Cerebral histoplasmosis in the azole era: report of four cases and review. (Case Report).

Abstract: We report four cases of cerebral histoplasmosis and discuss features of six additional cases reported in the medical literature in the past 10 years, when azoles have been available for therapy. Most patients with this disease are immunocompromised or have a history that suggests heavy exposure to Histoplasma capsulatum. Fever and other clinical findings of systemic toxicity caused by disseminated histoplasmosis may be absent; 5 of 10 patients did not manifest these findings. Although the mainstay of treatment for central nervous system histoplasmosis remains amphotericin B, 9 of the 10 patients received itraconazole or fluconazole either as initial therapy or after a course of treatment with amphotericin B.

**********

The dimorphic fungus Histoplasma capsulatum causes histoplasmosis, which is endemic in the Ohio and Mississippi river valleys of the United States. Bird and bat droppings enhance the growth of the mycelial phase of H. capsulatum. (1) Infection occurs by means of inhalation of airborne mycelia, with conversion to yeast forms in the lung and subsequent hematogenous dissemination. (2) Immunocompetent individuals with primary infection caused by low-level exposure are usually asymptomatic or experience minor respiratory illness, even though they have foci of microorganisms widely distributed throughout their bodies. Focal destructive lesions at these sites of hematogenous spread define disseminated histoplasmosis, which is more common among people with impaired cellular immune mechanisms (eg, those with the acquired immunodeficiency syndrome [AIDS]). (3-5)

Approximately 10 to 20% of patients with disseminated histoplasmosis have clinically apparent central nervous system (CNS) involvement, but not all patients with CNS histoplasmosis have symptomatic disease at other sites.6 Meningitis, parenchymal mass lesions or histoplasmomas of the brain (cerebral histoplasmosis), diffuse encephalitis, and symptomatic cerebral emboli associated with endocarditis are recognized forms of CNS histoplasmosisi (6,7) Since Wheat et a1 (6) reviewed GNS histoplasmosis in 1990, the triazole antifungal agents itraconazole and fluconazole have assumed a prominent role in the management of patients with histoplasmosis and other systemic mycoses. (6,8) Clinical trials that have evaluated itraconazole or fluconazole for the treatment of histoplasmosis have excluded patients with CNS disease, however. (9-12) We describe four patients with cerebral histoplasmosis, all of whom received a triazole as a component of their therapy, and discuss six additional cases from the recent literature. (13-18) Radiographs from one of our patients have been published previously. (19)

Discussion

For purposes of discussion we will consider our four patients plus six additional cases of cerebral histoplasmosis described as individual case reports. (13-18) Eight of 10 patients (each of our patients and four patients described by others (13, 16-18) resided in areas endemic for histoplasmosis. Two patients were living in Europe at the time of diagnosis but had previously resided in histoplasmosis-endemic areas, suggesting reactivation as the mechanism of disease in these individuals. (14, 15) Six of the 10 patients were immunocompromised at the time they presented with cerebral histoplasmosis. Three patients had HIV infection with CD4 T-lymphocyte counts less than 50 cells/[micro]A, and another three were taking immunosuppressive medications (two were receiving corticosteroids for underlying hematologic disease, and one renal transplant recipient was taking prednisone and azathioprine). Three additional patients described activities that could have exposed them to a high inoculum of H. capsulatum spores before the onset of symptoms (one routinely used chicken feces to fertilize his garden, one had cleaned out old chicken coops, and one had excavated around the foundation of an old home). Overall, 9 of the 10 patients with cerebral histoplasmosis considered in this report had AIDS, were taking immunosuppresive medications, or had histories that suggested the possibility of heavy exposure to infectious spores.

