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Prostatic and Central Nervous System Histoplasmosis in an Immunocompetent Host: Case Report and Review of the Prostatic Histoplasmosis Literature - Steven D. Mawhorter Gerald V. Curley Elroy D. Kursh Carol E. Farver   Clinical Infectious Diseases, Volume 30, Issue 3, 1 March 2000, Pages 595–598, https://doi.org/10.1086/313699

Published: 01 March 2000

Abstract

Histoplasmosis is a common cause of systemic mycosis in areas of the United States where it is endemic. Central nervous system and genitourinary histoplasmosis is rare, especially in immunocompetent hosts. We describe a case of disseminated histoplasmosis in a normal host that was associated with cerebral and prostatic histoplasmosis presenting as fever of undetermined origin, weight loss, and severe debilitating altered mental status. The patient subsequently developed acute renal failure that manifested as obstructive uropathy during antifungal therapy with amphotericin B. Transurethral resection of the prostate resulted in improved renal function during continuation of amphotericin B therapy. Pathological analysis of the prostate revealed necrotizing granulomas with intralesional fungal organisms. Blood and urine cultures were positive for Histoplasma capsulatum. Diagnostic issues and management are discussed. Treatment resulted in return of normal cognitive and motor function. This case is compared with the 8 previously reported cases of H. capsulatum prostatitis.

Histoplasma capsulatum infection is usually a benign self-limited respiratory disease that is most commonly seen in areas of endemicity in the upper Mississippi River and Ohio River valleys. Most of these infections are clinically silent and resolve without consequence [1].

Disseminated disease is an uncommon but well-recognized sequela of histoplasmosis that occurs primarily in patients with impaired cellular defenses or after introduction of a large inoculum [2]. Clinically manifested CNS involvement is rare, and genitourinary and prostatic involvement with disseminated histoplasmosis occurs even more rarely [3, 4]. Experience with cryptococcosis points out that the prostate can be an important cryptic focus of fungal disease that leads to relapse in cases after apparent therapeutic cure.

We describe a case of disseminated histoplasmosis with CNS and prostatic involvement in an immunocompetent host presenting with fever of undetermined origin, weight loss, and progressive dementia. We discuss the challenging and instructive diagnostic issues that this case highlights. To provide context, our case is compared with CNS and prostatic mycoses, especially the 8 previously reported cases of histoplasmosis involving the prostate gland [5–12].

Case Report

A 77-year-old retired policeman from northern Ohio developed persistent fever, weight loss, and confusion. His medical history was remarkable for hypertension, hyperlipidemia, benign prostatic hypertrophy, and smoking (40 packs/year). His surgical history was notable for uncomplicated bilateral carotid endarterectomies (August and September 1986) and elective aortic aneurysm repair (1981). Four months before, a year after the death of his wife, he had been diagnosed with major depression. Initiation of antidepressant medication produced no clinical change. His medications were metoprolol, verapamil, gemfibrozil, finasteride, and sertraline.

Two months after onset of fever, he was hospitalized at another institution with fever (temperature, 38.2°C), backache, dyspnea, productive cough, and hypoxemia; bilateral interstitial infiltrates and pleural effusions, which resolved over several weeks, were noted on a chest radiogram and a CT scan. Laboratory studies were unremarkable except for demonstration of an elevated serum glucose level (141 mg/dL) and intermittent microscopic hematuria. The prostate-specific antigen level was 1.5 ng/mL. Blood and urine cultures yielded no bacterial growth. Sputum was not obtained. He was treated empirically with ampicillin/sulbactam for pneumonia, and terazosin therapy for urinary frequency attributed to benign prostatic hypertrophy was started. His condition improved partially, but he was readmitted to the hospital for 2 weeks with a discharge diagnosis of fever of undetermined origin. All medications, except for sertraline, were discontinued.

