244.1 🎓 醫學生版

244.1.0.1 📌 一頁重點

244.1.0.1.1 Species

• C. neoformans (worldwide; mostly immunocompromise / HIV)
• C. gattii (tropical + sub-tropical; Pacific NW USA + Vancouver Island outbreak 1999+; sometimes immunocompetent severe disease)
• 5 serotypes (A, B, C, D, AD) — C. neoformans + C. gattii

244.1.0.1.2 Microbiology

• Encapsulated yeast (polysaccharide capsule — virulence factor)
• India ink stain of CSF — characteristic; halo around yeast cells
• Mucicarmine stain
• Methenamine silver stain

244.1.0.1.3 Transmission

• Inhalation of spores / yeast from environmental sources
• Bird droppings (pigeons) — C. neoformans
• Eucalyptus trees + decaying wood — C. gattii
• Disseminate to CNS, lungs, skin, blood
• NOT person-to-person

244.1.0.1.4 Burden (WHO 2024)

• Cryptococcal meningitis #1 cause of HIV-related meningitis in Africa
• ~ 200,000 cryptococcal meningitis cases/yr globally
• ~ 180,000 deaths/yr (mostly Sub-Saharan Africa, HIV-related)
• Decreasing with ART but persistent

244.1.0.1.5 Clinical

244.1.0.1.5.1 Cryptococcal Meningitis (Most Common Form)

• CD4 < 100 in HIV (especially < 50)
• Solid organ transplant + immunocompromise + advanced cancer
• Subacute / chronic onset (weeks):
  • Headache (severe, persistent)
  • Fever (low-grade or absent)
  • Altered mental status
  • Photophobia, meningismus
  • Increased intracranial pressure (papilledema, cranial nerve palsies)
  • Visual loss
  • Hearing loss
  • Seizures
• Long course untreated → coma + death

244.1.0.1.5.2 Pulmonary Cryptococcosis

• Asymptomatic nodule discovered incidentally
• Pneumonia (cough, dyspnea, chest pain)
• ARDS in severe / immunocompromise
• C. gattii: more frequent + larger lung lesions in immunocompetent

244.1.0.1.5.3 Cutaneous

• Disseminated infection
• Umbilicated papules (mimics molluscum contagiosum)
• Cellulitis
• Ulcers
• Often a sign of disseminated cryptococcosis (especially HIV)

244.1.0.1.5.4 Disseminated

• Skin, prostate, eye, bone, joint, peritoneum
• HIV with CD4 < 50
• Severe immunocompromise

244.1.0.1.5.5 C. gattii (Often Immunocompetent + Severe)

• Larger pulmonary nodules + cavitation
• Cerebral cryptococcomas (mass lesions)
• More chronic / severe in immunocompetent than C. neoformans typically
• Pacific NW USA + Vancouver Island endemic
• 1999 + ongoing cases

244.1.0.1.6 Diagnosis

244.1.0.1.6.1 Serum Cryptococcal Antigen (CrAg)

• Latex agglutination or lateral flow immunoassay
• Sensitivity 99%, specificity high
• WHO recommendation: serum CrAg screening when CD4 < 100 (asymptomatic patients)
• Positive → LP + treatment if asymptomatic; treat as cryptococcal meningitis if symptomatic
• Point-of-care lateral flow assay (LFA) widely available

244.1.0.1.6.2 CSF Findings

• Opening pressure elevated (often > 25 cm H2O, sometimes very high)
• Lymphocytic pleocytosis (sometimes low cells in advanced HIV)
• High protein (mildly to moderately elevated)
• Decreased glucose
• CSF Cryptococcal Antigen — diagnostic
• India ink staining (50-75% sensitivity in HIV; lower otherwise) — encapsulated yeast cells with halo
• Culture — gold standard but slower

244.1.0.1.6.3 Imaging

• CT/MRI brain: hydrocephalus, meningeal enhancement, cryptococcomas (especially C. gattii)

244.1.0.1.6.4 Pulmonary Workup

• Chest CT: nodules, infiltrates
• Sputum culture
• BAL if needed

244.1.0.1.7 Treatment (3 Phases)

244.1.0.1.7.1 Induction (2 Weeks)

• Liposomal Amphotericin B (AmBisome) 4 mg/kg/d IV + Flucytosine 100 mg/kg/d PO divided q6h
• Mortality reduction with combination vs single
• 14 days standard
• Single dose liposomal AmB 10 mg/kg alternative (Ambition-cm trial 2022) — for resource-limited HIV cryptococcal meningitis; equivalent outcomes; WHO 2024 recommendation

244.1.0.1.7.2 Consolidation (8 Weeks)

• Fluconazole 800 mg/d PO × 8 weeks
• Continue suppression of fungal burden

244.1.0.1.7.3 Maintenance (Until Immune Recovery)

• Fluconazole 200 mg/d PO
• Continue until:
  • HIV: CD4 > 100 for 3 months on ART (some say > 200; 2024 WHO refined)
  • Transplant: variable, often lifelong on continued immunosuppression

