Cryptococcal Infections

Descriptive text is not available for this imageBASICS

DESCRIPTION

Cryptococcosis is a ubiquitous opportunistic environmental fungal infection. Around the world, Cryptococcus neoformans is isolated in soils frequented by birds, especially pigeons and chickens. Infection caused by C. neoformans may involve several organ systems, including the central nervous system (CNS), lungs, bones, visceral organs, and skin. Cryptococcus gattii has emerged as an important fungal pathogen, manifesting most commonly as meningoencephalitis with and without concomitant pulmonary disease.

EPIDEMIOLOGY

  • Most pediatric infections occur in immunocompromised hosts, including those with malignancy, HIV, and solid organ or bone marrow transplantation.
  • Serotypes or genotypes of C. neoformans vary both geographically and according to whether or not the host is infected with HIV.
  • Prior to the AIDS epidemic, C. neoformans var grubii and var neoformans accounted for 80% of worldwide isolates. C. neoformans var grubii represents the majority of clinical isolates from patients with AIDS.
  • 20% of infections requiring hospitalization occur in normal hosts.
  • Occurs in 5–15% of HIV-infected adults, usually with CD4+ lymphocyte counts <50 cells/μL; occurs in 0.8–2.3% of HIV-infected children; the lower infection rate in children likely reflects lower exposure to sources of C. neoformans. Seroprevalence varies by age: neonates, 0%; school-aged children, 4.1%; and adults, 69%.
  • Despite access to medical care and highly active antiretroviral therapy (HAART), the 3-month mortality rate during treatment of acute cryptococcal meningitis approaches 20%.
  • 1–3% of solid organ transplant recipients develop C. neoformans infections, and 68% of cases occur >1 year after transplantation—most present with disseminated disease with CNS involvement.

GENERAL PREVENTION

  • Early initiation of HAART even at high CD4 counts is the best way to prevent cryptococcal disease in individuals with HIV.
  • In highly endemic areas, screening patients with low CD4 count for presence of cryptococcal antigen (CrAg) can guide early initiation of antifungal therapy. CrAg is detectable in serum at least 3 weeks prior to onset of neurologic symptoms caused by C. neoformans infection.
  • For long-term suppression, following induction and consolidation therapy, maintenance therapy for at least 1 year and until CD4 count is ≥100 cells/μL in patients receiving HAART; 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 aged ≥6 years receiving HAART with CD4+ lymphocytes >100/μL and undetectable viral loads for at least 3 months.
  • For HIV-negative immunocompromised patients, maintenance (suppressive) antifungal therapy with fluconazole PO (200 to 400 mg once daily for adults; 6 mg/kg/24 h once daily; max 200 mg/dose for children) is recommended for at least 1 year after the completion of acute treatment. Extended prophylaxis may be warranted based on the level of immunosuppression, (i.e., concomitant use of high-dose corticosteroid biologic modifiers, radiographic evidence of cryptococcomas).

PATHOPHYSIOLOGY

  • Primary infection occurs through the inhalation of aerosolized soil particles containing the yeast forms. The skin and GI tract are also portals of entry.
  • Efficient host protection requires intact and coordinated cell-mediated, innate, and humoral immune.
  • 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. Coinfection with other opportunistic organisms such as atypical mycobacteria, cytomegalovirus, Nocardia, and Pneumocystis should be considered.
  • Bone involvement occurs in 10% of cases of disseminated cryptococcal infection.
  • Cutaneous lesions can mimic lesions caused by acne vulgaris, molluscum contagiosum, squamous carcinoma, or basal cell carcinoma. Lesions can result from hematogenous spread of the organism or from direct extension of bone infection.

Descriptive text is not available for this imageDIAGNOSIS

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 (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 is 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 & INTERPRETATION

Initial Tests (screening, lab, imaging)

  • There are many excellent rapid diagnostic tests for suspected cryptococcal meningitis available, although a large quantity of cerebrospinal fluid (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 and can be markedly elevated. Almost 70% of AIDS patients with cryptococcal meningitis have opening pressures of >200 mmH2O and may require repeat therapeutic lumbar punctures. Increased intracranial pressure (ICP) is less common in patients without HIV.
    • CSF should be sent for cell count and differential; protein; glucose; bacterial and fungal cultures; and CrAg. Consider HSV or other viral PCR tests.
    • Examination of the CSF reveals <500 white blood cell (WBC)/μL (usually <50 WBC/μL), 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 approximately 75% of patients with HIV and 50% of patients without HIV.
    • CSF cultures are positive in ~90% of cases, and the organisms take 3 to 5 days to grow.
    • CrAg from CSF is both sensitive and specific. The titer generally correlates with organism burden, but serial measurement does not reliably indicate response to therapy. Testing of CrAg from serum can support the diagnosis of cryptococcosis but cannot be used to rule out cryptococcal meningitis and is subject to prozone phenomenon.
    • 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 CrAg 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.
  • A multiplex polymerase chain reaction (PCR) assay has been found to have >90 sensitivity and specificity for cryptococcal meningitis in patients with HIV 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/μL)
  • Serum electrolytes: detect hyponatremia, a complication of cryptococcal meningitis
  • Chest x-rays: Focal or solitary nodules, diffuse infiltrates, and pleural effusions may be seen in cryptococcal pneumonia.
  • Head computed tomography (CT) or magnetic resonance imaging (MRI): may demonstrate granulomatous lesions (cryptococcomas; ~15% of patients with meningitis) or elevated ICP; MRI is more sensitive than CT imaging for identifying CNS cryptococcal lesions.
  • Some brain lesions persist radiographically, despite good clinical response to appropriate therapy.

