OVERVIEW: What every clinician needs to know

Pathogen name and classification

Cryptococcus neoformans – a basidomycetous fungus that has two distinct varieties (C. neoformans var grubii, formerly Type A; and C. neoformans var neoformans, formerly Type D). Cryptococcus gattii (formerly C. neoformans Types B and C) is considered a separate species.

What is the best treatment?

The preferred therapy for cryptococcosis is dependent on the site and severity of infection and the underlying host disorder. Generally speaking, hosts are divided into one of three major groups: HIV positive individuals, organ transplant recipients/patients with other immunocompromising conditions, and phenotypically “normal” individuals. Most infections limited to the lungs can be effectively managed with fluconazole for non-life-threatening, mild to moderate disease. For patients with more severe pulmonary disease and for most patients with extra-pulmonary cryptococcosis, including all patients with central nervous system (CNS) involvement, amphotericin B, either in its conventional (deoxycholate) or a lipid formulation, is advised.

Cryptococcal Meningoencephalitis

HIV-Infected Individuals

Primary therapy with amphotericin B deoxycholate +/- flucytosine 100mg/kg per day orally in four divided doses is administered for at least 2 weeks followed by fluconazole at least 400mg daily (6 mg/kg) for a minimum of 8 weeks. Lipid formulations of amphotericin B at doses from 3 to 6mg/kg daily can be substituted for amphotericin deoxycholate in circumstances among patients with or predisposed to renal dysfunction. Maintenance therapy with fluconazole 200mg daily is generally advised for individuals until the CD4 cell count is consistently greater than 100 cells per cubic ml and there is a low or undetectable HIV viral RNA for at least 3 months.

Amphotericin B deoxycholate and lipid formulations of amphotericin B could be used alone or with fluconazole administered at a dose of 800mg per day (12mg/kg per day) for at least 2 weeks followed by fluconazole 800mg daily for a minimum of 8 weeks. In circumstances in which amphotericin is unavailable or unaffordable, fluconazole as monotherapy at a dose of 800-2000mg daily for at least 10-12 weeks is prudent. If fluconazole is used alone, then a dose of at least 1200mg daily is advisable. Fluconazole at a dose of 800-1200mg daily plus flucytosine 100mg/kg daily in four divided doses for 6 weeks is an acceptable all oral regimen. Oral Itraconazole 200mg twice daily has been used as monotherapy for cryptococcosis, although with this agent is discouraged for patients with CNS or other forms of life-threatening disease.

Organ Transplant Recipients

For CNS disease, a lipid formulation of amphotericin B 3-6mg/kg per day plus flucytosine 100mg/kg per day for at least 2 weeks as an induction regimen followed by fluconazole 400-800mg daily for 8 weeks, then fluconazole 200-400mg daily for 6-12 months is advised. A longer course of induction with a lipid formulation of amphotericin B (e.g., 4-6 weeks) should be considered if flucytosine is not used as part of the induction regimen. For patients with mild to moderate non-CNS disease, fluconazole 400mg daily for 6-12 months is acceptable. For moderately severe to severe non-CNS or disseminated disease without CNS involvement, treat as if the patient has CNS disease. For severe pulmonary disease, treatment should be the same as for CNS disease and for mild to moderate pulmonary cryptococcosis without diffuse lung involvement, 400mg daily for 6-12 months is appropriate.

In managing transplant recipients with cryptococcosis, immunosuppressive therapy should be reduced, but in a graduated step-wise fashion so as not to increase the risk of an IRS-like response. Final consideration in transplant recipients with cryptococcosis is the avoidance of conventional amphotericin B. Most experts favor a lipid formulation of amphotericin B for the treatment of cryptococcosis in transplant recipients because of the risk of nephrotoxicity and the concomitant use of other potentially nephrotoxic agents, such as cyclosporine and tacrolimus.

Non-HIV Infected Non-Transplant Patients with Cryptococcosis

For most patients with moderate to severe disease, amphotericin B deoxycholate plus 5-flucytosine should be administered for at least 4 weeks. For patients who are at risk for nephrotoxicity, most clinicians use a lipid formulation of amphotericin B 3-6mg/kg per day, followed by oral fluconazole 400mg daily for at least 8 weeks. If flucytosine is not available or poorly tolerated, then lengthening the duration of induction therapy with amphotericin B by at least 2 weeks is advisable. For those with a low risk of therapeutic failure, consider induction therapy with amphotericin B plus flucytosine for only 2 weeks followed by consolidation with fluconazole 800 mg for at least 8 weeks. For most patients, maintenance therapy with fluconazole 200mg daily is advised for 6-12 months following successful induction therapy.

