Cryptococcosis

Wael ElMaraachli and Antonino Catanzaro

MICROBIOLOGY AND EPIDEMIOLOGY

Cryptococcosis is an invasive fungal infection caused by Cryptococcus neoformans or C. gattii. Meningoencephalitis is the most frequent manifestation of disease, but pulmonary disease is frequently seen as well. Cryptococcus is a single-budding yeast and has a thick polysaccharide capsule that is responsible for its characteristic visualization by India ink. C. neoformans has been categorized into four serotypes, A, B, C, and D, based on the immunologic properties of their capsular polysaccharide. Serotypes B and C are now considered a separate species called C. gattii. Infection due to the two species (C. neoformans and C. gattii) is generally indistinguishable, although there may be some important distinctive features in the type of host (C. gattii has more of a propensity to infect healthy hosts), and in the prognosis of intracranial infection in HIV-negative hosts.

C. neoformans has been found in soil samples around the world in areas frequented by birds, especially chickens and pigeons, making cryptococcosis a mostly urban disease. However, human infection usually occurs without a history of direct contact with birds. C. gattii, generally occurs in the tropics and subtropics and is found in decaying vegetation, particularly the river red gum (eucalyptus) trees. An outbreak of C. gattii infections on Vancouver Island and surrounding areas of Canada and the Northwest United States was linked to the importation of eucalyptus trees from Australia. Most patients with cryptococcosis due to C. neoformans have underlying conditions that compromise cell-mediated immunity, such as HIV infection (dramatic increase in risk with CD4 cell counts below 100 cells/μL), lymphoproliferative disorders, corticosteroid therapy, organ transplantation, rheumatologic disorders, sarcoidosis, chronic liver diseases, and the use of tumor necrosis factor-α antagonists.

Widespread use of highly active antiretroviral therapy (HAART) has lowered the incidence of cryptococcosis in medically developed countries; however, it is the fourth most common opportunistic infection in AIDS. It is estimated that 1 million cases of cryptococcosis occur worldwide each year, with the largest burden in Africa. Prognosis in pulmonary cryptococcosis depends on the host’s immune status. Immunocompetent patients usually recover without sequelae. In HIV patients, however, prognosis depends on the presence and severity of acute meningoencephalitis. Despite the availability of HAART and appropriate treatment, the 3-month mortality approximates 20%.

PATHOGENESIS AND CLINICAL MANIFESTATIONS

Cryptococcus is a basidiomycetous yeast that survives environmentally in the sexual form, producing hyphae with terminal basidiospores (chains of unbudded yeast). However, it is the asexual form (encapsulated yeast), which is found in clinical specimens. The portal of entry of the organism is the respiratory tract. Basidiospores may break off from the hyphae, become aerosolized, and are small enough to deposit in the alveoli. After inhalation, the yeast comes into contact with alveolar macrophages, and more inflammatory cells are recruited through chemokine release. In immunocompetent individuals, the yeasts can remain dormant in hilar lymph nodes or pulmonary foci asymptomatically for years and then disseminate outside these complexes if local immunity becomes suppressed. In cases of severely suppressed cell-mediated immunity, the yeasts reactivate and disseminate to other sites.

Several virulence factors aid in infection. These include an antiphagocytic polysaccharide capsule, and an enzyme that catalyzes the conversion of diphenolic compounds (such as dopamine) to melanin, which may have a biologic role in protecting the yeast from oxidative stress (hence the proposed propensity of the organism for the central nervous system [CNS], where there is an abundance of dopamine). In addition, its ability to grow at 37°C adds to its virulence.

Clinical manifestations of pulmonary infection range from an asymptomatic pulmonary nodule on radiograph to subclinical, mild, and self-limited symptoms (in an immunocompetent host) up to life-threatening fungal pneumonia. Symptoms include fever, productive cough, chest pain, weight loss, and respiratory distress (with the more severe symptoms occurring in immunocompromised persons). Roentgenographic abnormalities include pulmonary nodules or masses (solitary or multiple), airspace consolidations, reticular patterns, and ground-glass attenuation. Nodules can be single or multiple, and consolidations can be uni- or multi-focal. Cavitation occurs more frequently in immunocompromised hosts. Other associated findings can include lymphadenopathy, pleural effusion, and, rarely, endobronchial lesions causing collapse.

Dissemination from lungs to CNS occurs in 65% to 94% of cases of HIV-associated pulmonary cryptococcosis. In fact, most immunocompromised patients present with CNS rather than pulmonary symptoms in a clinical syndrome of subacute meningoencephalitis.

C. gattii infections have been recognized in immunocompetent hosts, producing pulmonary or CNS cryptococcosis. In certain areas of the world, C. gattii tends to cause cerebral cryptococcomas and hydrocephalus with or without large pulmonary lesions in immunocompetent hosts. Other organs that may be involved include skin, prostate, eyes, bone, and blood.

DIAGNOSIS

Several methods are used for the diagnosis of cryptococcosis, including direct examination of body fluids, histopathology of infected tissues, serologic studies, and culture.

Direct examination using India ink staining on cerebrospinal fluid (CSF) can be performed, showing a halo around the organism representing the polysaccharide capsule. This has a sensitivity of 30% to 50% in non–AIDS-related cryptococcal meningitis and 80% in AIDS-related cryptococcal meningitis. Specificity can be an issue if the ink becomes contaminated. Cryptococcus also can be identified by histologic stains of tissues from affected organs (e.g., fine needle aspiration [FNA] of a lung nodule) showing the budding yeast. Testing for the cryptococcal polysaccharide antigen (CRAG) with latex agglutination is the primary tool used for diagnosis. Serum CRAG has a sensitivity and specificity of 93% to 100%, and 93% to 98% in disseminated cryptococcosis. The test is not as sensitive when there is no other extrapulmonary involvement. Serum CRAG is often used as a screening test; however, false-negative rates of up to 48% have been reported in non–HIV-infected individuals with only pulmonary involvement (with single pulmonary nodules having the lowest rate of antigen positivity than all other radiographic presentations). On the other hand, a positive serum CRAG in a patient with suspected pulmonary cryptococcosis appears to reflect extrapulmonary, or disseminated, disease. It is recommended that a lumbar puncture should be performed to evaluate for meningitis in all patients with suspected pulmonary cryptococcosis (even without CNS symptoms), except those who are immunocompetent and in whom there is no suspicion of extrapulmonary disease. Bronchoscopic sampling (washings and bronchoalveolar lavage) is often diagnostic when the specimens are properly stained. However, there does not appear to be added benefit from transbronchial biopsy. Direct CRAG measurements can also be performed on bronchoscopic lavage and transthoracic needle aspirates of infiltrates and have a higher sensitivity for pulmonary cryptococcosis (without dissemination) than serum measurements of the antigen. As alluded to earlier, if cryptococci are recovered from respiratory samples, the CSF should be examined in most, if not all, cases.

MANAGEMENT

Only gold members can continue reading. Log In or Register to continue