Approximately 50% of patients with CNS histoplasmosis have manifestations of progressive, disseminated histoplasmosis, an uncommon illness in individuals without AIDS or another condition associated with suppression of cellular immunity. (20) Patient 4 was seronegative for HIV and was not taking immunosuppressant medications, yet had progressive, disseminated disease. Both HIV-infected patients from the recent literature had signs and symptoms consistent with progressive, disseminated histoplasmosis, and consistent with the observation that the infection is widely disseminated in nearly all AIDS patients with histoplasmosis. (5, 7) It is somewhat surprising that Patient 3 had no symptoms or signs attributable to histoplasmosis other than the focal neurologic deficits caused by cerebral histoplasmosis and asymptomatic pulmonary opacities, despite advanced HIV disease. The only identified manifestation of histoplasmosis outside the CNS in Patient 1 was an adrenal abnormality detected by CT. Adrenal insufficienc y may have contributed to his illness, but this complication was not fully investigated before he died. The nonspecific symptoms of fever and weight loss in Patient 2 resolved with antifungal therapy and were likely manifestations of histoplasmosis. Combining our 4 patients and the 6 from the recent literature, only 5 of 10 patients had documented fever.

Neurologic abnormalities generally reflected the effects of single or multiple space-occupying brain lesions, with headache, focal deficits, and altered mentation predominating. Concomitant meningitis was associated with neck stiffness and other meningeal signs.(14,16) Cerebrospinal fluid (CSF) samples were obtained from 8 of 10 patients. Patient 2, Patient 4, and the patients described by Knapp et al(15) and Bamberger(17) had normal or trivially abnormal CSF studies. The remaining four patients had CSF pleocytosis; CSF from the two patients with concomitant meningitis had marked protein elevation and hypoglycorrhachia.(13,14,16,18)

All four patients from our case series had multiple enhancing, space-occupying brain lesions documented by imaging studies. Representative images from Patients 2 and 3 are shown in Figures 1 and 2, respectively. Among the six literature cases, four patients had multiple enhancing lesions

seen on MRI, and two each had a solitary mass on MRI.(13-18)

Serologic testing was negative in Patient 1 and in the patient reported by Knapp et al.(15) Patients 2, 3, and 4 did not undergo antibody testing. In two of the reviewed case reports, the authors do not state whether serologic testing was performed.(13,14) In the remaining cases, CSF and/or serum contained antibodies to H. capsulatum antigens. It is important to note that serologic tests are positive in only approximately 80% of patients with disseminated histoplasmosis, and test sensitivity is even lower among immunosuppressed patients.(20) Cross-reacting antibodies associated with other fungal infections and persisting antibodies to H. capsulatum from a previous episode of histoplasmosis or remote asymptomatic primary infection may cause false-positive results.

H. capsulatum polysaccharide antigen is detected in the urine of 90% of patients with disseminated histoplasmosis.(20) Both of our patients who underwent urine HPA testing had evidence of disease outside of the CNS, and both had positive results. The patients reported by Bamberger(17) and Mawhorter et al(18) had negative HPA assays in the urine and CSF and in the urine, respectively. The patient described by Klein et a1(16) had a negative urine HPA initially. Later in her course, when she experienced a relapse associated with return to CSF culture positivity, the CSF HPA became positive.

Brain biopsy, with appropriate stains and cultures, is the "gold standard" for the diagnosis of cerebral histoplasmosis. Brain biopsy proved the diagnosis of cerebral histoplasmosis in three of our four patients and in one patient from the recent literature.(13) An additional patient underwent brain biopsy, which revealed noncaseating granulomas without visible microorganisms; later, H. capsulatuin grew from the CSF of this patient.(16) In the remaining five cases (Patient 4 and four patients reported by others(14,15,17,18), the diagnosis of cerebral histoplasmosis was made on the basis of tissue obtained from non-CNS sites plus imaging studies of the brain. For practical purposes, parenchymal brain masses can be attributed reasonably to H. capsulatum infection in the patient who has concurrent evidence of disseminated histoplasmosis. If CNS manifestations progress or fail to improve during the course of therapy for histoplasmosis, brain biopsy would be the next step.

