Introduction
Background
Cryptococcus neoformans is an encapsulated yeast. In 1984, a pathologist named Busse first described the yeast in a paper he presented to the Greifswald Medical Society. Busse isolated the yeast from the tibia of a 31-year-old woman, noted its resistance to sodium hydroxide, and published the case report that same year. The following year, a surgeon named Buschke reported the same isolate from the same patient, thus establishing the early eponym of Busse-Buschke disease. This single case served to identify a new yeast and to prove its pathogenic potential.
Since the initial reports, researchers have identified the diverse spectrum of host responses to cryptococcal infection. The responses range from a harmless colonization of the airways and asymptomatic infection in laboratory workers (resulting in a positive skin test result) to meningitis or disseminated disease. Although virulence in animals and, possibly, humans varies among strains of cryptococci, virulence probably plays a relatively small role in the outcome of an infection. The crucial factor is the immune status of the host. The most serious infections usually develop in patients with defective cell-mediated immunity. For example, patients with AIDS, patients undergoing organ transplantation, patients with reticuloendothelial malignancy, patients undergoing corticosteroid treatment (but not those with neutropenia or immunoglobulin deficiency), and patients with sarcoidosis develop the most serious infections.
With the global emergence of AIDS, the incidence of cryptococcosis is increasing and now represents a major life-threatening fungal infection in these patients.
Mycology
C neoformans has 2 varieties— neoformans and gattii. The species has 4 serotypes based on antigenic specificity of the capsular polysaccharide; these include serotypes A and D (C neoformans var neoformans) and serotypes B and C (C neoformans var gattii). The C neoformans var neoformans is the most common variety in the United States and other temperate climates throughout the world and is found in aged pigeon droppings. C neoformans var gattii develops in tropical and subtropical climates and is not associated with birds, but it grows in the litter around certain species of eucalyptus trees (ie, Eucalyptus camaldulensis, Eucalyptus tereticornis).
Worldwide, C neoformans var neoformans serotype A causes most cryptococcal infections in immunocompromised patients, including patients infected with HIV. For unknown reasons, C neoformans var gattii rarely infects persons with HIV infection and other immunosuppressed patients. Patients infected with C neoformans var gattii are usually immunocompetent, respond slowly to treatment, and are at risk for developing intracerebral mass lesions (eg, cryptococcomas).
C neoformans reproduces by budding and forms round yeastlike cells that are 3-6 µm in diameter. Within the host and in certain culture media, a large polysaccharide capsule surrounds each cell. C neoformans forms smooth, convex, yellow or tan colonies on solid media at 20-37°C (68-98.6°F). This fungus is identified based on its microscopic appearance, biochemical test results, and ability to grow at 37°C (98.6°F); most nonpathogenic Cryptococcus strains do not grow at this temperature. In addition, C neoformans does not assimilate lactose and nitrates or produce pseudomycelia on cornmeal or rice-Tween agar.
Most strains of C neoformans can use creatinine as a nitrogen source, which may partially explain the growth of the organism in creatinine-rich avian feces. Another useful biochemical characteristic of C neoformans, which distinguishes it from nonpathogenic strains, is its ability to produce melanin. The fungal enzyme phenol oxidase acts on certain substrates (eg, dihydroxyphenylalanine, caffeic acid) to produce melanin.
C neoformans var gattii contains genotypes VGI and the more commonly identified VGIIa and VDIIb. Cryptococcus species can reproduce via same-sex mating, and VGIIa may have arisen from the same-sex mating of VGIIb and another strain that has yet to be identified.
In 1976, Kwon-Chung described the perfect (ie, sexual, teleomorphic) form of C neoformans, which was named Filobasidiella neoformans. Prior to the identification of F neoformans, which is mycelial, C neoformans was considered monomorphic yeast. F neoformans var neoformans results from the mating of suitable strains of serotypes A and D. The perfect state of C neoformans var gattii is Filobasidiella bacillisporus and results from the mating of serotypes B and C. Some strains of A and D can mate with strains of B and C.
