Cryptococcosis

OVERVIEW: What every practitioner needs to know

Are you sure your patient has cryptococcosis? What are the typical findings for this disease?

Headache and fever are the most common symptoms of cryptococcal meningitis. The next most common symptoms are meningismus, visual disturbances, altered mental status, cranial nerve palsies, rash, and cough.

What other disease/condition shares some of these symptoms?

Meningitis (especially chronic, e.g., fungal and mycobacterial) and pneumonia (especially chronic, e.g., fungal and mycobacterial). The meningitis can occasionally be confused with acute bacterial meningitis.

What caused this disease to develop at this time?

Cryptococcosis is usually associated with impaired immunity, although disease may occur in apparently healthy individuals. Patients with deficient T-cell immunity (as seen in patients with AIDS, transplant recipients, patients receiving chronic steroid therapy, and those with severe combined immunodeficiency) are especially at risk.

Other conditions associated with cryptococcosis include hyper-IgM syndrome, malignancy, rheumatologic conditions, and pregnancy. A variant of Cryptococcus neoformans, known as Cryptococcus gattii, has been associated with outbreak of meningitis in immunocompetent individuals in the Pacific Northwest, including areas of Canada and the United States. Patients with cryptococcal meningitis may have minimal physical findings, especially patients with AIDS who may be febrile and appear chronically ill.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

In patients with meningitis or meningoencephalitis at risk for cryptococcal infection, cerebrospinal fluid (CSF) should be tested for the presence of the organisms by India ink staining, cryptococcal antigen testing, and culture. A positive result is indicative of infection. Disseminated forms of disease, including meningitis, are typically accompanied by the presence of cryptococcal antigen in the serum. Changes in serum and CSF antigen in response to therapy have limited value.

Would imaging studies be helpful? If so, which ones?

In patients with suspected meningitis, computed tomography of the head should be performed to exclude the presence of space-occupying lesions.

In patients with suspected pneumonia, a chest radiography is typically sufficient.

If you are able to confirm that the patient has cryptococcosis, what treatment should be initiated?

In addition to antifungal therapy (Table I), it is critical that a determination of opening CSF pressure be made. For patients with elevated pressure (>25 cm H₂O), CSF pressure should be lowered by serial lumbar punctures with removal of CSF.

Table I.

Cryptococcal meningoencephalitis	Three stages of treatmentInduction therapy with amphotericin B deoxycholate 1 mg/kg together with flucytosine 100 mg/kg daily until significant clinical improvement and sterilization of the CSF (minimum 2 weeks), followed by consolidation therapy with fluconazole 10-12 mg/kg daily for 10 weeks (Adult dose: 400 mg daily).For children intolerant of amphotericin B deoxycholate or those with renal insufficiency, liposomal amphotericin B 5 mg/kg can be used.Children with AIDS should be maintained on fluconazole suppressive therapy (6 mg/kg). Adult dose: 200 mg/daily.
Disseminated cryptococcosis and severe pulmonary disease	Amphotericin B deoxycholate (1 mg/kg) combined with flucytosine 100 mg/kg for a minimum of 2 weeks followed by fluconazole 10-12 mg/kg for 10 weeks. Adult dose 400 mg daily.For children intolerant of amphotericin B deoxycholate or those with renal insufficiency, liposomal amphotericin B (5 mg/kg) can be used.Children with AIDS should be maintained on fluconazole suppressive therapy (6 mg/kg). Adult dose 200 mg/daily. All patients should have a lumbar puncture to exclude CNS involvement.
Cryptococcal pneumonia	For children with localized pulmonary disease that is either asymptomatic or minimally symptomatic, fluconazole 6 mg/kg for a period of 6-12 months based on resolution of symptoms. Adult dose 200 mg/daily.Children with AIDS should be maintained on fluconazole therapy. Lumbar puncture should be considered to exclude CNS diseases, especially among immunocompromised individuals.

Treatment

CNS = central nervous system; CSF = cerebrospinal fluid

The type of antifungal treatment should be based on the type of disease (central nervous system [CNS], disseminated, isolated pulmonary) and immune status of the host. Treatment guidelines for children (Table I) are based on studies in adults, and little to no pediatric data is available.

Treatment of CNS infection should be done in a staged approach, which includes induction and consolidation/maintenance phases. After initial treatment, patients with AIDS and transplant recipients should be treated with suppressive azole therapy to prevent disease recurrence.

