Rudolph's Pediatrics, 22nd Ed.

CHAPTER 299. Cryptococcosis

Deborah Lehman

Cryptococcosis is a sporadic, cosmopolitan mycotic disease caused by the yeastlike fungus Cryptococcus neoformans and its variant, Cryptococcus neoformans gattii. Both species cause similar clinical manifestations, primarily in the lung and central nervous system. C neoformans is most responsible for infection in immunocompromised individuals and occurs worldwide. C gattii more commonly infects immunocompetent hosts. C gattii was originally thought to be limited to tropical and subtropical regions, but a recent outbreak of C gattii on Vancouver Island in Canada demonstrated a wider distribution.1

Cryptococcosis is an opportunistic infection and occurs primarily in patients with impaired cell-mediated immunity. Susceptibility to the disease is markedly increased in those with T cell–immune dysfunction. Cryptococcosis has been described in children with AIDS, acute lymphoblastic leukemia, hyper IgM and IgE syndromes, Bruton agammaglobulinemia, as well as in children receiving prolonged corticosteroid therapy.2 Before the use of highly active antiretroviral therapy (HAART), cryptococcal infection was a major cause of morbidity and mortality in adult patients with advanced HIV, infecting up to 10% of individuals with AIDS. In contrast, children infrequently develop cryptococcal disease, and prevalence rates in children with AIDS are reported to be around 1%.3,4 Human disease is believed to be initiated by inhalation of cryptococcal cells, although infection via the gastrointestinal tract and direct inoculation into tissues can also be mechanisms of infection.

 CLINICAL MANIFESTATIONS

After cryptococcal cells are inhaled, they localize in the pulmonary parenchyma and may cause an isolated pneumonitis or disseminate hematogenously to any organ of the body. In immunocompromised hosts, the central nervous system is the most common extrapulmo-nary site of infection, and Cryptococcus is the most frequent cause of fungal meningitis.8 Cryptococcal infection of the central nervous system is frequently indolent, presenting with nonspecific symptoms such as fever and headache. Focal neurologic deficits and altered mental status are less common and are seen with more advanced disease. Cryptococcal meningitis and meningoencephalitis share many clinical and laboratory features with meningitis caused by M tuberculosis and Coccidiomycosis immitis. The cerebrospinal fluid (CSF) typically reveals lymphocytosis, elevated protein levels, and mildly reduced glucose levels. However, in patients with AIDS, CSF parameters may be unremarkable due to a lack of inflammatory host response. Slowly progressing symptoms in both immunocompetent and immunocompromised patients may lead to a delay in diagnosis. Untreated cryptococcal meningoencephalitis is generally fatal over weeks to months.

Isolated pulmonary infection is most commonly seen in immunocompetent patients and can be asymptomatic and discovered incidentally as a solitary nodule during radiography. When clinically apparent, disease may be associated with cough productive of mucoid sputum, chest pain, fever, weight loss, night sweats, and, occasionally, hemoptysis and respiratory failure. Chest radiographs may show interstitial or focal infiltrates, lymphadenopathy, or, rarely, pleural effusions. In immunocompromised patients, pulmonary disease is most frequently in association with disseminated disease.

C gattii in immunocompetent individuals may cause an exuberant inflammatory response and cause pulmonary and central nervous system masses. Other sites of infection, such as skin, bone, joints, lymph nodes, eye, and placenta, have been reported.9 It is imperative for patients with cryptococcal infection isolated from the lungs and other organs to have a lumbar puncture done to rule out central nervous system infection.

 DIAGNOSIS

The most rapid and reliable way to diagnose cryptococcal infection is to demonstrate cryptococcal capsular polysaccharide antigen in either serum or cerebrospinal fluid (CSF).

Cryptococcus can be grown on routine fungal culture media, but cultures are less sensitive than antigen detection when there is a small fungal burden. The visualization of budding organisms in an India ink wet preparation of the CSF establishes the diagnosis but the sensitivity of India ink is less than 50%.

 TREATMENT

Practice guidelines are available for the management of cryptococcosis.10 Immunocompetent hosts with pulmonary disease may experience disease resolution in the absence of any antifungal therapy.2However, most infectious diseases experts recommend treatment of patients with isolated pulmonary cryptococcosis with oral azole agents, given their low toxicity.10,11

For patients with either severe pulmonary disease or disease of the central nervous system, high-dose amphotericin B (0.7–1.0 mg/kg/day) or a combination of this drug with 5-flucytosine (100 mg/kg/day) is recommended. Several studies have demonstrated the superiority of high-dose amphotericin B in combination with 5-flucytosine as initial therapy for cryptococcal meningitis. This regimen results in higher rates of CSF sterilization and lower mortality.12Immunocompromised patients with cryptococcal meningitis or severe pulmonary disease require 3 stages of treatment: induction with amphotericin and 5-flucytosine for 2 weeks, followed by an 8- to 10-week course of an oral azole agent, and then long-term suppressive therapy of fluconazole at a lower dose. Because the cure rate in central nervous system cryptococcosis does not exceed 75%, and because relapses are common, patients require lengthy and sometimes lifelong suppressive therapy with an azole agent. The newer generation azoles, such as Voriconazole and Posaconazole, are also effective against cryptococcal infection. The echinocandins (Caspofungin and Micafungin) have no activity against Cryptococcus.