Management of Complications in Patients with CNS Cryptococcosis

Persistent Infection

Among patients with persistent CNS cryptococcosis that either remains culture positive or in whom symptoms do not resolve following initial therapy, it is essential to consider the following as potential interventions:

Ensure that adequate measures to improve immune status have been undertaken, including decreasing immunosuppressants and optimizing HAART.
Consider reinstitution of induction phase of primary therapy.
Consider increasing the dose of initial induction therapy with amphotericin B from 0.7 to 1.0mg/kg (for lipid formulation of amphotericin B, increase from 3 to 6mg/kg/d).
Consider combination of fluconazole and flucytosine if the patient is intolerant to amphotericin B.
If patient cannot tolerate flucytosine, consider adding fluconazole 800 mg daily to amphotericin B.
For patients with persistently positive cultures or other evidence of persistent disease, determine minimum inhibitory concentrations to fluconazole, amphotericin B, and flucytosine.
Adjunctive immunotherapy with interferon gamma is unproven, but anecdotally has provided some benefit to a select group of patients with persistent disease. The duration of therapy is unclear, but should probably not exceed 10 weeks.
The use of intrathecal or intraventricular amphotericin B is rarely necessary and is generally discouraged.

Pulmonary Cryptococcosis

Among immunosuppressed patients with pulmonary cryptococcosis, CNS involvement must be ruled out with a lumbar puncture. Once this has been excluded, then the treatment of pneumonia is generally based on severity of disease. For example, patients with severe pneumonia or acute respiratory distress syndrome are treated like those with CNS disease. For patients with mild to moderate pulmonary symptoms without diffuse pulmonary infiltrates and in the absence of severe immunosuppression, then fluconazole 400 mg daily is appropriate. Duration of therapy for 6-12 months is generally advised.

Among HIV-infected patients who are on antiretroviral therapy and whose CD4 counts are sustained above 100 cells per cubic mm, fluconazole 400 mg daily is advised and can be discontinued after approximately 1 year of treatment. Surgery should be considered among immunocompromised patients who have persistent pulmonary abnormalities radiographically despite appropriate antifungal therapy or in whom a diagnosis is uncertain.

Lumbar puncture should be considered among non-immunocompromised patients with pulmonary cryptococcosis to rule out asymptomatic CNS involvement. However, among normal hosts with limited pulmonary involvement, no CNS symptoms, and a negative, or very low, serum cryptococcal antigen, a lumbar puncture can safely be avoided.

For non-immunocompromised patients with pulmonary cryptococcosis, fluconazole 400 mg daily for 6-12 months is appropriate in most cases. Although it is true that all otherwise normal patients with pulmonary cryptococcosis do not require antifungal therapy, it is impossible to select those who would not benefit from therapy at the start. Therefore, pulmonary cryptococcosis in the noncompromised host, even if asymptomatic, merits treatment with fluconazole because of its low level of toxicity, reasonable expense, and efficacy.

For patients with moderately severe to severe disease, treat similar to those with CNS disease. Alternatives to antifungal therapy are based on in vitro susceptibility, rather than an abundance of clinical data. As such, itraconazole 200 mg twice daily, voriconazole 200 mg twice daily, and posaconazole 400 mg twice daily are acceptable alternatives if fluconazole is unavailable or contraindicated. Surgical resection in pulmonary cryptococcosis should be considered when a diagnosis is uncertain or in circumstances in which radiographic abnormalities and/or symptoms have not responded adequately to antifungal therapy.

Non-CNS Non-Pulmonary Cryptococcosis

Among patients with cryptococcemia or disseminated disease (defined as at least 2 contiguous sites), experts suggest treating as for CNS disease. If CNS disease is excluded, fungemia is not present, infection is evident at a single site, and there are no immunosuppressive risk factors, then fluconazole 400 mg daily for 6-12 months is appropriate.

