Cryptococcal Infections



Cryptococcosis is an opportunistic fungal infection caused by Cryptococcus neoformans that may involve several organ systems, including the CNS, lungs, bones, visceral organs, and skin. Cryptococcus gattii is a less common human pathogen.


  • Most pediatric infections occur in immunocompromised hosts, including those with malignancy, HIV, and solid organ or bone marrow transplantation.
  • 20% of infections requiring hospitalization occur in normal hosts.
  • Occurs in 5–15% of HIV-infected adults, usually with CD4+ lymphocyte counts <50 cells/mm3; occurs in 0.8–2.3% of HIV-infected children. The lower infection rate in children reflects lower exposure to sources of C. neoformans. Seroprevalence varies by age: neonates, 0%; school-aged children, 4.1%; and adults, 69%.
  • 1–3% of solid organ transplant recipients develop C. neoformans infections, typically >1 year after transplantation. It is the third most common invasive fungal infection in these patients.

General Prevention

  • Use of highly active antiretroviral therapy (HAART) prevents most cases of cryptococcosis in HIV-infected patients. Incidence remains high in developing countries.
  • Primary prophylaxis with fluconazole prevents new-onset cryptococcal disease in HIV-infected patients but is not routinely recommended except for those with limited access to HAART and with high levels of antiretroviral drug resistance.
  • Maintenance (suppressive) therapy after completion of therapy for cryptococcal infection is recommended for HIV-infected patients. In those with low CD4+ lymphocyte counts, relapse is 100% without maintenance antifungal therapy, 18–25% with amphotericin B or itraconazole, and 2–3% with fluconazole.
    • Prophylaxis may be discontinued in asymptomatic children 6 years or older receiving HAART with CD4+ lymphocytes >100/mm3 and undetectable viral loads for at least 3 months.
  • There is no consensus on the duration of fluconazole suppressive therapy after treatment of cryptococcosis in HIV-negative immunocompromised patients. Most experts provide maintenance (suppressive) antifungal therapy with fluconazole PO (6 mg/kg/24 hr) for at least 1 year after the completion of acute treatment and then reassess ongoing use based on the level of immunosuppression.


  • Primary infection occurs through the inhalation of aerosolized soil particles containing the yeast forms. The skin and GI tract are also portals of entry.
  • Protective immune response requires specific T cell–mediated immunity.
  • CNS infection with C. neoformans results from hematogenous dissemination.

Commonly Associated Conditions

  • C. neoformans is the most common cause of fungal meningitis in the United States.
  • Dissemination is rare in immunocompetent patients.
  • Concurrent Pneumocystis jiroveci pneumonia was detected in 13% of adults with cryptococcal meningitis.
  • Pulmonary involvement is asymptomatic in up to 50% of cases, and disease may be either focal or widespread.
  • Bone involvement occurs in 10% of cases of disseminated cryptococcal infection.
  • Cutaneous involvement mimics acne-type eruptions that ulcerate and results from hematogenous spread of the organism or from direct extension of bone infection.



  • Cryptococcal meningitis may present as either an indolent infection or acute illness.
  • Symptoms of cryptococcal meningitis include headache, malaise, and low-grade fever. Nausea, vomiting, altered mentation (including behavioral changes), and photophobia are less common. Stiff neck, focal neurologic symptoms (e.g., decreased hearing, facial nerve palsy, or diplopia), and seizures are rare.
  • Primary pulmonary cryptococcal disease is not well described in children because most cases are disseminated at the time of diagnosis. 50% of adults have cough or chest pain, and fewer have sputum production, weight loss, fever, and hemoptysis.
  • In immunocompromised hosts, the onset of infection is more rapid and the course more severe. Pulmonary involvement is minimal when dissemination occurs quickly.

Physical Exam

  • None of the presenting signs of cryptococcal infection are sufficiently characteristic to distinguish it from other infections, particularly in immunocompromised patients.
  • CNS involvement: nuchal rigidity, photophobia, and focal neurologic deficits
  • Respiratory tract involvement: cough, tachypnea, grunting, and subcostal or intercostal retractions. May present as acute respiratory distress syndrome. Decreased breath sounds or dullness to percussion may be present, or the lung exam may be normal.
  • Cutaneous manifestations: erythematous or verrucous papules, nodules, pustules, acneiform lesions, ulcers, abscesses, or granulomas. Lesions can occur anywhere but are found most often on the face and neck.
    • Mucocutaneous findings are present in 10–15% of cases of disseminated disease.