Amphotericin B is the initial antifungal therapy of choice for patients with CNS histoplasmosis, including focal parenchymal disease. (21) Except for Patient 1, who developed renal insufficiency and died early in the course of his disease, our patients received 1.0 to 2.0 g of amphotericin B, followed by at least 2 months of therapy with an oral azole (Table 1). Because Patient 3 had ADS, she would have been maintained on itraconazole after receiving a course of amphotericin B, even if she had not had CNS disease. (22) Subsequent azole therapy was administered to Patients 2 and 4 with the hope of reducing the risk of recurrence (ie, as consolidation therapy). Obviously, our small case series cannot form the basis for firm recommendations regarding the use of azoles as consolidation therapy for cerebral histoplasmosis; however, this approach seems reasonable, especially for immunosuppressed patients.

If azole therapy is used for cerebral histoplasmosis, it is unclear whether itraconazole or fluconazole should be the preferred agent. Itraconazole is highly effective as initial therapy for both AIDS and non-AIDS patients with mild to moderate histoplasmosis that does not involve the CNS; noncomparative data suggest that fluconazole is less effective than itraconazole. (9) Itraconazole also effectively prevents relapse of histoplasmosis in patients with AID AIDS. (22) Failure of fluconazole to prevent relapse of histoplasmosis in an AIDS patient was associated with the development of in vitro resistance during therapy. (23) Generally, fluconazole is an alternative to itraconazole for the treatment of histoplasmosis for the patient who cannot tolerate itraconazole, cannot take itraconazole because of drug interactions, or cannot absorb itraconazole adequately. (10) Ketoconazole, an older imidazole, is moderately effective for some forms of histoplasmosis and has been used successfully for the treatment of ce rebral histoplasmosis. (24) Over the past several years, however, itraconazole, which is better tolerated and probably more effective, has replaced ketoconazole as the azole of choice for the treatment of histoplasmosis. (21)

Fluconazole is generally considered to be superior to itraconazole for the management of fungal CNS infections, particularly meningitis caused by Coccidioides immitis and cryptococcal meningitis. (25-27) Fluconazole freely crosses the blood-brain barrier, achieving levels in the CSF in excess of 70% of serum levels, whereas itraconazole appears in the CSF at levels that are less than 1% of serum level. (8) For parenchymal brain infection, tissue levels may be of greater importance than CSF levels, and data suggest that there is substantial penetration of fluconazole into brain tissue. (28) Animal studies suggest that a P-glycoprotein-mediated efflux mechanism markedly limits the accumulation of itraconazole in brain tissue. (29) Therefore, although itraconazole is more active than fluconazole against H capsulatum, CNS histoplasmosis, including focal parenchymal disease, may represent a situation wherein fluconazole is the preferred azole.

The treatment received by our patients and the six additional patients reported in the recent literature is summarized in Table 1. Of the three patients who we successfully treated, two were given itraconazole and one received fluconazole after an initial course of amphotericin B. The patient described by Knapp et al (15) had a satisfactory clinical and radiographic response to fluconazole without any prior amphotericin B therapy. Similarly, Bamberger (17) cured his patient with oral itraconazole therapy alone. Azole therapy failed to cure an AIDS patient who relapsed with CNS histoplasmosis while receiving maintenance itraconazole and weekly amphotericin B and an apparently immunocompetent patient who relapsed with meningitis while taking fluconazole. (14,16) One patient with cerebral histoplasmosis was apparently cured with 2.5 g of amphotericin B without subsequent azole therapy, but the duration of follow-up was not stated. (13)

Recognizing the absence of data from controlled trials, treatment guidelines sponsored by the Infectious Diseases Society of America suggest that itraconazole, given in doses of 200 mg two or three times per day, be used for cerebral histoplasmosis after adequate response to a course of treatment with amphotericin B. (21) If fluconazole is used as consolidation therapy for cerebral histoplasmosis, we believe the daily dose for an adult with normal renal function should be greater than 400 mg. We favor a fluconazole dose of 800 mg/d.