Special Populations

Pregnant Women with Cryptococcosis

Conventional and lipid formulations of amphotericin B can be administered to pregnant women without concern for fetal toxicity. Flucytosine and fluconazole are both category C drugs in pregnancy; therefore, their use has to be assessed by considering perceived benefit versus risk. As such, among pregnant women with non-life-threatening forms of cryptococcosis (e.g., asymptomatic pulmonary nodular disease), consideration for delaying fluconazole therapy until after delivery with close interval follow-up is reasonable.

Children

Treatment for children with cryptococcosis generally follows recommendations for treatment of adults. Amphotericin B deoxycholate is better tolerated in children than adults. Thus, doses of 1 mg/kg daily plus flucytosine 100 mg/kg daily in four divided doses is recommended for induction therapy for patients with disseminated or CNS disease. Fluconazole at a dose of 10-12 mg/kg daily for 8 weeks is recommended for the consolidation phase of therapy.

For amphotericin B intolerant patients, a lipid formulation of amphotericin B 5-6 mg/kg daily is acceptable. For maintenance therapy with fluconazole, 6 mg/kg per day is recommended. Discontinuation of fluconazole following institution of antiretroviral therapy has not been studied well in children, but an approach similar to that in adults seems prudent. For children with mild to moderate cryptococcal pneumonia, fluconazole 6-12 mg/kg daily for 6-12 months is advised.

Cryptococcus gatti

Cryptococcus gattii infection differs from Cryptococcus neoformans infection in that the organism has a greater propensity toward the development of intracerebral and intrapulmonary cryptococcomas, and, in general, it responds more slowly to antifungal therapy. In addition, there are concerns regarding fluconazole resistance in a subset of Cryptococcus gattii infection. These considerations notwithstanding, induction, consolidation, and suppressive treatment are the similar as for C. neoformans.

For known Cryptococcus gattii infections, attention to the development of cryptococcomas, either in the CNS or in the lungs, is important. Management of these complications is the same as for C. neoformans-infected patients; however, these patients may require a longer period of therapy.

For patients with pulmonary cryptococcosis in whom large or multiple cryptococcomas are present, consider the combination of amphotericin B deoxycholate plus flucytosine therapy for 4-6 weeks followed by fluconazole for 6-18 months. Surgery is recommended when there is failure to reduce the size of the cryptococcoma after 4-6 weeks of therapy, failure to thrive, or obvious extrinsic compression of vital structures due to cryptococcoma.

Cryptococcus neoformans resistance to amphotericin B is very uncommon and, rarely, an explanation for treatment failure. In contrast, fluconazole resistance has been reported with increasing frequency, especially from regions of the world where fluconazole has been used in large populations of HIV-infected persons who are perceived to be at increased risk of complications from infection. Also, fluconazole resistance has been reported commonly among C. gattii isolates. Most C. neoformans isolates are resistant to the echinocandins, although the mechanism of resistance is poorly understood.

The best method for detecting resistance is outlined in the CLSI-approved microdilution techniques. The E-test has been used but remains expensive and limited to area institutions at which antifungal susceptibility testing is performed routinely. There are relatively few alternatives to conventional therapy with amphotericin B with or without flucytosine followed by fluconazole. Current alternatives are limited to the azoles and possibly terbinafine. Despite good in vitro data, clinical data supporting the use of azoles other than fluconazole for the treatment of cryptococcosis are limited. Published data with itraconazole, voriconazole, and posaconazole are limited to small studies and a few anecdotal reports, and the experience has generally been limited to patients with refractory or relapsing disease.

How do patients contract this infection, and how do I prevent spread to other patients?

There is no recognized seasonality to the development of cryptococcosis. C. neoformans has been found in soil samples from around the world and is especially found in association with certain trees and rotting organic material, including wood and soils that have been enriched by bird guano. Most observations suggest that birds uncommonly develop disease due to this organism but are frequently colonized in the gastrointestinal tract. The connection between birds and spread of the organism throughout their environment remains unclear.

In contrast to C. neoformans, C. gattii has not been isolated from bird droppings and is much more restricted geographically. C. gattii has been associated with river red gum trees and forest gum trees in Australia and, more recently, with fir and maple trees in more temperate areas, such as Vancouver Island, British Columbia. Recent data further suggests that C. gattii is found in the warmer, dryer soils in regions within which it is endemic.

