Cryptococcosis
Summary
Cryptococcosis is a systemic fungal infection caused by encapsulated yeasts, primarily Cryptococcus neoformans (associated with bird droppings) and Cryptococcus gattii (associated with eucalyptus trees). Infection typically occurs via inhalation of spores. In immunocompetent individuals, it may cause asymptomatic pulmonary infection or mild pneumonia. In immunocompromised patients, particularly those with HIV/AIDS (CD4 <100), it disseminates to the central nervous system causing cryptococcal meningitis — a leading cause of death in HIV patients globally. The hallmark presentation is subacute meningitis with headache, fever, and raised intracranial pressure. Diagnosis is by CSF cryptococcal antigen (CrAg), India ink staining, and culture. Treatment involves induction with amphotericin B + flucytosine, followed by consolidation and maintenance with fluconazole. Management of raised ICP with therapeutic lumbar punctures is critical.
Key Facts
- Organism: Cryptococcus neoformans (bird droppings); C. gattii (trees; immunocompetent hosts)
- Risk: HIV/AIDS with CD4 <100; Transplant recipients; Corticosteroids
- CNS tropism: Causes subacute meningitis; Raised ICP
- Diagnosis: CSF CrAg (highly sensitive); India ink (encapsulated yeasts); Culture
- CSF findings: Lymphocytic pleocytosis; Elevated protein; Low glucose; HIGH opening pressure
- Treatment (AIDS): Induction = Amphotericin B + Flucytosine (2 weeks) → Consolidation = Fluconazole (8 weeks) → Maintenance = Fluconazole (until CD4 >200)
- ICP management: Serial therapeutic lumbar punctures
- Mortality: 10-25% even with treatment (higher in resource-limited settings)
Clinical Pearls
"Subacute Meningitis in AIDS = Cryptococcus": Any HIV patient with CD4 <100 presenting with headache and fever has cryptococcal meningitis until proven otherwise. Always check CrAg.
"High Opening Pressure Kills": Raised ICP is the major cause of early death. Therapeutic LPs (removing 20-30 mL CSF) are life-saving. The goal is to reduce pressure below 25 cm H2O.
"CrAg Is Extremely Sensitive": CSF and serum cryptococcal antigen (CrAg) testing is highly sensitive (>95%) and rapid. A negative CrAg essentially rules out cryptococcal meningitis.
"India Ink Shows Halos": The encapsulated yeast cells are seen as a ring or "halo" against the ink background. However, CrAg is more sensitive than India ink.
"Delay ART for 4-6 Weeks": Starting antiretroviral therapy immediately in cryptococcal meningitis increases mortality due to immune reconstitution inflammatory syndrome (IRIS). Delay ART by 4-6 weeks.
Why This Matters Clinically
Cryptococcal meningitis is a major cause of death in HIV/AIDS patients, particularly in sub-Saharan Africa. Early suspicion, rapid diagnosis with CrAg, antifungal therapy, and aggressive ICP management save lives. All clinicians caring for immunocompromised patients should recognise this condition.[1,2]
Incidence & Prevalence
| Parameter | Data |
|---|---|
| Global burden | ~180,000 deaths/year (majority in sub-Saharan Africa) |
| Risk group | HIV with CD4 <100 cells/μL |
| Incidence in HIV/AIDS | 15-30% of AIDS-related deaths in some regions |
| Organ transplant | ~2-5% of solid organ transplant recipients |
Risk Factors
| Factor | Notes |
|---|---|
| HIV/AIDS (CD4 <100) | Most important; accounts for >80% cases |
| Organ transplant | Immunosuppressive therapy |
| Corticosteroids | Prolonged, high-dose |
| Haematological malignancy | CLL, lymphoma |
| Sarcoidosis | Immunosuppression |
| Idiopathic CD4+ lymphopenia | Rare |
| C. gattii | Can affect immunocompetent hosts |
Infection Pathway
Step 1: Inhalation
- Spores inhaled from environmental sources (bird droppings; soil; trees)
- Deposition in alveoli
Step 2: Pulmonary Infection
- In immunocompetent: Contained by alveolar macrophages; often asymptomatic
- In immunocompromised: Uncontrolled replication
Step 3: Dissemination
- Haematogenous spread
- CNS tropism (capillary glucose, laccase activity attract yeasts)
Step 4: Meningitis
- Invasion of meninges and brain parenchyma
- Polysaccharide capsule inhibits phagocytosis
- Production of melanin (antioxidant protection)
Capsule Virulence
| Feature | Role |
|---|---|
| Polysaccharide capsule | Antiphagocytic; Immunomodulatory |
| Glucuronoxylomannan (GXM) | Major capsular component; Detectable as antigen (CrAg) |
| Melanin production | Protects against oxidative stress |
| Laccase | Enzyme promoting CNS tropism |
Cryptococcal Meningitis
