Cryptococcus/Cryptococcosis

Cryptococcosis is an opportunistic, fungal infection caused by the Cryptococcus species. The principal pathogens in humans are C. neoformans (primary) and C. gattii. Cryptococcus neoformans is typically found in pigeon droppings and acquired by inhaling dust from contaminated soil. The majority of affected patients are immunocompromised. Patients with AIDS, chronic steroid use, and organ transplant are particularly affected. The primary virulence factor is an antiphagocytic capsule, consisting of repeating capsular polysaccharide antigens. The infection typically affects the lungs and presents as a primary lesion or pneumonia. Dissemination can occur to involve the brain and meninges, skin, bones, and visceral organs. Treatment for cryptococcal meningitis is usually amphotericin B and flucytosine, followed by fluconazole. Cryptococcosis is an AIDS-defining illness and typically associated with CD4 count < 100 cells/μL.

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General Characteristics of Cryptococcus

Features

  • Morphology: round or oval-shaped, heavily encapsulated yeast (not dimorphic)
    • 5–10 µm in diameter
    • Variable capsule thickness: can be > 50% of the yeast diameter
  • Characteristics:
    • Obligate aerobe
    • Urease positive
    • Can be visualized on India ink, methenamine silver, and mucicarmine stains

Clinically relevant species

  • The Cryptococcus genus contains over 50 species. 
  • Only C. neoformans and C. gattii are pathogenic in humans.
  • C. neoformans is the primary pathogenic member of the genus.

Forms of disease

  • Pulmonary cryptococcosis
  • Cryptococcal meningitis 
  • Cutaneous cryptococcosis
  • Other forms (less common):
    • Osteomyelitis
    • Ocular cryptococcosis 
    • Pyelonephritis
    • Endocarditis
    • Hepatitis
    • Sinusitis

Epidemiology

Incidence

  • The incidence of cryptococcosis notably increased during 1981–1992 due to the AIDS epidemic. 
  • The development and use of corticosteroids, along with improved patient survival rates, also contributed to an increased incidence.
  • Global incidence rate: 1 million annually
  • The majority of cases reported have been in patients with AIDS:
    • Approximately 7%–15% of patients with AIDS develop cryptococcal infections
    • Incidence has declined over the past 20 years due to advances in antiretroviral therapy.

Morbidity and mortality

  • Approximately 625,000 deaths per year globally
  • The use of amphotericin B has dramatically improved patient outcomes.
  • 14% mortality rate with amphotericin B + flucytosine

Pathogenesis

Infectious process

  • Habitat:
    • Largely found in soil contaminated with old bird droppings
    • Also found in decaying wood and tree hollows
  • Transmission: Yeast spores are inhaled from contaminated soil.
  • Pathogenicity and disease process:
    • Spores are deposited into the pulmonary alveoli → phagocytized by macrophages
    • Cryptococcal polysaccharide capsule prevents recognition within macrophages → prevents leukocyte migration
    • Glucuronoxylomannan and glucuronoxylomannogalactan (known together as GXM): 
      • Components of the capsule
      • Highly immunosuppressive
    • C. neoformans and C. gattii also produce phenol oxidase:
      • ↑ Production of melanin
      • Melanin accumulates in the cell wall and prevents attacks from the host immune system.
  • Healthy individuals: Infection is often self-contained.
  • Immunocompromised:
    • The initial site is infected and then spreads via hematogenous dissemination
    • If contained, reactivation at the initial site can occur later due to declined immune status.

Host risk factors

The most significant risk factor for infection is an immunocompromised state. In decreasing frequency, the following conditions are most frequently associated with infection:

  • HIV and AIDS
  • Chronic steroid use
  • Organ transplant
  • Malignancy
  • Liver disease
  • Sarcoidosis

Clinical Presentation

General findings

Clinical presentation varies depending on the affected area and immune status of the host: 

  • In immunocompetent individuals, infection is often asymptomatic and self-resolving. 
  • The lungs are most often infected, followed by the CNS. 
  • Other parts of the body can also be affected by disseminated infection.

Pulmonary cryptococcosis

  • The pattern can be highly variable: Up to 30% of immunocompetent individuals are asymptomatic.
  • Mild-to-moderate symptoms:
    • Fever
    • Malaise
    • Cough with scant sputum
    • Pleuritic pain
    • Hemoptysis (rare)
  • Frequent radiological findings: single or multiple nodular lesions
    • Well defined
    • Noncalcified
  • ARDS can occur in severe cases.

