Cryptococcus & CNS Mycoses
Microbiology · Mycology · lean revision notes
Cryptococcus & CNS Mycoses
The fungi that invade the central nervous system and the lung are a NEET PG favourite, and the post-COVID surge of mucormycosis has pushed this group into near-guaranteed territory. This chapter covers Cryptococcus neoformans, Aspergillus, and the Mucorales (mucormycosis) — three organisms with classic, instantly recognisable single-best-answer triggers.
Why this topic is high-yield
Three opportunistic moulds/yeasts dominate the exam: the encapsulated yeast Cryptococcus (chronic meningitis in HIV/AIDS), the septate-acute-angle mould Aspergillus (invasive pulmonary disease, aspergilloma, ABPA), and the broad-aseptate-wide-angle mould Mucorales (rhino-orbito-cerebral disease in diabetic ketoacidosis and steroid-treated COVID patients). Each has a signature microscopy picture, a signature host, and a signature drug — and those three "signatures" are exactly what gets tested.
High-yield: The single most repeated triad — India ink + HIV + pigeon droppings = Cryptococcus; acute-angle septate hyphae + neutropenia/voriconazole = Aspergillus; broad aseptate ribbon-like hyphae + DKA/COVID + liposomal amphotericin B = Mucor.
Classification of CNS / opportunistic mycoses
| Organism | Morphology | Microscopy hallmark | Classic host | Drug of choice |
|---|---|---|---|---|
| Cryptococcus neoformans | Encapsulated budding yeast | India ink halo, narrow-based bud | HIV/AIDS (CD4 < 100) | Liposomal amphotericin B + flucytosine → fluconazole |
| Aspergillus fumigatus | Septate mould | Acute-angle (45°) dichotomous branching | Neutropenia, transplant | Voriconazole |
| Mucorales (Rhizopus, Mucor) | Aseptate/pauci-septate mould | Broad ribbon-like, wide-angle (90°) branching | Diabetic ketoacidosis, COVID | Liposomal amphotericin B + surgical debridement |
High-yield: "Septate, acute angle = Aspergillus; aseptate, wide angle = Mucor." Examiners flip the two constantly — anchor it firmly.
1. Cryptococcus neoformans
Microbiology
Cryptococcus neoformans is a round, budding yeast (5–10 µm) surrounded by a thick polysaccharide capsule of glucuronoxylomannan (GXM) — its principal virulence factor and the antigen detected in diagnostic tests. It reproduces by narrow-based budding (contrast with the broad-based budding of Blastomyces). It is urease positive and produces melanin via phenol oxidase (laccase), which protects against host oxidative killing — the basis of the birdseed/niger seed (Guizotia abyssinica) agar test, where colonies turn brown-black.
- Species & serotypes: C. neoformans var. grubii (serotype A) and var. neoformans (serotype D) → associated with pigeon droppings, immunocompromised hosts. C. gattii (serotypes B, C) → associated with eucalyptus trees, infects immunocompetent hosts (notable Pacific Northwest/Vancouver Island outbreaks).
- Capsule is anti-phagocytic and immunomodulatory — the dominant virulence determinant.
High-yield: C. neoformans → pigeon droppings + immunocompromised; C. gattii → eucalyptus + immunocompetent. Both are urease positive and grow at 37 °C.
Pathophysiology
Inhaled yeast/basidiospores reach the alveoli → usually a self-limited pulmonary focus in the immunocompetent → haematogenous dissemination to the CNS when cell-mediated immunity fails (low CD4 count). The fungus has a marked tropism for the brain — neurotransmitter precursors (catecholamines) feed melanin synthesis. The capsule blunts inflammation, so the classic gross finding is a "soap bubble" gelatinous accumulation in the basal ganglia and cortex with minimal inflammatory reaction.
Clinical features
- Subacute / chronic meningitis or meningoencephalitis — the dominant presentation. Insidious headache, fever, malaise over weeks; meningismus is often mild or absent.
- Raised intracranial pressure (papilloedema, visual loss, cranial nerve palsies) is a key prognostic factor — managed with serial lumbar punctures / CSF drainage.
- Pulmonary cryptococcosis (cough, nodules), skin lesions (molluscum-like umbilicated papules in HIV), cryptococcoma.
Diagnosis & investigation of choice
Stepwise CSF approach: Lumbar puncture (measure opening pressure!) → India ink → cryptococcal antigen (CrAg) → culture on SDA/birdseed agar.