244.1.0.1.7.4 Repeated Lumbar Puncture (Critical)

• Daily or every-other-day LP for high opening pressure (> 25 cm H2O)
• Drains CSF, normalizes pressure
• Reduces mortality dramatically
• Continue until ICP normalized
• Lumbar drain or VP shunt for refractory high ICP

244.1.0.1.7.5 Why High ICP?

• Massive yeast burden + polysaccharide capsule
• Obstructs CSF flow
• Cerebral edema

244.1.0.1.7.6 When to Start ART (HIV Cryptococcal Meningitis)

• Delay 4-6 weeks after starting cryptococcal Tx (COAT trial 2014 — early ART = high mortality from IRIS)
• 2024 WHO: 4-6 weeks delay
• After initial induction completed + clinically stable

244.1.0.1.8 Pre-Emptive Therapy

• Serum CrAg screening at HIV diagnosis when CD4 < 100
• Positive but asymptomatic: pre-emptive fluconazole 800 mg/d × 14 days then 200 mg/d
• Prevents progression to overt cryptococcal meningitis
• WHO recommendation since 2018

244.1.0.1.9 Pulmonary-Only Disease

• Asymptomatic immunocompetent: observation
• Symptomatic: fluconazole 200-400 mg/d × 6-12 months
• Severe / immunocompromise: liposomal AmB + flucytosine then fluconazole

244.1.0.1.10 Skin / Disseminated

• Same regimen as cryptococcal meningitis
• Treat as severe disease

244.1.0.1.11 C. gattii Specific

• Similar treatment but often longer duration
• Cerebral cryptococcomas may need surgery
• Immunocompetent: still need full treatment course

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244.1.0.2 1️⃣ Microbiology + Life Cycle

244.1.0.2.1 Species + Serotypes

• C. neoformans var grubii (serotype A) — most clinical relevance worldwide; HIV/immunocompromise
• C. neoformans var neoformans (serotype D) — Europe + some places; sometimes immunocompetent
• C. gattii (serotypes B, C) — tropical + sub-tropical + Pacific NW USA + Vancouver Island; sometimes immunocompetent severe

244.1.0.2.2 Morphology

• Encapsulated yeast (polysaccharide capsule = virulence factor)
• 5-10 µm with thick capsule
• Reproduce by budding (narrow base attachment)
• India ink stain: capsule appears as clear halo around dark yeast

244.1.0.2.3 Cell Wall

• Capsule = polysaccharide (GXM — glucuronoxylomannan + GalXM)
• Polysaccharide capsule resists phagocytosis
• Detectable in CSF (cryptococcal antigen test)

244.1.0.2.4 Environmental Sources

• C. neoformans: bird droppings (especially pigeons), soil
• C. gattii: eucalyptus trees, decaying wood, tropical
• Worldwide vs geographic restrictions

244.1.0.2.5 Pacific NW Outbreak (1999+)

• C. gattii first detected on Vancouver Island 1999
• Spread to Pacific NW USA (Washington, Oregon)
• Climate change hypothesized
• Some immunocompetent cases (more severe)
• 2024: continued sporadic cases

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244.1.0.3 2️⃣ Pathogenesis

244.1.0.3.1 Inhalation

• Yeast or spores inhaled
• Alveolar macrophages — primary defense
• Capsule resists phagocytosis
• Disseminate from lung
• Hematogenous spread to CNS (especially)

244.1.0.3.2 Tropism for CNS

• Cryptococcus has affinity for CNS (multiple factors)
• Capsule allows BBB crossing
• Polysaccharide accumulates in CSF
• Inflammatory response → edema + ICP

244.1.0.3.3 Immune Response

• Th1 + macrophage activation primary defense
• Cell-mediated immunity critical
• Failure in:
  • HIV (T cell depletion)
  • Steroids
  • Solid organ + HSCT
  • Hematologic malignancy
  • Anti-TNF
  • Idiopathic CD4 lymphocytopenia
  • Sarcoidosis

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244.1.0.4 3️⃣ Cryptococcal Meningitis

244.1.0.4.1 Risk

• HIV CD4 < 100 (especially < 50)
• Solid organ transplant
• HSCT
• Anti-TNF therapy
• High-dose steroids
• Hematologic malignancy
• Liver disease (cirrhosis)
• Idiopathic CD4 lymphocytopenia (rare immunocompetent)

244.1.0.4.2 Clinical

244.1.0.4.2.1 Subacute / Chronic

• Headache (severe, persistent, weeks)
• Fever (low-grade or absent)
• Altered mental status (confusion, somnolence)
• Cranial nerve palsies (especially CN VI, CN VII)
• Photophobia
• Meningismus (variable; may be absent in immunocompromise)
• Visual loss: papilledema, optic neuritis, increased ICP
• Hearing loss (less common)
• Seizures

244.1.0.4.2.2 Course

• Weeks → coma → death without treatment
• Mortality even with treatment: 20-50%
• Major mortality from increased ICP + complications

244.1.0.4.3 Diagnosis

244.1.0.4.3.1 Serum CrAg

• Latex agglutination or LFA
• Sensitivity 99%, specificity high
• WHO recommendation: screen serum CrAg when CD4 < 100 (asymptomatic screening)
• Positive → LP for evaluation

