BASICS
DESCRIPTION
- There are over 30 different species of Cryptococcus, but 2 species cause nearly all cryptococcocal disease in humans-Cryptococcus neoformans and Cryptococcus gattii, (encapsulated yeasts). C. neoformans is the principal human pathogen:
- C. neoformans infection is more common in immunocompromised persons.
- Two varieties: C. neoformans var grubii, C. neoformans var neoformans
- C. gattii causes disease in otherwise healthy persons (1).
- Cryptococcus is found in the droppings of wild birds, often pigeons. Dust from the droppings (soil or vegetation) can infect humans (or pets) by inhalation.
- Infected humans and animals are not infectious.
- Primary route of infection is inhalation of spores, followed by hematogenous spread.
- Predisposition for nervous system and skin
- Can remain latent in the lungs for varying periods
- Cryptococcal meningitis is a common AIDS-defining infection in HIV-seropositive persons.
EPIDEMIOLOGY
- Predominant age: immunosuppressed adults
- Predominant sex: male > female (reflects HIV prevalence)
- Major disease burden in sub-Saharan Africa followed by South and Southeast Asia, Oceania, and Western and Central Europe. North Africa, Middle East, and North America are the regions with the fewest cases (2).
Incidence
- Incidence decreasing due to highly active antiretroviral therapy (HAART) for HIV in developed countries:
- 1 million new cases worldwide each year
- 600,000 deaths worldwide each year mostly in sub-Saharan Africa (500,000)
- 2-7% of opportunistic infections in AIDS patients
- 0.5-1% incidence among HIV-infected children in United States
- 0.4 to 1.3 cases per 100,000 people in the general population
Prevalence
- U.S. AIDS patients: 3%
- AIDS patients in developing world: up to 38%
- U.S. organ transplantation recipients: 3%
- Common in renal transplant patients
- Can be seen in extrathoracic sarcoidosis (3)[A]
ETIOLOGY AND PATHOPHYSIOLOGY
- Cryptococcus is found in pigeon droppings. Transmission is likely through exposure to contaminated soil or vegetation rather than direct exposure.
- Virulence factors: polysaccharide capsule and capacity for biofilm formation. Unencapsulated forms are readily phagocytosed. Polysaccharide capsule resists phagocytosis and inhibits leukocyte migration to areas of fungal replication.
RISK FACTORS
- Immunosuppression due to HIV disease (CD4 <100 cells/mm3)
- Immunosuppression from chronic steroid use or other medications (biologic agents)
- Organ transplant, malignancy, or sarcoidosis
GENERAL PREVENTION
- Early HAART in HIV-positive patients is the most important and cost-effective preventive strategy.
- Primary antifungal prophylaxis with fluconazole or itraconazole in patients with advanced HIV disease (CD4 <100 cells/mm3) decreases the incidence of cryptococcal disease. No overall mortality benefit has been demonstrated (4)[A].
- Fluconazole (200 mg/day) is effective as secondary antifungal prophylaxis after 10 weeks of induction and consolidation therapy. Itraconazole is inferior to fluconazole and should not be used to prevent relapse (4)[A].
COMMONLY ASSOCIATED CONDITIONS
HIV/AIDS
DIAGNOSIS
HISTORY
- Cryptococcal meningitis
- Insidious onset, subtle findings such as impaired mentation, lethargy, or memory loss in immunosuppressed patients
- Immunocompetent patients may have fluctuating symptoms over several months.
- Frontal or temporal headache (80-95%): more common in HIV-positive patients
- Fever (60-80%)
- Seizures or focal neurologic signs (less common)
- Meningismus/photophobia (absent in up to 40% of patients)
- Pulmonary cryptococcosis
- May be asymptomatic
- Cough, shortness of breath, hemoptysis, and fever are the most common symptoms.
- Disseminated cryptococcus
- Painless skin nodules (5-10%) mimic molluscum contagiosum.
- Cutaneous erythematous papules, vesicles, macules, or ulcers
- Skeletal involvement (bony pain) occurs in 5-10% of reported cases of disseminated cryptococcal infection.
- Heart, bone, kidney, adrenals, eyes, liver, prostate, and lymph nodes may harbor infection with symptoms referable to affected organ.
PHYSICAL EXAM
- Fever
- Focal neurologic signs
- Pulmonary signs (rales, rhonchi, wheeze)
- Altered mental status
- Skin nodules: flesh-colored, umbilicated, or erythematous papules, vesicles, or ulcers
DIFFERENTIAL DIAGNOSIS
- Central nervous system (CNS) disease
- Toxoplasmosis, lymphoma, AIDS dementia complex, progressive multifocal leukoencephalopathy, herpes encephalitis
- Pulmonary disease
- Tuberculosis (TB), Pneumocystis jiroveci, histoplasmosis, coccidioidomycosis, Kaposi sarcoma, lymphoma
- Lung lesions show high FDG (fluorodeoxyglucose) uptake on PET scan, simulating a possible malignancy.
