THE JOURNAL OF UROLOGY

Vol. 113, January

Copyright© 1975 by The Williams & Wilkins Co.

Printed in U.S.A.

GENITOURINARY ASPECTS OF DISSEMINATED COCCIDIOIDOMYCOSIS WILLIAM T . CONNER,* GEORGE W. DRACH

AND

WILLIAM C. BUCHER, JR.

From the Departments of Surgery and Pathology, University of Arizona, College of Medicine, Tucson, Arizona

One of the few disadvantages of living in the desert climate of the Southwestern United States is the potential for infection with the dimorphous fungus, Coccidioides immitis. Arthrospores produced by the vegetative mycelian phase of the fungus in its natural desert habitat cause a subclinical r espiratory infection in 60 per cent of pat ients and mild to severe disease in t he remainder. A posit ive coccidioidin skin test is usually the only lasting evidence of previous infection. It becomes positive in all immunologically competent people and persists in about 60 per cent. Immunologic diagnosis is based on precipitation tests which become positive during the acute disease, and immunodiffusion and complement fixation tests which become strongly positive only with dissemination. 1 Immediate or delayed dissemination of coccidioidomycosis is a treacherous disease which affects less than 1 per cent of the white population but is up to 20 t imes more common in the dark skin population. In addition to racial predilection for dissemination, other risk factors include treatment with immunosuppressive drugs 1 and d iabetes mellitus. Involvement of the genitourinary tract implies active or previous dissemination of coccidioidomycosis. Oth er than a rare incident of cutaneous inoculation from trauma 2 the only mode of primary human infection is by inhalation of arthrospores. An,!!ly~~- of 50 autap&i.gs af patients who died of disseminated coccidiaidam ycasis revealed t h e kidney to be t he si xth most common organ of involvem~ t with renal lesions in 30 of t he 50 patients. Involvement of the prostate was uncom mon, wit h only 3 prostates being involved. 3 Epididymal coccidioidomycosis was not described in the autopsy study but a number of case reports have described t his unusual manifestation of the disease. •-12 Experience with several patients with genitouriAccepted for pub lication May 31, 1974. Read at annual meeting of Western Section, American Urological Association, San Francisco, California, March 31- April 5, 1974. * Requests for reprints: Department of Surgery, University of Anzona Medical Center, Tucson, Anzona 85724. 1 Winn, W. A.: A working classification of coccidioidomycosis and its application to t herapy. In: Coccidioido mycosis. Edited by L. Ajello. Tucson, Arizona : The University of Arizona Press, 1967. 'Wilson, J . W., Smith, C. E. and P lunkett, 0. A. : A primary cutaneous coccidioidomycosis; the criteria for d iagnosis and report of a case. Calif. Med., 79: 233, 1953. 3 Forbus, W. D. and Bestebreurtje, A. M.: Coccidioidomycosis: a study of95 cases of the disseminated type with special reference to t he pathogenesis of t he disease. Mil. Surg., 99: 653, 1946 . ' Amromin, G. a nd Blumenfeld, C . M. : Coccidioido-

nary coccidioidomycosis raised questions which were not answered by a review of the literature. Thus, t his study was done to attempt to defin e the incidence and a natomy of genitourinary coccidioidomycosis as a n aspect of disseminated disease, and to demonstrate radiologic, histologic and m icrobiologic characteristics of t he disease. METHODS

From 1970 through January 1974, 96 patient s were discharged from the hospital with coccidioidomycosis. Of t he 96 charts 70 were available and were reviewed in detail, with special attention to indicators of genitourinary disease: symptoms, physical find ings, urinalysis, excretory urograms, renal function studies and urine cultures . T hese data were tabulated and available patients with any evidence of genitourinary coccidioidomycosis were examined by one of us (W. T. C.). Review of culture data from the clinical laboratory identified 4 additional patients with positive urine cult ures for coccidioidomycosis, and their charts a nd radiograms were reviewed. The ch art and radiograms of an addit ional patient, studied in detail by one of us (G. W. D .), were analyzed . All available histologic specimens were exam ined and special attention was given to urogenital organs during autopsy of 1 patient who died of coccidioidal meningitis. RESULTS