| Feature | Notes |
|---|---|
| Headache | Universal; Often severe; May be only symptom |
| Fever | Variable; May be low-grade |
| Altered consciousness | Confusion; Somnolence; Coma |
| Neck stiffness | May be absent (~20-30%) |
| Visual disturbance | Papilloedema (raised ICP); Cranial nerve palsies |
| Seizures | Less common |
| Gradual onset | Subacute (days to weeks) |
Pulmonary Cryptococcosis
| Feature | Notes |
|---|---|
| Asymptomatic | Many cases |
| Cough | Dry or productive |
| Fever | Low-grade |
| Chest pain | Pleuritic |
| CXR | Nodules; Infiltrates; Cavitation; Effusion |
Disseminated Cryptococcosis
| Site | Features |
|---|---|
| Skin | Papules; Nodules; Umbilicated lesions (mimic molluscum) |
| Bone | Osteolytic lesions |
| Prostate | Reservoir for relapse |
Red Flags — Raised ICP
[!CAUTION] Signs of Raised Intracranial Pressure:
- Severe headache not responding to analgesia
- Vomiting
- Altered consciousness
- Papilloedema
- Visual disturbance (diplopia, blurring)
- Opening pressure >25 cm H2O on LP ACTION: Therapeutic LP immediately
Neurological Examination
| Finding | Significance |
|---|---|
| Reduced GCS | Raised ICP; Advanced disease |
| Neck stiffness | Meningism (may be absent) |
| Papilloedema | Raised ICP — requires therapeutic LP |
| Cranial nerve palsies | VI most common (abducens); Raised ICP |
| Focal neurology | Cryptococcoma |
General Examination
| Finding | Notes |
|---|---|
| Fever | May be absent |
| Skin lesions | Umbilicated papules; Mimics molluscum |
| Lymphadenopathy | May indicate dissemination |
| Respiratory signs | Crackles (pneumonia) |
Lumbar Puncture
| Parameter | Typical Finding |
|---|---|
| Opening pressure | Elevated (>25 cm H2O; often >35) |
| Appearance | Clear or slightly hazy |
| WCC | Variable; Lymphocytic; May be low in severe AIDS |
| Protein | Elevated |
| Glucose | Low |
| India ink | Positive ~70-80%; Encapsulated yeasts with "halo" |
| Cryptococcal antigen (CrAg) | Highly sensitive (>95%); Rapid |
| Fungal culture | Gold standard; May take days |
Serum Tests
| Test | Notes |
|---|---|
| Serum CrAg | Positive in >99% of meningitis; Used for screening in HIV |
| CD4 count | Usually <100 cells/μL |
| HIV viral load | Typically high if untreated |
Imaging
| Modality | Findings |
|---|---|
| CT head | Often normal; Hydrocephalus; Cryptococcomas |
| MRI brain | Cryptococcomas; Leptomeningeal enhancement |
| CXR | Nodules; Infiltrates (pulmonary disease) |
Management Algorithm
CRYPTOCOCCAL MENINGITIS MANAGEMENT
↓
┌─────────────────────────────────────────────────────────────┐
│ DIAGNOSIS │
├─────────────────────────────────────────────────────────────┤
│ ➤ Lumbar puncture (if no contraindication) │
│ • Opening pressure (critical) │
│ • CSF CrAg (highly sensitive) │
│ • India ink stain │
│ • Fungal culture │
│ ➤ Serum CrAg │
│ ➤ HIV test + CD4 count │
└─────────────────────────────────────────────────────────────┘
↓
┌─────────────────────────────────────────────────────────────┐
│ INDUCTION THERAPY (2 WEEKS) │
├─────────────────────────────────────────────────────────────┤
│ PREFERRED: │
│ ➤ Amphotericin B deoxycholate 1 mg/kg/day IV │
│ + Flucytosine 100 mg/kg/day PO in 4 divided doses │
│ │
│ ALTERNATIVE (Resource-limited): │
│ ➤ Amphotericin B + Fluconazole 1200 mg/day │
│ ➤ OR Fluconazole 1200 mg/day + Flucytosine (if no AmB) │
│ │
│ DURATION: 14 days (or until CSF sterile) │
│ │
│ MONITOR: │
│ ➤ Renal function (nephrotoxic) │
│ ➤ Potassium + Magnesium (amphotericin) │
│ ➤ FBC (flucytosine — marrow suppression) │
└─────────────────────────────────────────────────────────────┘
↓
┌─────────────────────────────────────────────────────────────┐
│ ICP MANAGEMENT (CRITICAL) │
├─────────────────────────────────────────────────────────────┤
│ ⚠️ RAISED ICP = MAJOR CAUSE OF EARLY DEATH │
│ │
│ ➤ Measure opening pressure at LP │
│ ➤ If OP >25 cm H2O: Therapeutic LP │
│ • Remove 20-30 mL CSF │
│ • Daily LPs until OP <25 cm H2O for 2 days │
│ │
│ ➤ If refractory: Consider lumbar drain or VP shunt │
│ ➤ Avoid corticosteroids (no benefit; may harm) │
│ ➤ Mannitol/acetazolamide NOT effective │
└─────────────────────────────────────────────────────────────┘
↓
┌─────────────────────────────────────────────────────────────┐
│ CONSOLIDATION (8 WEEKS) │
├─────────────────────────────────────────────────────────────┤
│ ➤ Fluconazole 800 mg/day (400 mg if resource-limited) │
│ ➤ Duration: 8 weeks │
└─────────────────────────────────────────────────────────────┘