- Disseminated disease
- TB, histoplasmosis, lymphoma
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
- Serum cryptococcal antigen
- If positive, perform lumbar puncture.
- Cerebrospinal fluid CSF) cryptococcal antigen
- >90% sensitivity with high titers
- India ink preparation of CSF
- 50% sensitive in immunocompetent patients, >75% sensitive in HIV-infected patients
- Fungal culture up to 90% sensitive
- Direct examination of urine is a noninvasive test to diagnose disseminated cryptococcosis, especially when used with techniques (nigrosine) that demonstrate capsule.
- Cryptococcal meningitis
- CT of brain is negative unless focal cryptococcal mass is present; helps exclude other mass lesions or HIV-related pathology
- Pulmonary cryptococcosis
- No specific features on chest x-ray; may appear as diffuse interstitial pneumonia with or without hilar adenopathy
Diagnostic Procedures/Other
- Lumbar puncture; radiographic imaging of the brain is recommended prior to initial lumbar puncture to rule out space-occupying lesion, particularly with impaired mentation or focal neurologic signs.
- Check opening CSF pressure; increased pressure associated with poor prognosis:
- In non-AIDS patients: elevated opening pressure, elevated CSF protein, decreased glucose, and lymphocytic pleocytosis
- In AIDS patients: CSF often shows minimal inflammation with normal glucose and protein, but uncontrolled fungal growth; high opening pressure (>25 cm H2O) in 70% of patients
- Skin biopsy may be diagnostic.
TREATMENT
MEDICATION
- Treat based on underlying immune status and disease stage.
- Treatment of Cryptococcus is recommended prior to initiating HAART therapy in HIV-infected patients to avoid immune reconstitution inflammatory syndrome (IRIS).
First Line
- Immunocompetent hosts with asymptomatic pulmonary or culture-positive non-CNS infection may be observed without medication.
- Immunocompetent and immunosuppressed adults with mild to moderate pulmonary disease should be treated with fluconazole (400 mg/day) PO for 6 to 12 months (4,5)[A].
- Immunocompetent adults with CNS disease should be treated with (5)[A]:
- Amphotericin B (AmB) deoxycholate (AmBd) (0.7 mg/kg/day) IV or
- Liposomal AmB (3 to 4 mg/kg/day) or
- AmB lipid complex (ABLC) plus
- Flucytosine (100 mg/kg/day PO) for 2 weeks followed by fluconazole (400 to 800 mg/day) for an additional 8 weeks
- Maintenance therapy with fluconazole (200 mg/day) for 6 to 12 months.
- HIV-infected adults with cryptococcal meningitis require three-step antifungal therapy (5)[A]:
- Induction therapy with liposomal AmB (3 to 4 mg/kg/day) or AmBd (0.7 mg/kg/day) IV plus flucytosine 100 mg/kg/day PO for 2 weeks
- Consolidation therapy with fluconazole (400 mg/day) PO or IV for at least 8 weeks; followed by
- Maintenance therapy with fluconazole (200 mg/day) PO for at least 1 year
- HAART therapy initiated 5 weeks after diagnosis-treatment is associated with significantly improved survival (6)[A].
- Liposomal AmB (3 to 4 mg/kg/day) is preferred over AmBd due to lowered nephrotoxicity (5)[A].
- Precautions:
- With AmB, permanent renal impairment, hypokalemia, or hypomagnesemia may occur. Flucytosine carries risk of serious bone marrow suppression. Fluconazole has been associated with hepatotoxicity.
- Fever, chills, and headache during infusion are possible. Pretreat with diphenhydramine (25 to 50 mg), acetaminophen (650 mg), or hydrocortisone (50 to 100 mg) 30 minutes before infusion (5)[A].
Second Line
- AmB formulations may be used alone for 4 to 6 weeks for induction and consolidation therapy (4,5)[A].
- Liposomal AmB (3 to 4 mg/kg/day) or AmBd (0.7 mg/kg/day) IV plus fluconazole (800 mg/day) PO or IV for 2 weeks, followed by fluconazole (800 mg/day) IV or PO for at least 8 weeks (5)[A],(4,7)[B]
- Fluconazole (800 to 1,200 mg/day) PO or IV + flucytosine (100 mg/kg/day) PO for 6 weeks followed by maintenance with azole
- Fluconazole (800 to 2,000 mg/day) PO for 10 to 12 weeks (5)[A]
- Itraconazole (400 mg/day) PO is an acceptable but less effective alternative to fluconazole for induction, consolidation, and maintenance therapy. Drug monitoring is strongly advised (4,5)[A].
ADDITIONAL THERAPIES
- Elevated intracranial pressures >250 mmH2O are common in patients with cryptococcal meningitis and increase mortality risk. Serial therapeutic lumbar punctures improve survival and are indicated until CSF opening pressure is normal (8)[A].