T he initial group of 70 charts revealed 5 patients with widely disseminated coccid ioidomycosis, plus mycosis of epid idymis: report of two cases. Calif. Med., 78: 136, 1953 . 'Bellin, H.J. a nd Bhagavan, B. S.: Coccidioidomycosis of t h e prostate gland. Report of a case and review of the literature. Arch. Path. , 96: 114, 1973 . 6 Cheng, S . F .: Bilateral coccidioidal epididymit is. Urology, 3: 362, 1974. 7 McDouga ll , T. G. a nd K leiman, A. H.: Prostatitis due to Coccidioides immitis. J. Urol. , 49: 472, 1943. 'Pace, J. M.: Coccidioidomycosis of t he ep ididymis. South. Med. J ., 48: 259, 1955. 'Rhon , J . G., Davila , J . C. and Gibson , T . E. : Urogenital aspects of coccidioidomycosis: review of t h e literature and report of two cases. J. Urol. , 65: 660, 1951. 10 Stewa rt, B. G.: Epididymitis and prostatitis due to coccidioidomycosis: a case report with five-year fo llowup. J. Urol. , 91: 280, 1964. 11 Weitzner, S.: Coccidioidomycosis of prostate a nd epididymis-case report and review of the literature. Southwest. Med., 49: 67, 1968. 12 Weyrauch, H. M., Norman , F. W . and Bassett, J . B .: Coccidioidomycosis of the genital t ract. Calif. Med., 72: 136, 1953. 82

GENITOURINARY ASPECTS OJF DISSEMINATED COCCIDIO!DOMYCOSIS

1 of the patients studied extensively by the urology service for coccidioidal epididymitis. Of these 6 patients 4 had genitourinary involvement. The patient with epididymal disease has repeatedly positive prostatic cultures for coccidioidomycosis and will be discussed in detail. The second patient had an acute renal abscess of (fig. 1). with no involvement of testes or seminal vesicles at autopsy. Another patient had extensive genitourinary inantemortem volvement, with urine cultures and postmortem cultures from kidneys, prostate and epididymides. Disseminated coccidioidomycosis occurred in the fourth patient, described herein in some detail,

while receiving for successful renal transplant. One urine culture for Coccidioides immitis and examination was suggestive of granulomatous fifth patient with coccidioidal meningitis has no evidence of genitourinary specific cultures have not been sixth patient died after no response t.o amphotericin and autopsy revealed no evidence of coccidioidomycosis in the prostate, seminal vesicles or testes. Thus, of the 4 genitourinary involvement in this disseminated disease, 1 had involvei-nen' alone, 1 had involvement of prostate ancl epididymides, 1 had involvement on!y of

FIG. l. A acute renal abscess of coccidioidomycosis. Note cluster of 3 coccidioidal spherules in 1 area and cluster 10 in anothe'r area. Reduced from x 176. B, spherules of Coccidioides immitis in renal cortex, with acute abscess. limited inflammatory infiltrate, suggesting embolization of group of spherules. Reduced from x440.

