Encapsulated yeast Cryptococcus neoformans causing subacute meningoencephalitis in HIV/AIDS; C. gattii causes disease in immunocompetent hosts.
Also known as: Cryptococcus neoformans, Cryptococcus gattii, cryptococcal meningitis, crypto meningitis
Overview
Infection caused by the encapsulated yeasts Cryptococcus neoformans and Cryptococcus gattii, acquired by inhalation. Most clinically significant manifestation is subacute or chronic meningoencephalitis, especially in patients with HIV/AIDS. Pulmonary, cutaneous, and disseminated disease also occur.
Epidemiology
C. neoformans is distributed worldwide, classically associated with pigeon droppings, and primarily infects immunocompromised hosts (especially HIV with CD4 <100). C. gattii is endemic to tropical and subtropical regions and the Pacific Northwest of North America and infects immunocompetent hosts. Cryptococcal meningitis remains a major cause of HIV-related mortality globally.
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HIV/AIDS with CD4 <100 cells/microL (especially <50)
Solid organ transplantation, hematopoietic stem cell transplant
Chronic corticosteroid therapy
Idiopathic CD4 lymphopenia
Sarcoidosis, hematologic malignancy
Cirrhosis
C. gattii: outdoor exposure in endemic regions (eucalyptus trees, Pacific Northwest)
Pathophysiology
Inhaled yeast cells deposit in alveoli; the polysaccharide capsule (glucuronoxylomannan) inhibits phagocytosis and complement activation. In immunocompromised hosts, the organism disseminates hematogenously with predilection for the central nervous system, causing meningoencephalitis with cryptococcomas and elevated intracranial pressure. The capsular polysaccharide also drives much of the pathology by blocking CSF outflow.
Clinical presentation
Symptoms
Subacute headache, fever, malaise progressing over days to weeks
Visual changes (papilledema, cranial nerve VI palsy from increased ICP)
Nausea, vomiting from elevated intracranial pressure
Seizures (less common)
Pulmonary cryptococcosis: cough, chest pain, dyspnea, often subclinical
Cutaneous: umbilicated papules resembling molluscum contagiosum in advanced HIV
C. gattii in immunocompetent hosts: more cryptococcomas (brain or lung) and slower clinical course
Signs / physical exam
Often minimal meningismus despite extensive CNS involvement
Papilledema, cranial nerve palsies (VI most common)
Skin lesions: umbilicated, flesh-colored papules
Focal neurologic deficits from cryptococcomas
Pulmonary findings often minimal on exam
Classic findings
HIV patient with CD4 <100, subacute headache, and a positive serum CrAg. India ink staining of CSF reveals encapsulated yeast with a clear halo against a dark background. Elevated CSF opening pressure (>25 cm H2O) is the most important prognostic factor.
Differential diagnosis
Tuberculous meningitis — Subacute lymphocytic meningitis, low CSF glucose, elevated protein; AFB testing and TB-specific PCR; both can coexist in advanced HIV
Bacterial meningitis — Acute onset, neutrophilic CSF, very low glucose; gram stain and bacterial culture
Viral (HIV) aseptic meningitis — Lymphocytic CSF, normal glucose, milder course; PCR for HSV/enteroviruses
Toxoplasmosis (CNS) — Multiple ring-enhancing lesions on MRI in HIV with CD4 <100; positive Toxo IgG; response to empirical pyrimethamine-sulfadiazine
CNS lymphoma — Solitary periventricular lesion, EBV DNA in CSF; biopsy if not improving on empirical treatment
Neurosyphilis — Reactive RPR with CSF VDRL, cranial nerve abnormalities; treat with IV penicillin
Carcinomatous meningitis — Known malignancy, malignant cells on CSF cytology
Diagnostic workup
Diagnostic criteria
Diagnosis established by positive CSF cryptococcal antigen, India ink stain, or culture. Serum CrAg supports diagnosis and is used for screening in advanced HIV.
