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Systemic symptoms in a human immunodeficiency virus type 1--positive 30-year-old man. (Pathologic Quiz Case).

A 30-year-old African American man positive for human immunodeficiency virus type 1 (HIV-1) presented in November 1999 with shortness of breath, nausea, and vomiting for 1 week. Also, the patient had fatigue, anorexia, and weight loss. He had history of seropositivity for HIV-1 for 9 years, herpes zoster infection, and 4 hospital admissions since April 1999 for meningitis. His CD4 count in May 1999 was 50 cells/[micro]L (normal range: 400 to 1770 cells/[micro]L). He was treated with bactrim, azithromycin, and fluconazole, which had replaced amphotericin B in October 1999. He was noncompliant with his treatment regimen. A computed tomographic scan revealed posterior fossa atrophy, multiple basal ganglia and internal capsule infarcts, mild fourth ventricle enlargement, and periventricular white matter changes. Cerebrospinal fluid was submitted for cytologic examination. The cerebrospinal fluid showed rare macrophages (macrophage, black arrow) with cytoplasmic yeastlike organisms (blue arrow) (Figure 1, Papanicolaou stain, original magnification x1000). Diff-Quik stain showed numerous fungal forms with narrow neck budding (arrow) and clear capsules, ranging in size between 3 and 12 [micro]m (Figure 2, original magnification x1000). Periodic acid-Schiff stained the capsule (arrow) deep red (Figure 3, original magnification x1000). Cerebrospinal fluid cultures were negative for acid-fast bacilli.


What is your diagnosis?

Pathologic Diagnosis: Central Nervous System Cryptococcosis

Rapid tests in serum and cerebrospinal fluid using a cryptococcal-antigen latex agglutination system were positive for Cryptococcus neoformans antigen; (1) India ink showed thick capsules. The cerebrospinal fluid culture grew C neoformans. The patient was treated with intravenous fluconazole. Also, bactrim and azithromycin were continued for Pneumocystis carinii and Mycobacterium avium intracellulare prophylaxis, respectively. Elevated intracranial pressures were relieved by lumbar punctures. The patient's condition deteriorated; he had periods of altered mental status, went into a coma, and died on day 17 of his admission because of cryptococcal meningitis and fungemia. No autopsy was performed.

Cryptococcosis is a chronic or subacute fungal infection that has respiratory, meningitic, or systemic effects. (2-4) The primary reservoir of C neoformans is birds; their droppings allow for transmission to humans via inhalation. (2) Most cases are mild or asymptomatic. Symptomatic infections are most commonly seen in immunocompromised HIV, lymphoma, leukemia, and transplant patients. Currently, the greatest number of cases is among HIV patients. Cryptococcosis is the fourth leading opportunistic infection in acquired immune deficiency syndrome (AIDS) patients; (3) about 96% of cases are HIV related. (5) The primary cryptococcal pulmonary infection is usually subclinical, but a large amount of pathogen or immunosuppression can result in pneumonia. Pulmonary infection with or without symptoms usually resolves spontaneously. Clinical symptoms in immunocompromised individuals are commonly seen after dissemination from the respiratory tract to other organs, primarily to the central nervous system; skin and skeletal compromise are less common. Cryptococcosis is the most life-threatening opportunistic infection in AIDS patients; about 6% to 10% of them will develop cryptococcal meningitis. (6) People with AIDS who have CD4 counts less than 100 cells/[micro]L have the greatest risk of central nervous system infection. Consequently, 75% to 90% of patients with AIDS-related cryptococcosis present with subacute meningitis or meningoencephalitis. (6) In normal individuals, there is a granulomatous immune response, and most fungal organisms are found within macrophages. In immunocompromised persons, however, fungi grow predominantly extracellularly in gelatinous masses and cysts ("soap bubbles") within the brain parenchyma. (6) C neoformans is a 4- to 20-[micro]m oval to spherical monomorphic fungus; it only grows as yeast with narrow-based buds and thick capsule. (3,4) Mucicarmine and periodic acid-Schiff stain the characteristic thick mucopolysaccharide capsule. Fontana-Masson silver stains the melanin in the cell wall when the capsule is deficient or present. (7) Some dimorphic fungi with similar clinical features, including lung involvement via inhalation and systemic dissemination, are considered in the differential diagnosis. Unlike C neoformans, dimorphic fungi first grow as mold forms and then convert to yeast forms (tissue form). Blastomyces dermatitidis causes blastomycosis, and it is an 8- to 15-[micro]m spherical yeast with broad-based single buds. (3,4) The histoplasmosis agent is Histoplasma capsulatum, a 3- to 5-[micro]m oval to spherical yeast with narrow-neck single buds. (3,4) Coccidioidomycosis may extend to meninges, bone, skin, lymph nodes, and subcutaneous tissue; it is caused by Coccidioidis immitis, a 10- to 60-[micro]m spherule yeast that contains endospores. (3,4) Paracoccidioidomycosis extends to mucous membranes, where it produces ulcerative lesions, and it is caused by Paracoccidioides brasiliensis, a 10- to 30-[micro]m thick-walled spherical yeast with multiple buds with narrow neck (pilot wheel). (3,4) Blastomycosis, histoplasmosis, and coccidioidomycosis are endemic in regions of the United States, and paracoccidioidomycosis is endemic in South America. In contrast, no high-risk geographical area exists for cryptococcosis.