Conclusion

Histoplasmosis is an uncommon cause of cerebral mass lesions among patients who have resided or who currently reside in an area endemic for histoplasmosis. In the appropriate epidemiologic context, cerebral histoplasmosis should be a diagnostic consideration when imaging studies show multiple brain lesions, even in the absence of other manifestations of disseminated histoplasmosis. A higher index of suspicion is appropriate if the patient is immunocompromised or has a history that suggests possible heavy exposure to H. capsulaturm. A definitive diagnosis requires brain biopsy, but specimens from other sites of disease, serology, and HPA testing are often helpful. Consolidation therapy with itraconazole or fluconazole may reduce the risk of relapse after a 1.0- to 2.0-g course of amphotericin B therapy, but no controlled trials have addressed this issue.

Table 1

Therapy and outcome of 10 patients with cerebral histoplasmosis in the
azole era (a)

Patient reference   Initial therapy
       (b)

    1     Case 1            ABLC, total dose
                              550 mg

    2     Case 2            AmB, total dose
                              2.0 g

    3     Case 3            AmB, total dose
                              1.0 g



    4     Case 4            Itraconazole 200 mg IV
                              every 12 h for 2 d,
                              followed by 200 mg IV
                              per d for 5 d, followed
                              by AmB, total dose 2.0
                               g * (d)

    5     Livas et al,      AmB, total dose
            1995 (13)         2.5 g

    6     Vullo et al,
            1997 (14)
          A (e)             AmB, total dose
                              280 mg
          B (e)             AmB, total dose
                              560 mg


    7     Knapp et al,      Fluconazole, 800
            1999 (15)         mg/d IV (f)



    8     Klein et al,
            1999 (16)
          A                   AmB, total dose 2.5 g

          B                   AmB, total dose NS


    9     Bamberger,        Itraconazole 200 mg
            1999 (17)         tid PO for 3 d

   10     Mawhorter et al,  AmB, total dose 1.5 g
            2000 (18)



          Subsequent therapy       Outcome

    1     Itraconazole, 200 mg     Death 12 d after
            PO bid for 2 d           brain biopsy

    2     Fluconzole, 400 mg PO    Apparent cure
            qd for 6 mo

    3     Itraconazole, 200 mg PO  Minor residual numbness
            bid for 8 mo followed    in left hand while
            by 100 mg bid            taking chronic
            (indefinitely)           suppressive therapy

    4     Itraconazole, 200 mg     Apparent cure
            PO bid for 2 mo





    5     None                     Apparent cure


    6

          Itraconazole, 400 mg/d   Relapse
            PO for 4 mo
          AmB, 40 mg/wk, plus      Death
            itraconazole, 400
            mg/d PO

    7     Fluconazole, 800 mg/d    Resolution of all
            PO (indefinitely)        symptoms and
                                     radiographic
                                     abnormalities

    8

          Fluconazole, 200 mg tid  Relapse while taking
            PO for 3 wk              fluconazole therapy (g)
          Fluconazole, dose and    Improving; persistent
            duration NS              ocular deficits

    9     Itraconazole 200 mg bid  Apparent cure
            PO for 1 yr

   10     Itraconazole, dose NS    Resolution of all
            (indefinitely)           symptoms

          Duration of
           follow-up
           (mo) (c)

    1         NA


    2         11


    3         38




    4          8






    5         NS


    6



              NA



    7         >8




    8



              ~4


    9         30


   10         36


(a) NA, not applicable; NS, not stated in reference; ABLC, amphotericin
B liapid complex; AmB, conventional amphotericin B deoxycholate; IV,
intravenously; PO, orally; tid, three times per day; bid, two times per
day; qd, per day.