- India ink (negative stain): clear halo (capsule) around the yeast against a dark background. Sensitivity only ~50% (better in HIV with high burden). Cheap, rapid, classic exam image.
- Cryptococcal antigen (CrAg): detects GXM by latex agglutination or lateral flow assay (LFA). Highly sensitive and specific in CSF and serum — the investigation of choice / best test. CrAg titres track burden and prognosis.
- Culture: mucoid cream colonies; confirms diagnosis. Urease positive, brown on niger seed agar.
- Mucicarmine / Fontana–Masson stain the capsule/melanin in tissue.
CSF biochemistry: high opening pressure, raised protein, low glucose, lymphocytic pleocytosis (may be paucicellular in advanced AIDS).
High-yield: India ink is the rapid bedside clue, but CrAg (LFA/latex agglutination) is the most sensitive and specific test and the answer to "investigation of choice." A positive serum CrAg in an HIV patient warrants an LP to exclude meningitis.
Management / drug of choice
Three phases (IDSA):
- Induction (≥2 weeks): Liposomal amphotericin B + flucytosine (5-FC). (WHO 2022 also endorses a single high-dose liposomal amphotericin B + 14 days flucytosine + fluconazole regimen in resource-limited settings.)
- Consolidation (8 weeks): Fluconazole 400–800 mg/day.
- Maintenance / secondary prophylaxis: Fluconazole 200 mg/day until immune reconstitution (CD4 > 100–200 for ≥6 months on ART).
- Manage raised ICP aggressively with therapeutic LPs — a major cause of death/morbidity.
- Defer/time ART carefully (risk of IRIS — immune reconstitution inflammatory syndrome) — typically start ART ~4–6 weeks after antifungal initiation.
High-yield: Induction = amphotericin B + flucytosine, NOT fluconazole alone. Fluconazole is for consolidation/maintenance. Flucytosine monotherapy is never used (rapid resistance).
Mnemonic: "Crypto Caps the Cranium Cream-coloured, Catches melanin, Cured by ampho-Cytosine." (encapsulated, CNS tropic, cream mucoid colonies, melanin/niger seed, ampho B + flucytosine).
2. Aspergillus
Microbiology
Aspergillus is a ubiquitous septate mould with hyaline, dichotomously branching hyphae at acute (≈45°) angles. On culture/microscopy it forms a conidiophore with a vesicle bearing radiating chains of conidia ("aspergillum"/holy-water-sprinkler appearance). Key species: A. fumigatus (commonest, thermotolerant, invasive disease), A. flavus (sinus disease, aflatoxin → hepatocellular carcinoma), A. niger (otomycosis, oxalate crystals), A. terreus (amphotericin-resistant).
High-yield: A. flavus → aflatoxin, a hepatocarcinogen contaminating stored groundnuts/maize. A. niger → otomycosis. A. terreus → intrinsically amphotericin B resistant (use voriconazole).
Spectrum of disease (host-dependent)
| Form | Host immune status | Hallmark |
|---|---|---|
| Allergic bronchopulmonary aspergillosis (ABPA) | Asthma / cystic fibrosis (hyperimmune) | High IgE, eosinophilia, central bronchiectasis |
| Aspergilloma (fungus ball) | Pre-existing lung cavity (old TB) | "Air-crescent / Monod sign", mobile ball on imaging |
| Invasive pulmonary aspergillosis (IPA) | Neutropenia, transplant, steroids | Angioinvasion, "halo sign" then air-crescent |
| Chronic pulmonary aspergillosis | Mild immune defect/structural lung disease | Cavities, slow progression |
Pathophysiology & clinical features
In IPA, hyphae are angioinvasive, producing thrombosis, infarction and haemorrhage → haemoptysis, pleuritic pain, fever unresponsive to antibiotics in a neutropenic patient. CNS aspergillosis arises by haematogenous spread or direct sinus extension → abscess, infarcts, mycotic aneurysm (poor prognosis). ABPA reflects a type I + type III hypersensitivity to Aspergillus colonising the airways.
Diagnosis & investigation of choice
- Serum/BAL galactomannan (cell-wall antigen) — key for IPA; BAL galactomannan more sensitive than serum.
- (1→3)-β-D-glucan — pan-fungal (positive in Aspergillus, Candida, Pneumocystis; negative in Mucor and Cryptococcus).