The safety of discontinuing fluconazole suppressive therapy in the context of improving immune function (i.e., CD4⁺ T cells >100/L) after combined antiretroviral therapy (in HIV-infected individuals) has not been established in children and should be undertaken with caution. In adults, suppressive therapy can be discontinued when CD4 cell count is greater than 100 cells/µL and sustained viral suppression (≥ 3 months) have been achieved. A minimum of 12 months of antifungal therapy is recommended.

For transplant recipients a suppressive regimen 6 to 12 months in duration is recommended.

Itraconazole is considered an alternative to fluconazole, although this drug has limited CNS penetration and has important drug interactions and gastrointestinal side effects.

The extended azoles (voriconazole and posaconazole) have good in vitro activity against
C. neoformans, but clinical experience is limited.

Azoles and flucytosine are contraindicated during pregnancy.

Surgical management for large cryptococcomas should be considered

What are the adverse effects associated with each treatment option?

The main toxicities associated with amphotericin B relate to impaired renal function and electrolyte disturbances (hypokalemia and hypomagnesemia). Infusion-related side effects include fever, chills, and nausea.These events may be limited by the administration of diphenhydramine, acetaminophen, or hydrocortisone 30 to 60 minutes before administration and, if needed, meperidine during infusion to relieve rigors. Other common side effects include anemia, pain at injection site, phlebitis, and generalized musculoskeletal pain. Both renal toxicity and infusion-associated events are significantly less common with liposomal amphotericin B.

The main toxicities associated with flucytosine relate to bone marrow suppression. Other adverse effects include renal and hepatic toxicity. Cardiac and CNS dysfunction along with rash, hearing problems, and electrolyte disturbances have also been described. Because of its narrow therapeutic index, monitoring of drug levels is indicated. Dosage must be adjusted for renal dysfunction.

Fluconazole is recognized to cause elevated transaminase levels. In rare cases, severe, fatal hepatotoxicity has been described. Since it inhibits the P450 cytochrome enzyme, fluconazole has many drug interactions and may increase certain drug levels because of decreased metabolism. Fluconazole has been reported to cause arrhythmias, including prolonged Q-T syndrome. This tendency appeared to be enhanced when other arrhythmogenic drugs are coadministered. Other reported side effects include nausea, vomiting, diarrhea, rash, anaphylaxis and Stevens-Johnson syndrome.

What are the possible outcomes of cryptococcosis?

For patients with meningitis, 3-month mortality is approximately 20%. Untreated, the disease is 100% fatal. Long-term prognosis, especially for patients with AIDS, is related to the ability to reduce immunosuppression and reduce HIV viral load. For patients with AIDS and organ-transplant recipients, ongoing suppressive therapy is needed to prevent disease recurrence. In patients without known recognized risk factors, testing for underlying immunosuppression, including HIV testing, is important.

What causes this disease and how frequent is it?

Cryptococcus neoformans is an opportunistic pathogen that generally causes disease in individuals with depressed cellular immunity. Among patients with AIDS, disease is typically manifested in patients with severely depressed immune function (CD4⁺ lymphocyte counts of <100 cells/µL). Pulmonary infection is typically asymptomatic in immunocompetent individuals. Both reactivation and primary progressive forms of cryptococcosis have been described.

Cryptococcus neoformans is ubiquitous within the environment. It is especially recognized for its association with bird droppings, including pigeon droppings.
Cryptococcus gattii, the cause of the Pacific Northwest outbreak, is associated with trees, including Eucalyptus trees. This species of Cryptococcus also causes disease in tropical areas and is recognized as a cause of disease in Australia and Papua New Guinea.

How do these pathogens/genes/exposures cause the disease?

Cryptococcus neoformans is a facultative intracellular fungal pathogen that is well adapted to survive in macrophages. It has been hypothesized that the ability of this organism to survive intracellularly evolved initially in the context of interactions with soil amoeba. The infection starts in the lung and spreads to the brain. The precise mechanism of entry into the CNS is not well understood, but both Trojan horse (infected macrophages) entry and transcellular penetration mechanisms have been proposed. Several virulence factors have been described and are reviewed below.

Polysaccharide capsule: The capsule of C. neoformans helps the organism evade detection by the immune system. It also possesses a variety of immunomodulatory properties, including induction of the antiinflammatory cytokine interleukin-10.

Melanin: This pigment is synthesized by the laccase enzyme and is deposited in the cell wall. It helps protect the organism against oxidative stress.

Extracellular enzymes: Several secreted enzymes have been identified (urease, phospholipase) and appear to promote intracellular invasion and dissemination of infection.