(b) Patients 1-4 are those whose cases are reported in this article.

(c) Number of months from completion of therapy to last physician
contact, except for Patients 3, 7, and 10, for whom the duration of
follow-up is defined as the number of months from switch to oral therapy
to last physician contact.

(d) Therapy switched from intravenous itraconazole to amphotericin B
when cerebral histoplasmosis was diagnosed.

(e) A designates therapy given for the first episode of disease, and B
designates therapy given for relapse.

(f) Duration of intravenous fluconazole before switch to oral
fluconazole was not stated.

(g) Rescurent disease prompted switch from fluconazole back to
amphotericin B and removal of ventriculoperitoneal shunts.

Accepted April 23, 2002.

References

(1.) Bradsher RW. Histoplasmosis and blastomycosis. Clin Infect Dis 1996; 22:S102-S111.

(2.) Mcdoff G, Kobayashi GS, Painter A. Morphogenesis and pathogenicity of Histoplasma capsulatum. Infect Immun 1987;55:1355-1358.

(3.) Wheat LJ, Slama TG, Zeckel ML. Histoplasmosis in the acquired immunodeficiency syndrome. Am J Med 1985;78:203-210.

(4.) Huang CT, McGarry T, Cooper S. Disseminated histoplasmosis in the acquired immunodeficiency syndrome: Report of five eases from a nonendemic area. Arch Intern Med 1987;147:1181-1184.

(5.) Wheat LJ, Connolly-Stringfield PA, Baker RL, Curfinan MF, Eads ME, Israel KS, et al. Disseminated histoplasmosis in the acquired immune deficiency syndrome: clinical findings, diagnosis and treatment, and review of the literature. Medicine (Baltimore) 1990;69:361-374.

(6.) Wheat LJ, Batteiger BE, Sathapatavongs B. Histoplasma capsulatum infections of the central nervous system: A clinical review. Medicine (Baltimore) 1990;69:244-260.

(7.) Anaissie E, Fainstein V, Samo T, Bodey GP, Sarosi GA. Central nervous system histoplasmosis: An unappreciated complication of the acquired immunodeficiency syndrome. Am J Med 1988;84:215-217.

(8.) Como J, Dismukes W. Oral azole drugs as systemic antifungal therapy. N Engl J Med 1994;330:263-272.

(9.) Wheat J, Hafner R, Korzun AH, Limjoco MT, Spencer P, Larsen RA, et al. Itraconazole treatment of disseminated histoplasmosis in patients with the acquired immunodeficiency syndrome: AIDS Clinical Trial Group. Am J Med 1995;98:336-342.

(10.) McKinsey DS, Kauffman CA, Pappas PG, Cloud GA, Girard WM, Sharkey PK, et al. Fluconazole therapy for histoplasmosis: The National Institute of Allergy and Infectious Diseases Mycoses Study Group. Clin Infect Dis 1996;23:996-1001.

(11.) Wheat J, MaWhinney S, Hafner R, McKinsey D, Chen D, Korzun A, et al. Treatment of histoplasmosis with fluconazole in patients with acquired immunodeficiency syndrome: National Institute of Allergy and Infectious Diseases Acquired Immunodeficiency Syndrome Clinical Trials Group and Mycoses Study Group. Am J Med 1997;103:223-232.

(12.) Dismukes WE, Bradsher RW Jr, Cloud GC, Kauffman CA, Chapman SW, George RB, et al. Itraconazole therapy for blastomycosis and histoplasmosis. NIAID Mycoses Study Group. Am J Med 1992;93:489-497.

(13.) Livas IC, Nechay PS, Nauseff WM. Clinical evidence of spinal cord and cerebral histoplasmosis twenty years after renal transplantation. Clin Infect Dis 1995;20:692-695.