Exposure to C. neoformans probably varies considerably among regions of the world, and infections have been reported in all countries. There are few data suggesting any specific activities are associated with development of the disease. Unfortunately, there is no routinely available skin test or serologic assay to screen for past exposure to this organism; however, most adults do possess an antibody to C. neoformans antigens. Based on data from New York City, most children acquire antibodies to cryptococcal antigen before 10 years of age.

There are an estimated 1 million cases of HIV associated cryptococcal disease worldwide annually. The best estimates for rates of cryptococcosis in the United States were determined during the peak of the AIDS epidemic at which time there were almost 5/100,000 persons in several large cities. This rate declined dramatically following the introduction of combined antiretroviral (ARV) therapy and is currently less than 1/100,000. In less well-developed countries, the incidence of cryptococcosis is considerably higher, although precise measurements are unavailable, except in South Africa, where the most recent population-based survey suggested an overall incidence in HIV infected patients was 95/100,000, and among those with AIDS, it was 14/1,000.

There is currently little evidence that these rates have declined substantially, although, with the improved availability of antiretroviral therapy, it is reasonable to assume that rates of symptomatic cryptococcal disease will decline in areas where access to ARV is improved.

Nosocomial infection control is not an issue when caring for patients with cryptococcosis, regardless of the infecting species (e.g., C. neoformans or C. gattii) or the sites of disease.

There is no vaccination for prevention of cryptococcosis. Primary prevention with fluconazole prophylaxis is commonly practiced in many areas of the world (e.g., South Africa, Thailand) where the incidence of cryptococcosis is particularly high.

Although there are data suggesting that the use of primary prophylaxis in this setting is useful in the prevention of cryptococcosis, it is unclear whether the benefits of early intervention exceed the potential risks, particularly as it relates to the development of fluconazole resistance in this population. In settings in which primary prophylaxis is practiced, fluconazole is dosed variably from 200 mg daily to 400 mg weekly with similar rates of success.

What host factors protect against this infection?

The vast majority of cryptococcal infections are diagnosed among patients with compromised cell-mediated immunity. As such, a strong cellular immune response leading to granulomatous inflammation is essential for containment. Thus, a TH1 response mitigated through an effective cytokine response through tumor necrosis factor, interferon-γ, and interleukin-2 are required. In addition, natural killer cells have been demonstrated to have anti-cryptococcal effects, as well as CD4 and CD8 lymphocytes. Clinical observation demonstrates that the number of CD4 cells influences the risk of developing disease. Based on many observational studies that the CD4 lymphocyte counts less than 100 cells per ml of blood are associated with a marked increase in risk of infection among patients with HIV.

Humoral immunity is also important in an effective immune response to Cryptococcus. First, there is the observation that individuals with antibody deficiency, such as CVID, are at enhanced risk of developing cryptococcosis. In addition, there are abundant animal data suggesting that monoclonal antibody directed at cryptococcal capsular antigens improves survival among experimentally infected animals. These antibodies enhance phagocytosis, natural killer cell function, and improvement in clearing of capsular polysaccharides, which is an important mediator of virulence.

Many patients who develop complications of cryptococcosis have no phenotypic abnormalities. Preliminary studies suggest that these “otherwise normal” patients display a variety of genetic polymorphisms that may lead to enhanced risk of developing complications of cryptococcosis. Although most patients who develop cryptococcosis have an identifiable underlying disorder associated with immunosuppression, as many as 25% of patients with CNS cryptococcosis have no obvious predisposing condition. Cryptococcosis occurs slightly more commonly in males than in females; it is very uncommon in children, even among those with significant predisposing conditions.

Pathologically cryptococcal infection typically elicits a granulomatous response. As such, a TH1 response mitigated through an effective cytokine response through tumor necrosis factor, IFN-γ, and interleukin-2 are required. In addition, natural killer cells have been demonstrated to have anti-cryptococcal effects, as well as CD4 and CD8 lymphocytes. Dissemination to extra-pulmonary sites probably occurs within the macrophage, and the organism can survive intracellularly for an indefinite period of time. This observation suggests a mechanism for reactivation disease years after primary infection.

What are the clinical manifestations of infection with this organism?

