Cryptococcus neoformans

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Chapter 227 Cryptococcus neoformans

Epidemiology

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.

Pathogenesis

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.

Clinical Manifestations

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.

Treatment

The choice of treatment depends on the sites of involvement and the host immune status. The immunocompetent patient with asymptomatic or mild disease limited to the lungs may be closely observed without therapy or, alternatively, treated with oral fluconazole (pediatric dose 6-12 mg/kg/day and adult dose 200-400 mg/day) or itraconazole (pediatric dose 5-10 mg/kg/day divided every 12 hours and adult dose 200-400 mg/day) for 3-12 mo, with the duration dependent on clinical response.

Patients with cryptococcemia or severe symptoms and non–HIV-immunocompromised hosts with lung disease with cryptococcal antigen titers of >1:8 or with CNS, urinary tract, or cutaneous disease should be treated in a staged approach, because these factors suggest disseminated disease. In general, these patients receive induction therapy with amphotericin B (0.7-1 mg/kg/day) plus flucytosine (100-150 mg/kg/day divided every 6 hours assuming normal kidney function) for a minimum of 2 wi, keeping serum flucytosine concentrations between 40 and 60 µg/mL. Depending on the clinical response, induction therapy may be continued as long as 6-10 wk.

Induction is followed by a consolidation phase with oral fluconazole or itraconazole for 6-12 mo. Itraconazole does not penetrate well into CSF, so consolidation therapy for CNS disease should be accomplished with fluconazole. Lifelong maintenance therapy may be required for children who remain immunocompromised. Lipid-complex amphotericin B (3-6 mg/kg/day) is recommended for patients intolerant of the deoxycholate amphotericin, although experience with this agent in children with cryptococcosis is limited. The current echinocandins do not have clinical activity against cryptococcal infections. Effectiveness of anticryptococcal therapy is monitored by serial cryptococcal antigen testing. Serum or CSF values of ≥1:8 predict relapse. Ventriculoperitoneal shunts may be required for patients with hydrocephalus, and aggressive medical management of increased intracranial pressure might also be required.

Because of the high rate of relapse, pulmonary, CNS, or disseminated cryptococcal infections in HIV-infected patients require induction, consolidation, and maintenance therapy. Patients with pulmonary disease most often require lifelong therapy with fluconazole or itraconazole. For those with CNS disease, the most commonly used regimen is amphotericin B (0.7 mg/kg/day) and flucytosine (100 mg/kg/day) for a minimum of 2 wk and as long as 6-10 wk (induction), followed by fluconazole for a minimum of 8-10 wk (consolidation). Fluconazole should be continued for life (maintenance therapy) after the completion of consolidation therapy. Itraconazole should be used only in cases where the patient is intolerant or has failed fluconazole therapy due to the higher relapse rates with itraconazole. Cessation of maintenance therapy in children whose HIV infection is well controlled on HAART has not been well studied to date.

Cutaneous infections are usually treated medically, although surgical biopsy may be required for diagnosis. Skeletal infections generally require surgical débridement in addition to systemic antifungal therapy. Chorioretinitis also requires systemic antifungal therapy with amphotericin B and either fluconazole or flucytosine, both of which achieve high drug concentrations in the vitreous.

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