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Most cases of cryptococcosis in HIV-infected patients are caused by Cryptococcus neoformans; C. gatti (formerly C. neoformans variety gatti) infection occurs primarily in tropical and subtropical areas. Cryptococcal infections occur much less frequently among HIV-infected children than among adults (339Leggiadro RJ, Kline MW, Hughes WT. Extrapulmonary cryptococcosis in children with acquired immunodeficiency syndrome. Pediatr Infect Dis J 1991;10:658-62., 340Gonzalez CE, Shetty D, Lewis LL, et al. Cryptococcosis in human immunodeficiency virus-infected children. Pediatr Infect Dis J 1996;15:796-800., 341Abadi J, Nachman S KA, Pirofski L. Cryptococcosis in children with AIDS. Clin Infect Dis 1999;28:309-13.). During the pre-HAART era, most cases of cryptococcosis in HIV-infected children (overall incidence, 1%) occurred in those aged 6-12 years and in those with CD4 counts indicating severe immunosuppression (341Abadi J, Nachman S KA, Pirofski L. Cryptococcosis in children with AIDS. Clin Infect Dis 1999;28:309-13.). Access to HAART has dramatically decreased the overall incidence of cryptococcal infection (342Mirza S, Phelan M, Rimland D, et al. The changing epidemiology of cryptococcosis: an update from population-based active surveillance in 2 large metropolitan areas, 1992-2000. Clin Infect Dis 2003;36:789-94., 343), and cryptococcosis in HIV-infected children on HAART remains exceedingly uncommon. Data from various PACTG studies during the pre-HAART and post-HAART eras indicate that the rate of invasive fungal infection, including cryptococcosis, has remained <0.1 per 100 child-years (1Dankner WM, Lindsey JC, Levin MJ, et al. Correlates of opportunistic infections in children infected with the human immunodeficiency virus managed before highly active antiretroviral therapy. Pediatr Infect Dis J 2001;20:40-8., 3Gona P, Van Dyke RB, Williams PL, et al. Incidence of opportunistic and other infections in HIV-infected children in the HAART era. JAMA 2006;296:292-300.). In the Perinatal AIDS Collaborative Transmission Study, no cases of cryptococcosis were identified during the HAART era (4Nesheim SR, Kapogiannis BG, Soe MM, et al. Trends in opportunistic infections in the pre- and post-highly active antiretroviral therapy eras among HIV-infected children in the Perinatal AIDS Collaborative Transmission Study, 1986-2004. Pediatrics 2007;120:00 100–9.).

Cryptococcosis often presents with subtle and nonspecific findings such as fever and headache. Early diagnosis requires consideration of this infection in a symptomatic patient whose CD4 counts indicate severe immunosuppression. In both HIV-infected adults and children, meningoencephalitis is the most common initial manifestation of cryptococcosis. The disease typically evolves over days to weeks with fever and headache. Less frequent findings include nuchal rigidity, photophobia, and focal neurologic signs, as were seen among 30 HIV-infected children with cryptococcosis reported from the United States (341Abadi J, Nachman S KA, Pirofski L. Cryptococcosis in children with AIDS. Clin Infect Dis 1999;28:309-13.). In contrast to this indolent presentation, children in Zimbabwe presented with an acute form of neurologic cryptococcosis (69% with nuchal rigidity, 38% with seizure activity, and 23% with focal neurologic signs) (344Gumbo T, Kadzirange G, Mielke J, et al. Cryptococcus neoformans meningoencephalitis in African children with acquired immunodeficiency syndrome. Pediatr Infect Dis J 2002;21:54-6.). CNS mass lesions (cryptococcomas) have not been reported among HIV-infected children.

Disseminated cryptococcosis can be associated with cutaneous lesions, including small, translucent umbilicated papules (indistinguishable from molluscum contagiosum), nodules, ulcers, and infiltrated plaques resembling cellulitis. Diagnosis of pulmonary cryptococcosis without dissemination is unusual among children. Presenting findings include unexplained recurrent fever, cough with scant sputum, intrathoracic lymphadenopathy, and focal or diffuse pulmonary infiltrates. Alternatively the infection may be asymptomatic, with pulmonary nodules revealed on routine chest radiograph (340Gonzalez CE, Shetty D, Lewis LL, et al. Cryptococcosis in human immunodeficiency virus-infected children. Pediatr Infect Dis J 1996;15:796-800.).

