Cryptococcosis

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Cryptococcosis

BASICS

DESCRIPTION

Surgery may be required for persistent pulmonary or bone disease but is rarely needed. Recommend infectious disease consultation.

Case fatality rate of cryptococcal meningitis:

Meningitis and increased intracranial pressure causes significant morbidity and mortality.

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.

• 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 neoformansC. 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.

• 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).

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 decreasing due to highly active antiretroviral therapy (HAART) for HIV in developed countries:1 million new cases worldwide each year600,000 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

• 1 million new cases worldwide each year
• 600,000 deaths worldwide each year mostly in sub-Saharan Africa (500,000)

• 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

DIAGNOSIS

HISTORY

• Cryptococcal meningitisInsidious onset, subtle findings such as impaired mentation, lethargy, or memory loss in immunosuppressed patientsImmunocompetent patients may have fluctuating symptoms over several months.Frontal or temporal headache (80-95%): more common in HIV-positive patientsFever (60-80%)Seizures or focal neurologic signs (less common)Meningismus/photophobia (absent in up to 40% of patients)
• Pulmonary cryptococcosisMay be asymptomaticCough, shortness of breath, hemoptysis, and fever are the most common symptoms.
• Disseminated cryptococcusPainless skin nodules (5-10%) mimic molluscum contagiosum.Cutaneous erythematous papules, vesicles, macules, or ulcersSkeletal 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.

• 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)

• May be asymptomatic
• Cough, shortness of breath, hemoptysis, and fever are the most common symptoms.

• 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.

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) diseaseToxoplasmosis, lymphoma, AIDS dementia complex, progressive multifocal leukoencephalopathy, herpes encephalitis
• Pulmonary diseaseTuberculosis (TB), Pneumocystis jiroveci, histoplasmosis, coccidioidomycosis, Kaposi sarcoma, lymphomaLung lesions show high FDG (fluorodeoxyglucose) uptake on PET scan, simulating a possible malignancy.
• Disseminated diseaseTB, histoplasmosis, lymphoma

• Toxoplasmosis, lymphoma, AIDS dementia complex, progressive multifocal leukoencephalopathy, herpes encephalitis

• Tuberculosis (TB), Pneumocystis jiroveci, histoplasmosis, coccidioidomycosis, Kaposi sarcoma, lymphoma
• Lung lesions show high FDG (fluorodeoxyglucose) uptake on PET scan, simulating a possible malignancy.

• TB, histoplasmosis, lymphoma

DIAGNOSTIC TESTS & INTERPRETATION

• Serum cryptococcal antigenIf positive, perform lumbar puncture.
• Cerebrospinal fluid CSF) cryptococcal antigen>90% sensitivity with high titers
• India ink preparation of CSF50% 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 meningitisCT of brain is negative unless focal cryptococcal mass is present; helps exclude other mass lesions or HIV-related pathology
• Pulmonary cryptococcosisNo specific features on chest x-ray; may appear as diffuse interstitial pneumonia with or without hilar adenopathy

• If positive, perform lumbar puncture.

• >90% sensitivity with high titers

• 50% sensitive in immunocompetent patients, >75% sensitive in HIV-infected patients

• CT of brain is negative unless focal cryptococcal mass is present; helps exclude other mass lesions or HIV-related pathology

• No specific features on chest x-ray; may appear as diffuse interstitial pneumonia with or without hilar adenopathy

• 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 pleocytosisIn 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.

• 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

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).

• 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 orLiposomal AmB (3 to 4 mg/kg/day) orAmB lipid complex (ABLC) plusFlucytosine (100 mg/kg/day PO) for 2 weeks followed by fluconazole (400 to 800 mg/day) for an additional 8 weeksMaintenance 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 weeksConsolidation therapy with fluconazole (400 mg/day) PO or IV for at least 8 weeks; followed byMaintenance therapy with fluconazole (200 mg/day) PO for at least 1 yearHAART 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].

• 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.

• 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].

• 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].

• 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 PREGNANCYDisseminated 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].

• 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

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

• 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 suppressionMay 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].

• 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]

PROGNOSIS

• 35-70% in Asia and sub-Saharan Africa
• 10-20% in most developed countries

COMPLICATIONS

REFERENCES

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

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).