Definition of Disseminated Cryptococcosis
Disseminated cryptococcosis is defined as either cryptococcemia (positive blood cultures), involvement of at least 2 noncontiguous anatomical sites, or evidence of high fungal burden based on a cryptococcal antigen titer ≥1:512. 1
Core Diagnostic Criteria
The Infectious Diseases Society of America establishes that disseminated disease meets one or more of the following criteria:
- Cryptococcemia: Positive blood cultures for Cryptococcus species, which is frequent in HIV-infected patients with disseminated infection 1
- Multi-site involvement: Infection documented at 2 or more noncontiguous anatomical sites (e.g., lung plus skin, CNS plus bone) 1
- High fungal burden: Serum cryptococcal antigen titer ≥1:512, indicating widespread organism distribution even if only one site is clinically apparent 1
Important Clinical Context
With rare exceptions such as primary skin infection from direct inoculation, any nonmeningeal, nonpulmonary cryptococcosis represents dissemination even if the clinical syndrome appears confined to a single anatomical site. 1 This is a critical concept—the presence of cryptococcal infection outside the lungs or CNS almost always indicates hematogenous spread has occurred.
Sites of Disseminated Disease
Disseminated cryptococcosis can involve virtually any organ system following hematogenous spread: 1
- Skin lesions (15% of disseminated cases): papules, pustules, purpura, ulcers, cellulitis, umbilicated papules resembling molluscum contagiosum in AIDS patients 1
- Skeletal system (<10% of cases): vertebrae most commonly, appearing as osteolytic lesions 1
- Other organs: liver, lymph nodes, peritoneum, adrenal glands, eyes, urogenital tract (kidney/prostate) 1
Critical Management Implication
All patients with disseminated cryptococcosis—regardless of presentation—must have CNS disease specifically ruled out with lumbar puncture and CSF analysis, as CNS involvement fundamentally changes treatment intensity and duration. 1 This is non-negotiable because cryptococcemia is associated with CNS disease in the majority of cases, particularly in immunocompromised hosts. 1
Treatment Paradigm Based on Definition
Once disseminated disease is identified by the above criteria, treatment follows CNS disease protocols even if meningitis is ruled out: 1
- Induction therapy: Amphotericin B plus flucytosine for at least 2 weeks 1, 2
- Consolidation: Fluconazole 400 mg daily for 8 weeks 1, 2
- Maintenance: Fluconazole 200-400 mg daily for 6-12 months 1, 2
Common Pitfall to Avoid
Do not assume isolated organ involvement means localized disease. Recent case reports demonstrate that disseminated cryptococcosis can present with low antigen titers (1:80) and still have positive blood cultures, indicating widespread infection despite minimal serologic evidence. 3 Additionally, negative routine cultures do not exclude cryptococcosis—bedside inoculation and extended culture techniques may be necessary. 4
The definition is intentionally broad because Cryptococcus has strong CNS tropism and the consequences of undertreating disseminated disease are severe, with mortality rates approaching 100% if untreated. 1