Descriptive text is not available for this imageTREATMENT

  • Clinical management depends on extent of disease and immune status of the host.
  • Optimal management strategies for C. gattii are lacking; however, clinical experience suggests that choice and duration of therapy are influenced more by site(s) of infection than by host immune status.
  • Pulmonary and extrapulmonary disease (HIV-negative, nontransplant)
    • Normal hosts with isolated pulmonary nodules may not need treatment if the serum CrAg 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 once daily (max 400 mg) for 6 to 12 months for mild/moderate disease; alternate regimen: itraconazole 5 to 10 mg/kg/24 h PO divided once or twice daily (max 400 mg/24 h) for 6 to 12 months (steady-state trough level >1 mcg/mL and ≤10 mcg/mL) or amphotericin B deoxycholate 0.7 to 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 (IV/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 deoxycholate (1 mg/kg/24 h IV) plus flucytosine (100 mg/kg/24 h PO, divided q6h; therapeutic levels: 30 to 80 mcg/mL) for 2 weeks and then fluconazole IV/PO (10 to 12 mg/kg/24 h, 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, for children with 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 deoxycholate (0.7 to 1 mg/kg/24 h) (IV) plus flucytosine (100 mg/kg/24 h divided q6h) (PO) for at least 2 weeks, followed by fluconazole PO (6 mg/kg/24 h; max 400 mg/24 h) for a minimum of 8 weeks
    • 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 (3 to 4 mg/kg/24 h) or amphotericin B lipid complex (5 mg/kg/24 h) IV for at least 2 weeks may be substituted for amphotericin B deocycholate, 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.

Descriptive text is not available for this imageONGOING 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.
  • Patients with severe cryptococcal meningoencephalitis may have persistent increased ICP. Patients with continued requirement for serial lumbar puncture to manage ICP will likely require permanent ventriculoperitoneal shunt.
  • Some patients who initiate antiretroviral therapy (ART) can also develop an inflammatory CSF profile with symptomatic increased ICP that is related to immune recovery.
  • Repeat lumbar punctures documenting sterility of culture are useful in evaluating response to treatment. Increased ICP is associated with persistently positive cultures and increased risk of mortality. Evaluate patients with cryptococcal meningitis for neurologic sequelae.
  • HIV-infected patients require suppressive antifungal therapy (see “General Prevention”).

PROGNOSIS

  • Cryptococcal meningitis treatment outcomes:
    • Successful induction and consolidation therapy with switch to ongoing maintenance therapy and clinical improvement
    • Successful induction and consolidation therapy followed by recurrent symptoms during maintenance therapy (culture-positive relapse or cryptococcal immune reconstitution inflammatory syndrome [C-IRIS])
    • Unsuccessful induction or consolidation therapy with persistently positive CSF culture for ≥ ÷ weeks should prompt re-evaluation of treatment adherence, drug resistance, and host factors.
  • In normal hosts with meningitis, poor prognostic factors include serum or CSF cryptococcal titers >1:32 or CSF WBC <20/mm3.
  • 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 ICP, 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”).

COMPLICATIONS

  • Elevated ICP 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.
  • 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

  • Department of Health and Human Services. Guidelines for the prevention and treatment of opportunistic infections in children with and exposed to HIV. Update September 14, 2024. Accessed March, 23, 2024. https://clinicalinfo.hiv.gov/en/guidelines/pediatric-opportunistic-infection
  • Joshi NS , Fisher BT , Prasad PA , Zaoutis TE . Epidemiology of cryptococcal infection in hospitalized children. Pediatr Infect Dis J. 2010;29(12):e91-e95. doi:10.1097/INF.0b013e3181fbc83d  [PMID:20935590]
  • 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. doi:10.1086/649858  [PMID:20047480]

CODES

ICD 10

  • 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

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 (except in the case of human-to-human allograft).
  • 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

Authors

Kim D. Swindell, MD


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