Four weeks later, persistent fever, weight loss up to 35 lb, and progressive dementia led to admission at our hospital. He also reported profound fatigue with occasional headaches and rare visual hallucinations. Physical examination revealed an elderly male in no acute distress who was having significant confusion, short-term memory impairment, and ataxia. There was no meningismus, hepatosplenomegaly, lymphadenopathy, or mucosal ulcerations. Head and neck, heart, lung, abdomen, testis, extremity, and vascular examinations were unremarkable. Rectal examination revealed an enlarged symmetrical firm nontender prostate. There were multiple variably pigmented papules and plaques on the skin that were distributed widely over the body. Biopsy was negative for melanoma.

Laboratory studies were remarkable for relative pancytopenia (WBC count, 3.57/mm3; hemoglobin level, 12.6 g/dL; and platelet count, 158/mm3). Serum chemistry analysis, blood urea nitrogen level, serum creatinine level, hepatic enzyme levels, and urinalysis were normal. Reversible dementia tests were normal. He had not traveled recently, nor did he have a history of toxic exposure. He had no identifiable risk factor for HIV infection except for blood transfusions during his aortic aneurysm repair in 1981 (EIA was nonreactive for HIV types 1 and 2). Purified protein derivative skin testing was negative with reactive anergy despite remote exposure to tuberculosis from his mother. Lumbar puncture was performed with mild obvious trauma. Opening pressure was normal, and analysis of CSF from tube 1 showed 815 RBCs/mm3, 14 WBCs/mm3 (43% neutrophils, 38% lymphocytes, 14% monocytes, 4% other mononuclear cells, 1% eosinophils), glucose concentration of 44 mg/dL (serum level, 116 mg/dL), and protein concentration of 69 mg/dL. VDRL testing of CSF was negative.

A head CT scan revealed very small remote lacunar infarcts involving the left side of the caudate head and the left external capsule. An electroencephalogram showed diffuse slowing. An MRI of the brain revealed 2 × 3-cm and 3 × 4-cm lesions in the right and left sides of the caudate head, respectively, with associated acute-to-subacute hemorrhages within each lesion. After gadolinium administration, multiple ring-enhancing and small punctate solid areas were visualized throughout the brain. A previous MRI obtained 1 year earlier for evaluation of tinnitus and sensorineural hearing loss, which subsequently resolved, was normal. Differential diagnosis given the MRI findings included hemorrhagic metastasis of melanoma, leukemic deposits, intracranial neoplasm, toxoplasmosis, or other infectious processes.

Two days after MRI, serological tests for H. capsulatum revealed that the titer of CF antibody to yeast in the blood was 1 : 256, and the titer of CF antibody to mycelial antigen in the serum was 1 : 512. CSF analysis showed that the titer of CF antibody to yeast was 1 : 4, and the titer of CF antibody to mycelial antigen was 1 : 4. Immunodiffusion testing of serum and CSF also revealed a reactive M band. Blood and urine cultures identified H. capsulatum via a DNA gene probe during the third week of incubation. Urinary H. capsulatum antigen was negative and remained negative throughout his treatment and follow-up. Antibiotic therapy was discontinued, and treatment with amphotericin B (1 mg/kg/d) was started. His mental status gradually improved over the next several weeks. He was transferred to a subacute nursing facility for physical therapy and rehabilitation.

The patient received 25 mg/kg of amphotericin B (∼1500 mg) over 14 weeks. His treatment course was complicated by development of nonoliguric acute renal failure (peak blood urea nitrogen, 107 mg/dL; serum creatinine, 5.2 mg/dL) that resulted in readmission to the hospital. Ultrasound examination demonstrated bilateral hydronephrosis, and cysto-scopy disclosed an enlarged obstructing prostate. Postrenal azotemia secondary to bladder outlet obstruction promptly resolved after insertion of a Foley catheter (blood urea nitrogen level, 19 mg/dL; serum creatinine level, 1.3 mg/dL). Ten days later, he underwent transurethral resection of the prostate. Pathological examination showed necrotizing granulomas scattered diffusely throughout the prostatic tissue. Grocott-Gomori methenamine—silver nitrate staining revealed yeast organisms within the granulomas that were morphologically consistent with H. capsulatum.

