopsies performed in the Veterans Administration Hospital in Los Angeles, calcified lesions were found in 39. 2. C. immitis and H. capsulatum were demonstrated six and twenty times respectively. One case had a double infection with both fungi. M. tuberculosis was not demonstrated in any of the cases. In thirteen cases no specific agent could be demonstrated. 3. The place of birth did not necessarily coincide with the expected fungus infection. 4. Morphologic differences between the complexes caused b y tuberculosis, histoplasmosis and coccidioidomycosis are discussed. 5. Results of skin tests and serologic tests often considered to be "cross reactions" m a y represent true homologous reactions if data from a small, and to a certain degree, selected, group should prove to be a true reflection of the population at large. ACKNOWLEDGEMENT

EDWIN T. WI~IGHT, M.D., Chief of Dermatology, was kind enough to make available the skin testing results for evaluation. References 1. BRAUNSTEIN,H. & ADRIANO, S. M. (1961). Fluorescent stain for Tubercle bacilli in histologic sections. Amer. J. clin. Path., 36:37--4[0. 2. ]~DWARDS, P. Q. & PALMER, C. ]~. (1957): Prevalence of sensitivity to coccidioidin, with special reference to specific and nonspecific reactions to coccidioidin and to histoplasmim Dis. Chest, 31:35--60. 3. EMMONS, C. W., OLSON, B. J. • ]~LDRIDGE, W. W. (1945): Studies of the role of fungi in pulmonary disease; cross-reactions of histoplasmin. Pub. Health Rep., 60:1383--1394. 4. FURCOLOW, M. L. (1958): Histoplasmosis. G. P., 18:117--127. 5. GRIDLEY,M. F. (1953) A stain for fungi irt tissue sections. Amer. J. clin. Path., 23:303--307.

RESIDUAL PULMONARY LESIONS OF FUNGAL ORIGIN

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6. GRocomT, R. G. (1955): A stain for fungi in tissue sections and smears. Amer. J. clin. Path., 25: 975--979. 7. PALMER,C. E. & EDWARDS, P.Q. (1960): The histoplasmin skin test, in SWEANY, H.C., ttistoplasmosis, Charles C. Thomas, Publisher, Springfield, Illinois, pp. 189--210. 8. STRAUB, M. • SCItWARZ, J. (1955): The healed primary complex in histoplasmosis. Amer. J. clin. Path., 25:727--741. 9. STRAUB, l~/i. & SCHWARZ, J. (1960): General pathology of human and canine histoplasmosis. Amer. Rev. Resp. Dis., 82:628--541.