84

CONNER, DRACH AND BUCHER

the lower urinary tract and 1 had proved disease of the prostate and epididymis. The clinical laboratory reported 7 positive urine cultures for Coccidioides immitis during 1973 and early 197 4. These cultures identified 5 patients who were not included in the chart review. Including 1 patient from our center, 12 with proved disseminated disease, with or without genitourinary involvement, were identified. In 9 patients urine cultures were positive for Coccidioides immitis; cultures were not obtained for the remaining 3. Three were receiving immunosuppressive therapy when the disseminated disease occurred. Of the 12 patients 5 were black or had dark skin. Four patients died of disseminated disease, including 1 of 2 renal transplant patients. Of the 8 living patients 6 were examined and 3 of these will be described in detail: J. H. who has had proved coccidioidomycosis of the lower urinary tract for at least 15 years, J. 0. whose radiographic changes in the kidney were clearly demonstrated to be caused by coccidioidomycosis and A. M. who has disseminated coccidioidomycosis, controlled with amphotericin treatment and has a successful renal transplant under continuing immunosuppressive therapy. A fourth patient in this group of 8 is a 37-year-old man who had had the neTJhrotic syndrome since 1972. Renal biopsy reveal€d nonspecific glomerular changes suggestive of lupus nephritis. Renal failure was progressing rapidly and immunosuppressive therapy with cytoxan and prednisone was started. Herpes labialis, bone marrow suppression, bacteremia and disseminated coccidioidomycosis were noted with a positive pleural biopsy, positive pleural fluid culture and positive urine culture as well as high complement fixation titers. Immunosuppressive treatment was stopped and 3 gm. intravenous amphotericin have been given. Renal function improved and has remained stable. A second renal biopsy was done because of the puzzling character of the renal disease. Massive hematuria occurred after biopsy and the urology service was consulted. There was no evidence of lower tract genitourinary involvement. The percutaneous needle biopsy revealed no evidence of lupus nephritis but a spherule of Coccidioides immitis was seen in the renal parenchyma. Of the 8 living patients 3 are in the process of further evaluation. Two have had positive urine cultures with no evidence of lower tract disease but localization studies have not been performed and 1 has had no positive urine cultures for Coccidioides immitis.

skin tests were grave prognostic factors. The patient was treated with transfer factor and 13 amphotericin, details of which will be reported later. Involvement of the genitourinary tract was clearly demonstrated by positive urine cultures for Coccidioides immitis, demonstration of a spherule of Coccidioides immitis in the urine and serial x-ray changes. A prostatic biopsy was negative for granulomatous disease and spherules, and cystoscopy was normal. Urine cultures for tuberculosis were negative. Calcification in the right kidney was seen on an abdominal radiogram and constriction of a right lower infundibulum with caliceal ballooning indicated marked granulomatous disease in the right kidney (fig. 2, A). Indistinct irregularities in the upper pole calix of the left kidney (fig. 3) progressed to chronic scarring with finely stippled calcification within several months (fig. 2, B). The renal lesions gradually improved as the disseminated disease was controlled. Since the patient has no involvement of the lower urinary tract, repeated positive urine cultures for Coccidioides immitis and negative cultures for tuberculosis, the described radiographic findings are attributed to renal infection with Coccidioides immitis. To our knowledge, such radiographic changes have not been reported previously. Case 2. J. H., a 66-year-old retired Air Force sergeant, had a long history of rheumatoid arthritis. Other than a 10-day course of steroid treatment more than 15 years ago he had used only aspirin for relief of pain. In 1958 the right testis and epididymis were removed for a draining sinus. Histologic diagnosis was acute epididymitis with chronic orchitis. In 1969 a left renal cyst was unroofed, with no evidence of granulomatous disease. Several months after a left inguinal hernia repair in 1972, softening and slight enlargement of the left scrotal contents occurred. A draining sinus in the left lower scrotum developed 9 months after the hernia repair and the patient was hospitalized 2 months later. Examination revealed a pinpoint fistulous orifice of the left lower scrotal wall from which a small amount of yellowish fluid could be expressed. There was mild erythema in the surrounding skin but no fluctuance. The lower pole of the testis and the epididymis were thick and corded but the vas was normal. Routine cultures yielded staphylococci. Fungal and acid fast cultures had no growth at the time of the operation. The left epididymis, and adjacent scrotal sac and sinus were excised, leaving the testis intact. The wound healed uneventfully. Sections of the epididymis

showed a chronic granulomatous

o:~

process wHb

CASE REPORTS 1;t!~euci~r~~ B;cause of the :::t~mk~g Case 1. J O 17 b~cause endospores were not e ar East a_nd Mexican A · ."' a -year-old mentally retarded - mencan male th diagnosis was schistoso . . Rpresent, tentative pediatric service for diss:~~ ~as tre~t~d- by the mias1s. ecta] biopsy was cosis. Widely disseminat d m~ e coc?1d101domy'' Graybill, J. R., Silva J Jr Alf: d cerebrospinal fluid comple:i d~~~ase. wit~ positive D. E.: Immunologic and '1· ·: 1·,. or , R.H. and Thor serum complement f t· en . ixat1on titers, high si · c mica ve cocci·d·w1domycosis :t: II 1mprovem . ~n.t of progres-' ixa wn titers and negative O 0

t

transfer factor Cell Im wmg adm1mstration of · · mun., 8 : 120, 1973.