Epidemiology
C neoformans is distributed worldwide. Most cases of cryptococcosis involve serotypes A and D. Serotypes B and C are restricted to tropical and subtropical areas and are isolated from certain species of eucalyptus trees and the air beneath them. C neoformans var neoformans, which is recovered from aged pigeon feces, bird nests, and guano, is invariably serotype A or D. Although serotypes A and D exist in high concentrations in the pigeon feces, the fungus does not infect the birds. In moist or desiccated pigeon excreta, C neoformans may remain viable for 2 years or longer. In saprobic environments, C neoformans grows unencapsulated; however, unencapsulated strains regain their virulence following reacquisition of their polysaccharide capsule. C neoformans var gattii usually causes disease in patients with intact cell-mediated immunity.
Naturally occurring cryptococcosis occurs in both animals and humans, but neither animal-to-human transmission nor person-to-person transmission via the pulmonary route has not been documented. Transmission via organ transplantation has been reported when infected donor organs were used. C neoformans var neoformans causes the vast majority of cryptococcal infections in immunosuppressed hosts, including patients with AIDS, whereas C neoformans var gattii causes 70-80% of cryptococcal infections among immunocompetent hosts.
Although C neoformans var neoformans is found worldwide, C neoformans var gattii is usually identified in subtropical areas such as Australia, South America, Southeast Asia, and Central and sub-Saharan Africa. In the United States, C neoformans var gattii is found in Southern California.
As noted above, C neoformans var gattii may be found in association with several different trees, such as river red gum trees (E camaldulensis) and forest red gum trees (E tereticornis). Infection is acquired by inhalation of air-borne propagules that infect the lungs and may extend via fungemia to involve the CNS.
In 1999, C neoformans var gattii emerged on Vancouver Island, British Columbia, Canada. Infections were reported among residents and visitors to the island, as well as among domesticated and wild animals. Disease has been most often identified in cats, dogs and ferrets. Marine mammals have also been identified to carry the infection. Vectors can disperse the spores from an endemic area to a previously unaffected area. This may have been the route of spread in the case of Vancouver Island. Since 2003, cryptococcal disease has become a provincially notifiable infection in British Columbia. Isolates have been identified in coastal Douglas fir and coastal western hemlock biogeoclimatic zones.
The incidence of infection related to age, race, or occupation does not significantly differ. Healthy persons with a history of exposure to pigeons or bird feces and laboratory workers exposed to an aerosol of the organism have a higher rate of positive delayed skin reaction to cryptococcal antigen or cryptococci. Occasionally, laboratory accidents result in transmission of C neoformans, but pulmonary and disseminated disease is rare in this setting. Accidental cutaneous inoculation with C neoformans causes localized cutaneous disease.
Pathophysiology
Of the 19 species that comprise the genus Cryptococcus, human disease is associated with only C neoformans. Animal models provide much of the understanding of the pathogenesis and the host defense mechanisms involved in C neoformans infections. The organism is primarily transmitted via the respiratory route and not directly from human to human.
Following inhalation, the yeast are deposited into the pulmonary alveoli, where they must survive the neutral-to-alkaline pH and physiologic concentrations of carbon dioxide before they are phagocytized by alveolar macrophages. Glucosylceramide synthase (GCS) has recently been identified as an essential factor in the survival of C neoformans in this extracellular environment. Although GCS is a critical factor in extracellular survival of the yeast, the yeast no longer requires GCS to survive the intracellular, more acidic, environment of within the macrophage once it is phagocytized by alveolar macrophages.
Unencapsulated yeast are readily phagocytosed and destroyed, whereas encapsulated organisms are more resistant to phagocytosis. A cryptococcal polysaccharide capsule has antiphagocytic properties and may be immunosuppressive. The antiphagocytic properties of the capsule block recognition of the yeast by phagocytes and inhibit leukocyte migration into the area of fungal replication.
The host response to cryptococcal infection includes both cellular and humoral components. Animal models demonstrate that natural killer cells participate in the early killing of cryptococci and, possibly, antibody-dependent cell-mediated killing. In vitro monocyte-derived macrophages, natural killer cells, and T lymphocytes can inhibit or kill cryptococci. A successful host response includes an increase in helper T-cell activity, skin test conversion, and a reduction in the number of viable organisms in the tissues. In addition to cellular mechanisms, anticryptococcal antibodies and soluble anticryptococcal factors have been described. Antibodies to a cryptococcal antigen and its complement play a critical role in enhancing the macrophage- and lymphocyte-mediated immune response to the organism. Researchers use monoclonal antibodies to capsular polysaccharide to passively immunize mice against C neoformans.