Detection of cryptococcal antigen in serum, CSF or other body fluids is highly effective for rapid and accurate diagnosis of cryptococcal infection.

Microscopic examination of CSF on India ink-stained wet mounts should be performed to diagnose suspected CNS disease. CSF cell count, glucose, and protein can be virtually normal with CNS cryptococcosis, but the opening pressure usually is elevated. Cryptococcal antigen can be detected in CSF or serum by latex agglutination test (several manufacturers) from >90% of patients with cryptococcal meningitis. However, CSF antigen detection may be negative in culture-positive cryptococcal meningitis; high titers of antigen (prozone effect), low levels of antigen, and nonencapsulated strains contribute to this contradictory result (345Chuck SL, Sande MA. Infections with Cryptococcus neoformans in the acquired immunodeficiency syndrome. N Engl J Med 1989;321: 794-9., 346Currie BP, Freundlich LF, Soto MA, et al. False-negative cerebrospinal fluid cryptococcal latex agglutination tests for patients with culture-positive cryptococcal meningitis. J Clin Microbiol 1993;31:2519-22.).

Fungal cultures from CSF, sputum, and blood can identify the organism; the lysis-centrifugation method is the most sensitive for blood specimens. In some cases (e.g., refractory or relapsed disease), susceptibility testing of the C. neoformans isolate can be beneficial. Overall in vitro resistance to antifungal agents remains uncommon (347Pfaller MA, Messer SA, Boyken L, et al. Global trends in the antifungal susceptibility of Cryptococcus neoformans (1990 to 2004). J Clin Microbiol 2005;43:2163-7.).

Diffuse pulmonary disease can be diagnosed through bronchoalveolar lavage and direct examination of India ink-stained specimens, culture, and antigen detection. Focal pulmonary and skin lesions may require biopsy with culture and staining.

Not applicable.

The most common and well-studied presentation of cryptococcal infection in HIV-infected patients is CNS disease. In light of studies in adults (354Bennett JE, Dismukes WE, Duma RJ, et al. A comparison of amphotericin B alone and combined with flucytosine in the treatment of cryptoccal meningitis. N Engl J Med 1979;301:126-31., 355van der Horst CM, Saag MS, Cloud GA, et al. Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. National Institute of Allergy and Infectious Diseases Mycoses Study Group and AIDS Clinical Trials Group. N Engl J Med 1997;337:15-21., 356Saag MS, Graybill RJ, Larsen RA, et al. Practice guidelines for the management of cryptococcal disease. Infectious Diseases Society of America. Clin Infect Dis 2000;30:710-8.), combination therapy with amphotericin B and flucytosine for 2 weeks (induction therapy) followed by fluconazole for a minimum of 8 weeks (consolidation therapy) is recommended for children (AI). Cryptococci were cleared from CSF significantly more rapidly from adults with CNS disease who received initial therapy with amphotericin B (0.7 mg/kg/day) and flucytosine (100 mg/kg/day) than it was in those who received amphotericin B alone, amphotericin B plus fluconazole, or triple-antifungal therapy (357Brouwer AE, Rajanuwong A, Chierakul W, et al. Combination antifungal therapies for HIV-associated cryptococcal meningitis: a randomised trial. Lancet 2004;363:1764-7., 358Dromer F, Mathoulin-Pélissier S, Launay O, et al. Determinants of disease presentation and outcome during cryptococcosis: the CryptoA/D study. PLOS Med 2007;4:e21.). In one study of adults, liposomal amphotericin B (AmBisome®) dosed at 4 mg/kg/day resulted in significantly earlier CSF culture conversion than did amphotericin B at 0.7 mg/kg/day (359Leenders AC, Reiss P, Portegies P, et al. Liposomal amphotericin B (AmBisome) compared with amphotericin B both followed by oral fluconazole in the treatment of AIDS-associated cryptococcal meningitis. AIDS 1997;11:1463-71.). Although the cost of specific amphotericin B formulations is an important factor in selection of a specific preparation, the indication for use of the drug is also important. For example, the liposomal preparation is preferred for patients with renal insufficiency (AII). Monitoring for and managing raised intracranial pressure is crucial to the optimal management of CNS cryptococcosis (see below).