(14.) Vullo V, Mastroianni CM, Ferone U, Trinchieri V, Folgori F, Lichtner M, et al. Central nervous system involvement as a relapse of disseminated histoplasmosis in an Italian AIDS patient. J Infect 1997;35:83-84.

(15.) Knapp S, Turnherr M, Dekan G, Willinger B, Stingl G, Rieger A. A case of HIV-associated cerebral histoplasmosis successfully treated with fluconazole. Eur J Clin Microbiol Infect Dis 1999;18:658-661.

(16.) Klein CJ, Dinapoli RP, Temesgen Z, Meyer FB. Central nervous system histoplasmosis mimicking a brain tumor: Difficulties in diagnosis and treatment. Mayo Clin Proc 1999;74:803-807.

(17.) Bamberger DM. Successful treatment of multiple cerebral histoplasmomas with itraconazole. Clin Infect Dis 1999;28:915-916.

(18.) Mawhorter SD, Curley GV, Kursh ED, Farver CE. Prostatic and central nervous system histoplasmosis in an immunocompetent host: Case report and review of the prostatic histoplasmosis literature. Clin Infect Dis 2000;30:595-598.

(19.) Tabbal SD, Harik SI. Images in clinical medicine: Cerebral histoplasmosis. N Engl J Med 1999;340:1176.

(20.) Wheat J. Histoplasmosis: Experience during outbreaks in Indianapolis and review of the literature. Medicine (Baltimore) 1997;76:339-354.

(21.) Wheat J, Sarosi G, McKinsey D, Hamill R, Bradsher R, Johnson P, et al. Practice guidelines for the management of patients with histoplasmosis: Infectious Diseases Society of America. Clin Infect Dis 2000;30:688-695.

(22.) Wheat J, Hafner R, Wulfsohn M, Spencer P, Squires K, Powderly W, et al. Prevention of relapse of histoplasmosis with itraconazole in patients with the acquired immunodeficiency syndrome: The National Institute of Allergy and Infectious Diseases Clinical Trials and Mycoses Study Group Collaborators. Ann Intern Med 1993;118:610-616.

(23.) Wheat J, Marichal P, Vanden Bossche H, Le Monte A, Connolly P. Hypothesis on the mechanism of resistance to fluconazole in Histoplasma capsulatum. Antimicrob Agents Chemother 1997;41:410-414.

(24.) Goodpasture HC, Hershberger RE, Barnett AM, Peterie JD. Treatment of central nervous system fungal infection with ketoconazole. Arch Intern Med 1985;145:879-880.

(25.) Galgiani JN, Catanzaro A, Cloud GA, Higgs J, Friedman BA, Larsen RA, et al. Fluconazole therapy for coccidioidal meningitis: The NIAID-Mycoses Study Group. Ann Intern Med 1993;119:28-35.

(26.) Saag MS, Cloud GA, Graybill JR, Sobel JD, Tuazon CU, Johnson PC, et al. A comparison of itraconazole versus fluconazole as maintenance therapy for AIDS-associated cryptococcal meningitis: National Institute of Allergy and Infectious Diseases Mycoses Study Group. Clin Infect Dis 1999;28:291-296.

(27.) van der Horst CM, Saag MS, Cloud GA, Hamill RJ, Graybill JR, Sobel JD, et al. Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome: National Institute of Allergy and Infectious Diseases Mycoses Study Group and AIDS Clinical Trials Group. N Engl J Med 1997;337:15-21.

(28.) Thaler F, Bernard B, Tod M, Jedynak CP, Petitjean O, Derome P, et al. Fluconazole penetration in cerebral parenchyma in humans at steady state. Antimicrob Agents Chemother 1995;39:1154-1156.

(29.) Miyama T, Takanaga H, Matsuo H, Yamano K, Yamamoto K, Iga T, et al. P-glycoprotein-mediated transport of itraconazole across the blood-brain barrier. Antimicrob Agents Chemother 1998;42:1738-1744.