Thermotolerance: The ability of this organism to survive at human body temperature is essential to virulence.

Other clinical manifestations that might help with diagnosis and management

Although the main clinical manifestations of cryptococcosis involve the lungs and brain, the organism can disseminate to most organ systems in the body.

Skin: Skin manifestations can occur as a result of direct inoculation or in the context of disseminated disease. A variety of presentations ranging from cellulitis to ulcers have been described.

Eyes: Both endophthalmitis and choroiditis have been described.

Genitourinary tract: The prostate has been hypothesized to be a sanctuary for
C. neoformans, although infection here may not be symptomatic.

Bone, joint, and muscle: This is uncommon, but there are reported sites of involvement.

What complications might you expect from the disease or treatment of the disease?

Complications of the disease relate to CNS involvement and include brain infarcts, cranial nerve palsies, blindness, and hearing loss. An immune reconstitution syndrome related to enhanced inflammation may occur in AIDS patients in association with antiretroviral therapy.

Are additional laboratory studies available; even some that are not widely available?

Antifungal susceptibility testing: Routine antifungal susceptibility for
C. neoformans is not typically indicated. In patients with recurrent disease who are receiving azole therapy, consider testing for resistance.

How can cryptococcosis be prevented?

There is no vaccine for cryptococcosis. Routine prophylaxis with fluconazole is generally not used because of concerns of emerging resistance. In areas with a high incidence of disease (e.g., Africa and Asia) some experts have proposed screening of HIV-infected individuals with serum cryptococcal antigen testing. At-risk patients should consider limiting exposure to birds and bird droppings.

Genetic testing (other than for potential primary immundeficiency as suspected) is not indicated.

Severe malnutrition can impair T-cell function and could theoretically enhance susceptibility to cryptococcosis, although this element of pathogenesis has not been studied.

What is the evidence?

Because of the small numbers of cases of pediatric cryptococcosis, diagnostic and treatment recommendations are based on extrapolations from adult studies (see below).

Brouwer, AE, Rajanuwong, A, Chierakul, W. “Combination antifungal therapies for HIV-associated cryptococcal meningitis: a randomised trial”. Lancet. vol. 363. 2004. pp. 1764-7. (Comparison of amphotericin B amphotericin B + flucytosine, amphotericin B + fluconazole, and amphotericin B + flucytosine + fluconazole for the treatment of cryptococcal meningoencephalitis. Amphotericin B + flucytosine was found to produce the most rapid CSF clearance. High baseline CSF fungal burden was found to be a bad prognostic indicator.)

Dromer, F, Mathoulin-Pelissier, S, Launay, O. “Determinants of disease presentation and outcome during cryptococcosis: the CryptoA/D study”. PLoS Med. vol. 4. 2007. pp. e21(Prospective, multicenter study that found that disseminated disease at presentation, high serum antigen levels, and lack of flucytosine therapy correlated with microbiologic failure at 2 weeks.)

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. vol. 50. 2010. pp. 291-322. (Overview of Infectious Diseases Society of America recommendations for the management of cryptococcosis.)

Saag, MS, Powderly, WG, Cloud, GA. “Comparison of amphotericin B with fluconazole in the treatment of acute AIDS-associated cryptococcal meningitis. The NIAID Mycoses Study Group and the AIDS Clinical Trials Group”. N Engl J Med. vol. 326. 1992. pp. 83-9. (One of earliest studies to demonstrate the potential utility of fluconazole for the initial treatment of cryptococcal meningoencephalitis. Patients treated with fluconazole had higher mortality at 2 weeks. Time to sterilization of CSF with fluconazole was also more prolonged, although this difference was not statistically significant.)

van der Horst, CM, Saag, MS, Cloud, GA. “Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. National Institute of Allergy and Infectious Diseases Mycoses Study Group and AIDS Clinical Trials Group”. N Engl J Med. vol. 337. 1997. pp. 15-21. (Study demonstrates the utility of a staged approach to cryptococcal meningoencephalitis therapy with amphotericin + flucytosine in the initial treatment, followed by fluconazole or itraconazole.)

Ongoing controversies regarding etiology, diagnosis, treatment

There are no pediatric studies to validate the extrapolation of adult treatment approaches to children (only case reports and small series). Ongoing controversies exist over the treatment of immune reconstitution syndrome and treatment of cryptococcosis in resource-limited countries. New approaches being studied for the treatment of cryptococcosis include approaches designed to enhance the immune response either through cytokine administration or fungus-specific monoclonal antibody.

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