- Placement of a ventriculoperitoneal shunt may be required for persistent neurologic symptoms or persistently elevated intracranial pressures.
- Corticosteroids and acetazolamide are not recommended for reducing intracranial pressure in patients without signs of IRIS (4)[A].
- TREATMENT IN PREGNANCY
- Disseminated and CNS disease, use liposomal AmB, with or without flucytosine (Category C)
- Start fluconazole after delivery.
- For limited and stable pulmonary cryptococcosis, follow closely and administer fluconazole after delivery.
- Watch for IRIS in the postpartum period (5)[A].
SURGERY/OTHER PROCEDURES
Surgery may be required for persistent pulmonary or bone disease but is rarely needed. Recommend infectious disease consultation.
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
- In immunosuppressed patients with cryptococcal meningitis, lifelong secondary prophylaxis is generally required for suppression:
- Without suppression, relapse is common (50% in AIDS patients within 1 year).
- Fluconazole (200 mg/day) or itraconazole (400 mg/day) for suppression
- May consider discontinuing suppressive antifungal therapy when patient responds to antiretroviral therapy with CD4 count >100 cells/mm3 for >3 months but must restart suppressive antifungal therapy if CD4 cell count decreases to <100 cells/mm3 (5)[A]
- Primary prophylaxis or screening for serum CrAg is not recommended for either asymptomatic adults or children (4)[A].
PROGNOSIS
Case fatality rate of cryptococcal meningitis:
- 35-70% in Asia and sub-Saharan Africa
- 10-20% in most developed countries
COMPLICATIONS
Meningitis and increased intracranial pressure causes significant morbidity and mortality.
REFERENCES
11 Velagapudi R, Hsueh YP, Geunes-Boyer S, et al. Spores as infectious propagules of Cryptococcus neoformans. Infect Immun. 2009;77(10):4345-4355.22 Park BJ, Wannemuehler KA, Marston BJ, et al. Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS. AIDS. 2009;23(4):525-530.33 Bernard C, Maucort-Boulch D, Varron L, et al. Cryptococcosis in sarcoidosis: cryptOsarc, a comparative study of 18 cases. QJM. 2013;106(6):523-539.44 Masur H, Brooks JT, Benson CA, et al. Prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: updated guidelines from the Centers for Disease Control and Prevention, National Institutes of Health, and HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis. 2014;58(9):1308-1311.55 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):291-322.66 Boulware DR, Meya DB, Muzoora C, et al. Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis. N Engl J Med. 2014;370(26): 2487-2498.77 Pappas PG, Chetchotisakd P, Larsen RA, et al. A phase II randomized trial of amphotericin B alone or combined with fluconazole in the treatment of HIV associated cryptococcal meningitis. Clin Infect Dis. 2009;48(12):1775-1783.88 Rolfes MA, Hullsiek KH, Rhein J, et al.The effect of therapeutic lumbar punctures on acute mortality from cryptococcal meningitis. Clin Infect Dis. 2014;59(11):1607-1614.
ADDITIONAL READING
- Antinori S. New insights into HIV/AIDS-associated cryptococcosis. ISRN AIDS. 2013;2013:471363.
- Gullo FP, Rossi SA, Sardi Jde C, et al. Cryptococcosis: epidemiology, fungal resistance, and new alternatives for treatment. Eur J Clin Microbiol Infect Dis. 2013;32(11):1377-1391.
- Pappas PG, Alexander BD, Andes DR, et al. Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET). Clin Infect Dis. 2010;50(8):1101-1111.
SEE ALSO
HIV/AIDS
CODES
ICD10
- B45.9 Cryptococcosis, unspecified
- B45.1 Cerebral cryptococcosis
- B45.0 Pulmonary cryptococcosis
- B45.2 Cutaneous cryptococcosis
- B45.3 Osseous cryptococcosis
- B45.7 Disseminated cryptococcosis
- B45.8 Other forms of cryptococcosis
ICD9
- 117.5 Cryptococcosis
- 321.0 Cryptococcal meningitis
SNOMED
- Cryptococcosis (disorder)
- Cryptococcal meningitis (disorder)
- Pulmonary cryptococcosis (disorder)
- Cryptococcosis associated with AIDS (disorder)
- Osseous cryptococcosis (disorder)
- Mucocutaneous cryptococcosis (disorder)
CLINICAL PEARLS
- Cryptococcal meningitis is not spread from person to person.
- Skin nodules imply disseminated disease; look for CNS and pulmonary involvement and treat accordingly.
- Up to 15% of HIV-positive patients have no headache with cryptococcal meningitis and may present solely with altered mental status or skin findings.
- Always measure CSF opening pressure when performing LP as part of evaluation for cryptococcal meningitis.
- Treat Cryptococcus prior to initiating HAART in HIV-infected patients to avoid complications associated with immune reconstitution inflammatory syndrome (IRIS).