Diseases » Cryptococcal Meningitis

Cryptococcal Infections

Cryptococcal Infections: Excerpt from The 5-Minute Pediatric Consult

Samir S. Shah, MD

Cryptococcal Infections - BASICS

Cryptococcal Infections - description

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

Cryptococcal Infections - general prevention

• The dramatic reduction of cryptococcal infections since the introduction of highly active antiretroviral therapy (HAART) suggests that the best prophylaxis for cryptococcosis is effective treatment of human immunodeficiency virus (HIV).
• In HIV-infected patients 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.
  • Some studies of HIV-infected adults suggest that prophylaxis may be safely discontinued in patients receiving HAART with CD4+ lymphocyte counts >100/mm³ and undetectable viral loads.
• Prophylaxis with fluconazole is also effective in preventing new-onset cryptococcal disease. Cryptococcal meningitis occurred once (0.4%) among 231 HIV-infected children receiving fluconazole 200 mg 3 times a week.
• There is no consensus on the duration of fluconazole therapy after acute therapy in HIV-negative immunocompromised patients. Most experts provide suppressive antifungal therapy for at least 1 year after the completion of acute treatment and then reassess its ongoing use based on the level of current immunosuppression.

Cryptococcal Infections - epidemiology

• Infection occasionally occurs in normal hosts.
• There is no person-to-person spread of the infection.

Cryptococcal Infections - incidence

• Occurs in 5–15% of HIV-infected adults, usually with CD4+ lymphocyte counts <50 cells/mm³. It is less common in human immunodeficiency virus-infected children, occurring in 0.8–2.3% of cases. The 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.

Cryptococcal Infections - pathophysiology

• 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 with Cryptococcus neoformans results from hematogenous dissemination.

Cryptococcal Infections - 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 Infections - DIAGNOSIS

Cryptococcal Infections - signs & symptoms

Cryptococcal Infections - history

• 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.

Cryptococcal Infections - 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.

Cryptococcal Infections - tests

Cryptococcal Infections - lab

• Lumbar puncture: Diagnose cryptococcal meningitis:
  • CSF should be sent for cell count and differential; protein; glucose; cultures for bacterial, fungal, and viral pathogens; India ink stain; and cryptococcal antigen.
  • 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.
• 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.

Cryptococcal Infections - imaging

• Chest x-rays (anteroposterior and lateral): Nodules, diffuse infiltrates, and pleural effusions may be seen in cryptococcal pneumonia.
• Head CT: May demonstrate granulomatous lesions or elevated intracranial pressure

Cryptococcal Infections - differencial 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 patients)
• Meningitis: Viruses and Mycobacterium tuberculosis
• Pneumoni: 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

Cryptococcal Infections - TREATMENT

Cryptococcal Infections - general measures

• Clinical management depends on extent of disease and immune status of the host.
• Pulmonary and extrapulmonary disease, HIV-negative:
  • A normal host with isolated pulmonary nodules does not need treatment if the serum cryptococcal antigen is negative and the patient is asymptomatic.
  • Patients with extensive pulmonary disease or evidence of extrapulmonary disease require treatment.
  • Fluconazole 6–12 mg/kg/d PO (max. 400 mg) for 6–12 months. Alternate regimen: Itraconazole 4–10 mg/kg/d PO (max. 400 mg) for 6–12 months; or amphotericin B 0.7–1 mg/kg/d PO for 3–6 months.
  • HIV-negative, immunocompromised hosts with pulmonary or extrapulmonary disease and those with severe symptoms are treated with amphotericin B in the same fashion as patients with CNS disease.
  • Because of the high rate of relapse in immunocompromised patients, maintenance therapy with fluconazole should continue as long as the patient is immunocompromised (see “Prevention”).
• CNS, HIV-negative:
  • Induction/consolidation: Amphotericin B plus flucytosine 100–150 mg/kg/d PO, divided q6h for 2 weeks, then fluconazole PO (see above for dosing) for a minimum of 10 weeks. Alternate regimen: Amphotericin B plus flucytosine for 6–10 weeks.
• Pulmonary and extrapulmonary disease, human immunodeficiency virus-infected:
  • Fluconazole (PO) lifelong
  • Alternate regimen: Itraconazole (PO) lifelong
  • Consider surgical débridement for patients with persistent or refractory pulmonary or bone lesions.
• CNS disease, HIV-infected:
  • Induction/consolidation: Amphotericin B (IV) plus flucytosine (PO) for at least 2 weeks, followed by fluconazole PO lifelong
  • Alternate regimen: Fluconazole plus flucytosine for 6 weeks, followed by fluconazole or itraconazole lifelong (see above for dosing)
  • 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.
  • Lipid formulation of amphotericin B 3–6 mg/kg/d IV may be substituted for amphotericin B.
  • Flucytosine is used only in combination with amphotericin B and not as a single agent because of the rapid emergence of drug resistance.
  • Itraconazole for IV administration is available, but there are insufficient data to guide its current use. 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.
  • Adjunctive therapy with recombinant interferon gamma-1b promising but still considered experimental for patients with cryptococcal meningitis.

