Blastomycosis: The great pretender can also be an opportunist. Initial clinical diagnosis and underlying diseases in 123 patients.

Lemos LB, Baliga M, Guo M. Department of Pathology, University of Texas, Houston; and the Department of Pathology, University of Mississippi, Jackson. Ann Diagn Pathol 2002 Jun;6(3):194-203 

Clinically, blastomycosis can be difficult to recognize even in the endemic areas where clinicians are aware of this problem. In only 18% of 123 patients from the University of Mississippi Medical Center (Jackson, MS) blastomycosis was correctly suspected at the initial patient evaluation. Pneumonia (40%), malignant tumors (16%), and tuberculosis (14%) were the most common misdiagnoses. The false first impression frequently resulted in unnecessary surgeries or treatment delays, with patients receiving inefficient antibiotic therapy for months. The presence of cutaneous involvement by the disease makes its' recognition easier for the clinician, raising the percentage of correct initial diagnosis to 64%. To evaluate the association with immunodepression, the presence of other diseases was also searched among the 123 patients. An immunodepressive condition preceded the fungal disease in 25% of patients. Another associated disease commonly found in blastomycotic patients was diabetes mellitus (22%).

Blastomycosis is correctly suspected at the first clinical evaluation in only a small percentage of patients; pneumonia, cancer, and tuberculosis are the most common clinical considerations. Cutaneous involvement leads the clinician to the correct diagnosis in the majority of cases. One fourth of the patients with blastomycosis had underlying immunodepressive conditions, and underlying diabetes mellitus is present in 22% of patients.

The Epidemiology of Blastomycosis in Illinois and Factors Associated with Death.

Author(s) Mark S. Dworkin, Amy N. Duckro, Laurie Proia, Jeffery D. Semel, and Greg Huhn. Clinical Infectious Diseases, volume 41 (2005), pages e107–e111

Abstract  Background.  Blastomycosis is a systemic fungal disease that may be asymptomatic or progressive and may lead to death. Methods.  In response to a reported increase in the number of cases of blastomycosis in Illinois, surveillance data reported to the Illinois Department of Public Health from January 1993 to August 2003 were analyzed and the medical records of 4 patients who died were reviewed. Results.  Among the 500 cases reported, the median age of the patients was 43 years (range, 487 years), and 34 patients (7%) died. Higher rates of mortality were observed among persons who were black, who were 65 years of age and older, and who were male. Death was associated with a time from onset of illness to diagnosis of 128 days (OR, 2.1; 95% CI, 1.04.8). During the period from 1993 through 2002, the number of cases reported per year increased from 24 to 87 (P<.05)Conclusions:  The incidence of blastomycosis has been increasing in Illinois. To reduce mortality related to delay in diagnosis and treatment, medical providers need to be educated about blastomycosis, with an emphasis on symptom recognition, methods of diagnosis, and appropriate antifungal treatment.

N Engl J Med. 1986 Feb 27;314(9):529-34.    
Klein BS et al. Isolation of Blastomyces dermatitidis in soil associated with a large outbreak of blastomycosis in Wisconsin.

In investigating six cases of blastomycosis in two school groups that had separately visited an environmental camp in northern Wisconsin in June 1984, we identified a large outbreak of the disease and isolated Blastomyces dermatitidis from soil at a beaver pond near the camp. Of 89 elementary-school children and 10 adults from the two groups, 48 (51 percent) of the 95 evaluated in September had blastomycosis. Of the cases, 26 (54 percent) were symptomatic (the median incubation period was 45 days; range, 21 to 106 days). No cases were identified in 10 groups that visited the camp two weeks before or after these two groups. A review of camp itineraries, a questionnaire survey, and environmental investigation showed that blastomycosis occurred in two of four groups that visited a beaver pond and in none of eight groups that did not. Walking on the beaver lodge and picking up items from its soil were associated with illness. Cultures of soil from the beaver lodge and decomposed wood near the beaver dam yielded B. dermatitidis. We conclude that B. dermatitidis in the soil can be a reservoir for human infection.

Pulmonary blastomycosis: an appraisal of diagnostic techniques.