None of the other dimorphic fungi have the propensity for central nervous system involvement that C neoformans does. The clinical course of cryptococcosis varies from months to 20 years, with periods of remission and exacerbation. (2) Without treatment, a fatal outcome from cryptococcal meningitis is imminent; amphotericin B is the drug of choice for cryptococcal meningitis, and combination therapy with flucytosine has cured patients and reduced relapses. (8) High-dosage amphotericin B therapy has markedly lowered rates of fatal outcome from the previously existing 14% to 25% mortality rate. (8) Fluconazole is the most effective drug for maintenance in C neoformans infection. (8) Monitoring and reducing elevated intracranial pressures seem to be important in decreasing cryptococcal meningitis mortality. (8)

Accepted for publication July 12, 2001.


(1.) Kaufman L, Blumer S. Value and interpretation of serological tests for the diagnosis of cryptococcosis. Appl Microbiol. 1968;16:1907-1912.

(2.) Rippon JW. Medical Mycology. Philadelphia, Pa: WB Saunders; 1988.

(3.) Koneman EW. Diagnostic Microbiology. Philadelphia, Pa: Lippincott-Raven; 1997.

(4.) Henry J B. Clinical Diagnosis and Management by Laboratory Methods. Philadelphia, Pa: WB Saunders; 1996.

(5.) Currie BE Casadevall A. Estimation of the prevalence of cryptococcal infection among patients infected with the human immunodeficiency virus in New York City. Clin Infect Dis. 1994;19:1029-1033.

(6.) Powderly WG. Cryptococcal meningitis and AIDS. Clin Infect Dis. 1993;17: 837-842.

(7.) Ro JY, Lee SS, Ayala AG. Advantage of Fontana-Masson stain in capsule-deficient cryptococcal infection. Arch Pathol Lab Med. 1987;111:53-57.

(8.) Van der Horst CM, Saag MS, Cloud GA, et al. Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. N Engl J Med. 1997;337:15-21.

From the Medical School (Dr Carter) and the Department of Pathology and Laboratory Medicine (Drs Leon and England), MCP-Hahnemann University, Philadelphia, Pa.

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Article Details
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Title Annotation:central nervous system Cryptococcosis
Author:Carter, Jochebed I.; Leon, Marino E.; England, James M.
Publication:Archives of Pathology & Laboratory Medicine
Geographic Code:1USA
Date:Apr 1, 2002
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