Mortality and morbidity
Unrecognized and untreated cryptococcosis can be fatal, especially in immunocompromised patients, and untreated cryptococcal meningoencephalitis is uniformly fatal. The estimated 1-year mortality for people with HIV-associated cryptococcal meningitis is 70% in low-income countries and 20% to 30% in high-income countries.[10]Rajasingham R, Smith RM, Park BJ, et al. Global burden of disease of HIV-associated cryptococcal meningitis: an updated analysis. Lancet Infect Dis. 2017 Aug;17(8):873-81.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5818156
http://www.ncbi.nlm.nih.gov/pubmed/28483415?tool=bestpractice.com
[23]World Health Organization. Guidelines for diagnosing, preventing and managing cryptococcal disease among adults, adolescents and children living with HIV. June 2022 [internet publication].
https://www.who.int/publications/i/item/9789240052178
Outcomes in other immunosuppressed patients vary according to the underlying disease. Patients with idiopathic CD4 lymphopenia seem to have relatively favorable outcomes.[74]Zonios DI, Falloon J, Huang CY, et al. Cryptococcosis and idiopathic CD4 lymphocytopenia. Medicine (Baltimore). 2007 Mar;86(2):78-92.
http://www.ncbi.nlm.nih.gov/pubmed/17435588?tool=bestpractice.com
Early appropriate treatment reduces morbidity and prevents progression to potentially life-threatening central nervous system disease. The cryptococcal polysaccharide antigen (CrAg) status has been found to be an independent predictor of mortality in HIV-positive patients.[55]Jarvis JN, Dromer F, Harrison TS, et al. Managing cryptococcosis in the immunocompromised host. Curr Opin Infect Dis. 2008 Dec;21(6):596-603.
http://www.ncbi.nlm.nih.gov/pubmed/18978527?tool=bestpractice.com
Toxic side effects from antifungal therapy are common, and up to 30% of patients with cryptococcal meningitis and HIV develop immune reconstitution inflammatory syndrome (IRIS) following initiation or reinitiation of antiretroviral treatment (ART).[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. July 2021 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis?view=full
[55]Jarvis JN, Dromer F, Harrison TS, et al. Managing cryptococcosis in the immunocompromised host. Curr Opin Infect Dis. 2008 Dec;21(6):596-603.
http://www.ncbi.nlm.nih.gov/pubmed/18978527?tool=bestpractice.com
[58]Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010 Feb 1;50(3):291-322.
https://cid.oxfordjournals.org/content/50/3/291.long
http://www.ncbi.nlm.nih.gov/pubmed/20047480?tool=bestpractice.com
Treatment failure and relapse
Treatment failure is defined as the lack of clinical improvement after 2 weeks of therapy (including management of increased intracranial pressure [ICP] with continued positive cultures) or relapse after initial clinical response (i.e., recurrence of symptoms with a positive cerebrospinal fluid [CSF] culture after ≥4 weeks of treatment).[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. July 2021 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis?view=full
Patients requiring suppressive therapy for more than 1 to 2 years are also considered treatment failures.[58]Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010 Feb 1;50(3):291-322.
https://cid.oxfordjournals.org/content/50/3/291.long
http://www.ncbi.nlm.nih.gov/pubmed/20047480?tool=bestpractice.com
In the absence of maintenance therapy, there is a high risk of relapse among HIV-positive patients with cryptococcal meningitis who have been treated successfully. Positive CSF cultures after 2 weeks of therapy are predictive of future relapse and a less favorable clinical outcome.[1]Chayakulkeeree M, Perfect JR. Cryptococcosis. Infect Dis Clin North Am. 2006 Sep;20(3):507-44.
http://www.ncbi.nlm.nih.gov/pubmed/16984867?tool=bestpractice.com
Serum CrAg titers do not correlate with clinical improvement; however, pre-ART serum CrAg titers are predictive of future IRIS.[1]Chayakulkeeree M, Perfect JR. Cryptococcosis. Infect Dis Clin North Am. 2006 Sep;20(3):507-44.
http://www.ncbi.nlm.nih.gov/pubmed/16984867?tool=bestpractice.com
[75]Boulware DR, Meya DB, Bergemann TL, et al. Clinical features and serum biomarkers in HIV immune reconstitution inflammatory syndrome after cryptococcal meningitis: a prospective cohort study. PLoS Med. 2010 Dec 21;7(12):e1000384.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3014618
http://www.ncbi.nlm.nih.gov/pubmed/21253011?tool=bestpractice.com
[76]Sungkanuparph S, Filler SG, Chetchotisakd P, et al. Cryptococcal immune reconstitution inflammatory syndrome after antiretroviral therapy in AIDS patients with cryptococcal meningitis: a prospective multicenter study. Clin Infect Dis. 2009 Sep 15;49(6):931-4.
https://cid.oxfordjournals.org/content/49/6/931.long
http://www.ncbi.nlm.nih.gov/pubmed/19681708?tool=bestpractice.com
If new clinical symptoms arise, a careful lumbar puncture should be performed to rule out the possibility of increased ICP or IRIS. The risk of recurrence seems to be low in HIV-positive patients who have successfully completed a course of initial therapy, remain asymptomatic, and have a sustained increase (i.e., >6 months) in the CD4 count to ≥200 cells/mm³ after potent ART.[1]Chayakulkeeree M, Perfect JR. Cryptococcosis. Infect Dis Clin North Am. 2006 Sep;20(3):507-44.
http://www.ncbi.nlm.nih.gov/pubmed/16984867?tool=bestpractice.com
[9]Hajjeh RA, Conn LA, Stephens DS, et al. Cryptococcosis: population-based multistate active surveillance and risk factors in human immunodeficiency virus-infected persons. J Infect Dis. 1999 Feb;179(2):449-54.
https://academic.oup.com/jid/article/179/2/449/1000299
http://www.ncbi.nlm.nih.gov/pubmed/9878030?tool=bestpractice.com
[11]Dromer F, Mathoulin-Pelissier S, Fontanet A, et al. Epidemiology of HIV-associate cryptococcosis in France (1985-2001): comparison of the pre-and post-HAART eras. AIDS. 2004 Feb 20;18(3):555-62.
http://www.ncbi.nlm.nih.gov/pubmed/15090810?tool=bestpractice.com