Martynowicz MA, Prakash UB. Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Mayo Medical School and Mayo Medical Center, Rochester, MN 55905-0001, USA.  Chest 2002 Mar;121(3):768-73 Abstract quote

OBJECTIVES: Pulmonary blastomycosis often mimics bacterial pneumonia or bronchogenic carcinoma, which may result in delayed therapy or the performance of unnecessary diagnostic procedures. We have reviewed the utilization of diagnostic techniques in the workup of patients with pulmonary blastomycosis, defined their diagnostic yields, and proposed an optimal diagnostic approach for the patient in whom pulmonary blastomycosis is considered. DESIGN: Retrospective chart review of all patients with the diagnosis of blastomycosis at a major academic medical center.

RESULTS: Of the 119 patients with blastomycosis, 56 (47%) had pulmonary involvement. A total of 92 specimens were obtained by noninvasive means (sputa, 72 specimens; tracheal secretions, 5 specimens; and gastric washings, 15 specimens) in 35 patients. KOH smears were prepared from 22 of those specimens (24%). The diagnostic yield from these culture specimens obtained by noninvasive means was 86% per patient, and 75% per single sample. The diagnostic yields from KOH smears were 46% and 36%, respectively. Flexible bronchoscopy was performed in 24 patients and yielded a diagnosis in 22 (92%). Cultures of bronchial secretions (19 patients) and BAL fluid (6 patients) were positive in 100% and 67% of patients, respectively. The corresponding yields of KOH preparations were 17% (1 of 6 preparations) and 50% (3 of 6 preparations), respectively. Pathology specimens including those from bronchoscopic lung biopsies (nine patients), bronchial brushings (two patients), and bronchoscopic needle aspiration (one patient) were positive in 22%, 50%, and 0% of cases, respectively. Cytology was usually performed to exclude malignancy and was positive for Blastomyces dermatitidis in five patients (sputum, three patients; bronchial washings, two patients). Thoracotomy was performed in 11 cases, and in all patients the procedure yielded a diagnosis. Serology results were available in 25 patients. Immunodiffusion was positive in 10 patients (40%), and complement fixation in 4 patients (16%).

CONCLUSIONS: In patients with pulmonary blastomycosis, the positive yield from respiratory specimen cultures is high, but the confirmation of a diagnosis may take up to 5 weeks. Wet smears and cytology examinations of respiratory specimens provide quicker diagnoses but are underutilized. Their routine use is recommended in endemic areas. Commonly used serologic assays are insensitive and are not useful for diagnostic screening.

Culture   Sabouraud glucose agar, brain heart infusion agar, yeast-extract-phosphate agar, and a medium with cycloheximide, and then incubate at 30C.  Grows best on the yeast extract agar or agar containing yeast extract such as Mould Inhibitory Agar (IMA) Mould form to yeast form conversion is necessary to ensure that the fungus suspected to be B. dermatitidis is not a similar fungus-accomplished by inoculating Kelley's agar or blood agar supplemented with glutamine and then incubating the inoculated tubes at 37C. Exoantigen technique and a DNA culture confirmation kit.

Practice Guidelines for the Management of Patients with Blastomycosis Stanley W. Chapman et al

Guidelines for the treatment of blastomycosis are presented; these guidelines are the consensus opinion of an expert panel representing the National Institute of Allergy and Infectious Diseases Mycoses Study Group and the Infectious Diseases Society of America. The clinical spectrum of blastomycosis is varied, including asymptomatic infection, acute or chronic pneumonia, and extrapulmonary disease. Most patients with blastomycosis will require therapy. Spontaneous cures may occur in some immunocompetent individuals with acute pulmonary blastomycosis. Thus, in a case of disease limited to the lungs, cure may have occurred before the diagnosis is made and without treatment; such a patient should be followed up closely for evidence of disease progression or dissemination. In contrast, all patients who are immunocompromised, have progressive pulmonary disease, or have extrapulmonary disease must be treated. Treatment options include amphotericin B, ketoconazole, itraconazole, and fluconazole. Amphotericin B is the treatment of choice for patients who are immunocompromised, have life-threatening or central nervous system (CNS) disease, or for whom azole treatment has failed. In addition, amphotericin B is the only drug approved for treating blastomycosis in pregnant women. The azoles are an equally effective and less toxic alternative to amphotericin B for treating immunocompetent patients with mild to moderate pulmonary or extrapulmonary disease, excluding CNS disease. Although there are no comparative trials, itraconazole appears more efficacious than either ketoconazole or fluconazole. Thus, itraconazole is the initial treatment of choice for non–life-threatening non-CNS blastomycosis.