RELATED ARTICLES: Key Points

* Cerebral histoplasmosis should be included in the differential diagnosis when a patient who has resided in a histoplasmosis-endemic area presents with brain masses.

* Histoplasma capsulatum can infect the brain and cause cerebral histoplasmosis without causing overt disease in other organ systems.

* Although other diagnostic studies are sometimes helpful, the "gold standard" for the diagnosis of cerebral histoplasmosis is brain biopsy, with appropriate special stains and fungal culture.

* Although amphotericin B remains the initial drug of choice for the treatment of cerebral histoplasmosis, oral azoles are useful for consolidation therapy.

Case Reports

Patient 1

An asplenic 75-year-old man with a myclodysplastic syndrome and cryptogenic cirrhosis was in his usual state of health until mental status changes began 2 months before admission. Three weeks later, magnetic resonance imaging (MRI) revealed three cerebral masses. Corticosteroid therapy was given with transient improvement, but soon thereafter his condition worsened. He had no history of fever, headache, or focal neurologic deficit. A second MRI scan of the brain showed five enhancing lesions with associated vasogenic edema. Plain radiography and computed tomography (CT) of the chest showed no abnormalities; abdominal CT demonstrated adrenal hyperplasia or mass lesions. Complement fixation titers to H. capsulatum were less than 1:8 for both yeast and mycelial antigens in the serum.

The patient underwent stereotactic brain biopsy, and staining of fixed tissue with the Grocott-Gomori methenamine silver procedure demonstrated numerous intracellular and extracellular yeast forms morphologically consistent with H. capsulatum. Subsequently, culture of brain tissue grew H. capsulatum. The patient received amphotericin B lipid complex, 50 mg/d for 1 day, then 100 mg/d. After 6 days of therapy, renal insufficiency developed, and oral itraconazole was given in place of amphotericin B lipid complex. Renal and hepatic function worsened, and the patient died 12 days after the brain biopsy. An autopsy was not performed.

Patient 2

A 60-year-old white man was in his usual state of health until approximately 3 months before presentation, when progressive symptoms, including weakness of the left lower extremity, dysarthria, diplopia, headache, anorexia, nausea, vomiting, weight loss, and low-grade fever began. About i week before presentation, he became unable to walk. He worked in the poultry industry, and he often fertilized his garden with chicken feces.

Examination revealed bilateral lower extremity weakness, bilateral Babinski signs and ankle clonus, and weakness of the left sixth cranial nerve. His cognition was normal. Lymphadenopathy and hepatosplenomegaly were absent. Chest radiographs did not reveal any abnormalities. Magnetic resonance imaging showed numerous ring-enhancing lesions in the cerebrum, cerebellum, brainstem, and upper cervical spinal cord. A representative image is shown in Figure 1. Serology for human immunodeficiency virus (HIV) was negative. Stereotactic brain biopsy revealed lymphohistiocytic inflammation with focal necrosis. Grocott-Gomori methenamine silver staining revealed numerous small, budding yeasts morphologically consistent with H. capsulatum. Because no cultures were obtained, the diagnosis of histoplasmosis in this case was presumptive.

The patient received a total of 2.0 g amphotericin B at a dose of 1 mg/kg/d. He then took oral fluconazole 400 mg/d for 6 months. His neurologic deficits and general condition gradually improved. There was no evidence of recurrent disease at the time of the last follow-up examination approximately 11 months after completion of fluconazole therapy.

Patient 3

A 50-year-old white woman with no known medical problems was well until several weeks before presentation, when she noted headache and left-sided numbness and weakness. Fever, night sweats, weight loss, and respiratory symptoms were absent. White plaques, typical of candidiasis, were present on the oral mucosa. There was no lymphadenopathy or hepatosplenomegaly. Strength was diminished in the left arm and leg, and she had difficulty walking, with a tendency to fall to the left. Magnetic resonance imaging of the brain showed an enhancing 2-cm right parietal mass with a large amount of surrounding edema (Fig. 2), an enhancing 1-cm right medullary mass, and an enhancing 5-mm mass in the right posterior frontal lobe. Because the working diagnosis was metastatic cancer, mammography and CT of the chest, abdomen, and pelvis were performed. The chest CT scan revealed small, bilateral lung nodules and ill-defined, bilateral densities consistent with an infiltrative process.