Cryptococcal Infections - FOLLOW UP

Cryptococcal Infections - prognosis

• Survival is good with early treatment but, in HIV-infected patients, relapse rates are high (see “Prevention”).
• Up to 40% of patients with cryptococcal meningitis have residual neurologic deficits.
• In the normal host with cryptococcal meningitis, patients with serum or CSF cryptococcal titers >1:32 or CSF WBC <20/mm³ have a worse prognosis. In HIV-infected patients, it is unclear whether the magnitude of titers affects outcome.
• In HIV-infected patients with cryptococcal meningitis, poor prognostic factors include the presence of hyponatremia, concomitant growth of Cryptococcus neoformans from another site, increased intracranial pressure, and any alteration of mental status.
• In solid organ transplant and hematologic malignancy patients with cryptococcal meningitis, mortality is ~10%.
• Patients with isolated pulmonary or cutaneous disease have a favorable prognosis.

Cryptococcal Infections - complications

• CNS involvement occurs in ~3/4 of patients.
• 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.

Cryptococcal Infections - patient monitoring

• Because of the risk of relapse, follow-up is very important. Patients should be seen at 3-month intervals for 12–18 months following treatment, with cultures obtained for fungal isolation. 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 lifelong suppressive antifungal therapy (see “Prevention”)

Cryptococcal Infections - bibliography

1. Gonzalez CE, Shetty D, Lewis LL, et al. Cryptococcosis in human immunodeficiency virus-infected children. Pediatr Infect Dis J. 1996;15:796–800.
2. Husain S, Wagener MM, Singh N. Cryptococcus neoformans infection in organ transplant recipients: Variables influencing clinical characteristics and outcome. Emerg Infect Dis. 2001;7:375–381.
3. Powderly WG, Cloud GA, Dismukes WE, et al. Measurement of cryptococcal antigen in serum and cerebrospinal fluid: Value in the management of AIDS-associated cryptococcal meningitis. Clin Infect Dis. 1994;18:789–792.
4. 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;33:690–699.
5. Saag MS, Graybill RJ, Larsen RA, et al. Practice guidelines for the management of cryptococcal disease. Clin Infect Dis. 2000;30:710–718.
6. Vibhagool A, Sungkanuparph S, Mootsikapun P, et al. Discontinuation of secondary prophylaxis for cryptococcal meningitis in human immunodeficiency virus-infected patients treated with highly active antiretroviral therapy: A prospective, multicenter, randomized study. Clin Infect Dis. 2003;36:1329–1331.

Cryptococcal Infections - CODES

Cryptococcal Infections - icd9

117.5 Cryptococcosis

Cryptococcal Infections - FAQ

• 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

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Book Source Details

• Book Title: The 5-Minute Pediatric Consult
• Author(s): M. William Schwartz MD; et al.
• Year of Publication: 2008
• Copyright Details: The 5-Minute Pediatric Consult, Copyright © 2008 Lippincott Williams & Wilkins.

More About Cryptococcal Meningitis

• Back to disease: Cryptococcal Meningitis: Introduction
• Next Book Extract About Cryptococcal Meningitis: Meningitis (The 5-Minute Pediatric Consult)
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Copyright notice for book excerpts: Copyright © 2008 Lippincott Williams & Wilkins. All rights reserved.

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More About This Book: Title: The 5-Minute Pediatric Consult Authors: M. William Schwartz MD; et al. Publisher: Lippincott Williams & Wilkins Copyright: 2008 ISBN: 0-7817-7577-9

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