In patients who cannot tolerate flucytosine, amphotericin B (or its liposomal preparation) alone can be used for initial therapy (BI). Fluconazole plus flucytosine is superior to fluconazole alone (360Larsen RA, Bozzette SA, Jones BE, et al. Fluconazole combined with flucytosine for treatment of cryptococcal meningitis in patients with AIDS. Clin Infect Dis 1994;19:741-5., 361Mayanja-Kizza H, Oishi K, Mitarai S, et al. Combination therapy with fluconazole and flucytosine for cryptococcal meningitis in Ugandan patients with AIDS. Clin Infect Dis 1998;26:1362-6.) and provides an alternative to amphotericin B for acute therapy of invasive disease (BII); however, few data are available regarding use of this combination in children, and it should be used only if amphotericin B-based therapy is not tolerated (BIII). Although fluconazole monotherapy was an effective alternative to amphotericin B in adults with AIDS-associated cryptococcal meningitis (362Saag MS, Powderly WG, Cloud GA, et al. Comparison of amphotericin B with fluconazole in the treatment of acute AIDS-associated cryptococcal meningitis. The NIAID Mycoses Study Group and the AIDS Clinical Trials Group. N Engl J Med 1992;326:83-9.), concerns in this study about differences in early death, delayed CSF sterilization, and drug resistance (363Bicanic T, Harrison T, Niepieklo A, et al. Symptomatic relapse of HIV-associated cryptococcal meningitis after initial fluconazole monotherapy: the role of fluconazole resistance and immune reconstitution. Clin Infect Dis 2006;43:1069-73., 364Bicanic T, Meintjes G, Wood R, et al. Fungal burden, early fungicidal activity, and outcome in cryptococcal meningitis in antiretroviral-naive or antiretroviral-experienced patients treated with amphotericin B or fluconazole. Clin Infect Dis 2007;45:76-80.) make fluconazole monotherapy less favorable for initial therapy of CNS disease. Because of rapidly developing resistance, flucytosine alone should never be used to treat cryptococcosis (EII).

After a minimum of 2 weeks of induction therapy with evidence of clinical improvement and a negative CSF culture after repeat lumbar puncture, amphotericin B and flucytosine can be discontinued and consolidation therapy initiated with fluconazole (AI). Consolidation therapy is continued for a minimum of 8 weeks (365Saag MS, Cloud GA, Graybill JR, et al. A comparison of itraconazole versus fluconazole as maintenance therapy for AIDS-associated cryptococcal meningitis. National Institute of Allergy and Infectious Diseases Mycoses Study Group. Clin Infect Dis 1999;28:291-6.). Itraconazole is an alternative to fluconazole for the consolidation phase of CNS therapy and for secondary prophylaxis (BI). Fluconazole is preferred because studies comparing the two agents demonstrate higher rates of CSF sterilization during consolidation therapy (355van der Horst CM, Saag MS, Cloud GA, et al. Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. National Institute of Allergy and Infectious Diseases Mycoses Study Group and AIDS Clinical Trials Group. N Engl J Med 1997;337:15-21.) and less frequent relapse (365Saag MS, Cloud GA, Graybill JR, et al. A comparison of itraconazole versus fluconazole as maintenance therapy for AIDS-associated cryptococcal meningitis. National Institute of Allergy and Infectious Diseases Mycoses Study Group. Clin Infect Dis 1999;28:291-6.) during maintenance therapy in fluconazole recipients.

No controlled clinical studies describe the outcome of non- CNS cryptococcosis in HIV-infected patients. CNS disease should be ruled out in all patients, after which the choice of antifungal medication and length of initial therapy can be decided in light of the clinical severity of illness. Patients with severe pulmonary disease or disseminated cryptococcosis should be treated with amphotericin B with or without the addition of flucytosine, as for CNS disease (AIII). Usually combination therapy should be provided until symptoms resolve. Those with mild-to-moderate pulmonary illness or other localized disease can be managed with fluconazole monotherapy (AIII). Regardless of the antifungal agent selected for initial therapy, secondary prophylaxis with fluconazole or itraconazole should be continued (AIII) until a decision about when to stop prophylaxis can be determined on a case-by-case basis (see note below on discontinuing secondary prophylaxis).