April 2000. This guideline is part of a series of updated or new guidelines from the IDSA. Clinical Infectious Diseases 2000;30:679–83 q 2000 by the Infectious Diseases Society of America.    

Blastomycosis: organ involvement and etiologic diagnosis. A review of 123 patients from Mississippi.

Lemos LB, Guo M, Baliga M. Cytopathology Service, Pathology Department, University of Mississippi Medical Center, Jackson, MS, USA.  Ann Diagn Pathol 2000 Dec;4(6):391-406 Abstract quote

Blastomycosis can only be diagnosed through the identification of the yeasts of Blastomyces dermatitidis in body fluids, tissues, or cultured material.  The charts from 123 patients treated for blastomycosis at the University of Mississippi Medical Center from January 1980 through May 2000 were reviewed to determine the role of wet preparation, cytology, histology, and culture in diagnosing this fungal disease. Cytology uncovered the etiologic agent in 56.1% of all cases and in 71.8% of pulmonary cases. Cytology also was the first method to disclose the fungus in 57.7% of pulmonary cases. Sputum was the cytology specimen examined in 51% of the patients. In 69 patients with lung involvement, pulmonary cytology was positive in 97% of cases. Wet preparation was the second method to most commonly uncover the fungus in 37.4% of all cases. Histology was the third method with 32.5% of positive cases. Cultures were positive in 64.2% of all cases but they were the first to detect the fungus in only 3.2% of all patients. There was pulmonary involvement in 87% of patients, cutaneous involvement in 20%, osseous involvement in 15%, and central nervous involvement in 3%. In the medical literature the relative proportion of pulmonary versus disseminated disease clearly increased in series reported after 1959.

Proportionally to the pattern of patients admitted to the University of Mississippi Medical Center, there is a clear predominance of black males among patients with blastomycosis followed by black females. White females constitute the sex/ethnic group least affected by this fungal disease.

Laryngeal blastomycosis: a commonly missed diagnosis.

Hanson JM, Spector G, El-Mofty SK. Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, Missouri, USA.                           Ann Otol Rhinol Laryngol 2000 Mar;109(3):281-6 Abstract quote

Blastomycosis is a relatively uncommon fungal disease that most commonly affects the lungs. Other organs may be involved, usually secondary to dissemination of the organism. Laryngeal blastomycosis may occur in isolation from active pulmonary disease. The signs, symptoms, clinical features, and pathological findings of laryngeal blastomycosis mimic those of squamous cell carcinoma. Misdiagnosis may result in inappropriate treatment with potential morbidity. Proper understanding of the clinical presentation and familiarity with the histopathologic features of this disease are therefore imperative. In this paper, we report 2 cases of laryngeal blastomycosis, 1 of which was misdiagnosed as squamous cell carcinoma, clinically and microscopically, with consequent radiotherapy and laryngectomy. In the other case, a clinical diagnosis of glottic squamous cell carcinoma was rendered. However, blastomycosis was identified in a biopsy specimen. We also review cases of isolated laryngeal blastomycosis that have been reported in the English-language literature during the last 80 years. A number of those cases were misdiagnosed clinically and microscopically as squamous cell carcinoma.

Peritoneal blastomycosis.

Perez-Lasala G, Nolan RL, Chapman SW, Achord JL. Division of Infectious Diseases, University of Mississippi Medical Center, Jackson. Am J Gastroenterol 1991 Mar;86(3):357-9 Abstract quote

Blastomycosis is a systemic fungal infection caused by Blastomyces dermatitidis. Involvement of the peritoneum is unusual, with only two previously reported cases that occurred in association with disseminated disease. A single case of histopathologically proven blastomycosis involving the peritoneum is presented, as well as a short overview of previously published cases on gastrointestinal and peritoneal blastomycosis. The case is unique in that chronic peritonitis was the only manifestation of disease. The diagnosis was made by laparoscopy.

Blastomycosis of the lumbar spine: case report and review of the literature, with emphasis on diagnostic laboratory tools and management. Eur Spine J. 1998;7(5):416-21
Hadjipavlou AG et al University of Texas Medical Branch, Department of Orthopaedics and Rehabilitation, Galveston 77555-0792, USA.