C neoformans infection is usually characterized by little or no necrosis or organ dysfunction until late in the disease. Organ damage may accelerate in persons with heavy infections. The lack of identifiable endotoxins or exotoxins partly causes the absence of extensive necrosis early in cryptococcal infections. Organ damage is primarily due to tissue distortion secondary to the expanding fungal burden. Extensive inflammation or fibrosis is rare. The characteristic lesion of C neoformans consists of a cystic cluster of yeast with no well-defined inflammatory response. Well-formed granulomas are generally absent.
C neoformans can cause an asymptomatic pulmonary infection followed later by the development of meningitis, which is often the first indication of disease. If limited to the lungs, C neoformans infection may cause pneumonia, poorly defined mass lesions, pulmonary nodules, and, rarely, pleural effusion. Although immune defects are common in patients with meningitis or disseminated infection, patients with disease that is confined to the lungs are usually immunocompetent.
Frequency
United States
Prior to 1946, only 200 patients with cryptococcal disease had been reported in the medical literature. The development and use of corticosteroids and improvement in patient survival with some malignancies increased the reported incidence of cryptococcal disease. Since the mid 1980s, most cryptococcal disease has occurred in patients with AIDS. A study published in March 2005 that reviewed data from 1981-2000, the first 2 decades of the AIDS epidemic, showed that the annual incidence per million person-years was 19 cases in men and 2.6 cases in women. The highest incidence occurred from 1981-1992, and the incidence then began to decline. In women, the peak incidence occurred in 1997. The overall incidence in cryptococcal disease decreased and preceded the availability of highly active antiretroviral therapy for AIDS.
Approximately 7-15% of patients with AIDS develop cryptococcal infections. In 1993, the US Centers for Disease Control and Prevention reported that 6% of 274,150 patients with AIDS developed cryptococcal disease. Furthermore, patients with AIDS-associated cryptococcal infections now account for 80-90% of all patients with cryptococcosis.
International
C neoformans has a worldwide distribution and, similar to in the United States, preferentially infects immunosuppressed individuals, especially those with AIDS. In sub-Saharan Africa, 15-30% of all patients with AIDS develop cryptococcal disease. However, in some areas, such as Zimbabwe, 88% of patients with AIDS have cryptococcal infection as their AIDS-defining illness. Overall, most case reports of C neoformans var gattii have been from Australia, with a few case reports from the southern California coast and tropical regions of Central and South America.
Mortality/Morbidity
Prior to the use of amphotericin B (Throughout this article, the term amphotericin B refers to amphotericin B desoxycholate.), cryptococcal meningitis and disseminated disease were invariably fatal; however, with the availability of amphotericin B, flucytosine, fluconazole, and the azoles, the mortality rate of cryptococcal disease dramatically decreased. In 1995, Speed and Dunt reported a 14% mortality rate among patients with cryptococcal disease who were treated with amphotericin B plus flucytosine and a 28% mortality rate among patients treated with other regimens.1
Race
No clear racial predilection has been reported for either cryptococcal infection or disease. No occupational predilection has been defined.
Sex
In most studies, cryptococcal disease is reportedly more common in men than in women.
Age
In a 1972 review, Lewis and Rabinovich reported that almost two thirds of patients with cryptococcal disease were older than 40 years2 ; furthermore, in patients aged 50 years and older, cryptococcal disease was more than 3 times as common in men as in women. However, the pandemic of AIDS has lead to a simultaneous and dramatic rise in the incidence of cryptococcal disease and a reduction in the average age of affected patients.
Clinical
History
The principal site or sites of infection (ie, pulmonary, CNS, disseminated disease) dictate the medical history of patients with symptomatic cryptococcal disease. Factors that are especially important include the presence of coexisting conditions associated with immunosuppression (eg, steroid use, malignant disease, transplantation) or HIV infection. Other key factors in the history often relate to organ-specific problems (eg, cough, headaches, focal neurological defects, skin rashes).
- Pulmonary cryptococcosis
- The pattern of cryptococcal pulmonary disease varies greatly, ranging from asymptomatic saprophytic airway colonization to acute respiratory distress syndrome, which affects immunocompromised hosts (eg, patients with AIDS, organ transplant recipients). On occasion, cryptococcal pulmonary disease may even manifest as a slowly progressive mass that may compress thoracic structures such as the vena cava.