Patients who develop IRIS related to cryptococcosis are more likely than those who do not develop cyrptococcal IRIS to be severely immunocompromised with disseminated infection and to have initiated potent antiretroviral therapy soon after diagnosis of cryptococcal disease (370Lortholary O, Fontanet A, Mémain N, et al. Incidence and risk factors of immune reconstitution inflammatory syndrome complicating HIVassociated cryptococcosis in France. AIDS 2005;19:1043-9.); in antiretroviral-naïve patients newly diagnosed with cryptococcal meningitis, delay in potent antiretroviral therapy may be prudent until the end of the first 2 weeks of induction therapy (CIII).

IRIS related to cryptococcosis can present within weeks (e.g., meningitis) or months (e.g., lymphadenitis) after start of HAART. Symptoms of meningitis are similar to those described for meningitis presenting as the initial manifestation of cryptococcosis. In one study, about 30% of all HIV-infected adults hospitalized for infection with C. neoformans who received HAART were readmitted with symptoms attributed to an inflammatory response (350Shelburne SA, Darcourt J, White AC, et al. The role of immune reconstitution inflammatory syndrome in AIDS-related Cryptococcus neoformans disease in the era of highly active antiretroviral therapy. Clin Infect Dis 2005;40:1049-52.). Of the 18 patients with C. neoformans-related IRIS in the cited study, 17 had culture-negative meningitis, and most cases occurred during the first 30 days after initiation of HAART. The most common presentation of late cryptococcal IRIS is lymphadenitis, particularly mediastinal lymphadenitis (371Skiest DJ, Hester LJ, Hardy RD. Cryptococcal immune reconstitution inflammatory syndrome: report of four cases in three patients and review of the literature. J Infect 2005;51:e289-97.).

The optimal management of cryptococcal IRIS has not been defined. Antifungal therapy should be initiated in patients not already receiving it, and antiretroviral therapy should be continued (AII). Although many cases resolve spontaneously, some experts also have used anti-inflammatory therapy (e.g., short-course corticosteroids) in patients with severely symptomatic IRIS (BIII) (371Skiest DJ, Hester LJ, Hardy RD. Cryptococcal immune reconstitution inflammatory syndrome: report of four cases in three patients and review of the literature. J Infect 2005;51:e289-97., 372Lesho E. Evidence base for using corticosteroids to treat HIV-associated immune reconstitution syndrome. Expert Rev Anti Infect Ther 2006;4: 469-78.).

Treatment failure is defined as clinical deterioration despite appropriate therapy, including management of intracranial pressure; lack of improvement in signs and symptoms after 2 weeks of appropriate therapy; or relapse after an initial clinical response. Differentiating IRIS from treatment failure is important because treatment approaches and outcomes differ. Optimal management of patients with treatment failure is not known. If cultures are positive at treatment failure, evaluation of antifungal susceptibilities might be considered, although fluconazole resistance with C. neoformans is rare in the United States (but more common in some international settings) (363Bicanic T, Harrison T, Niepieklo A, et al. Symptomatic relapse of HIV-associated cryptococcal meningitis after initial fluconazole monotherapy: the role of fluconazole resistance and immune reconstitution. Clin Infect Dis 2006;43:1069-73.). Patients in whom initial azole-based therapy fails should be switched to amphotericin B-based therapy (363Bicanic T, Harrison T, Niepieklo A, et al. Symptomatic relapse of HIV-associated cryptococcal meningitis after initial fluconazole monotherapy: the role of fluconazole resistance and immune reconstitution. Clin Infect Dis 2006;43:1069-73.), ideally in combination with flucytosine (BIII); the possibility of drug interactions resulting in subtherapeutic azole levels (e.g., concurrent rifampin use or other drugs metabolized by the liver) should be explored (363Bicanic T, Harrison T, Niepieklo A, et al. Symptomatic relapse of HIV-associated cryptococcal meningitis after initial fluconazole monotherapy: the role of fluconazole resistance and immune reconstitution. Clin Infect Dis 2006;43:1069-73.). Use of liposomal amphotericin B should be considered, as one study suggests improved efficacy in CSF sterilization with liposomal preparations than with standard amphotericin B (AII) (359Leenders AC, Reiss P, Portegies P, et al. Liposomal amphotericin B (AmBisome) compared with amphotericin B both followed by oral fluconazole in the treatment of AIDS-associated cryptococcal meningitis. AIDS 1997;11:1463-71.). Some data from HIV-infected adults indicate higher dosages (e.g., 400-800 mg/ day) of fluconazole in combination with flucytosine also can be considered for salvage therapy (BII) (356Saag MS, Graybill RJ, Larsen RA, et al. Practice guidelines for the management of cryptococcal disease. Infectious Diseases Society of America. Clin Infect Dis 2000;30:710-8., 373Lortholary O. Management of cryptococcal meningitis in AIDS: the need for specific studies in developing countries. Clin Infect Dis 2007;45:81-3.). Clinical experience with new antifungal agents in managing cryptococcosis is limited. A few patients with cryptococcal infections refractory or intolerant to standard antifungal therapy have been treated with posaconazole or voriconazole with variable success (352Perfect JR, Marr KA, Walsh TJ, et al. Voriconazole treatment for lesscommon, emerging, or refractory fungal infections. Clin Infect Dis 2003;36:1122-31. Vol. 58 / RR-11 Recommendations and Reports 109, 353Pitisuttithum P, Negroni R, Graybill JR, et al. Activity of posaconazole in the treatment of central nervous system fungal infections. J Antimicrob Chemother 2005;56:745-55.). Echinocandins do not have clinical activity against cryptococcal infections and should not be used.