We report on the conservative and surgical management of a patient with blastomycosis of the lumbar spine, causing severe and crippling deformity. The diagnosis was made through biopsy. Curative removal, reconstruction and realignment of the spine were achieved. Imaging modalities were highlighted, with a detailed discussion of the histology and conservative and surgical management. We emphasize the importance of early, aggressive treatment of blastomycosis to prevent deformity and disability, and to enable identification of the best management of a destructive lesion with deformity. This case demonstrates that empirical treatment should not be used in cases of unusual sinus and abscess locations. Specific diagnosis and early treatment are indicated to prevent dreadful complications and spinal deformity resulting from blastomycosis. Aggressive antifungal therapy can cure the disease but does not control complications related to deformity. The latter can only be addressed by surgical reconstruction. We review the literature of surgical treatment, focusing on abscess drainage, bone fusion and posterior instrumentation in the absence of addressing the deformity component.

Giant forms of Blastomyces dermatitidis in the pulmonary lesions of blastomycosis. Potential confusion with Coccidioides immitis.

Watts JC, Chandler FW, Mihalov ML, Kammeyer PL, Armin AR.Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, Michigan 48072.  Am J Clin Pathol 1990 Apr;93(4):575-8 Abstract quote

Typical yeast-phase cells of Blastomyces dermatitidis have a characteristic appearance in tissue sections. Fungal morphologic variation occurs infrequently in the lesions of blastomycosis, yet it can complicate the differential diagnosis, particularly if fresh tissue is not available for microbiologic culture. The authors report a case of pulmonary blastomycosis, confirmed by culture and direct immunofluorescence, in which some of the yeast-like cells were abnormally large. These giant yeast-like cells exceeded the size range accepted for the tissue forms of B. dermatitidis; therefore, coccidioidomycosis was considered initially in the differential diagnosis. Otherwise characteristic morphologic features of these cells, in particular multinucleation and the production of broad-based blastoconidia, helped resolve the differential diagnosis. The diagnosis can be confirmed by direct immunofluorescence or microbiologic culture.

Delayed diagnosis of osseous blastomycosis in two patients following environmental exposure in nonendemic areas.

Veligandla SR, Hinrichs SH, Rupp ME, Lien EA, Neff JR, Iwen PC.Department of Internal Medicine, University of Nebraska Medical Center, Omaha 68198-6495, USA Am J Clin Pathol 2002 Oct;118(4):536-41 Abstract quote

Blastomycosis generally results from inhalation of Blastomyces dermatitidis conidia following exposure to contaminated soil in an endemic area. Primary infections commonly involve the lungs, although secondary dissemination to other body sites may occur. We describe 2 cases of osseous blastomycosis in people living outside the endemic areas. Both patients reported exposure to soil following injury to the knee from occupational activities. Mold isolated from each case was identified as B dermatitidis by micromorphologic characteristics including yeast conversion testing and by a positive AccuProbe Blastomyces dermatitidis test (GenProbe, San Diego, CA). Retrospective review of histologic slides, initially reported as negative, identified rare poorly staining, broad-based budding yeast forms in each case. Both patients were treated successfully with itraconazole with no evidence of recurrent infection after 1 year. These cases illustrate the importance of considering blastomycosis in the differential diagnosis of bony lesions, even though the patient may live outside an endemic area for B dermatitidis.

Blastomycosis: report of three cases from Alberta with a review of Canadian cases. Mycopathologia. 1979 Aug 31;68(1):53-63

Sekhon AS, Bogorus MS, Sims HV.