After documenting control of the CNS process by MRI and repeated lumbar puncture, amphotericin B was changed to itraconazole. Four months later, his mental status and weight were back to preillness levels. Three years later, he was well and continued maintenance therapy with itraconazole. He is an avid golfer, and his performance (as an indicator of neurological recovery) has returned to premorbid levels.

Discussion

We present an unusual case of an immunocompetent host who developed disseminated H. capsulatum infection with CNS involvement and significant granulomatous prostatic involvement. Several instructive diagnostic and management issues resulting from this case are discussed.

Although the symptoms are clearly nonspecific, in retrospect, our patient's original presentation is compatible with acute pulmonary histoplasmosis progressing to dissemination. Clinical findings of progressive disseminated histoplasmosis are often nonspecific and include fever and weight loss, as in our case. [1]. Endocarditis is a rare complication that occasionally manifests as systemic emboli or as isolated endocarditis with negative cultures. Our patient did not have evidence of histoplasma endocarditis to explain his multiple CNS lesions. Other less common areas of dissemination include the brain, meninges, kidneys, skin, bone, and joints [1, 2, 4]. Our patient's presentation with prominent dementia is atypical, although his other symptoms and signs fit well with disseminated histoplasmosis.

The true incidence of CNS involvement in disseminated histoplasmosis is difficult to determine; however, on the basis of data from autopsy studies, it occurs in up to 25% of cases [3, 6]. The brain, meninges, and spinal cord may be sites of symptomatic (25% of cases) or asymptomatic (75% of cases) extrapulmonary dissemination [3]. Before a patient seeks medical attention, symptoms have often been present for weeks to months and rarely for years. Our patient's normal brain MRI 1 year earlier during an evaluation of tinnitus helps rule out chronic CNS disease in this case. CNS manifestations include lymphocytic meningitis, focal brain or spinal cord lesions, stroke caused by vascular involvement or cerebral emboli, and diffuse encephalitis [3].

Neurodiagnostic tests are of value in CNS histoplasmosis. Electroencephalograms are abnormal in most cases, typically showing diffuse slowing with CNS involvement [3]. Head CT scans are abnormal in ∼90% of cases, usually showing contrast-enhancing mass lesions, cerebral atrophy, or hydrocephalus [3]. For our patient, the CT scan noted only small lesions consistent with a remote infarct. However, the MRI revealed multiple large and small enhancing lesions, some with complex internal hemorrhages. Although not obtained in our case, cerebral arteriograms may reveal mass lesions, cerebral infarction, or cerebral emboli.

Fungal infections of the genitourinary tract may involve any of the structures including the prostate [9, 13, 14]. Most, if not all, cases of mycotic prostatitis are part of systemic hematogenous dissemination. However, it is difficult to demonstrate conclusively whether prostatitis is the result of direct hematogenous seeding (versus contiguous spread from the kidney via the ureter) or is from the epididymis or seminal vesicles by orthograde flow of seminal fluid [13]. A 10-year review of systemic mycoses by Orr et al. [9] revealed 150 cases in which the incidence of genitourinary tract involvement was 6%. Although fungal infections of the genitourinary tract have been reported with increasing frequency in recent years, involvement of the prostate is still rarely noted [13, 15]. The true incidence of mycotic prostatitis is obscure because of several factors, including the fact that many cases are asymptomatic. Furthermore, either the prostate is often not examined or the results are not recorded during many autopsies except in symptomatic cases [13].

Prostatic involvement is well documented in blastomycosis and cryptococcosis and is much less often documented in para-coccidioidomycosis and histoplasmosis [9, 13]. Coccidioidomycosis is somewhat unique; on the basis of large reviews of 95 and 214 cases in the era before effective treatment became available [16, 17], the incidence of renal involvement was high (27%–60%) compared with that of prostate disease (1.8%–6%). Similar to our case, cryptococcosis is known to disseminate to both the CNS and the prostate in the same patient [13].