Cryptococcal meningitis/meningoencephalitis

  • Major clinical manifestation of cryptococcal infection and the most common site of dissemination from the lungs
  • Most common CNS mycosis in immunocompromised patients:
    • 90% of cases seen in patients with AIDS 
    • AIDS-defining condition: CD4 count < 100 cells/µL
  • Gradual onset of symptoms:
    • Develops over the course of weeks to months from initial infection
    • Headache: most common presenting symptom
    • Altered mental status
    • Photophobia
    • Behavioral changes
    • Nausea and/or vomiting
    • Neck stiffness
    • Focal neurological deficits 
      • Typically ocular or facial
      • Tend to develop in later stage
  • Immunocompromised patients:
    • May have minimal or nonspecific symptoms
    • Fever is often absent or low grade.

Cutaneous cryptococcosis

  • Occurs in about 10%–15% of cases
  • Skin findings can be variable:
    • Papules
    • Pustules
    • Nodules
    • Ulcers
    • Draining sinuses
  • Cellulitis complicated with necrotizing vasculitis has been reported in organ-transplant patients.
Cutaneous cryptococcosis

Cutaneous cryptococcosis: Papulonodular lesions (some showing crusts and umbilicated center) are on the face and upper dorsum. Cryptococcus infection is confirmed in the skin lesions.

Image: “Disseminated cryptococcosis with cutaneous involvement in an immunocompetent patient” by Gabriely Lessa Sacht et al. License: CC BY 4.0

Diagnosis

Laboratory tests

  • Infection outside the CNS:
    • Specimens:
      • Pulmonary: sputum, bronchopulmonary washing, pleural fluid
      • Cutaneous: skin/tissue samples 
    • Tests:
      • Visualization of yeast with stains (capsule seen)
      • Culture on Sabouraud agar
      • Serum cryptococcal antigen (CrAg) by latex agglutination, enzyme immunoassays, or lateral flow assay
  • Cryptococcus meningitis/meningoencephalitis:
    • Lumbar puncture preceded by neuroimaging
    • CSF studies and culture:
      • India ink stain showing “halos”
      • Elevated protein
      • Low or normal glucose
      • Positive CrAg in CSF

Imaging

  • Chest X-ray and CT:
    • Chest X-ray findings vary according to extent and presentation:
      • Nodules
      • Consolidation
      • Cavitation
      • Lobar infiltrates
      • Hilar lymphadenopathy
      • Pleural effusion
      • Lung collapse
    • CT findings can provide greater detail and are indicated for suspected pulmonary cases in immunocompromised patients.
  • Neuroimaging:
    • Perform CT or MRI of the brain prior to lumbar puncture in patients.
    • Especially useful in patients with focal neurological deficits or papilledema (looking for sources of increased intracranial pressure)
    • MRI is significantly more sensitive than CT for detecting brain lesions:
      • Single or multiple focal mass lesions
      • Granulomas
      • Gelatinous pseudocysts (i.e. characteristic “soap bubble lesions”)

Management

Principles

  • Because most infections affect the CNS (meningeal infection) and the lungs (pulmonary infection), most evaluated regimens focus on these sites.
  • Cryptococcal infections not affecting the CNS or lungs generally represent disseminated infection (although single-site infection is possible).
  • Options differ depending on the immune status of the host and site of infection:
    • CNS infection regimen:
      • Induction: flucytosine + IV amphotericin B for at least 2 weeks
      • Consolidation: fluconazole for 8 weeks
      • Maintenance: fluconazole (lower dose) for 12 months after diagnosis
    • Fluconazole: 6–12 months
    • Alternatives are available in certain populations or situations.
  • Fungal growth is monitored with CSF analysis during the treatment of CNS infection.

Treatment approach

  • Immunocompetent:
    • Pulmonary (no CNS infection):
      • Mild pulmonary symptoms or focal infection (no diffuse infiltrates): fluconazole for 6–12 months
      • Severe pulmonary symptoms (diffuse pulmonary infiltrates): CNS infection regimen
    • CNS infection or disseminated infection (≥ 2 noncontiguous sites): CNS infection regimen
  • Immunocompromised: 
    • Treatment is indicated in all patients with AIDS.
    • Antiretroviral therapy is delayed until initial cryptococcal treatment (possible immune reconstitution inflammatory syndrome (IRIS)).
    • Mild pulmonary infection: fluconazole 6–12 months
    • CNS infection, severe pulmonary disease, or disseminated infection: CNS infection regimen
  • Reduce intracranial pressure:
    • Daily lumbar puncture until asymptomatic
    • Lumbar or ventricular drains
Table: Treatment of cryptococcal infections
Condition Treatment
CNS infection Amphotericin B + flucytosine, followed by consolidation and maintenance therapy
Immunocompetent and immunosuppressed with mild pulmonary infection (focal) Fluconazole
Immunocompetent and immunosuppressed with severe pulmonary infection CNS infection treatment
Immunocompetent and immunosuppressed with extrapulmonary, non-CNS infection (≥ 2 noncontiguous sites) CNS infection treatment