C. neoformans and C. gattii can infect virtually any organ in the body. The two most common sites for infection, however, include the lung and the CNS. In most large series, 35-40% of patients are diagnosed with pulmonary involvement alone, and roughly one-half of the patients are diagnosed with CNS disease. Other common sites of extra-pulmonary dissemination include the skin, prostate, eye, and musculoskeletal system. Clinical manifestations of the disease are, in part, dependent on the underlying disorder. Specifically, patients with HIV and solid organ transplant recipients have more extrapulmonary, extra CNS complications, including isolation of Cryptococcus from the bloodstream and skin manifestations. Otherwise “normal” patients rarely manifest disease outside of the lungs and CNS.

Lung

Lungs are the portal of entry for primary infection in the vast majority of patients. Pulmonary infection ranges from asymptomatic infection to severe pneumonia with acute respiratory distress syndrome (ARDS). Occasionally, pulmonary colonization with C. neoformans occurs, typically in patients with underlying chronic pulmonary disease. By definition, these patients have no clinical, radiographic, or serologic evidence of disease, and this is the only circumstance in which isolation of the organism from a patient represents colonization.

Pulmonary infection can be manifested in a solitary pulmonary nodule or multiple nodules. Lobar involvement, mass-like infiltrates, hilar lymphadenopathy, and lung cavitation may occur. Pleural effusions are relatively uncommon. Among patients with cryptococcal disease clinically and radiographically limited to the lungs, it is important to exclude asymptomatic CNS infection with a lumbar puncture. An exception to this suggestion includes individuals who are otherwise immunologically normal, who have only mild to moderate pulmonary disease, and who have low or negative serum cryptococcal antigen assays.

Central Nervous System

The CNS is the most common extra-pulmonary site of cryptococcosis. Most patients present with headache and/or confusion with or without fever. The signs are most consistent with meningoencephalitis and commonly associated with cranial nerve abnormalities, lethargy, altered mental status, or coma. Symptoms are generally subacute with onset over 1-2 weeks but can persist and progress for several months (occasionally over 12 months) before diagnosis is established.

Among patients with CNS involvement, absent headache symptoms of “sinus fullness” or altered mental status are often present. Occasionally, patients with CNS cryptococcosis are completely asymptomatic. Most common CNS complications of cryptococcosis include blindness, deafness, other persistent cranial nerve abnormalities, cognitive impairment, seizure disorders, and hemiparesis.

C.gattii infections commonly lead to intracerebral and intrapulmonary cryptococcomas, necessitating longer duration of therapy and more surgical intervention. Specifically, the need for permanent CSF shunting due to persistently elevated intracranial pressures and to resect pulmonary cryptococcomas appears to be more common with C. gattii infections. However, there is little evidence to suggest that the two organisms differ substantially in terms of influence on mortality.

Other Sites

Skin manifestations among patients with cryptococcosis are generally limited to those individuals with significant impairment of their host immune system. Among transplant recipients, cellulitis has been described, and this may appear in virtually any anatomic site and may be associated with ulcers or bullous lesions. Full-thickness necrosis is common among these patients, particularly in association with too rapid withdrawal of immunosuppressive agents, triggering an immune reconstitution inflammatory syndrome (IRIS)-like response among these patients. Among patients with HIV, cutaneous manifestations are usually limited to diffuse papular, umbilicated lesions resembling molluscum contagiosum. Occasionally, ulcerative lesions will be found on the face and distal extremities.
Cryptococcus spp. can invade the prostate gland and indeed has been cited as a potential reservoir for persistent cryptococcal infection among immunocompromised patients. Symptoms related to this include urinary hesitancy and symptoms of obstruction. Diagnosis is usually established on the basis of culture of expressed prostatic secretions or urine cultures positive for Cryptococcus.
Ocular symptoms are quite common among patients with CNS cryptococcosis. Most can be attributed to increased intracranial pressure, papilledema, and optic nerve ischemia. However, there is good evidence of direct invasion of the eye on the basis of finding of vitritis and chorioretinitis among patients with CNS cryptococcosis. Once blindness due to cryptococcosis has developed, whether due to direct ocular involvement of the chorioid or retina or due to compression and ischemia of the optic nerve, sight rarely returns.

What common complications are associated with infection with this pathogen?

