Patient presentation
A 36-year-old previously healthy woman presented to the emergency center with gradual onset of headache, confusion, tremor and difficulty walking. Family members had noted behavioral changes in recent months. Physical examination revealed scattered scaly plaques and pedunculated nodules on her face and chest. The patient had memory deficits on mental status exam. Her pupils were equal and reactive to light and accommodation with grossly intact cranial nerve exam. No motor or sensory weakness was noted, and Babinski sign was negative.

A complete blood cell count with differential was normal. Routine chest X-ray revealed a right mid-lung opacity. Subsequent computed tomography (CT) identified a 5.5-cm by 5-cm right hilar mass with cavitation. Additional CT scanning of the brain identified multiple, rounded, high-density lesions within the basal ganglia bilaterally with peripheral edema. A lumbar puncture was performed, which demonstrated an elevated opening pressure (230 mm H2O). Subsequent cerebrospinal fluid (CSF) studies showed low glucose (15 mg/dl) and high protein (270 mg/dl). India ink staining of CSF was negative for encapsulated organisms. A skin biopsy was taken, and it demonstrated abundant capsular structures filling the dermis. The patient repeatedly tested negative for HIV-1 and HIV-2.

What is Your Diagnosis?

Diagnosis: Disseminated Cryptococcosis
Cryptococcosis is caused by Cryptococcus neoformans, a common infection worldwide. C. neoformans is found in contaminated soil and associated with bird droppings. Two varieties and five serotypes are known, with C. neoformans var. neoformans type A being the most common in the United States. The organisms are less than 2 µm in size.1 It may affect multiple organs, including the pulmonary, central nervous, hematogenous and cutaneous systems. However, more than 90% of infections remain localized to the lungs, and the respiratory route is the portal of entry.1 Disseminated infection is often a harbinger of systemic immunosuppression.

The organism has an affinity for central nervous system localization and is the most common cause of mycotic meningitis. Cell-mediated immunity is important to ward off infection
and immune deficits predispose patients to cryptococcal infection. This includes conditions such as HIV, lymphoma, carcinoma, sarcoidosis, collagen vascular disease and iatrogenic immunosuppression.

Clinical and Histologic Presentation
Hematogenous dissemination to any body region may occur following primary pulmonary infection.1 The central nervous system is the most common site of dissemination.1,2 Although primary cutaneous cryptococcosis has been reported, this is rare.3-7 Cutaneous manifestations of crypto-coccosis are most commonly seen on the head and neck.2 Lesions usually begin as papules with peripheral erythema progressing into ulcerated pustules or nodules. There is, however, great variability in the presentation of cutaneous disease.2,8 Variations may include papules, pustules, crusted or infiltrating plaques, erythematous swelling, firm nodules or cellulitis; any of which may or may not be ulcerated.9

Two types of histologic reactions to C. neoformans have been described. The gelatinous pattern is characterized by abundant organisms (4 µm to 12 µm in size) and minimal inflammation. The granulomatous pattern is characterized by few organisms and extensive tissue reaction.1 However, both patterns may be present simultaneously. The
distinguishing feature of the infection is the presence of aggregates of encapsulated yeasts. Variable degrees of pseudoepitheliomatous hyperplasia and/or ulceration may be present as well.

Diagnosis
Multiple infectious etiologies manifest with similar physical findings and further testing is necessary to further differentiate them. The main differential diagnoses include other deep fungal infections such as Coccidioides immitis, Penicillium marneffei and molluscum
contagiosum.

Consideration of an underlying immunocompromising state must also be considered. Sputum, urine, blood, CSF and tissue should be examined for evidence of the organism. C. neoformans can be visualized histologically with routine hematoxylin/eosin staining (See photo); however, additional stains with mucicarmine may be needed to highlight the capsule.10 Appropriate blood culture and radiographic studies are paramount for identification of dissemination.

Treatment
Treatment includes amphotericin B (AmBisome) and flucytosine (Ancobon). Subsequent fluconazole (Diflucan) is often used as maintenance therapy. During therapy, monitoring of cryptococcal antibody titers should reveal a downward trend. Our patient was managed with amphotericin B 0.5 mg/kg and flucytosine 100 mg/kg intravenously with rapid improvement. A repeat lumbar puncture showed a decrease in cryptococcal antigen titer to 1:32 (initial 1:512). Her skin lesions began to resolve. She was discharged from the hospital on fluconazole
400 mg/day. She had a relapse of cryptococcal meningitis 7 weeks later. HIV test again was negative.

Discussion
Cryptococcal infections are usually cleared in immunocompetent hosts. Prior to the AIDS epidemic, high-dose corticosteroids and organ transplantation were the major predisposing factors for cryptococcosis. On rare occasions, lymphoreticular malignancies (Hodgkin’s, non-Hodgkin’s lymphoma), sarcoidosis and diabetes have been linked to cryptococcosis.11 Recently, idiopathic CD4+ T lymphocytopenia has been described as an underlying cellular immunodeficiency leading to opportunistic infections including cryptococcal meningitis.12-14
Our patient had a mild CD4 deficiency of 368/mm3 that did not meet the Centers for Disease Control and Prevention (CDC) definition of idiopathic T4-lymphocytopenia (CD4 T-lymphocyte counts less than 300/mm3). Of note, our patient had a profound CD8 deficiency of 158/mm3 (n=315 to 788/mm3).

In humans, both CD4 and CD8 cells are activated in response to C. neoformans infection.15 Numerous studies have linked idiopathic CD4 T-lymphocytopenia to cryptococcosis. However, there has been no clinical report as yet to link CD8 deficiency to cryptococcosis. Thus, future studies are warranted to investigate the role of CD8 deficiency as a potential predisposing factor for disseminated cryptococcosis.