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Cryptococcus Species
The majority of human cryptococcal infections are caused by one of two species: Cryptococcus neoformans and Cryptococcus gattii. These species were previously separated into 3 varieties: C. neoformans var. neoformans, C. neoformans var. grubii, and C. neoformans var. gattii, which were classified into 8 molecular genotypes and 5 serotypes based on capsular polysaccharide antigens. Serotypes A and D and the hybrid diploid AD strains belong to C. neoformans, and serotype B and C strains are classified as C. gattii ( Table 249.1 ). Currently, serotype A strains are designated as C. neoformans var. grubii and serotype D strains are designated C. neoformans var. neoformans , although species designations have been proposed but have not been accepted uniformly ( Table 249.1 ) . C. neoformans var. grubii has a worldwide distribution and is the most common causative agent of cryptococcosis in people AIDS and other immunocompromised people, accounting for >95% of cryptococcal cases. , In contrast, C. gattii usually affects immunocompetent people living in the tropics and subtropics and has been associated with eucalyptus trees, which were considered its major environmental niche. As reported in 2004, C. gattii has caused a substantial outbreak of cryptococcal infections on Vancouver Island, further expanding its geographic boundaries and demonstrating its association with other trees as well.
TABLE 249.1
Characteristics of the Genus Cryptococcus
| Cryptococcus Species | |||
|---|---|---|---|
| Characteristic | Cryptococcus neoformans | Cryptococcus gattii | |
| Varieties | grubii | neoformans | — |
| Serotype | A | D | B, C |
| Proposed species names a | C. neoformans | C. deneoformans | C. gattii, C. bacillisporus, Cryptococcus deuterogattii, Cryptococcus tetragattii, Cryptococcus decagattii |
| Sexual state | Filobasidiella neoformans | Filobasidiella neoformans | Filobasidiella bacillispora |
| Geographic distribution | Worldwide (95% of cryptococcal cases) | Northern Europe | Tropics and subtropics; recent outbreak on Vancouver Island |
| Natural sources | Avian guano | Avian guano | Eucalyptus trees; other trees |
| Isolation from AIDS a patients | Common | Common | Uncommon |
a Proposed species designations have not been uniformally accepted.
Several factors contribute to the virulence of C. neoformans , including the ability to grow in the environment as well as at 37°C, production of a polysaccharide capsule and urease, and the ability to produce melanin. Acapsular strains of Cryptococcus exhibit a marked decrease in virulence. The ability to produce melanin is thought to play a role in both the virulence and the neurotropism of C. neoformans, as melanin-deficient mutants are less virulent in mice, and the central nervous system (CNS) is rich in precursors for production of melanin. Primary infection with cryptococcosis usually follows inhalation into the lungs. The organism is controlled principally by cell-mediated immunity in conjunction with phagocytosis. Initially, neutrophils play a role in containing the yeast in lungs, followed by activity of monocytes and macrophages. The presence of urease increases fitness within the mammalian phagosome, promotes non-lytic exocytosis, and delays intracellular replication reducing phagolysosomal membrane damage, events that could facilitate cryptococcal dissemination when transported inside macrophages. , CD4 + T lymphocytes have been shown to be essential in containing CNS infection, which may account for the much higher incidence of cryptococcosis in people with AIDS. Although antibody and complement cannot kill cryptococci directly, both enhance opsonization.
Epidemiology
C. neoformans and C. gattii differ in their natural habitat and geographic distribution. C. gattii causes infection in tropical and subtropical regions of the world and is associated with several species of eucalyptus trees as its ecologic niche, although the outbreak of C. gattii infections on Vancouver Island has demonstrated an association with other trees, including firs and oaks, and an expanded geographic range. For C. neoformans, both C. neoformans var. grubii (serotype A) and C. neoformans var. neoformans (serotype D) are isolated most frequently from soil contaminated with pigeon or other bird guano. The two varieties differ in their geographic distribution: serotype A has been isolated throughout the world, usually infecting people with AIDS or other immunocompromising conditions, whereas infections with serotype D are more prevalent in certain geographic areas, such as northern Europe.
Although Cryptococcus species can be isolated from pigeon droppings, documentation of infection following this type of exposure is limited. Molecular strain typing has not yet linked a specific environmental source with cryptococcosis but has demonstrated that some clinical and environmental isolates are indistinguishable. Host factors are important in determining the risk of developing cryptococcosis. HIV infection is now the most common immunocompromising illness in patients with cryptococcosis, although the incidence of cryptococcosis has decreased with the institution of active antiretroviral therapy (ART). However, in areas worldwide where ART is not available, cryptococcosis remains the most common life-threatening fungal infection. In people with HIV infection, cryptococcosis usually occurs in patients with CD4 + lymphocyte counts of <100 cells/μL. Other immunocompromised hosts with cell-mediated immunologic defects, such as patients with lymphoma and sarcoidosis, and people receiving corticosteroid treatment, also have increased risk for both C. neoformans and C. gattii infections. No association between cryptococcosis and ethnicity has been detected.