Approximately 120 cases of blastomycosis have been reported from Canada to-date. The great majority of these occurred in the Eastern provinces. Since 1970, three cases of blastomycosis have been seen in Alberta. The first case, with meningeal and pulmonary involvements, was diagnosed at post-mortem. The second case was that of a 75-year-old male with a history of pancytopenia, aortic arteriosclerosis, exposure to mercury, and fever. KOH and periodic-acid schiff (PAS) stained smears of the lung tissue, received after autopsy, showed numerous budding yeast cells of Blastomyces dermatitidis along with some hyphal filaments. Similarly, budding cells of B. dermatitidis and hyphal segments were observed in large numbers in the PAS and Gomori's methenamine-silver (GMS) stained sections made from adrenals, lung, kidney, and spleen tissues. Attempts to culture the fungus on a variety of selective and non-selective media were unsuccessful, due to heavy bacterial contamination. The indirect fluoroscent antibody results were 2+ with the B. dermatitidis conjugate. The third case was that of a 31-year-old male, who was admitted to the hospital with the chief complaint of chest pain. Biopsy tissue sections, stained with the GMS procedure revealed a few foci with B. dermatitidis yeast cells. The immunodiffusion and complement fixation (CF) tests gave positive results against B. dermatitidis antigen (titre, 1:16). The CF titre declined following treatment with amphotericin B and the immunodiffusion test became negative after the institution of antifungal therapy. Except for the last patient, the other two patients had no history of travel in any known endemic areas. In addition to these cases, a survey of blastomycosis occurring in this country has been presented along with on the disease in dogs and a cat.

Blastomycosis in the Immunocompromised Host

Recent reports indicate that B. dermatitidis may infrequently act as an opportunistic pathogen, notably in patients who are in the late stages of AIDS, transplant recipients, and patients treated with immunosuppressive or cytotoxic chemotherapy [11, 20]. Disease in these patients is more aggressive and more often fatal than disease in the normal host. Pulmonary disease is more likely to present with diffuse pulmonary infiltrates and respiratory failure. Dissemination to multiple organs, including the CNS, also occurs more frequently. Mortality rates of 30%–40% have been reported, and most deaths attributed to blastomycosis occur during the first few weeks of therapy. Thus, early and aggressive treatment with amphotericin B (0.7–1 mg/ kg/d) is indicated for blastomycosis in the immunocompromised patient (AII). Most experts recommend a total dose of 1.5–2.5 g, although treatment for selected patients without CNS infection may be switched to itraconazole after clinical stabilization with amphotericin B (usually a minimum dose of 1 g)(BIII). Despite amphotericin B treatment, frequent relapses occur in patients with AIDS and in those patients who continue immunosuppressive therapy [11, 20]. Some authorities therefore recommend chronic suppressive therapy with an azole, preferably itraconazole, for those patients who respond to a primary course of amphotericin B treatment (BIII). Treatment with ketoconazole is discouraged because relapse rates are  higher (DIII). Fluconazole treatment may be given special consideration  for selected patients who have had CNS disease or patients unable to tolerate itraconazole owing to toxicity or drug interactions (BIII)

Central nervous system and genitourinary blastomycosis: Confusion with tuberculosis.

Morse HG, Nichol WP, Cook DM, et al: West J Med 1983 Jul; 139:99-103. From the Department of Medicine, The Oregon Health Sciences University and Veterans Administration Medical Center, Portland

INFECTION WITH the dimorphic fungus Blastomyces dermatitidis causes a wide spectrum of disease, ranging from asymptomatic pulmonary infection to a fatal systemic illness. Although effective antifungal therapy is available, the difficulty in establishing an early diagnosis hampers management of the disease. We describe a fatal case of blastomycosis occurring in a nonendemic area that illustrates the difficulties in distinguishing blastomycosis from tuberculosis. Furthermore, this report shows the importance of carefully searching for evidence of blastomycosis elsewhere than the central nervous system when there is unexplained chronic meningitis. In addition, blastomycosis as a cause of hypothalamic-pituitary dysfunction, as described in this case, has only infrequently been reported.'

Report of a Case

The patient, a 54-year-old heavy equipment operator, first presented to the Portland Veterans Administration Medical Center on August 10, 1981, because of urinary frequency and hesitancy. On examination he had a tender prostate and analysis of urine showed 20 leukocytes per high power field without visible bacteria. Empiric treatment with trimethoprim-sulfamethoxazole resulted in symptomatic improvement. Culture of a urine specimen obtained before therapy was negative for bacteria. Three weeks later he was admitted to hospital because of shortness of breath, cough, night sweats, polyuria, polydipsia and a 6.8-kg ( 1 5-lb) weight loss. There was no history of recent travel outside of Oregon though the patient had traveled widely in the 1950s