Patients who have completed initial therapy for cryptococcosis should receive suppressive treatment (i.e., secondary prophylaxis or chronic maintenance therapy) (AI). Fluconazole (AI) is superior and preferable to itraconazole (BI) for preventing relapse of cryptococcal disease (365Saag MS, Cloud GA, Graybill JR, et al. A comparison of itraconazole versus fluconazole as maintenance therapy for AIDS-associated cryptococcal meningitis. National Institute of Allergy and Infectious Diseases Mycoses Study Group. Clin Infect Dis 1999;28:291-6., 374Bozzette SA, Larsen RA, Chiu J, et al. A placebo-controlled trial of maintenance therapy with fluconazole after treatment of cryptococcal meningitis in the acquired immunodeficiency syndrome. California Collaborative Treatment Group. N Engl J Med 1991;324:580-4., 375Powderly WG, Saag MS, Cloud GA, et al. A controlled trial of fluconazole or amphotericin B to prevent relapse of cryptococcal meningitis in patients with the acquired immunodeficiency syndrome. The NIAID AIDS Clinical Trials Group and Mycoses Study Group. N Engl J Med 1992;326:793-8.). Suppressive therapy typically is continued long term.

Until recently, lifelong secondary prophylaxis typically was recommended. The safety of discontinuing secondary prophylaxis for cryptococcosis after immune reconstitution with HAART has not been studied in children, and decisions in this regard should be made on a case-by-case basis. Adults at apparent low risk for recurrence of cryptococcosis have successfully completed a course of initial therapy, remain asymptomatic with regard to signs and symptoms of cryptococcosis, and have a sustained (≥6 months) increase in their CD4 counts to ≥200 cells/mm³ after HAART (376Kirk O, Reiss P, Uberti-Foppa C, et al. Safe interruption of maintenance therapy against previous infection with four common HIV-associated opportunistic pathogens during potent antiretroviral therapy. Ann Intern Med 2002;137:239-50., 377Vibhagool A, Sungkanuparph S, Mootsikapun P, et al. Discontinuation of secondary prophylaxis for cryptococcal meningitis in human immunodeficiency virus-infected patients treated with highly active antiretroviral therapy: a prospective, multicenter, randomized study. Clin Infect Dis 2003;36:1329-31., 378Mussini C, Pezzotti P, Miro JM, et al. Discontinuation of maintenance therapy for cryptococcal meningitis in patients with AIDS treated with highly active antiretroviral therapy: an international observational study. Clin Infect Dis 2004;38:565-71.). In light of these observations and inference from data regarding discontinuing secondary prophylaxis for other OIs in adults with advanced HIV infection, discontinuing chronic suppressive therapy for cryptococcosis (after being on it for ≥6 months) can be considered for asymptomatic children aged ≥6 years, on HAART, and with sustained (≥6 months) increase in their CD4 counts to ≥200 cells/mm³ (BII). Suppressive therapy should be reinitiated if the CD4 count decreases to <200 cells/mm³ (AIII).