Until the AIDS epidemic began, cryptococcosis was rare. Population-based active surveillance conducted in four areas of the US between 1992 and 1994 showed that cryptococcosis developed in 2%–5% of people with AIDS per year. The rate of cryptococcal infection in HIV-infected people decreased dramatically after the introduction of ART, decreasing by 46% in one study and from an incidence as high as 66 per 1000 to 2–7 per 1000 in another study. , Also notable is the fact that, of the 1083 cases of cryptococcosis detected during a population-based surveillance before ART, only 4 occurred in people <18 years of age, 2 of whom were HIV infected. These data were confirmed by other studies that showed cryptococcal infection was less common in HIV-infected children than adults, with occurrence rates of 1% and 1.4%. , Most of the cases of cryptococcosis occurred in children 6–12 years of age; 9 of 13 cases diagnosed after 1990 occurred in children with vertical HIV infection. Similarly, C. gattii infection is uncommon in children, with only 3 confirmed cases (all pulmonary and in HIV-negative patients) reported.
Occasional cases of cryptococcosis occur in children without HIV infection, the most common underlying conditions being lymphoproliferative disorders and immunosuppressive treatment. Rare cases occur in apparently healthy children. The reasons for the lower incidence reported in children is unknown but may relate to differences in environmental exposures or immunologic factors.
Clinical Manifestations
Cryptococcosis is acquired by inhalation of infectious airborne particles. The incubation period is unknown and could be weeks, months, or even longer. Whether the infectious particles are desiccated acapsular yeast cells or basidiospores of the sexual state of the fungus is unclear, but the encapsulated yeast cells are thought to be too large to penetrate the defenses of the upper respiratory tract. After inhalation, organisms then disseminate in immunocompromised patients from lungs to other sites, with or without evident pulmonary infection. Any organ can be affected, including bone and soft tissue, but the most serious form of the disease is meningitis or meningoencephalitis, which is fatal if untreated.
The clinical manifestations of cryptococcosis in children with AIDS are similar to those in adults. , , The presentation of cryptococcosis in patients with AIDS more commonly involves extrapulmonary disease, including cryptococcemia, and extensive CNS infection with a high burden of organisms, as manifest by positive India ink examinations and antigen titers, as well as a limited cerebrospinal fluid (CSF) inflammatory response.
Pulmonary Manifestations
Primary cryptococcosis is asymptomatic in up to one-third of immunocompetent people after inhalation of C. neoformans. Even in immunocompromised patients, including people with AIDS, primary pulmonary infection may not be diagnosed until extrapulmonary dissemination, particularly meningitis, occurs. More persistent pulmonary cryptococcosis often develops in people with HIV infection. Most patients come to medical attention with headache, fever, cough, dyspnea, and weight loss, and some have pleuritic chest pain and hemoptysis. The most frequent radiographic findings are focal or diffuse interstitial infiltrates and hilar lymphadenopathy. Unlike in patients with filamentous fungal infections, nodular and alveolar infiltrates are rare, as are large mass lesions and pleural effusions. ,
Neurologic Manifestations
Infection of the CNS is the most common clinical presentation of cryptococcosis and the complication most frequently associated with mortality. Although cryptococcal meningitis can be acute, it most often follows an indolent course with asymptomatic periods. In people with AIDS, the most common symptoms are headache, fever, and altered mental status; meningeal signs are uncommon. Focal neurologic signs are initially uncommon and occur in about 10% of patients. If focal lesions are detected, especially in patients with AIDS, another diagnosis, such as brain abscess due to another infectious cause (toxoplasmosis, tuberculosis, bacterial abscess, or other causes) or malignancy (primary CNS lymphoma), should be considered, as CNS mass lesions (cryptococcomas) have not been reported in HIV-infected children. Increased intracranial pressure is common in patients with CNS cryptococcosis, especially those with AIDS, and represents a life-threatening complication. These patients present with severe headache, abnormal mental status, visual disturbance, and frequently with hearing loss. , The underlying mechanism is unclear, but it is thought to be due in part to interference with CSF reabsorption in the arachnoid villi as a result of the accumulation of fungal polysaccharide. Aggressive management of elevated intracranial pressure by means of repeated lumbar CSF drainage is perhaps the most important factor in reducing mortality and minimizing the morbidity of acute cryptococcal meningitis.
Approximately 90% of patients with cryptococcal meningitis who are not HIV-infected have abnormal CSF findings, including increased opening pressure (65%), elevated protein concentration (90%), lowered glucose concentration (75%), and a lymphocytic pleocytosis. However, in people with AIDS, the CSF can appear normal, with normal protein and glucose concentrations and minimal or absent pleocytosis.
Skin Manifestations
Cryptococcal skin lesions occur in 10%–15% of patients with disseminated disease as a result of hematogenous spread. Direct extension from a bone lesion can also occur. Single or multiple pustules or papules are most common and sometimes progress to ulcers or abscesses. These lesions typically are described as molluscum contagiosum-like but cannot be distinguished without a biopsy and culture from other infections such as those due to Histoplasma capsulatum, Coccidioides immitis, or Talaromyces (formerly Penicillium ) marneffei. Although the most common site for skin lesions is the face and scalp, the trunk or limbs can also be involved.
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