Physical examination was unremarkable. A chest roentgenogram showed infiltrates of both apices and posterior upper lobes (Figure 1). Gram's stain of an expectorated sputum specimen showed numerous polymorphonuclear leukocytes, rare epithelial cells and predominant Gram-positive diplococci. Stains for acidfast bacilli were negative on three occasions. Analysis of urine again showed 20 leukocytes per high power field and bacterial cultures were negative. A tuberculin skin test (5 tuberculin units) was positive with 18 mm of induration. Screening tests of blood chemistries and complete blood count were normal.The patient was diagnosed as having pneumococcal pneumonia and possible active pulmonary and renal tuberculosis. Treatment with procaine penicillin, isoniazid and rifampin was begun. The patient reported symptomatic improvement and was discharged on a regimen of antituberculous therapy after completing a ten-day course of penicillin.

Readmission three days later was prompted by lethargy and orthostatic dizziness. Despite clinical evidence of volume depletion, he was noted to be polyuric. Results of water deprivation tests were suggestive of partial central diabetes insipidus. Further test results were considered typical of hypothalamic dysfunction and replacement therapy with hydrocortisone, levothyroxine and vasopressin was begun. A computerized tomographic (CT) scan of the head showed enhancing lesions in the suprasellar region, left cerebellum and right caudate nucleus (Figure 2). A low-density lesion in the left temporal area was felt most suggestive of an arachnoid cyst. Lumbar puncture done September 30, 1981, showed an opening pressure of 260 mm of water. Cerebrospinal fluid studies are recorded in Table 2. Results of Gram's stain; fluorochrome, india ink, cryptococcal antigen and VDRL tests; cytology examination, and bacterial and fungal cultures were negative.

Though tuberculous meningitis was the likely diagnosis, cultures of urine, sputum and cerebrospinal fluid specimens were all negative for mycobacteria at six  weeks. Diagnostic bronchoscopy with transbronchial biopsy, brushing and washing specimens was done with cytologic examination, cultures, fluorochrome, Gram's stain and potassium hydroxide preparation. These did not result in a diagnosis. Biopsy specimens of the upper lobes of the lung showed chronic inflammation without organisms or granulomata. The patient improved symptomatically with rehydration and was discharged receiving isoniazid, rifampin, hydrocortisone, desmopressin acetate and levothyroxine. Two weeks after discharge he was seen in the outpatient clinic and remained improved.

Third Admission, October 24, 1981

The patient was admitted because of confusion, lethargy and pronounced orthostatic hypotension. Neurologic examination showed meningism, ataxic gait and a mild left hemiparesis. Findings on a chest roentgenogram and CT scan of the head were unchanged. Lumbar puncture was repeated. A large volume cisternal tap showed similar values and smears, cultures and cytologic studies were also negative. Serologic tests of serum showed the following titers: coccidioidomycosis complement-fixing (CF) of 1:8, blastomycosis CF 1:8, histoplasmosis CF 1:32 and cryptococcal antigen test negative. Cerebrospinal fluid electrophoresis showed a polyclonal increase in immunoglobulin G. Culture of expressed prostatic secretions grew an organism initially identified as a Chrysosporium and felt to be a contaminant. The culture was sent to the Centers for Disease Control for further identification. A bone marrow biopsy specimen showed no organisms or granulomata.

Recurrent episodes of somnolence were attributed to rising serum sodium content and volume depletion. Vasopressin tannate was given subcutaneously and fluids intravenously to maintain intravascular volume. Ten days after admission, the patient became severely obtunded and an acute right hemiparesis and central hyperventilation developed. A CT scan of the head showed no change. Progressive obtundation and respiratory depression necessitated mechanical ventilation. Lumbar puncture was repeated November 6, 1981