Elevated Central Nervous System Pressure

The determination of opening cerebrospinal fluid (CSF) pressure is essential as a measure of intracranial pressure in the optimal management of patients with CNS cryptococcosis. Uncontrolled elevated intracranial pressure may lead to blindness, deafness, other focal cranial nerve abnormalities, cerebral infarction, and death. For patients with persistently elevated CSF opening pressure (i.e., ≥25cm of CSF), repeat lumbar puncture to reduce the opening pressure to less than 20cm is recommended. Among patients with extremely high opening pressure (e.g., >40cm CSF), a reduction of 50% is recommended. Repeat lumbar punctures on a daily or every other day basis is advised until the opening pressure is more consistently less than 25cm CSF.

A lumbar drain is an alternative for short-term management of persistently elevated intracranial pressure. Placement of a permanent ventricular peritoneal shunt should be considered only after a patient has received appropriate antifungal therapy and more conservative measures have failed. Pharmaceutical interventions, such as dexomethasone, acetazolamide, and mannitol, are associated with limited success and are not generally recommended. Untreated, elevated intracranial pressure may lead to permanent neurologic abnormalities, including blindness, deafness, other focal abnormalities, cognitive disorders, and death.

Cerebral Cryptococcomas

Among patients with cerebral cryptococcomas, a longer course of induction therapy with amphotericin B plus flucytosine is usually necessary. Consolidation therapy with fluconazole 400-800mg daily is warranted. Corticosteroids probably play a minor role in the absence of cerebral edema; surgery is reserved for patients with large (≥3cm) lesions that are accessible and associated with a mass effect.

How should I identify the organism?

Life Cycle

This basidiomycetous fungus exists in the soil in a variety of environments. Under conditions not well understood, primary infection with C. neoformans and C. gattii occur through inhalation of aerosolized propagules, which are rapidly converted to their yeast from within the macrophage at body temperature. Dissemination to extra-pulmonary sites probably occurs via circulating macrophages. Primary infection is usually asymptomatic and usually does not lead to any disease subsequently. Person-to-person transmission does not occur, except through the use of contaminated transplanted donor tissue or organs.

CSF and bronchoalveolar lavage (BAL) samples are the most easily sampled and reliable specimens, providing the highest yield among patients with CNS and pulmonary disease, respectively. Among patients with disseminated disease and significant underlying immunosuppression (e.g., advanced HIV, solid organ transplant), blood cultures may be positive in up to 80% of these patients.

The best staining techniques include those that highlight the polysaccharide capsule. As such, the Alcian blue and mucicarmine stains are the most commonly used stains to identify Cryptococci. Other stains include the Periodic-acid Schiff (PAS) and routine hematoxylin-eosin (H and E), which reveal narrow-based budding yeast. India ink is a standard preparation used for examination of CSF samples and reveals encapsulated yeasts with narrow-based budding on direct examination.

Cryptococci grow on a variety of bacterial and fungal media, including blood agar and Saboraud’s media.
On artificial media, colonies are white to cream colored, mucoid, and modest in size (a few millimeters)
A rapid urease test is positive for Cryptococci. Other assays include detection of laccase activity using special media that allow the colony to turn brown or black due to melanin production. Distinction between C neoformans and C gattii on based on growth on CGB agar. On CGB, C gattii is blue, whereas C neoformans is white or cream colored.
Growth occurs well on routine media at 30-35°C within 72 hours. Growth occurs well at 37°C.
Culture is generally less sensitive than serum or CSF cryptococcal antigen. In CSF, culture is positive in 50-80% of cases of CNS cryptococcosis, compared to 95% sensitivity for CSF cryptococcal antigen.

Polymerase chain reaction (PCR) is not routinely available for the diagnosis of cryptococcosis.

The cryptococcal antigen assay (CrAg) is the most widely used serologic fungal diagnostic assay. The most commonly used assays are based on latex agglutination and enzyme immunoassay (EIA) methodology. The most recent assay is a lateral flow assay (LFA), which has been approved for use as a diagnostic test for serum and plasma. The sensitivity of these assays is dependent on the site of disease and the host. Among patients with AIDS and CNS cryptococcosis, the CrAg is 95% sensitive, whereas in limited pulmonary disease in the normal host the sensitivity may be as low as 30%.