↓
┌─────────────────────────────────────────────────────────────┐
│ MAINTENANCE (SECONDARY PROPHYLAXIS) │
├─────────────────────────────────────────────────────────────┤
│ ➤ Fluconazole 200 mg/day │
│ ➤ Continue until: │
│ • CD4 >100-200 cells/μL sustained for >12 months │
│ • Undetectable HIV viral load on ART │
└─────────────────────────────────────────────────────────────┘
↓
┌─────────────────────────────────────────────────────────────┐
│ ART TIMING │
├─────────────────────────────────────────────────────────────┤
│ ⚠️ DELAY ART BY 4-6 WEEKS │
│ ➤ Early ART increases IRIS risk and mortality │
│ ➤ Start ART after induction phase completed │
└─────────────────────────────────────────────────────────────┘
Medication Summary
| Phase | Drug | Dose | Duration |
|---|---|---|---|
| Induction | Amphotericin B | 1 mg/kg/day IV | 2 weeks |
| Induction | Flucytosine | 100 mg/kg/day PO | 2 weeks |
| Consolidation | Fluconazole | 800 mg/day PO | 8 weeks |
| Maintenance | Fluconazole | 200 mg/day PO | Until immune reconstitution |
| Complication | Notes |
|---|---|
| Raised ICP | Major cause of death; Requires therapeutic LPs |
| IRIS | Paradoxical worsening after ART initiation |
| Hydrocephalus | May require shunt |
| Relapse | If maintenance fluconazole stopped early |
| Visual loss | Optic nerve damage from raised ICP |
| Hearing loss | Rare |
| Factor | Outcome |
|---|---|
| Mortality (treated) | 10-25% (higher in resource-limited settings) |
| Opening pressure >25 | Poor prognostic factor |
| Altered consciousness | Poor prognosis |
| Low CSF WCC | Indicates severe immunosuppression; Poor outcome |
| Immune reconstitution | Long-term survival possible with ART |
Key Guidelines
| Guideline | Organisation | Year | Key Points |
|---|---|---|---|
| Guidelines for Diagnosis, Prevention, and Management of Cryptococcal Disease in HIV-Infected Adults | WHO | 2022 | Screening, treatment, ICP management |
Key Evidence
COAT Trial (Boulware et al. 2014)
- Early ART (within 1-2 weeks) vs Deferred ART (5 weeks) in cryptococcal meningitis
- Early ART increased mortality
- Established 4-6 week ART delay as standard
- PMID: 24795087
What is cryptococcal meningitis?
Cryptococcal meningitis is a serious brain infection caused by a fungus. It mainly affects people with weak immune systems, especially those with HIV whose CD4 count is very low.
How does someone get it?
The fungus is found in the environment (especially in bird droppings and soil). You breathe it in. If your immune system is weak, it can spread to your brain.
What are the symptoms?
- Severe headache
- Fever
- Confusion or drowsiness
- Stiff neck
- Blurred vision
How is it treated?
- Strong antifungal medicines given directly into a vein (intravenously)
- Spinal taps (lumbar punctures) to reduce pressure on the brain
- Treatment continues for many months
- HIV treatment is started a few weeks later
Is it serious?
Yes, it can be life-threatening if not treated quickly. But with early treatment, most people can recover.
-
Perfect JR, Dismukes WE, Dromer F, et al. Clinical Practice Guidelines for the Management of Cryptococcal Disease: 2010 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2010;50(3):291-322. PMID: 20047480
-
Boulware DR, Meya DB, Muzoora C, et al. Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis (COAT trial). N Engl J Med. 2014;370(26):2487-2498. PMID: 24795087
High-Yield Exam Topics
| Topic | Key Points |
|---|---|
| Risk | HIV with CD4 <100; Transplant |
| Presentation | Subacute meningitis; Headache |
| Diagnosis | CSF CrAg (highly sensitive); India ink |
| CSF features | High opening pressure; Lymphocytes; Low glucose |
| Treatment | Amphotericin B + Flucytosine (2 weeks) → Fluconazole |
| ICP management | Therapeutic LPs — critical |
| ART timing | Delay 4-6 weeks (COAT trial) |
Sample Viva Question
Q: How do you manage raised intracranial pressure in cryptococcal meningitis?
Model Answer: Raised ICP is the major cause of early death. Management: Measure opening pressure at every LP. If OP >25 cm H2O, perform therapeutic LP removing 20-30 mL CSF. Repeat LPs daily until pressure is <25 cm H2O for at least 2 consecutive days. If refractory, consider lumbar drain or VP shunt. Corticosteroids are NOT effective and may be harmful. Mannitol and acetazolamide are also not effective. The goal is to reduce pressure and symptoms (headache, visual changes).
Last Reviewed: 2025-12-24 | MedVellum Editorial Team