Serologic studies of a cerebrospinal fluid specimen for fungus showed histoplasmosis CF titer 1:8, blastomycosis CF titer 1:2 and cryptococcal antigen test negative. Because of a failure to respond to antituberculous therapy, an uncertain diagnosis and a severely worsening clinical condition, amphotericin B therapy was begun on November 6, 1981, for the possibility that fungal meningitis might be present. Diagnostic craniotomy was done after three days of amphotericin B administration, with biopsy specimens of brain and meninges showing nonspecific inflammation. No microorganisms or malignant cells were identified but the presence of a benign arachnoid cyst was confirmed. A follow-up CT scan showed decreased enhancement of the suprasellar lesion. Over the next several weeks the patient's mental state improved gradually but never returned to baseline. Five weeks after beginning amphotericin B therapy, a repeat lumbar puncture showed a return to normal of cerebrospinal fluid values (Table2). Subsequently, bacteremia and bilateral lower lobe aspiration pneumonia developed due to Staphylococcus aureus. Following profound and prolonged hypotension, the patient became decerebrate and a CT scan showed decreased density in the entire left hemisphere and a large midline shift, indicating a left cerebrovascular accident. A nuclear brain scan showed no perfusion of either hemisphere. An electroencephalogram showed no cerebral electrical activity and mechanical ventilation was discontinued.

Postmortem Findings

Serologic studies for fungi done on a cerebrospinal fluid specimen obtained just before death showed no change in histoplasmosis, blastomycosis, cryptococcal or coccidioidomycosis antibody titers. Four weeks after the patient died, culture of the expressed prostatic secretions taken nine weeks before his death was reported by the Centers for Disease Control to be growing Blastomyces dermatitidis. Postmortem examination showed extensive central nervous system and prostatic involvement with budding yeast forms on periodic acid-Schiff staining, morphologically typical of B dermatitidis (see photomicrographs, Figures 3 and 4). Organisms were identified in both lobes of the pituitary gland, in the pituitary stalk and in the leptomeninges at the base of the hypothalamus. A diffuse perivascular mononuclear cell infiltration associated with budding yeast was found in vessels from the circle of Willis. A recent left hemispheric infarction was present. The remainder of the brain including the hypothalamic region was not sufficiently preserved for accurate pathologic diagnosis. The lungs showed apical scarring and fibrosis without active disease and pneumonia of both lower lobes was found.

Acid-fast and periodic acid-Schiff stains showed no organisms in pulmonary tissue. Fungal culture of specimens taken at autopsy from lung, brain and prostate were negative.

Comments

Although originally felt to be a disease limited to North America, blastomycosis is now recognized to have a worldwide distribution. Endemic areas in North America, as defined by case reporting, include the southeastern and south central United States, as well as the Great Lakes region of the United States and Canada. The disease appears to be distinctly less prevalent west of the Rocky Mountains, though cases have been reported sporadically. The precise epidemiology of blastomycosis has yet to be defined. Occupational or recreational exposure to soil enriched with avian excreta has been suggested as a potential source of infection; attempts to culture the organism from soil, however, have usually failed. Our patient's occupation (heavy equipment operator) is likely to have provided ample opportunity for such exposure. No related cases in humans or dogs that would suggest a common source of exposure could be identified. Pulmonary infection due to B dermatitidis can present as acute pneumonia but more often results in minimally symptomatic or asymptomatic pneumonitis.

Spontaneous healing and late endogenous reactivation have been observed. The findings on chest roentgenograms in cases of pulmonary blastomycosis are not distinctive, with changes varying from a consolidated lobar pneumonia to multiple diffuse infiltrations. Hilar adenopathy is common but cavitation is rare. Our patient's chest roentgenogram showed changes typical of granulomatous disease but without prior films for comparison the activity of disease could not be assessed. Because of a positive tuberculin skin test, the abnormalities were initially considered due to tuberculosis.

No evidence of active pulmonary blastomycosis or tuberculosis was found on repeated cultures or histopathologic examination of the lungs either before or after death. Whether the roentgenographic abnormality represented healed blastomycosis or tuberculosis or both cannot be determined. Central nervous system involvement with blastomycosis is estimated to occur in 3% to 10% of cases. Estimates are as high as 33% in autopsy series.7 Central nervous system disease presents clinically as chronic meningitis or as intracranial or spinal mass lesions. A similarity between blastomycotic and tuberculous meningitis has been stressed in recent reviews7'8 and, indeed, the two diseases are indistinguishable on clinical grounds. Serodiagnosis of blastomycosis is insensitive and cross-reaction with Histoplasma capsulatum can occur.4'9 Although a complement-fixation titer of 1:32 or higher should encourage aggressive attempts to diagnose blastomycosis, no single titer is diagnostic of active disease. Skin tests are of no value in diagnosis and are no longer commercially available. More than 90% of reported cases of central nervous system blastomycosis have had culture-negative lumbar cerebrospinal fluid. Cisternal or ventricular fluid sampling has been considered more sensitive than lumbar puncture, 7 8 but in the current case a large-volume cistemral tap was negative for fungi by both smear and culture despite extensive central nervous system involvement proved at autopsy. Likewise, meningeal and brain biopsy studies showed no abnormalities, although specimens were not obtained from the basal meninges, the area found at autopsy to have the richest fungal invasion. Gonyea7 has stressed the importance of a vigorous diagnostic search for extraneural disease and that testing should include cutaneous and subcutaneous lesions, joint effusions, large volume urine culture, smear and culture of prostatic secretions or prostatic biopsy. A needle biopsy of the prostate would likely have provided an earlier diagnosis in our patient. Vasculitic response to deep mycotic infection has been well described in cases of histoplasmosis and coccidioidomycosis,' but to our knowledge has not been described in those of blastomycosis. Vasculitis may have contributed to our patient's recurrent focal neurologic events.