How does this organism cause disease?

The most distinctive feature of pathogenic Cryptococci is a large polysaccharide capsule. This capsule determines serotype specificity based on structural differences in the glucuronoxylomannan (GXM) contained within the capsule. The best evidence that the capsule is an important virulence factor is based on the observation that acapsular or hypocapsular strains are dramatically less virulent in animal models. In addition to providing a physical barrier to ingestion, the capsule is an important virulence factor in a number of different ways by:

Depleting complement
Producing antibody unresponsiveness
Deregulating cytokine secretion
Interfering with antigen presentation
Producing brain edema
Extruding itself into the extracellular environment with the potential for local toxicity in cellular organelles
Enhancing HIV replication

On the basis of the above observations, it has been hypothesized that more rapid removal of cryptococcal antigen in the infected host could potentially lead to better clinical outcomes.

C. neoformans utilizes compounds, such as L-dopa, norepinephrine, and other aromatic compounds, to form melanin. Melanin protects the yeast from host damage through the following mechanisms. It supports cell wall integrity that interferes with the host T-cell response, abrogates antibody-mediated endocytosis, and protects the organism from temperature changes and antifungal agents.

Traditional research for virulence factors in C. neoformans is focused on capsule, melanin, and growth at 37°C, but there are several other potential virulence factors, including mating types, phospholipase activity, urease production, and potentially other mechanisms.

C. neoformans and C. gattii grow well at 37°C. Other cryptococci that do not grow well at this temperature are avirulent, even if they produce capsules and generate melanin.

The virulence factors noted above are particularly germaine to disease in the CNS. The polysaccharide capsule exhibits tremendous pathogenic potential in the relatively protected CNS through mechanisms listed above. The CNS also provides a rich supply of L-dopa (particularly in the basal ganglia) for the generation of melanin. The ability to grow at 37°C allows the organism to regenerate within deep tissue in the host (e.g., lungs, brain).

WHAT'S THE EVIDENCE for specific management and treatment recommendations?

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. (This most recent update of the IDSA guidelines for the treatment of cryptococcosis is the most comprehensive and clinically useful document to date. The treatment guidelines cover a wide gamut of clinical conditions related to cryptococcosis. They are generally divided according to host underlying disease status: HIV, transplant-associated, and all other patients.)

Brouwer, AE, Rajanuwong, A, Chierakul, W, Griffin, GE, Larsen, RA, White, NJ, Harrison, TJ. “Combination antifungal therapies for HIV-associated cryptococcal meningitis: a randomised trial”. Lancet. vol. 363. 2004. pp. 1764-7. (This study was the first published study to utilize sequential quantitative cultures of CSF as a measure of the rapidity with which sterilization occurred. These results among 64 patients demonstrated that amphotericin plus 5FC is the most rapidly fungicidal combination when compared to amphotericin alone, amphotericin plus fluconazole, and amphotericin plus fluconazole and 5FC.)

Bicanic, T, Muzoora, C, Brouwer, AE. “Independent association between rate of clearance of infection and clinical outcome of HIV-associated cryptococcal meningitis: analysis of a combined cohort of 262 patients”. Clin Infect Dis. vol. 49. 2009. pp. 702-9. (This combined analysis of 262 patients is the first to demonstrate an independent association between speed of clearance of infection from CSF and improved outcome based on mortality. The authors combine the results of a Thai study and two African studies to generate these data.)

Hamill, R, Sobel, J, El-Sadr, W. “Comparison of 2 doses of liposomal amphotericin B and amphotericin B for the treatment of AIDS-associated acute cryptococcal meningitis: randomized double-blind clinical trial of efficacy and safety”. Clin Infect Dis. vol. 51. 2010. pp. 225-32. (This is the first double-blind study comparing two doses of liposomal amphotericin B (3 mg/kg and 6 mg/kg) to conventional amphotericin B (0.7 mg/kg) given daily for 2 weeks for HIV-associated cryptococcal meningitis. Liposomal amphotericin B at doses of 3 and 6 mg/kg demonstrated similar efficacy to amphotericin B.)