Differential Diagnosis

  • Although cryptococcosis occurs most commonly in HIV-infected patients with low CD4+ lymphocyte counts, the diagnosis warrants consideration in all febrile immunocompromised children (e.g., solid organ transplant, leukemia).
  • Meningitis: viruses, Mycobacterium tuberculosis, and other fungal causes
  • Pneumonia: other pulmonary mycoses, including aspergillosis, histoplasmosis, and blastomycosis; also consider Mycoplasma pneumoniae and M. tuberculosis.
  • Bone: osteogenic sarcoma
  • Cutaneous: molluscum contagiosum, herpes simplex virus infection, pyoderma gangrenosum, and cellulitis

Diagnostic Tests and Interpretation

Initial Tests

  • There are many excellent rapid diagnostic tests for suspected cryptococcal meningitis available, although a large quantity of CSF may be needed as specimens may contain only a few organisms.
  • Lumbar puncture: to diagnose cryptococcal meningitis
    • Opening pressures should be obtained if possible, to assess for increased intracranial pressure. Patients with signs and symptoms consistent with increased pressures may require repeat therapeutic lumbar punctures.
    • CSF should be sent for cell count and differential; protein; glucose; bacterial and fungal cultures; and cryptococcal antigen. Consider herpes simplex virus (HSV) or other viral PCR tests.
    • Examination of the CSF reveals <500 WBC/mm3 (usually <100 WBC/mm3), mostly mononuclear leukocytes, with minimal changes in protein. CSF glucose is <50 mg/dL in ~65% of patients.
    • India ink stain (less commonly performed) shows budding yeast in 50% of cases.
    • CSF cultures are positive in ~90% of cases.
    • The latex agglutination test for cryptococcal polysaccharide antigen is specific, sensitive, and rapid. Titers ≥1:4 suggest the diagnosis of cryptococcal infection if appropriate controls are negative.
    • HIV-infected patients with pneumonia and CD4+ T-lymphocyte counts <200 cells/mm3 should be evaluated with sputum fungal culture, blood fungal culture, and a serum cryptococcal antigen test. A lumbar puncture to exclude the possibility of occult meningitis should be considered. If any test is positive for C. neoformans, then a lumbar puncture should be performed to exclude cryptococcal meningitis.
  • Blood culture and serum cryptococcal antigen titers: diagnose disseminated cryptococcal infection. Serum cryptococcal antigen tests are positive in >90% of patients with cryptococcal meningitis.
  • Sputum culture: diagnose cryptococcal pneumonia
  • Skin or bone biopsy: diagnose cutaneous or osteoarticular cryptococcal infection
  • HIV testing: Evaluation for immunodeficiencies, including HIV, is warranted in any patient with cryptococcosis.
  • CBC with differential: may reveal hypereosinophilia (absolute eosinophil count >1,500/mm3)
  • Serum electrolytes: detect hyponatremia, a complication of cryptococcal meningitis
  • Chest radiographs: Focal or solitary nodules, diffuse infiltrates, and pleural effusions may be seen in cryptococcal pneumonia.
  • Head CT or MRI: may demonstrate granulomatous lesions (cryptococcomas; ~15% of patients with meningitis) or elevated intracranial pressure. MRI reveals dilation of perivascular spaces in almost half the cases.


  • Clinical management depends on extent of disease and immune status of the host.
  • Pulmonary and extrapulmonary disease (HIV-negative, nontransplant)
    • Normal hosts with isolated pulmonary nodules may not need treatment if the serum cryptococcal antigen is negative and the patient is asymptomatic.
    • Patients with symptoms, extensive pulmonary disease, or evidence of extrapulmonary disease require treatment.
    • Fluconazole 6 to 12 mg/kg/24 h PO (max 400 mg) for 6 to 12 months for mild/moderate disease; alternate regimen: itraconazole 5 to 10 mg/kg/24 h PO (max 400 mg) for 6 to 12 months (steady-state trough level >1 mcg/mL and ≤10 mcg/mL) or amphotericin B 0.7–1 mg/kg/24 h IV for 3 to 6 months
    • Severe disease: same as CNS (see below)
    • Maintenance therapy with fluconazole should be considered for immunocompromised patients (see “General Prevention”).
  • Pulmonary and extrapulmonary disease (HIV-infected or transplant)
    • Fluconazole (PO) 6 to 12 months for mild/moderate disease; same as CNS infection for severe disease
    • Consider surgical debridement for patients with persistent or refractory pulmonary or bone lesions.
  • CNS disease (HIV-negative, nontransplant)
    • Induction/consolidation: amphotericin B (1 mg/kg/24 h) plus flucytosine (100 mg/kg/24 h PO, divided q6h; therapeutic levels: 30 to 80 mcg/mL) for 2 weeks and then fluconazole PO (10 to 12 mg/kg/day, max 800 mg daily dose) for a minimum of 8 weeks or until CSF is sterile. Alternate induction/consolidation regimen: amphotericin B plus flucytosine for 6 to 10 weeks. Additional regimens are available for children with renal impairment, less severe disease, or in children who do not tolerate flucytosine.
  • CNS disease (HIV-infected or transplant)
    • Recommendations for treatment of cryptococcal infections in HIV-positive children are largely extrapolated from adult studies.
    • Induction/consolidation: amphotericin B (IV) plus flucytosine (PO) for at least 2 weeks, followed by fluconazole PO (10 to 12 mg/kg/day) for at least 8 weeks; consider subsequent long-term suppressive therapy with fluconazole PO (6 mg/kg/24 h).
    • Intrathecal amphotericin B is very toxic but may be used in refractory cases.
    • HIV-infected patients require continuation of antifungal drugs indefinitely because of the high recurrence rate of cryptococcosis.
    • Liposomal amphotericin (5 mg/kg/24 h) or amphotericin B lipid complex (5 mg/kg/24 h) IV may be substituted for amphotericin B, especially in patients with renal dysfunction and those receiving calcineurin inhibitors.
    • Flucytosine is used only in combination with amphotericin B and not as a single agent because of the rapid emergence of drug resistance.
  • Voriconazole, a triazole antifungal agent, demonstrates excellent in vitro activity against C. neoformans but requires clinical study.
  • Caspofungin, an echinocandin antifungal agent, is not active against C. neoformans.