- CT chest: early halo sign (ground-glass around nodule) → later air-crescent sign.
- Histopathology/culture of tissue: septate acute-angle hyphae (GMS/PAS).
- ABPA criteria (Rosenberg–Patterson / ISHAM): asthma, immediate skin test or specific IgE to A. fumigatus, total IgE > 1000 IU/mL, eosinophilia, central bronchiectasis, fleeting infiltrates, Aspergillus precipitins.
High-yield: Galactomannan = Aspergillus antigen; β-D-glucan positive in Aspergillus/Candida/Pneumocystis but NOT Mucor or Crypto. "Halo sign" early, "air-crescent" late in IPA.
Management / drug of choice
- IPA → Voriconazole (drug of choice). Alternatives: isavuconazole, liposomal amphotericin B. Posaconazole/isavuconazole for prophylaxis in high-risk neutropenics.
- Aspergilloma → surgical resection if haemoptysis; antifungals have limited penetration.
- ABPA → oral corticosteroids (mainstay) + itraconazole to reduce fungal burden.
High-yield: Drug of choice for invasive aspergillosis is voriconazole, not amphotericin. A. terreus is amphotericin-resistant. ABPA is treated with steroids, not just antifungals.
3. Mucormycosis (Zygomycosis)
Microbiology
Caused by the order Mucorales — Rhizopus (commonest, R. arrhizus/oryzae), Mucor, Lichtheimia (Absidia), Cunninghamella, Rhizomucor. Microscopy: broad (6–25 µm), ribbon-like, aseptate (coenocytic) or sparsely septate hyphae branching at wide (~90°) angles. Rhizopus has rhizoids (root-like) at the base of the sporangiophore.
Pathophysiology
Mucorales are angioinvasive, thriving in acidic, iron-rich, hyperglycaemic environments. Diabetic ketoacidosis is the textbook setting: acidosis releases iron from transferrin (free iron fuels growth), and the receptor GRP78 is upregulated by hyperglycaemia/acidosis, mediating endothelial invasion. Deferoxamine (an iron chelator that acts as a xeno-siderophore) and iron overload are classic risk factors. The COVID-associated mucormycosis (CAM) epidemic in India reflected the convergence of diabetes, corticosteroids, hypoxia and possibly zinc/iron dysregulation.
High-yield: Risk factors — DKA, uncontrolled diabetes, corticosteroids (incl. COVID), neutropenia, iron overload, deferoxamine, voriconazole prophylaxis (breakthrough), trauma/burns.
Clinical forms & features
Rhino-orbito-cerebral mucormycosis (ROCM) — the classic, most-tested form:
- Sinusitis → black necrotic eschar on palate/nasal turbinates/skin (tissue infarction).
- Orbital extension → proptosis, ophthalmoplegia, vision loss, periorbital swelling.
- Cavernous sinus thrombosis, internal carotid invasion, cerebral infarction.
Other forms: pulmonary (neutropenics — reverse-halo sign), cutaneous (trauma/burns), gastrointestinal (neonates/malnourished), disseminated.
Clinical flow: Diabetic with DKA → facial pain + nasal congestion + black eschar → proptosis/ophthalmoplegia → suspect ROCM → urgent biopsy + imaging + start liposomal amphotericin B + surgical debridement.
Diagnosis & investigation of choice
- KOH mount / histopathology of biopsy — the investigation of choice: broad aseptate ribbon-like hyphae, wide-angle branching, with tissue necrosis and angioinvasion.
- Culture grows rapidly ("lid-lifter" woolly colonies) but is often negative (hyphae killed by grinding tissue — mince, don't homogenise).
- MRI/CT sinuses & orbit/brain for extent; "black turbinate sign" on MRI = early necrosis.
- Note: serum galactomannan and β-D-glucan are NEGATIVE (Mucorales lack these cell-wall components) — useful to distinguish from Aspergillus.
High-yield: A negative galactomannan/β-D-glucan in an angioinvasive sinus infection of a diabetic points to Mucor, not Aspergillus. Diagnosis rests on biopsy histopathology (aseptate wide-angle hyphae), not serology.
Management / drug of choice
Three pillars — "Cut, Drug, Fix the host":
- Aggressive surgical debridement of all necrotic tissue (mortality falls dramatically with early surgery).
- Liposomal amphotericin B (high dose, ~5–10 mg/kg) — drug of choice. Isavuconazole and posaconazole are alternatives/step-down (delayed-release tablets/IV). Fluconazole and voriconazole have NO activity against Mucor.