GENITOURINARY ASPECTS OF DISSEMINATED COCCIDIOIDOMYCOSIS

85

FIG. 2. Case 1. A, renal coccidioidomycosis. Note constriction of infundibula of lower pole with caliceal ballooning.

B, bilateral renal calcification from healed coccidioidal granulomas.

FIG. 3. Case 1. Renal coccidioidomycosis-retrograde pyelogram. Note moth-eaten appearance of left upper pole calices.

negative and cystoscopy revealed no evidence of schistosomiasis. Serial sections of the epididymis revealed many spherules (fig. 4), with doubly refractile walls containing endospores. Culture of

epididymal tissue yielded Coccidioides immitis. Diagnosis was coccidioidomycosis of the epididymis and localization studies were done to identify the focus of disease. Repeated washings from the renal pelves and ureters were sterile. The first bladder washing was positive for Coccidioides immitis and several fractional urine cultures since epididymectomy have revealed Coccidioides immitis in the prostatic fraction. Slides from the operation in 1958 were obtained from the Armed Forces Institute of Pathology and careful review revealed many spherules of Coccidioides immitis in the epididymis (fig. 5), with further documentation by silver stain (fig. 6). The patient remains asymptomatic. Serum and cerebrospinal fluid complement fixation titers and precipitin tests were negative 1 month after epididymectomy. One serum immunodiffusion test was positive. Case 3. A. M., a 46-year-old white man, received a renal homograft from his brother in 1969. The patient had lived in Los Angeles for 17 years, moved to Indiana and then to Arizona for his health. Coccidioidomycosis with rapid dissemination and meningitis developed. One urine culture was positive for Coccidioides immitis. Intravenous and intrathecal amphotericin was given with transient decrease in renal function and apparent control of the disease. A daily immunosuppressive regimen of 5 mg. prednisone and 50 mg. imuran was continued and renal function remains stable, with serum creatinine values of 1.2 to 1.4 mg. per di. Examination of the genitalia 2 years after the onset of coccidioidomycosis revealed a small normal left testis and epididymis, and an enlarged

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CONNER, DRACH AND BUCHER

FIG. 4. Case 2. E pididy mit is wit h spherule of Coccidioides immitis within giant cell. Reduced from x440

right testis, which the patient t hought had always been enlarged. There was a 1 cm. firm nodule in the lower portion of the right epididymis, which could not be separated from the adjacent testis. The scrotal sac was normal and there was no evidence of fixation of testis or epididymis to t he scrotal wall or sinus formation. The prostate was symmetrical but the right lateral lobe was more firm t h an the left one. Fractional urine cultures y ielded no growth but are incomplete. DISCUSSION

Genitourinary involvement is common in disseminated caccid iaidom~ AlTilougnpulmon ary and meningeal lesions usually dominate the clinical picture, urologists whose patients live in or visit endemic areas may encounter perplexing problems of diagnosis and treatment. Confusion with prostatic carcinoma may require repeated biopsies, 7 and renal alllL.ep~ ay m imic tuberculosis. Awareness of the disease is the first requirement for diagnosis . Repeated cultures with localization studies, careful examination, ra diograms, skin tests and immunologic studies may be required to diagnose the disease with certainty.

Genitourinary aspects of disseminated coccidioidomycosis.

Genitourinary involvement is common in disseminated coccidioidomycosis. Urologic evaluation should include careful examination, cultures and radiogram...
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