- A patient with pulmonary cryptococcosis may present with mild-to-moderate symptoms, including fever, malaise, cough with scant sputum, pleuritic pain, and hemoptysis (rare). More specific and unusual findings include rales or pleural rub. Pleural effusions may be present but are uncommon.
- Cavitation and hilar lymphadenopathy are uncommon.
- Calcification and pulmonary fibrosis or stranding are usually absent.
- Although chronic infection can occur, immunocompetent patients usually have spontaneous regression of both clinical and radiological manifestations.
- Among patients who are HIV positive and have pulmonary Cryptococcus infection, 5-25% present with cough and dyspnea.
- Adult respiratory distress syndrome may ensue.
- Pulmonary disease more likely progresses in these patients, requiring antifungal therapy.
- Pulmonary disease may occur in the absence of extrapulmonary disease. Conversely, extrapulmonary disease (eg, meningitis) may develop in the absence of identifiable pulmonary pathology.
- CNS cryptococcosis
- Meningitis and meningoencephalitis are the most common manifestations and are usually subacute or chronic in nature.
- This form of infection is invariably fatal without appropriate therapy; death may occur from 2 weeks to several years after symptom onset.
- The clinical presentation and course of cryptococcal meningitis vary, relating in part to underlying medical conditions (eg, diabetes, sarcoidosis, glucocorticoid use) and the immune status of the host.
- The most common symptoms are headache and altered mental status, including personality changes, confusion, lethargy, obtundation, and coma.
- Nausea and vomiting are common; fever and stiff neck are less common.
- Some patients who are HIV positive may have minimal or nonspecific symptoms at presentation. Patients are often afebrile or have a mildly elevated temperature.
- Symptoms, including blurred vision, photophobia, and diplopia, may occur secondary to arachnoiditis, papilledema, optic nerve neuritis, and chorioretinitis.
- Other findings include hearing defects, seizures, ataxia, aphasia, and choreoathetoid movements.
- Dementia is a potential sequela and may indicate the presence of hydrocephalus as a late complication.
- Cryptococcosis in other sites
- After lung and CNS infection, the next most commonly involved organs in disseminated cryptococcosis include the skin, prostate, and medullary cavity of the bones.
- Cutaneous manifestations occur in 10-15% of cases and usually take the form of papules, pustules, nodules, ulcers, or draining sinuses.
- Umbilicated papules in patients with AIDS may resemble molluscum contagiosum.
- Cellulitis with necrotizing vasculitis is reported in patients who undergo organ transplantation.
- Bone lesions develop in 5-10% of patients and are usually osteolytic or resemble cold abscesses. These lesions may be confused with tuberculosis or neoplasm.
- Other less common forms of cryptococcosis include the following:
- Myocarditis
- Chorioretinitis
- Hepatitis
- Peritonitis
- Renal abscess
- Prostatitis
- Myositis
- Adrenal involvement
- Prostatic foci may persist after therapy for CNS disease and may act as a reservoir for relapse in men with AIDS.
Physical
The physical findings of patients with cryptococcal infection primarily depend on the patient immune status prior to infection and the site or sites involved. Because the inflammatory responses to encapsulated cryptococci are blunted, tissues may be extensively involved before the patient presents for medical care; furthermore, the limited inflammatory response associated with the encapsulated yeast can result in mild clinical findings.
- Pulmonary cryptococcosis
- Although C neoformans most often infects patients via the pulmonary route, less than 15% of patients present with a clinical picture of pneumonia. On occasion, isolation of Cryptococcus from sputum may represent colonization rather than true infection.
- One third of immunocompetent patients who develop pulmonary infection are asymptomatic or have symptoms so mild that they do not seek medical care.
- When symptoms develop immunocompetent hosts, they include cough (54%), cough with the production of scant mucoid sputum (32%), and pleuritic chest pain (46%). Low-grade fever, dyspnea, weight loss, and malaise may also be present.
- Night sweats, as observed in tuberculosis, are uncommon in cryptococcal pulmonary disease but may occur with disseminated or CNS disease.