The right parietal mass was resected without complication. The Grocott-Gomori methenamine silver stain demonstrated numerous yeast forms morphologically consistent with H. capsulatum. Amphotericin B, 0.6 mg/kg/d, was administered. Serologic testing for HIV was positive; the absolute [CD4.sup.+] T-lymphocyte count was 38 Cells/[micro]l. Testing of urine at the Histoplasmosis Reference Laboratory (Indianapolis, IN) was positive for H capsulatum polysaccharide antigen (HPA). Material obtained at surgery subsequently grew H. capsulatum.

She received a total of 1.0 g amphotericin B, with marked improvement of her neurologic deficits. Subsequently, she received oral itraconazole, 200 mg bid; 8 months later, the itraconazole dose was reduced to 100 mg bid with plans for lifelong therapy. Antiretroviral therapy was associated with significant and sustained reduction in plasma HIV RNA levels. Except for mild residual numbness of the left hand, this patient had no clinical evidence of CNS histoplasmosis 38 months after completing amphotericin B therapy.

Patient 4

A 38-year-old black man presented with a history of approximately 2 months of fever, night sweats, productive cough, and weight loss. He had no known exposure to tuberculosis, and a recent HIV serology had been nonreactive. He abused ethanol and worked as a farm laborer, spending most of his time plowing fields. He had cleaned out old chicken coops before the onset of illness. The examination revealed an emaciated, acutely ill-appearing man with tachycardia, tachypnea, and fever. Other pertinent findings included crackles in the lower lung zones; mild epigastric tenderness; hepatomegaly; and brown, guaiac-positive stool. There were no focal neurologic deficits. The partial pressure of oxygen in arterial blood while breathing room air was 59 mm Hg, and chest radiography revealed a prominent interstitial pattern throughout all lung fields.

The diagnosis of disseminated histoplasmosis was made on the basis of the finding of intracellular yeasts on bone marrow biopsy. Later, H capsulatum grew from bone marrow and expectorated sputum. Urine HPA was 9.3 U (negative, < 1.0 U; weakly positive, 1.0-2.0 U; positive, > 2.0 U). The patient was enrolled in a clinical trial and was randomized to receive intravenous itraconazole. Fever persisted, and confusion, worsening hypoxemia, progressive reticulonodular pulmonary opacities, hyperbilirubinemia, and worsening anemia complicated his hospital course. Computed tomography showed enhancing lesions in the right basal ganglia and corpus callosum, and therapy was changed to amphotericin B, 0.7 mg/kg/d. The patient slowly improved and received a total of 2.0 g amphotericin B, which was followed by 2 months of oral itraconazole therapy, 200 mg orally bid.

When last seen, approximately 4 months after his initial presentation, all of his symptoms had resolved, and his weight had increased by 7 kg since discharge. He did not keep subsequent clinic appointments, but 1 year after his initial presentation, his mother reported by telephone that he was feeling well and had returned to work.

From the Division of Infectious Diseases, Department of Medicine, University of Arkansas for Medical Sciences, and the Central Arkansas Veterans Health Care System, Little Rock, AR; and the Section of Infectious Diseases, Department of Medicine, University of Tennessee Medical Center at Knoxville, Knoxville, TN.

Reprint requests to Michael Saccente, MD, Department of Medicine, University of Arkansas for Medical Sciences, 4301 W. Markham Avenue, Slot 639, Little Rock, AR 72205. Email: [e-mail]

Copyright [c] 2003 by The Southern Medical Association

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