The male genitourinary tract is involved in 20% to 30% of cases of blastomycosis. Presentation with prostatitis or urinary retention is well documented. The importance of aggressive evaluation of a slowly resolving case of prostatitis, including fungal culture of prostatic secretions and a biopsy study, cannot be overemphasized.

Culture of expressed prostatic secretions eventually led to a correct diagnosis in our patient but delay in doing this caused a delay in instituting appropriate therapy. Because B dermatitidis may require two to three weeks for isolation and identification, histopathologic examination of biopsy material potentially provides a more rapid diagnosis.

Endocrine syndromes caused by blastomycosis have included primary adrenal insufficiency due to adrenal involvement,'2 hyperprolactinemia due to chronic  pleural disease'3 and, recently, diabetes insipidus of unclear cause.'4 Pathologic series have described thyroid and pituitary involvement but no clinical data are provided.' To our knowledge this is the first reported case of hypopituitarism due to blastomycosis with pathologic correlation. Pathogenesis of this syndrome is evident from the necropsy findings; fungal organisms were found in both lobes of the pituitary and in the stalk. In addition, the area of richest meningeal involvement was that of the median eminence. Hypothalamic invasion was suspected clinically on the basis of an enhancing suprasellar mass on CT scan that diminished in size during amphotericin B therapy. Endocrine evaluation also suggested hypothalamic dysfunction (elevated prolactin level with depressed luteinizing hormone, testosterone, thyroid-stimulating hormone and thyroxine levels). Hypothalamic tissue was not sufficiently preserved at autopsy to show destruction by fungi. The patient's endocrine dysfunction likely resulted from patchy involvement of both the pituitary and the hypothalamus with blastomycosis. Finally, the differential diagnosis between tuberculosis and blastomycosis deserves comment. These infections can be clinically indistinguishable and, in fact, have been reported to occur simultaneously.5",6 Our patient's presenting symptoms of fever, night sweats and weight loss, coupled with a positive tuberculin skin test and findings on a chest roentgenogram typical of tuberculosis, led to the empiric administration of antituberculous therapy while awaiting culture confirmation.

Chronic meningitis, sterile pyuria and hypothalamic dysfunction are all well described in cases of tuberculosis; however, several aspects of this case suggested a cause other than mycobacteria. Abnormal upper urinary tracts on a pyelogram with dye given intravenously are seen in more than 90% of patients with genitourinary tuberculosisl7; therefore, the normal findings on our patient's pyelogram should have prompted search for an alternate cause of sterile pyuria. Of the deep mycoses only blastomycosis commonly involves the lower genitourinary tract." Prostatic biopsy would likely have provided an earlier diagnosis and avoided more invasive diagnostic procedures. Second, his failure to respond to empiric antituberculous therapy and the development of progressive chronic meningitis while receiving therapy would be unusual for tuberculosis.

Failure to show improvement by cerebrospinal fluid measurements after eight weeks of isoniazid and rifampin therapy should prompt search for other causes of chronic meningitis.'8"19 Ventricular fluid sampling and brain and meningeal biopsy studies, although unrewarding in this case, may be indicated in the search for a specific diagnosis. Blastomycosis should be considered in the differential diagnosis of any systemic illness resembling tuberculosis, even when it occurs outside the usual endemic areas.

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