- Reverse the predisposing factor: correct DKA/hyperglycaemia, taper steroids, stop deferoxamine. Adjunct: deferasirox is not recommended (DEFEAT-Mucor trial showed harm).
High-yield: Voriconazole does not cover Mucor — in fact, voriconazole prophylaxis is a recognised risk factor for breakthrough mucormycosis. DOC = liposomal amphotericin B + surgery.
Putting it together — comparison table
| Feature | Cryptococcus | Aspergillus | Mucor |
|---|---|---|---|
| Form | Encapsulated yeast | Septate mould | Aseptate mould |
| Angle of branching | — (yeast) | Acute 45° | Wide ~90° |
| Classic host | HIV/AIDS | Neutropenia/transplant | DKA, COVID-steroid |
| Best diagnostic test | CrAg (LFA/latex) | Galactomannan | Biopsy KOH/histology |
| β-D-glucan | Negative | Positive | Negative |
| Drug of choice | Ampho B + flucytosine → fluconazole | Voriconazole | Liposomal ampho B + surgery |
| Signature sign | India ink halo, soap-bubble lesions | Halo/air-crescent sign | Black eschar, black turbinate |
Key differentials
- Chronic lymphocytic meningitis: Cryptococcus vs TB meningitis vs neurosyphilis vs partially-treated bacterial meningitis. CrAg and India ink separate Cryptococcus; ADA/CBNAAT for TB.
- Narrow-based budding yeast with capsule (Crypto) vs broad-based budding (Blastomyces) vs pseudohyphae/germ tube (Candida) vs spherules with endospores (Coccidioides).
- Angioinvasive sinus mould: Aspergillus (septate, GM+) vs Mucor (aseptate, GM−) — the most commonly tested differential.
- Cavity fungus ball: aspergilloma vs healed TB vs lung cancer vs hydatid.
Recently asked / exam angle
- Post-COVID mucormycosis questions exploded in 2021–2024 cycles: identify the risk-factor cluster (diabetes + steroids + COVID), the black eschar/black turbinate sign, aseptate wide-angle hyphae on KOH, and liposomal amphotericin B + debridement as treatment. Recognising that voriconazole worsens/does not treat Mucor is a frequent distractor.
- Image-based: an India ink photomicrograph showing a clear halo → Cryptococcus → next-best-test = CrAg; treatment = ampho B + flucytosine.
- Galactomannan vs β-D-glucan specificity (Mucor negative for both) recurs in microbiology and medicine.
- C. gattii infecting the immunocompetent and linked to eucalyptus is a classic "odd-one-out."
- ABPA diagnostic criteria (IgE > 1000, central bronchiectasis) and A. flavus → aflatoxin → HCC.
- Match-the-column: morphology ↔ angle of branching ↔ organism ↔ drug.
Rapid revision
- India ink halo + HIV + pigeon droppings = Cryptococcus neoformans (urease +, melanin/niger seed +).
- Best test for cryptococcal meningitis = cryptococcal antigen (LFA/latex agglutination); manage raised ICP with serial LPs.
- Cryptococcal meningitis induction = liposomal amphotericin B + flucytosine, then fluconazole consolidation/maintenance.
- C. gattii infects the immunocompetent, linked to eucalyptus; C. neoformans infects the immunocompromised.
- Aspergillus = septate hyphae, acute 45° branching; A. fumigatus causes invasive disease.
- Galactomannan = Aspergillus antigen; β-D-glucan positive in Aspergillus/Candida/Pneumocystis, negative in Mucor & Crypto.
- IPA imaging: halo sign early → air-crescent sign late; aspergilloma = Monod sign.
- Drug of choice for invasive aspergillosis = voriconazole; A. terreus is amphotericin-resistant; ABPA = steroids + itraconazole.
- A. flavus → aflatoxin → hepatocellular carcinoma; A. niger → otomycosis.
- Mucor = broad aseptate ribbon-like hyphae, wide ~90° branching, Rhizopus commonest; angioinvasive.
- Mucormycosis risk = DKA, uncontrolled diabetes, steroids/COVID, deferoxamine, iron overload, voriconazole prophylaxis.
- ROCM → black eschar/black turbinate → DOC = liposomal amphotericin B + aggressive surgical debridement + reverse DKA; voriconazole has no activity against Mucor.