Ongoing Care

Follow-Up Recommendations

Patient Monitoring

  • Because of the risk of relapse, patients should be seen at 3-month intervals for 12 to 18 months following treatment. Immunocompromised patients should be evaluated every 2 to 3 months, even while on suppressive therapy, to monitor clinically for relapse.
  • Repeat lumbar punctures documenting a decrease in CSF cryptococcal antigen and sterility of culture are useful in evaluating response to treatment. During therapy for acute meningitis, an unchanged or increased titer of CSF antigen correlates with clinical and microbiologic failure to respond to treatment. Serum antigen titers are not helpful for this purpose.
  • Evaluate patients with cryptococcal meningitis for neurologic sequelae.
  • HIV-infected patients require suppressive antifungal therapy (see “General Prevention”).


  • Mortality is rare in patients with isolated pulmonary or cutaneous disease.
  • In-hospital, mortality is ~20% for cryptococcal meningitis and ~8% for non-CNS cryptococcal infections.
    • In normal hosts with meningitis, poor prognostic factors include serum or CSF cryptococcal titers >1:32 or CSF WBC <20/mm3.
    • In HIV-infected patients with meningitis, poor prognostic factors include hyponatremia, concomitant growth of C. neoformans from another site, increased intracranial pressure, and any alteration of mental status.
  • Up to 40% of patients with cryptococcal meningitis have residual neurologic deficits.
  • Relapse rates are high in HIV-infected patients (see “General Prevention”).


  • Elevated intracranial pressure with meningitis
  • Pulmonary, cutaneous, and bone involvement may occur (see “Commonly Associated Conditions“).
  • In solid organ transplant patients, tacrolimus recipients are less likely to have CNS involvement and more likely to have skin, soft tissue, or osteoarticular involvement.
  • Cryptococcal immune reconstitution inflammatory syndrome (C-IRIS) may lead to a new presentation of the disease and/or a clinical deterioration after reversal of a host immune deficiency state, often weeks to months after initiating therapy. Cases have been described in children, but most information comes from the adult literature. The most common presentation is mediastinal lymphadenitis.

Additional Reading

  1. Joshi NS, Fisher BT, Prasad PA, et al. Epidemiology of cryptococcal infection in hospitalized children. Pediatr Infect Dis J. 2010;29(12):e91–e95.  [PMID:20935590]
  2. Pappas PG, Perfect JR, Cloud GA, et al. Cryptococcosis in human immunodeficiency virus-negative patients in the era of effective azole therapy. Clin Infect Dis. 2001;33(5):690–699.  [PMID:11477526]
  3. 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.  [PMID:20047480]
  4. U.S. Department of Health and Human Services. Panel on Opportunistic Infections in HIV-Exposed and HIV-Infected Children. Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Exposed and HIV-Infected Children. Rockville, MD: U.S. Department of Health and Human Services; 2013. Accessed February 27,2018.



117.5 Cryptococcosis


  • B45.9 Cryptococcosis, unspecified
  • B45.0 Pulmonary cryptococcosis
  • B45.8 Other forms of cryptococcosis
  • B45.1 Cerebral cryptococcosis
  • B45.3 Osseous cryptococcosis
  • B45.7 Disseminated cryptococcosis


  • 42386007 Cryptococcosis (disorder)
  • 20953001 Pulmonary cryptococcosis (disorder)
  • 406569004 Cryptococcus infection of the central nervous system
  • 283688006 Osseous cryptococcosis (disorder)
  • 240725003 Disseminated cryptococcosis (disorder)
  • 187091009 Systemic cryptococcosis (disorder)


  • Q: What are the sources of Cryptococcus in nature?
  • A: Pigeon droppings and soil. Naturally acquired infections occur in lower mammals, especially cats. However, neither animal-to-human nor human-to-human infections have been reported.
  • Q: Should all children with Cryptococcus infection be evaluated for immunodeficiency?
  • A: Yes, most cases of symptomatic cryptococcal infections are related to a defect in T cell–mediated immunity.
  • Q: Are repeat assessments of CSF necessary in cryptococcal meningoencephalitis?
  • A: Yes, to prove achievement of sterility and guide length of treatment.


Eric S. Kirkendall, MD, MBI, FAAP

Samir S. Shah, MD, MSCE

© Wolters Kluwer Health Lippincott Williams & Wilkins