Nussbaum, JC, Jackson, A, Namarika, D. “Combination flucytosine and high-dose fluconazole compared with fluconazole monotherapy for the treatment of cryptococcal meningitis: a randomized trial in Malawi”. Clin Inf Dis. vol. 50. 2010. pp. 338-44. (This recent randomized clinical trial performed in Africa compared open label fluconazole with or without flucytosine for treatment of cryptococcal meningitis. The study demonstrated the safety and efficacy of combination of higher dose fluconazole (800 mg daily) plus flucytosine, and demonstrated more rapid clearance of Cryptococcus from the CSF in a trend toward improved outcomes.)

Husain, S, Wagener, MM, Singh, N. “Cryptococcus neoformans infection in organ transplant recipients: variables influencing clinical characteristics and outcome”. Emerg Infect Dis. vol. 7. 2001. pp. 375-81. (This retrospective review of the literature pertains to C. neoformans infections in organ transplant recipients. The authors point to a number of clinical and laboratory characteristics that correlate with outcome and mortality.)

Singh, N, Lortholary, O, Alexander, BD. “An immune reconstitution syndrome-like illness associated with Cryptococcus neoformans infection in organ transplant recipients”. Clin Infect Dis. vol. 40. 2005. pp. 1756-61. (The authors describe, for the first time, an IRS-like illness associated with C. neoformans in organ transplant recipients relating to too rapid reduction of immunosuppressive therapy. This observation has become a paradigm in clinical mycology, where IRS has been recognized in other populations aside from HIV-associated and solid organ transplant recipients.)

Singh, N, Lortholary, O, Alexander, BD. “Antifungal management practices and evolution of infection in organ transplant recipients with Cryptococcus neoformans infection”. Transplantation. vol. 80. 2005. pp. 1033-9. (The authors discuss the different approaches to antifungal therapy in transplant recipients and re-emphasize the importance of slow reduction of immunosuppressive therapy to diminish the risk of IRS-like syndromes.)

MacDougall, L, Kidd, SE, Galanis, E. “Spread of Cryptococcus gattii in British Columbia, Canada, and detection in the Pacific Northwest, USA”. Emerg Infect Dis. vol. 13. 2007. pp. 42-50. (This is a detailed description of the outbreak of C. gattii infection in British Columbia, Canada. The report details not only the clinical features and risk factors, but also the environment from which this organism has been isolated.)

Park, BJ, Wannemuehler, KA, Marston, BJ, Govender, N, Pappas, PG, Chiller, TM. “Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS”. AIDS. vol. 23. 2009. pp. 525-30. (This global survey estimates the annual burden of cryptococcal disease in HIV-positive patients. The study found that approximately 1 million cases of cryptococcal meningitis and more than 600,000 deaths occur annually worldwide due to this infection.)

Pappas, PG, Perfect, JR, Cloud, GA. “Cryptococcosis in human immunodeficiency virus-negative patients in the era of effective azole therapy”. Clin Infect Dis. vol. 33. 2001. pp. 690-9. (This is a retrospective survey of cryptococcal disease in HIV-negative negative patients from 15 US centers between 1990 and 1996. This study provides important insights into the recent epidemiology, disease manifestations, complications, and therapeutic approach to these patients.)

Mitchell, DH, Sorrell, TC, Allworth, AM. “Cryptococcal disease of the CNS in immunocompetent hosts: influence of cryptococcal variety on clinical manifestations and outcome”. Clin Infect Dis. vol. 20. 1995. pp. 611-6. (This is an Australian retrospective study that describes clinical outcomes related to the variety of Cryptococcus, comparing C. neoformans and C. gattii. The authors conclude that C. gattii is associated with more CNS complications including cryptococcomas, requirement for ventricular shunting, and the need for more prolonged antifungal therapy.)

Graybill, JR, Sobel, J, Saag, MS. “Diagnosis and management of increased intracranial pressure in patients with AIDS and cryptococcal meningitis”. Clin Infect Dis. vol. 30. 2000. pp. 47-54. (This is the most detailed report available of the management of increased intracranial pressure in patients with AIDS. It is based on data generated from the first two large ACTG studies of primary treatment for cryptococcosis. The observations for this study have largely guided recommendations pertaining to the management of increased intracranial pressure in these patients and emphasized the need for frequent, repeated lumbar punctures among patients with consistently elevated increased intracranial pressure.)

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Cryptococcus neoformans