Cryptococcosis

Philip A. Chan, M.D., M.S.
Tara C. Bouton, M.D., M.P.H. & T.M.

Basic Information

Definition

Cryptococcosis is an infection caused by the encapsulated yeast Cryptococcus spp.

Synonyms

C. neoformans infection
C. gattii infection
C. albidus infection
C. laurentii infection

ICD-10CM CODES
B45.09	Pulmonary cryptococcosis
B45.1	Cerebral cryptococcosis
B45.2	Cutaneous cryptococcosis
B45.3	Osseous cryptococcosis
B45.7	Disseminated cryptococcosis
B45.9	Cryptococcosis, unspecified

Epidemiology & Demographics

Incidence (In U.S.)

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0.8 cases per million persons/year; C. neoformans is an important opportunistic infection in patients with deficits in cell-mediated immunity.
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2 to 7 per 1000 persons living with AIDS/year.

Peak Incidence

20 to 40 years (parallel to HIV/AIDS epidemic).

Predominant Sex

Equal sex distribution when adjusted for HIV status.

Predominant Age

Less than 2 years of age; 20 to 40 years of age.

Neonatal Infection

Very uncommon.

Physical Findings & Clinical Presentation

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More than 90% present with meningitis (generally subacute); almost all have fever and headache.
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Meningismus, photophobia, mental status changes are seen in approximately 25%.
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Increased intracranial pressure may be present.
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Most common infections outside the CNS:
1. 1.
  
  In the lungs (fever, cough, dyspnea, and typically with lobar consolidation).
2. 2.
  
  In the skin (cellulitis, papular eruption).
3. 3.
  
  In the lymph nodes (lymphadenitis).
4. 4.
  
  Potential involvement of virtually any organ (e.g., prostate and bone).

Etiology

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There are four Cryptococcus spp. that cause disease in humans, although most laboratories are not able to differentiate between species. C. neoformans is the cause of a majority of global disease burden, primarily in immunocompromised patients. C. gattii infections are much less common and occur more often in normal hosts, with recent outbreaks in the Pacific Northwest. C. albidus and C. laurentii are even rarer causes of disease.
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Infection originates by inhalation into the respiratory tract followed by dissemination to the CNS in most cases, usually without recognizable lung involvement.
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Almost always in the setting of AIDS (most with CD4 counts <100) or other disorders of cellular immune function, such as organ transplantation.
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Neutropenia alone poses a much lower risk of significant cryptococcal infection.

Diagnosis

Differential Diagnosis

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Subacute meningitis (caused by Listeria monocytogenes, Mycobacterium tuberculosis, Histoplasma capsulatum, viruses).
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Intracranial mass lesion (neoplasms, toxoplasmosis, TB).
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Pulmonary involvement confused with Pneumocystis jiroveci pneumonia when diffuse or confused with TB or bacterial pneumonia when focal or involving the pleura.
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Skin lesions can take many forms and may be confused with bacterial cellulitis or molluscum contagiosum.

Workup

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Lumbar puncture to exclude cryptococcal meningitis, with measurement of opening pressure because CSF opening pressure is elevated in 60% to 80% of HIV patients and may require drainage. In cryptococcal meningitis, CSF reveals lymphocytic pleocytosis (although a paucity of WBCs may be found in CSF of HIV patients).
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CT scan of the head when focal lesion or increased intracranial pressure is suspected.
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Biopsy of enlarged lymph nodes and skin lesions if feasible.

Laboratory Tests

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Culture and India ink stain (60% to 80% sensitive in culture-proven cases [Fig. E1]); examination of the CSF in all cases when CNS involvement is suspected.

FIG.E1

India ink preparation of cerebrospinal fluid revealing encapsulated cryptococci. Note the large capsules surrounding the smaller organisms.

From Andreoli TE [ed]: Cecil essentials of medicine, ed 4, Philadelphia, 1997, Saunders.
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Blood and serum cryptococcal antigen assay (>90% sensitivity and specificity in immunocompromised patients; lower sensitivity in immunocompetent patients).
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Culture and histologic examination of biopsy material.
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HIV antibody testing.

Imaging Studies

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CT scan or MRI of the head if focal neurologic involvement or cryptococcoma is suspected.
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Chest x-ray examination to exclude pulmonary involvement.

Treatment

Acute General Rx

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Treatment of cryptococcosis consists of three stages: induction, consolidation, and maintenance. Induction therapy for CNS disease (meningitis) was historically initiated with IV amphotericin B deoxycholate (0.7-1.0 mg/kg/day) with flucytosine 100 mg/kg/day PO in 4 divided doses; however, there is growing clinical evidence for liposomal amphotericin B (3-6 mg/kg/day) plus flucytosine, especially in HIV-infected patients and in those with renal dysfunction. Induction therapy is generally recommended for 2 to 4 weeks and until repeat CSF cultures are negative; it is then recommended to transition to consolidation therapy with fluconazole 400 mg PO q24h for 8 weeks, followed by ongoing fluconazole 200 mg PO q24h maintenance therapy (up to 2 years) to reduce relapse rate. Maintenance therapy is indicated in patients with AIDS until these patients have been receiving antifungal therapy for at least 1 year and they have responded to antiretroviral therapy (CD4 cell count ≥100/microliter for ≥3 months). In patients without HIV, the duration of maintenance therapy is generally 6 to 12 months. Lifelong antifungal therapy is needed in organ transplant patients.
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Alternative: IV fluconazole combined with flucytosine for initial therapy in patients unable to tolerate amphotericin B.
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If symptomatic increased intracranial pressure, consider multiple therapeutic lumbar taps or intraventricular shunt.
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Data support increased mortality with early initiation of antiretroviral therapy in the setting of cryptococcal meningitis due to immune reconstitution syndrome; therefore, it is generally recommended to wait 2 to 10 weeks after starting cryptococcal therapy prior to starting antiretroviral therapy.

Chronic Rx

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Fluconazole (200-400 mg PO qd) is highly effective in preventing a relapse in HIV-infected patients; development of resistance may occur. Itraconazole is an alternative agent, along with growing evidence for voriconazole and posaconazole use.

Disposition

Without maintenance therapy, relapse rate is >50% among AIDS patients.

Referral

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For consultation with infectious diseases specialist in all cases.
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For neurologic consultation if level of consciousness is depressed or focal lesion is present.

Ferri – Cryptococcosis