Chapter 227 Cryptococcus neoformans
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.
Disseminated infection usually follows primary pulmonary disease, especially among immunocompromised persons. Advanced HIV infection is the most common predisposing factor for disseminated cryptococcosis. Other major predisposing conditions include lymphoproliferative disorders, corticosteroid therapy, primary immunodeficiencies affecting both T- and B-cell lineages, and immunosuppressive therapy for rheumatic disorders, celiac disease, and organ transplantation.
Subacute or chronic meningitis is the most common clinical manifestation of disseminated cryptococcal infection. The clinical presentation is variable and prognostic. Good outcomes are associated with headache as the initial symptom, normal mental status, absence of a predisposing condition, normal cerebrospinal fluid (CSF) opening pressure, normal CSF glucose, negative India ink stain, absence of extraneural infection by culture, and cryptococcal antigen titers in CSF and serum of <1:32. Overt symptoms of meningitis and HIV infection predict a poor outcome. HIV-infected patients typically present with unexplained fevers, headache, and malaise; cryptococcal antigen titers in these patients are often >1:1,024. CT of the brain identifies cryptococcomas in as many as 30% of patients with disseminated infection, even with no clinical signs of CNS involvement. The mortality rate for cryptococcal meningitis is 15-30%, and most deaths occur within several weeks of diagnosis. The fatality rates are higher among HIV-infected patients, who had relapse rates of >50% before the use of lifelong maintenance highly active antiretroviral therapy (HAART). In adults, relapse rates have decreased to <5% with daily fluconazole therapy. Relapse is unusual in adequately treated immunocompetent persons. Postinfectious sequelae are common and include hydrocephalus, decreased visual acuity, deafness, cranial nerve palsies, seizures, and ataxia.
Sepsis syndrome is a rare manifestation of cryptococcosis and occurs almost exclusively among HIV-infected patients. Fever is followed by respiratory distress and multiorgan system disease that is often fatal.
Cutaneous disease most commonly follows disseminated cryptococcosis and rarely local inoculation. Early lesions are erythematous, may be single or multiple, and are variably indurated and tender. Lesions often become ulcerated with central necrosis and raised borders. Cutaneous cryptococcosis in immunocompromised patients can resemble molluscum contagiosum.
Skeletal infection occurs in approximately 5% of patients with disseminated infection but rarely in HIV-infected patients. The onset of symptoms is insidious and chronic. Bone involvement is typified by soft tissue swelling and tenderness, and arthritis is characterized by effusion, erythema, and pain on motion. Skeletal disease is unifocal in approximately 75% of cases. The vertebrae are the most common sites of infection, followed by the tibia, ileum, rib, femur, and humerus. Concomitant bone and joint disease results from contiguous spread.
Chorioretinitis is rare, occurs primarily in adults, and is usually a manifestation of disseminated disease, although direct inoculation of the eye has been described. Eye infection is characterized by the acute loss of visual acuity, eye pain, visual floaters, and photophobia. Examination usually reveals choroiditis with or without retinitis. Retinal and vitreal masses and anterior uveitis are seen less commonly. Eye disease is often a manifestation of disseminated infection and is associated with a mortality rate of >20%. Only 15% of survivors recover full vision.
Lymphonodular disease has been reported in 2 children, 1 of whom had an underlying immunodeficiency. Lymphonodular cryptococcosis is characterized by disseminated lymphadenopathy including thoracic and abdominal nodes, subcutaneous lesions, liver granulomas, and concomitant pulmonary disease.
Recovery of the fungus by culture or demonstration of the fungus in histologic sections of infected tissue is definitive. A latex agglutination test, which detects cryptococcal antigen in serum and CSF, is the most useful diagnostic test. Titers of >1:4 in bodily fluid strongly suggest infection, and titers of >1:1,024 reflect high burden of yeast, poor host immune response, and greater likelihood of therapeutic failure. India ink preparations of CSF are useful prognostically but are less sensitive than culture and antigen detection. Skin test antigens are poorly characterized, and the sensitivity and specificity of this test are unknown. Serum cryptococcal antibody tests have poor sensitivity and specificity and are generally not helpful in diagnosing cryptococcosis. Cryptococci can grow easily on standard fungal and bacterial culture media. Colonies can be seen within 48 to 72 hours when grown aerobically at standard temperatures.
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.
Persons at high risk should avoid exposures such as bird droppings. Effective HAART for persons with HIV infection reduces the risk of cryptococcal disease. Fluconazole prophylaxis is effective for preventing cryptococcosis in patients with AIDS and CD4+ lymphocyte counts <100/µL. A cryptococcal glucuronoxylomannan (GXM)−tetanus toxoid conjugate vaccine has been developed that elicits protective antibodies in mice but awaits clinical trials in children. Passive immunization with protective monoclonal antibodies has yet to be studied in children.
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