- In immunocompromised patients who do not have HIV infection, cryptococcal pulmonary infection is associated with an accelerated course, often with early dissemination. As many as 83% of these patients present with constitutional symptoms (eg, fever, malaise).
- Patients co-infected with HIV and Cryptococcus present with fever (84%), cough (63%), dyspnea (50%), headache (41%), and weight loss (47%). Often, patients with co-infection have cryptococcal antigens and cultures that are positive in cerebrospinal fluid (CSF), blood, and urine. Any part of a lung may be involved, and infiltrates may be bilateral, unilateral, multilobar, or lobar.
- CNS cryptococcosis
- Although C neoformans enters the body via the lungs, the CNS is the main site of clinically evident infection in both immunocompetent and immunocompromised hosts. Following pulmonary infection, cryptococci disseminate widely and may infect any organ. The organs most often involved include the CNS, bones, prostate, eyes, and skin. Prior to the discovery of amphotericin B in 1955, 80% of patients with CNS involvement died within 2 years of diagnosis.
- Cryptococcal CNS infections usually involve both the brain and meninges, causing diffuse disease. Immunocompetent hosts may present with either meningitis or focal cryptococcomas. Meningitis manifests with diffuse, nonfocal findings (eg, altered mental status, vomiting), whereas cryptococcomas often manifest with focal neurologic defects.
- Cryptococcal skin infection
- Approximately 10-15% of patients infected with C neoformans develop skin involvement. In immunocompetent hosts, the skin may be the only site of infection; however, immunosuppressed patients, especially those with AIDS, have skin involvement that must be considered evidence of disseminated disease.
- Cutaneous lesions include nodules, ulcers, papules, and vasculitic lesions.
- Cryptococcal osteomyelitis
- Bone involvement is documented in 5-10% of patients with cryptococcal infection.
- Bone lesions are usually osteolytic and may be misinterpreted as neoplastic lesions or osseous tuberculosis.
- Other sites of cryptococcal infection
- The eyes and prostate are often involved. Eye involvement often manifests as vision loss caused by optic neuritis or endophthalmitis. Rapid diagnosis and treatment are essential to preserve the patient's sight.
- In men, eradication of cryptococci from the prostate is often difficult; furthermore, the prostate can act as a reservoir for relapse of systemic infections.
- Other considerations
- A CT scan or MRI in patients with cryptococcal infection may reveal diffuse atrophy or cerebral edema with focal, homogenous, or contrast-enhanced areas. These findings may help distinguish cryptococcal infection from other causes of intracranial mass lesions and infections.
- Early cryptococcal meningitis may resemble other mycoses, syphilis, tuberculosis, or meningeal metastases. Do not confuse this condition with chronic meningitis caused by other infections or by noninfectious causes (eg, sarcoidosis, chronic benign lymphocytic meningitis).
- Pulmonary findings may be indistinguishable from those of patients with acute pneumonia caused by Pneumocystis carinii, Mycobacterium tuberculous, Histoplasma capsulatum, or other organisms.
- Cutaneous lesions are nonspecific and may be mistaken for a large variety of lesions related to other causes, including acne, syphilis, lipoma, tuberculosis, molluscum contagiosum, or basal cell carcinoma.
- Bone lesions may be mistaken for tubercular cold abscess or neoplasm.
Causes
Infection with either C neoformans var neoformans or C neoformans var gattii causes cryptococcal disease. The most common pathogen of the genus Cryptococcus in immunocompromised patients is C neoformans var neoformans. The most common variety that causes disease in immunocompetent patients is C neoformans var gattii.
More on Cryptococcosis |
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| Differential Diagnoses & Workup: Cryptococcosis |
| Treatment & Medication: Cryptococcosis |
| Follow-up: Cryptococcosis |
| References |
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Further Reading
Keywords
cryptococcosis, Busse-Buschke disease, European blastomycosis, torulosis, Cryptococcus neoformans, C neoformans, Cryptococcus neoformans var gattii, C neoformans var gattii, C neoformans var neoformans, Cryptococcus neoformans var neoformans, cryptococcal infection, yeast infection, cryptococci, fungal infection, cryptococcoma, pigeon feces, bird feces, pigeon excreta, bird excreta, avian feces, avian excreta, meningitis, cryptococcal meningitis, cryptococcal lung infection
