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. Jun 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.[83]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 people with HIV.[64]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 adverse 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 therapy (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. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
[64]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
[67]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://academic.oup.com/cid/article/50/3/291/392360
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. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
Patients requiring suppressive therapy for more than 1-2 years are also considered treatment failures.[67]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://academic.oup.com/cid/article/50/3/291/392360
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 people with HIV and 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
[84]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://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1000384
http://www.ncbi.nlm.nih.gov/pubmed/21253011?tool=bestpractice.com
[85]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.
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 people with HIV 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/microliter 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.
http://www.ncbi.nlm.nih.gov/pubmed/9878030?tool=bestpractice.com
[11]Dromer F, Mathoulin-Pelissier S, Fontanet A, et al; French Cryptococcosis Study Group. 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