Prostatic involvement with mycotic disease may resemble tuberculosis, neoplasms, benign prostatic hypertrophy, syphilis, or bacterial prostatitis [9]. Presenting complaints include dysuria, urinary outlet obstruction, perineal or suprapubic discomfort, hematuria, and hematospermia [14]. In our patient, renal failure due to bladder outlet obstruction was eventually diagnosed. This diagnosis led to transurethral resection of the prostate, which revealed fungal prostatitis after granulomatous lesions with characteristic fungal elements were found by histological analysis.

Overall, only 8 cases of histoplasma prostatitis have been previously reported (table 1) [5–12]. The first mention of prostatic involvement occurred in a 1958 case where intestinal polyposis was found during antemortem biopsy and subsequent autopsy to be due to both Peutz-Jeghers syndrome and histoplasmosis [5]. The prostate was mentioned in a long list of organs where the organism was found at autopsy. Further cases in 1961 and 1970 reported significant caseating prostatic involvement in addition to disease in the lungs and adrenal glands in previously healthy individuals [7, 8]. In the 1961 case, there was no evidence of genitourinary involvement before autopsy [7]. Hematuria was noted late in the course of the second case, and significant granulomatous bladder lesions were also found at autopsy [8].

Larger reviews have corroborated the rare nature of this form of disseminated disease. Of 123 patients with culture-proven cases in 1959, 25 had disseminated disease, and only 1 had prostatic involvement [6]. An even larger review of 530 cases of active histoplasmosis in 1970 found at least 1 site of extrapulmonary disease in 25 cases [4]. Six patients had positive urine cultures, although only 1 had renal involvement (without prostatic changes) at autopsy, suggesting filtered fungemia [4].The only case of prostatic involvement in this series had already been reported [8]. Of note, many large series reported no evidence of histoplasma prostatitis, including a 1980 review of 102 disseminated cases from Vanderbilt [1].

Although most patients with earlier cases, and our patient, had no identifiable immunodeficiency, the 3 most recent cases of prostatic histoplasmosis all occurred in patients with HIV infection or AIDS [10–12]. Consistent with more severe disease in immunocompromised hosts, all cases were detected at the stage of prostatic abscess. Yet, overall genitourinary involvement in disseminated histoplasmosis in patients with AIDS remains rare, with only 1 of 72 cases in which a urine culture was positive [18]. Well-characterized relapses of cryptococcal disease from prostatic reservoirs raise questions about this form of histoplasmosis functioning in the same manner [10, 11]. These data, together with the high mortality rate noted for patients with AIDS, favor aggressive and prolonged treatment.

Treatment data regarding disseminated histoplasmosis involving the prostate are limited. In the genitourinary tract, surgery may not be an option because of the possibility of further dissemination with surgical intervention [4]. Whether maintenance therapy with amphotericin B, ketoconazole, or the new triazoles (itraconazole or fluconazole) is best remains unknown at this time [11]. Although some experts use fluconazole in consolidation therapy for disseminated histoplasmosis with CNS involvement because of documented penetration of the blood-brain barrier, itraconazole also has a record of efficacy in some cases [2, 3]. Given cases of relapse due to CNS histoplasmosis and prostatic involvement with other fungi, we have chosen maintenance therapy with itraconazole for our patient [3, 11].

In summary, we present a case of disseminated histoplasmosis with significant granulomatous prostatic and CNS involvement. Although CT scanning is often adequate for diagnosis, the need to consider MRI to reveal the extent of CNS disease is demonstrated in this case. An accurate diagnosis requires recognition of the common clinical manifestations, a high index of suspicion, and knowledge of the accuracy and limitations of tests used to diagnose fungal infections. The possibility of prostatic involvement is also highlighted in this case. The diagnostic and treatment implications related to causes of renal insufficiency in a patient receiving amphotericin B treatment are important. In addition, the possibility of the prostate as a reservoir for relapse should be considered in patients being treated for disseminated histoplasmosis, especially immunocompromised hosts. Despite a historically high mortality rate, our patient has had a significant recovery with return of cognitive and motor function and normalized renal function.