Prevention

  • Antiretroviral therapy for patients with AIDS
  • Routine testing for CrAg in newly diagnosed HIV-infected persons (CD4 counts ≤ 100 cells/µL) without signs of meningitis:
    • Positive test → CSF evaluation
    • Treat isolated, positive-serum cryptococcal antigenemia without meningitis like a focal pulmonary infection.
    • Routine primary antifungal prophylaxis in CrAg-negative patients is generally not recommended, despite CD4 count:
      • Unclear survival benefit with prophylaxis
      • Possible drug interactions
      • Potential for drug resistance

Differential Diagnosis

  • Opportunistic fungal infections: a group of infections occurring in patients with weakened immune systems (especially CD4 counts < 200 cells/μL). The infections typically do not cause disease in healthy patients with a normal immune system. General signs and symptoms can be similar to cryptococcosis. Microscopy and culture of sputum or bronchoalveolar lavage with identification of specific organisms can help to differentiate.
  • Tuberculosis (TB): an infectious disease caused by bacteria of the Mycobacterium tuberculosis complex. Like Cryptococcus, the bacteria usually infects the lungs, but can also spread to other parts of the body. Both are associated with a period of latency and can present with similar signs and symptoms. Look for a history of exposure to an environment with TB prevalence (e.g., healthcare setting, homeless shelter). A CD4 count of < 300 cells/μL is typically associated with TB versus < 200 cells/μL for cryptococcosis. The diagnosis is established with a tuberculin skin test, blood tests, sputum culture, and lung imaging.
  • Histoplasmosis: an infection caused by Histoplasma capsulatum. Like cryptococcosis, histoplasmosis is a fungal infection acquired by inhalation and associated with contaminated soil and immunocompromised individuals. Unlike cryptococcosis, histoplasmosis is associated with bat droppings (in addition to bird droppings). Symptoms may be nonspecific, or consistent with pneumonia. The skin may be affected as well. Diagnosis can be made by fungal cultures or urine/serum antigen testing. If present, a biopsy of a skin lesion with culture and histology can help to differentiate.
  • Blastomycosis: a pulmonary disease caused by inhaling the spores of Blastomyces. Patients can develop pneumonia or disseminated-extrapulmonary disease. Unlike cryptococcosis, skin involvement is the most common site of dissemination. History of exposure to the Great Lakes, the Ohio River Valley, and the Mississippi River Valley regions may be present as Blastomyces is endemic to the regions. Diagnosis is made by cultures and imaging.

References

  1. Buchanan, K. L. & Murphy, J. W. (1998). What makes Cryptococcus neoformans a pathogen? Emerg Infect Dis 4, 71–83.
  2. Cox, G., Perfect, J. (2021). Microbiology and epidemiology of Cryptococcus neoformans infection. UpToDate. Retrieved June 9, 2021, from https://www.uptodate.com/contents/microbiology-and-epidemiology-of-cryptococcus-neoformans-infection
  3. Cox, G., Perfect, J. (2021). Cryptococcus neoformans infection outside of the central nervous system. UpToDate. Retrieved June 10, 2021, from https://www.uptodate.com/contents/cryptococcus-neoformans-infection-outside-the-central-nervous-system
  4. Cox, G., Perfect, J. (2021). Cryptococcus neoformans: Treatment of meningoencephalitis and disseminated infection in HIV seronegative patients. UpToDate. Retrieved June 9, 2021, from https://www.uptodate.com/contents/cryptococcus-neoformans-treatment-of-meningoencephalitis-and-disseminated-infection-in-hiv-seronegative-patients
  5. Cryptococcosis: NIH. Cryptococcosis | NIH. (n.d.). Retrieved June 10, 2021, from https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-opportunistic-infection/cryptococcosis?view=full. 
  6. Mada, P. (2021). Cryptococcosis: Practice Essentials, Background, Pathophysiology. Medscape. Retrieved June 9, 2021, from https://emedicine.medscape.com/article/215354-overview#a1
  7. Mada, P.K., Jamil, R.T., Alam, M.U. (2020). Cryptococcus. StatPearls. Treasure Island (FL): StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK431060/
  8. Revankar, S. (2019). Cryptococcosis. Merck Manuals. Retrieved June 9, 2021, from https://www.merckmanuals.com/professional/infectious-diseases/fungi/cryptococcosis?query=cryptococcus#v36860800

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