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Chapter 227 Cryptococcus neoformans
Jane M. Gould, Stephen C. Aronoff
Cryptococcosis is an invasive fungal disease caused by a monomorphic, encapsulated yeast. Cryptococcus neoformans var. neoformans is the most common etiologic agent worldwide and is the predominant pathogenic fungal infection among persons infected with HIV.
C. neoformans var. neoformans (serotypes A, D, and AD) is distributed in temperate climates predominantly in soil contaminated with droppings from certain avian species, including pigeons, canaries, and cockatoos. It may also be found on fruits and vegetables and may be carried by cockroaches. C. neoformans var. gattii (serotypes B and C) is found in the tropics and subtropics and has been associated with several species of eucalyptus trees. This species causes endemic disease primarily in immunologically competent hosts living in the tropics and is associated with the formation of large granulomas known as cryptococcomas. The distribution and ecology of C. gattii seem to be changing, and this organism can now be found in association with a wide range of trees, including firs and oaks. C. gattii has caused disease in 19 patients residing in Oregon and Washington, most occurring since 2006. Pulmonary disease with or without meningoencephalitis was the most common manifestation. It is critical to distinguish between the two cryptococcal species because C. gattii is less susceptible to fluconazole. Cryptococcus laurentii has been occasionally reported as a cause of invasive fungal disease, usually in immunocompromised patients and most recently in the premature neonatal population.
C. neoformans exposure is much more common than previously thought. Seroprevalence studies in temperate urban environments have shown that most children >2 yr of age and nearly all adults have been exposed to this organism. Despite this high prevalence, clinical disease is unusual in immunocompetent persons and is rare in children. Pigeon breeders and laboratory personnel who work with Cryptococcus are at greatest risk. Cryptococcosis is also rare (<1%) among HIV-infected children but occurs in 5-10% of HIV-infected adults, with higher rates of infection reported from developing countries. Pediatric cases of cryptococcosis are evenly divided among immunocompetent and immunocompromised persons. Cryptococcosis is the third most common invasive fungal infection after candidiasis and aspergillosis in solid organ transplant patients. Other risk factors for cryptococcal infection include diabetes mellitus, renal failure, cirrhosis, and use of corticosteroids, chemotherapy agents, and monoclonal antibodies such as etanercept, infliximab, and alemtuzumab. Interestingly organ transplant recipients who are receiving calcineurin-inhibitor based immunosuppression are less likely to have cryptococcal CNS infection and more likely to have disease limited to the lung, because these agents have antifungal activity in vivo.
In most cases C. neoformans is acquired by inhalation of fungal spores (<5-10 µm), which are engulfed by alveolar macrophages. Local inoculation leads to cutaneous or ophthalmic infection rarely. An additional portal of entry can be seen with organ transplantation of infected tissue. Direct entry through the gastrointestinal tract can also occur. After entry into the body, either latent infection or acute disease is produced. Cell-mediated immunity is the most important host defense for producing granulomatous inflammation and thus containing cryptococcal infection. Patients with compromised cell-mediated immunity have the highest risk for developing cryptococcal disease. In most immunocompetent persons, infection is limited to the lung. When the immune system fails to contain the infection, dissemination follows, with potential involvement of the brain, meninges, skin, eyes, prostate, and skeletal system.
In immunocompetent patients, C. neoformans can produce both a suppurative and granulomatous tissue reaction or a granulomatous reaction alone with varying degrees of necrosis. Healing is characterized by fibrosis usually without calcification. In immunocompromised patients tissue reactions may be minimal or absent, leading to the proliferation of yeast and the development of mucoid cystic lesions. Pulmonary cryptococcosis produces granulomas that are often subpleural in location and contain yeast forms. Cystic cryptococcomas occur in the CNS of 20% of non–HIV-infected patients with disseminated disease and may be found in the absence of overt meningitis. Granulomas and microabscesses containing yeast occur in patients with skin and bone infection.
The manifestations of cryptococcal infection reflect the route of inoculation and the immunocompetence of the host. Sites of infection include lung, CNS, blood, skin, bone, and mucous membranes.
Pneumonia is the most common form of cryptococcosis. Asymptomatic pulmonary infections occur often, especially among pigeon breeders, bird fanciers, and laboratory workers. Asymptomatic carriage can occur in persons with underlying chronic lung disease. Progressive pulmonary disease is symptomatic with fever, cough, pleuritic chest pain, and constitutional symptoms. In a 2006 review of 24 patients with pulmonary cryptococcosis, cough was the most common symptom. Pulmonary disease often precedes disseminated infection in immunocompromised persons. Chest radiographs can demonstrate a poorly localized bronchopneumonia, nodular changes, or lobar consolidations; cavities and pleural effusions are rare. Immunocompromised patients can have alveolar and interstitial infiltrates that can mimic pneumocystis pneumonia. In adults with HIV infection, cryptococcal pneumonia is usually asymptomatic, although >90% of patients have concomitant CNS infection.
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