Labs
Serum cryptococcal antigen (CrAg) — highly sensitive and specific lateral flow assay; recommended screening in HIV patients with CD4 <100
Lumbar puncture with opening pressure measurement — CSF CrAg, India ink, culture, cell count, glucose, protein
Typical CSF: lymphocytic pleocytosis, low glucose, elevated protein, very high opening pressure (often >30 cm H2O)
Fungal blood cultures (positive in 30-70% of HIV-associated cases)
HIV testing and CD4 count if not known
BMP, LFTs, CBC
Imaging
MRI brain with contrast: may show meningeal enhancement, dilated Virchow-Robin spaces, cryptococcomas, hydrocephalus
Chest x-ray or CT for pulmonary involvement: nodules, infiltrates, cavities
Imaging should not delay lumbar puncture unless focal deficits, papilledema, or altered mental status suggest mass lesion
Diagnostic algorithm
flowchart TD
A[HIV CD4 <100<br/>headache, fever] --> B[Serum CrAg]
B -->|Positive| C[Lumbar puncture<br/>measure opening pressure]
C --> D[CSF CrAg, India ink, culture]
D --> E[Confirmed cryptococcal meningitis]
E --> F[Induction:<br/>Liposomal ampho B + flucytosine x 2 wk]
F --> G[Consolidation:<br/>Fluconazole 400-800 mg x 8 wk]
G --> H[Maintenance:<br/>Fluconazole 200 mg daily<br/>until CD4 >100 on ART]
C --> I{Opening pressure<br/>>=25 cm H2O?}
I -->|Yes| J[Therapeutic LPs<br/>daily until controlled]
E --> K[Delay ART start<br/>4-6 weeks<br/>to avoid IRIS]
Cryptococcal meningitis in HIV: diagnosis, induction-consolidation-maintenance therapy, ICP management, and ART timing.
Treatment
First-line
HIV-associated cryptococcal meningitis — Induction: liposomal amphotericin B 3-4 mg/kg/day IV plus flucytosine 100 mg/kg/day PO divided QID for 2 weeks (combination superior to monotherapy)
WHO/IDSA preferred in resource-rich settings: single high-dose liposomal amphotericin B 10 mg/kg x 1 plus 14 days flucytosine + fluconazole (modern simplified regimen)
Consolidation: fluconazole 400-800 mg PO daily for at least 8 weeks
Maintenance / secondary prophylaxis: fluconazole 200 mg PO daily until CD4 >100 for at least 3 months on ART and viral suppression
Aggressive management of elevated ICP — therapeutic LPs (drain to <20 cm H2O or to half the opening pressure), repeat daily until pressure controlled; consider lumbar drain or VP shunt for persistent hydrocephalus
Delay ART initiation by 4-6 weeks after starting antifungal therapy to reduce risk of cryptococcal IRIS
Non-HIV / non-transplant host: liposomal amphotericin B + flucytosine x 4 weeks, then fluconazole 400 mg daily 8 weeks, then 200 mg daily 6-12 months
Second-line / adjunct
Amphotericin B deoxycholate if liposomal unavailable (more nephrotoxicity)
Echinocandins are INACTIVE against Cryptococcus and should not be used
Fluconazole monotherapy only when amphotericin and flucytosine unavailable (inferior outcomes)
Cryptococcal antigen screening in HIV: preemptive fluconazole if positive without overt meningitis
Complications
Elevated intracranial pressure with permanent neurologic damage, blindness, or death — single most important determinant of outcome
Cryptococcal immune reconstitution inflammatory syndrome (IRIS) when ART started too early
Hydrocephalus requiring shunting
Drug toxicity: amphotericin B nephrotoxicity and electrolyte wasting, flucytosine marrow suppression (monitor levels, target 25-100 microg/mL), fluconazole hepatotoxicity
Relapse if maintenance therapy stopped before immune recovery
PANCE pearls
Opening pressure management is at least as important as antifungal therapy in cryptococcal meningitis — drain CSF aggressively.
Echinocandins do NOT cover Cryptococcus — this is a high-yield exam point.
Delay ART by 4-6 weeks after antifungal initiation in HIV to reduce IRIS mortality (COAT trial).
Beta-D-glucan is typically NEGATIVE in cryptococcosis — use cryptococcal antigen instead.
C. gattii infects immunocompetent hosts and is endemic to the Pacific Northwest of the US and Canada.
References
IDSA 2010 — Clinical Practice Guidelines for the Management of Cryptococcal Disease: 2010 Update by the Infectious Diseases Society of America (Perfect et al., Clin Infect Dis 2010)
WHO 2022 — WHO Guidelines for Diagnosing, Preventing and Managing Cryptococcal Disease among Adults, Adolescents and Children Living with HIV (2022)
AIDSinfo — Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV — Cryptococcosis section
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