Cryptococcosis¶

Chapter 221 | Part 5: Infectious Diseases · Part 5 – Infectious Diseases: Fungal · Chapter 221

Key Clinical Points¶

Cryptococcus neoformans and C. gattii are WHO critical priority pathogens.
C. neoformans is associated with soil/bird droppings; C. gattii is associated with arboreal species (e.g., eucalyptus).
Disease is rare in immunocompetent hosts but common in HIV (CD4+ <200/μL), transplant recipients, and those on glucocorticoids.
CNS cryptococcosis typically presents as chronic meningitis (headache, fever, lethargy) without significant meningismus.
Diagnosis requires detection of cryptococcal cells or antigen in sterile tissues (CSF, blood).
CRAg assay is highly sensitive/specific and available as a point-of-care test.
Induction therapy for severe disease: Lipid AmB + Flucytosine for 2–6 weeks.
Consolidation/Maintenance: Fluconazole (400–800 mg daily) followed by long-term maintenance.
Pregnancy: Use lipid AmB (3–5 mg/kg) to avoid teratogenic azoles.
C. gattii is associated with autoantibodies to granulocyte-macrophage colony-stimulating factor.

DEFINITION & CLASSIFICATION¶

• Definition (Harrison's 22e): Cryptococcus, a genus of yeast-like fungi, is the etiologic agent of cryptococcosis. • WHO Status: Declared Cryptococcus neoformans as a critical priority pathogen in 2022. • Species Complexity: ◦ Genome sequencing shows high diversity; current classifications (C. neoformans and C. gattii) are considered species complexes. ◦ Clinical disease caused by these complexes is indistinguishable.

1.1 Species Classification¶

• C. neoformans: ◦ var. grubii (serotype A) is more common than var. neoformans (serotype D). ◦ Found in soil contaminated with avian excreta (e.g., pigeon droppings). • C. gattii: ◦ Previously thought limited to tropical regions; now found in the US/Pacific Northwest. ◦ Associated with arboreal species, including eucalyptus trees. ◦ Not found in bird feces.

EPIDEMIOLOGY¶

• Prevalence: Rare in immunocompetent individuals; common in those with impaired immunity since the 1980s (HIV pandemic). • Global Burden: ~1 million cases and >600,000 deaths annually (2012 estimate).

2.1 Risk Factors¶

• C. neoformans Risks: ◦ Hematologic malignancies ◦ Solid-organ transplants ◦ Advanced liver disease ◦ Diabetes mellitus ◦ Glucocorticoid therapy ◦ HIV with CD4+ <200/μL • C. gattii Risks: ◦ Not generally associated with specific immune deficits. ◦ Associated with autoantibodies to granulocyte-macrophage colony-stimulating factor.

ETIOLOGY & PATHOPHYSIOLOGY¶

• Transmission: Almost always acquired via inhalation of aerosolized particles (small desiccated yeast cells or basidiospores). ◦ Rare direct skin inoculation. • Infection Dynamics: ◦ Common infection but rare disease suggests highly effective pulmonary defenses in immunocompetent individuals. ◦ Unknown if initial infection leads to immunity or repeated infections that resolve without symptoms.

3.1 Virlance Factors¶

• Polysaccharide capsule • Melanin production • Enzymes: Phospholipase and urease (enhance survival in tissue).

CLINICAL FEATURES¶

• General: Manifestations depend on site of infection; can affect any tissue.

4.1 CNS Disease¶

• Presentation: Chronic meningitis. ◦ Symptoms: Headache, fever, lethargy, sensory deficits, memory deficits, cranial nerve paresis, vision deficits. ◦ Note: Meningismus is often absent unlike bacterial meningitis.

4.2 Pulmonary Disease¶

• Symptoms: Cough, increased sputum production, chest pain. ◦ Radiographic findings: Nodules, infiltrates, masses.

4.3 Skin and Soft Tissue Infections¶

• Presentation: Common in disseminated disease; highly variable. ◦ Types: Papules, plaques, purpura, vesicles, tumor-like lesions, rashes. ◦ Note: Figure 221-2 shows a lesion resembling molluscum contagiosum.

DIAGNOSTIC APPROACH¶

Clinical Suspicion: Include in differential for any patient with chronic pulmonary or CNS infection.
CSF Examination: ◦ Findings: Mononuclear cell pleocytosis, increased protein levels. ◦ Techniques: India ink (rapid), Gram stain, cultures.
Antigen Testing: ◦ CRAg assay in CSF and blood; highly sensitive/specific. ◦ Point-of-care tests available for resource-limited regions.

MANAGEMENT & TREATMENT¶

Nonsevere Pulmonary/Non-CNS: → Fluconazole 400 mg daily for 6–12 months.
Severe or CNS Disease (Induction): → Combination of AmB and Flucytosine (5-FC) for 2–6 weeks. → Lipid formulations preferred over deoxycholate due to lower toxicity. → Doses: Liposomal AmB 3–5 mg/kg daily; AmB lipid complex 5 mg/kg; Deoxycholate AmB 0.7–1 mg/kg.
Consolidation Phase: → Fluconazole 400–800 mg daily for 8 weeks.
Maintenance Phase: → Fluconazole 200–400 mg daily for ≥1 year.
Pregnancy Protocol: → Lipid AmB 3–5 mg/kg daily for 6–8 weeks. → Avoid azole antifungals (teratogenicity: craniofacial, skeletal, cardiac defects).
Monitoring Note: → Cryptococcal cells or elevated antigen may persist in CSF/blood after culture clearance; this does not indicate treatment failure.

COMPLICATIONS & PROGNOSIS¶

• Mortality: Mortality rates for blastomycosis range from 5 to 13%. ◦ Most deaths associated with respiratory failure due to ARDS. • Table Reference: Table 220-1 (Blastomycosis) provides specific treatment pathways for various severities and sites (e.g., Lung, CNS, Disseminated). → Note: For CNS infections of any severity, the table suggests Lipid AmB followed by a choice of voriconazole, itraconazole, or fluconazole.

Reference Tables¶

TABLE 220-1 Treatment of Blastomycosis¶

Harrison's 22e, p.1703

PATIENT POPULATION	SEVERITY OF INFECTION	SITE OF INFECTION	THERAPY
Immunocompetent	Mild to moderatea	Lung	Itraconazole for 6–12 monthsb
		Disseminated	Itraconazole for 6–12 monthsb (≥12 months for osteomyelitis)
	Severec	CNS	Lipid AmB (5 mg/kg dailyd,e for 4–6 weeks) followed by voriconazole (200–400 mg bid), itraconazoleb or fluconazole (800 mg daily) for at least 12 months of treatment
		Lung	Lipid AmB (3–5 mg/kg dailye,f for 7–14 days) followed by itraconazoleb for 6–12 months
		Disseminated	Lipid AmB (3–5 mg/kg dailye,f for 7–14 days) followed by itraconazoleb for 12 months of treatment (≥12 months for osteomyelitis)
	Any severity	CNS
		Lung or disseminated
Pregnanth	Any severity	Any site	Lipid AmB (3–5 mg/kg dailye,f for 6–8 weeks), with avoidance of azole antifungals
221	Cryptococcosis Arturo Casadevall, Shmuel Shoham