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Anicryptococcal Infections, Pediatric

Samir S. Shah Reviewed 05/2014



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Subject: Anicryptococcal Infections, Pediatric

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Cryptococcosis, an opportunistic fungal infection caused by Cryptococcus neoformans, may involve several organ systems, including the CNS, lungs, bones, visceral organs, and skin. 


  • 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.

  • There is no person-to-person spread of the infection.


  • 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 their lower exposure to sources of Cryptococcus neoformans. The overall seroprevalence is 0% in neonates and 4.1% in school-age children, compared to 69% in adults.

  • 1–3% of solid-organ transplant recipients develop Cryptococcus neoformans infections; typically >1 year after transplantation.

General Prevention

  • Most studies on prevention address HIV-infected patients.

  • Use of highly active antiretroviral therapy (HAART) prevents most cases of cryptococcosis in HIV-infected patients.

  • Primary prophylaxis with fluconazole prevents new-onset cryptococcal disease in HIV-infected patients. However, primary prophylaxis is not routinely recommended except for those with limited access to HAART and those 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 rates are 100% without maintenance antifungal therapy, 18–25% with amphotericin B or itraconazole, and 2–3% with fluconazole.

    • Prophylaxis may be discontinued in patients receiving HAART with CD4+ lymphocytes >100/mm3 and undetectable viral loads.

  • 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/d) for at least 1 year after the completion of acute treatment and then reassess its ongoing use based on the level of current immunosuppression.


  • Primary infection occurs through the inhalation of aerosolized soil particles containing the yeast forms. The skin and gastrointestinal tract are also portals of entry.

  • Protective immune response requires specific T-cell–mediated immunity.

  • CNS infection with Cryptococcus neoformans results from hematogenous dissemination.

Associated Conditions

  • Cryptococcus neoformans is the most common cause of fungal meningitis in the US.

  • Disseminated infection occurs more commonly among immunocompromised hosts.

  • Concurrent Pneumocystis carinii 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, 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. 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 on the body, but are found most often on the face and neck.

    • Mucocutaneous findings are present in 10–15% of cases of disseminated disease.



  • Lumbar puncture: Diagnose cryptococcal meningitis:

    • CSF should be sent for cell count and differential; protein; glucose; cultures for bacterial, fungal, and viral pathogens; and cryptococcal antigen (India ink stain is less commonly performed).

    • 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.

    • Budding yeast are seen on India ink stain in 50% of cases.

    • CSF cultures are positive in ∼90% of patients.

    • 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 (to exclude the presence of rheumatoid factor or other nonspecific agglutinins) 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 Cryptococcus 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 >85% 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 x-rays (anteroposterior and lateral): 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.

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 and Mycobacterium tuberculosis

  • Pneumonia: Other pulmonary mycoses, including aspergillosis, histoplasmosis, and blastomycosis. Also consider Mycoplasma pneumoniae and Mycobacterium tuberculosis.

  • Bone: Osteogenic sarcoma

  • Cutaneous: Molluscum contagiosum, herpes simplex virus infection, pyoderma gangrenosum, and cellulitis


Additional Treatment

General Measures

  • 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 6–12 mg/kg/d PO (max 400 mg) for 6–12 months for mild/moderate disease. Alternate regimen: Itraconazole 4–10 mg/kg/d PO (max 400 mg) for 6–12 months (monitor drug levels); or amphotericin B 0.7–1 mg/kg/d PO for 3–6 months.

    • Same as CNS for severe disease

    • Maintenance therapy with fluconazole should be considered for immunocompromised patients (see “Prevention”).

  • CNS, HIV-negative, non-transplant:

    • Induction/consolidation: Amphotericin B (0.7–1 mg/kg/d) plus flucytosine (100–150 mg/kg/d PO, divided q6h) for 4 weeks, then fluconazole PO (10–12 mg/kg/d) for a minimum of 8 weeks followed by maintenance therapy with fluconazole PO (6 mg/kg/d) for 6–12 months. Alternate induction/consolidation regimen: Amphotericin B plus flucytosine for 6–10 weeks.

  • Pulmonary and extrapulmonary disease, HIV-infected, or transplant:

    • Fluconazole (PO) 6–12 months for mild/moderate disease; same as CNS infection for severe disease.

    • Consider surgical débridement for patients with persistent or refractory pulmonary or bone lesions.

  • CNS disease, HIV-infected or transplant:

    • Induction/consolidation: Amphotericin B (IV) plus flucytosine (PO) for at least 2 weeks, followed by fluconazole PO (10–12 mg/kg/d) for at least 8 weeks; consider subsequent suppressive therapy with fluconazole PO (6 mg/kg/d)

    • 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/d) or amphotericin B lipid complex (5 mg/kg/d) IV may be substituted for amphotericin B, especially in patients with pre-existing 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 new triazole antifungal agent, demonstrates excellent in vitro activity against Cryptococcus neoformans but requires clinical study. Caspofungin, a new echinocandin antifungal agent, is not active against Cryptococcus neoformans.

Ongoing Care

Follow-Up Recommendations

Patient Monitoring

  • Because of the risk of relapse, patients should be seen at 3-month intervals for 12–18 months following treatment. Immunocompromised patients should be evaluated every 2–3 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 “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 Cryptococcus 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 “Prevention”).


  • Elevated intracranial pressure with meningitis.

  • Pulmonary, cutaneous, and bone involvement may occur (see “Associated Conditions”).

  • In solid-organ transplant patients, those receiving tacrolimus immunosuppression are less likely to have CNS involvement and more likely to have skin, soft tissue, or osteoarticular involvement.

Additional Reading

Gonzalez CE, Shetty D, Lewis LL. Cryptococcosis in human immunodeficiency virus-infected children. Pediatr Infect Dis J.  1996;15:796–800.  [View Abstract]
Joshi NS, Fisher BT, Prasad PA. Epidemiology of cryptococcal infection in hospitalized children. Pediatr Infect Dis J.  2010;29:e91–e95.  [View Abstract]
Pappas PG, Perfect JR, Cloud GA. Cryptococcosis in human immunodeficiency virus-negative patients in the era of effective azole therapy. Clin Infect Dis.  2001;33:690–699.  [View Abstract]
Perfect JR, Dismukes WE, Dromer F Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis.  2010;50:291–322.  [View Abstract]



  • 117.5 Cryptococcosis

  • 321.0 Cryptococcal meningitis


  • B45.1 Cerebral cryptococcosis

  • B45.9 Cryptococcosis, unspecified


  • 42386007 cryptococcosis (disorder)

  • 14232007 Cryptococcal meningitis (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 be evaluated for immunodeficiency?

  • A: Yes.