244.1.0.4.3.2 CSF Analysis

• Opening pressure > 25 cm H2O (often very elevated)
• Lymphocytic pleocytosis (sometimes low in AIDS)
• High protein
• Low glucose
• CSF Cryptococcal Antigen positive — diagnostic
• India ink staining (lower sensitivity than CrAg)
• CSF culture — gold standard but slow

244.1.0.4.3.3 Imaging

• CT/MRI brain:
  • Hydrocephalus common
  • Meningeal enhancement
  • Cryptococcomas (mass lesions — especially C. gattii)
  • Basal meningeal involvement

244.1.0.4.4 Treatment

244.1.0.4.4.1 Phase 1: Induction (2 Weeks)

• Liposomal Amphotericin B 4 mg/kg/d IV + Flucytosine 100 mg/kg/d PO divided q6h
• Standard for 2 weeks
• Single high-dose liposomal AmB 10 mg/kg × 1 alternative (AMBITION-cm trial 2022) for resource-limited HIV cryptococcal meningitis — equivalent outcomes
• WHO 2024 endorsement

244.1.0.4.4.2 Phase 2: Consolidation (8 Weeks)

• Fluconazole 800 mg/d PO
• Reduces fungal burden, prevents relapse

244.1.0.4.4.3 Phase 3: Maintenance

• Fluconazole 200 mg/d PO
• Continue until immune recovery
• HIV: until CD4 > 100 for 3 months on ART with virologic suppression
• Non-HIV immunocompromised: variable, often lifelong on continued immunosuppression
• Reduce immunosuppression if possible

244.1.0.4.4.4 Repeated Lumbar Puncture

• Critical for managing high ICP
• Daily or every-other-day for opening pressure > 25 cm H2O
• Drains 20-30 mL or until normalized
• Reduces mortality dramatically
• Continue until ICP < 20-25 cm H2O on multiple LP
• Lumbar drain or VP shunt for refractory high ICP

244.1.0.4.4.5 ART Timing (HIV)

• Delay ART 4-6 weeks after cryptococcal Tx initiation
• COAT trial 2014: early ART significantly higher mortality
• IRIS risk
• WHO 2024: still 4-6 weeks delay

244.1.0.4.4.6 Adjunctive

• Antiepileptics for seizures
• Acetazolamide for edema (less common now)
• Steroids — NOT routine (no benefit)
• Severe IRIS: short course steroid

244.1.0.4.5 Pre-Emptive Therapy

244.1.0.4.5.1 Serum CrAg Screening

• All HIV patients with CD4 < 100 (some guidelines < 200) — at HIV diagnosis + before ART
• Latex / LFA at point of care
• Positive → LP to evaluate for meningitis
• If asymptomatic + LP negative or normal: pre-emptive fluconazole 800 mg/d × 14 days then 200 mg/d
• Prevents progression to overt meningitis
• WHO recommendation 2018+

244.1.0.4.6 Salvage / Refractory

• Repeat induction
• Higher liposomal AmB doses
• Extended induction
• Combination
• Source control if mass effect

244.1.0.4.7 IRIS

• Paradoxical worsening with immune recovery (especially HIV + ART)
• Repeat LP
• Continue cryptococcal Tx + ART
• Steroid for severe

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244.1.0.5 4️⃣ Pulmonary Cryptococcosis

244.1.0.5.1 Forms

• Asymptomatic pulmonary nodule (incidental imaging finding)
• Symptomatic pneumonia (cough, dyspnea, fever, chest pain)
• ARDS in severe / immunocompromise
• C. gattii: more frequent in immunocompetent, larger lesions, cavitations

244.1.0.5.2 Diagnosis

• Imaging
• Sputum culture
• BAL culture + CrAg
• Lung biopsy histology

244.1.0.5.3 Treatment

244.1.0.5.3.1 Asymptomatic Immunocompetent

• Observation
• Sometimes excision (incidental find)
• No antifungal needed in select stable cases

244.1.0.5.3.2 Symptomatic Immunocompetent

• Fluconazole 400 mg/d × 6-12 months

244.1.0.5.3.3 Severe + Immunocompromise

• Treat as disseminated / CNS
• AmB + flucytosine
• Lung biopsy if needed

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244.1.0.6 5️⃣ C. gattii Specific Considerations

244.1.0.6.1 Background

• 1999 Vancouver Island outbreak
• Pacific NW USA cases since
• Tropical + sub-tropical worldwide
• Australia + New Guinea + parts Africa + Asia

244.1.0.6.2 Differences from C. neoformans

• More frequent immunocompetent infection
• More severe in immunocompetent (vs C. neoformans often immunocompromise)
• Larger pulmonary lesions + cavitations
• Cerebral cryptococcomas more common (mass effect, surgical consideration)
• Longer treatment course often

244.1.0.6.3 Treatment

• Similar to C. neoformans cryptococcal meningitis
• May need longer course
• Surgery for symptomatic cryptococcomas

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