Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in HIV-infected patients Authors Gary M Cox, MD John R Perfect, MD Section Editor John G Bartlett, MD Deputy Editor Jennifer Mitty, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Aug 2016. | This topic last updated: Jan 04, 2016. INTRODUCTION — Disseminated Cryptococcus neoformans infection is a serious opportunistic infection that occurs in patients with untreated AIDS [ 1 ]. Although cryptococcal infection begins in the lungs, meningitis is the most frequently encountered manifestation of cryptococcosis among those with advanced immunosuppression. However, the infection is more properly characterized as "meningoencephalitis" rather than meningitis since the brain parenchyma is almost always involved on histologic examination [2,3 ]. The clinical manifestations and diagnosis of C. neoformans meningoencephalitis in AIDS patients will be reviewed here. Treatment and monitoring of AIDS patients with cryptococcal meningoencephalitis is found elsewhere. The microbiology, clinical manifestations, and treatment of this infection in other patient populations, such as transplant patients, are discussed elsewhere. C. gattii infection is also presented separately. (See "Treatment of Cryptococcus neoformans meningoencephalitis in HIV- infected patients" and "Clinical management and monitoring during antifungal therapy of the HIV- infected patient with cryptococcal meningoencephalitis" and "Microbiology and epidemiology of Cryptococcus neoformans infection" and "Clinical manifestations and diagnosis of Cryptococcus neoformans meningoencephalitis in HIV-seronegative patients" and "Treatment of Cryptococcus neoformans meningoencephalitis and disseminated infection in HIV seronegative patients" and "Cryptococcus neoformans infection outside the central nervous system" and "Cryptococcus gattii infection: Microbiology, epidemiology, and pathogenesis" and "Cryptococcus gattii infection: Clinical features and diagnosis" and "Cryptococcus gattii infection: Treatment" .) EPIDEMIOLOGY — Globally, it has been estimated that approximately 957,900 cases of cryptococcal meningoencephalitis occur each year, resulting in more than 600,000 deaths [ 4,5 ]. The vast majority of cases occur among patients with AIDS and a CD4 count <100 cells/microL. The region with the highest number of estimated cases in 2006 was sub-Saharan Africa (720,000 cases; range, 144,000 to 1.3 million), followed by South and Southeast Asia (120,000 cases; range, 24,000 to 216,000) [ 4 ]. Although the incidence of cryptococcal meningoencephalitis has declined in patients who have access to antiretroviral therapy (ART) [ 6 ], cryptococcal disease remains a leading cause of mortality in the developing world where access to ART is limited and HIV prevalence remains high [ 7 ]. Early diagnosis and treatment may help reduce cryptococcal meningitis-related mortality [8 ]. One way to diagnose cryptococcal infection early in the course disease is through the detection of serum cryptococcal antigen (CrAg), which can be detected at least three weeks prior to the onset of neurologic symptoms. The prevalence of antigenemia has been found to vary depending upon the geographical area. As an example, in the United States, the prevalence of cryptococcal antigenemia among patients with a CD4 count <100 cells/microL was reported to be approximately 3 percent, whereas in Uganda the prevalence among such patients was 13.5 percent [ 9,10 ]. A discussion on the use of screening and early therapy to prevent meningoencephalitis is found elsewhere.
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Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in HIV-infected patients Authors Gary M Cox, MD John R Perfect, MD Section Editor John G Bartlett, MD Deputy Editor Jennifer Mitty, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Aug 2016. | This topic last updated: Jan 04, 2016.
INTRODUCTION — Disseminated Cryptococcus neoformans infection is a serious opportunistic
infection that occurs in patients with untreated AIDS [1]. Although cryptococcal infection begins in the
lungs, meningitis is the most frequently encountered manifestation of cryptococcosis among those with
advanced immunosuppression. However, the infection is more properly characterized as
"meningoencephalitis" rather than meningitis since the brain parenchyma is almost always involved on
histologic examination [2,3].
The clinical manifestations and diagnosis of C. neoformans meningoencephalitis in AIDS patients will
be reviewed here. Treatment and monitoring of AIDS patients with cryptococcal meningoencephal itis is
found elsewhere. The microbiology, clinical manifestations, and treatment of this infection in other
patient populations, such as transplant patients, are discussed elsewhere. C. gattii infection is also
presented separately. (See "Treatment of Cryptococcus neoformans meningoencephalitis in HIV-
infected patients" and "Clinical management and monitoring during antifungal therapy of the HIV-
infected patient with cryptococcal meningoencephalitis" and "Microbiology and epidemiology of
Cryptococcus neoformans infection" and "Clinical manifestations and diagnosis of Cryptococcus
neoformans meningoencephalitis in HIV-seronegative patients" and "Treatment of Cryptococcus
neoformans meningoencephalitis and disseminated infection in HIV seronegative
patients" and "Cryptococcus neoformans infection outside the central nervous
system" and "Cryptococcus gattii infection: Microbiology, epidemiology, and
pathogenesis" and "Cryptococcus gattii infection: Clinical features and diagnosis" and "Cryptococcus
gattii infection: Treatment".)
EPIDEMIOLOGY — Globally, it has been estimated that approximately 957,900 cases of cryptococcal
meningoencephalitis occur each year, resulting in more than 600,000 deaths [4,5]. The vast majority of
cases occur among patients with AIDS and a CD4 count <100 cells/microL. The region with the
highest number of estimated cases in 2006 was sub-Saharan Africa (720,000 cases; range, 144,000 to
1.3 million), followed by South and Southeast Asia (120,000 cases; range, 24,000 to 216,000) [4].
Although the incidence of cryptococcal meningoencephalitis has declined in patients who have access
to antiretroviral therapy (ART) [6], cryptococcal disease remains a leading cause of mortality in the
developing world where access to ART is limited and HIV prevalence remains high [7].
Early diagnosis and treatment may help reduce cryptococcal meningitis-related mortality [8]. One way
to diagnose cryptococcal infection early in the course disease is through the detection of serum
cryptococcal antigen (CrAg), which can be detected at least three weeks prior to the onset of
neurologic symptoms. The prevalence of antigenemia has been found to vary depending upon the
geographical area. As an example, in the United States, the prevalence of cryptococcal antigenemia
among patients with a CD4 count <100 cells/microL was reported to be approximately 3 percent,
whereas in Uganda the prevalence among such patients was 13.5 percent [9,10]. A discussion on the
use of screening and early therapy to prevent meningoencephalitis is found elsewhere.
Abnormal mental status on baseline examination or a deterioration of mental status can reflect
increased intracranial pressure (ICP). Raised ICP should be considered an urgent medical issue
requiring prompt intervention. (See "Clinical management and monitoring during antifungal therapy of
the HIV-infected patient with cryptococcal meningoencephalitis", section on 'Monitoring of intracranial
pressure'.)
SUMMARY AND RECOMMENDATIONS
●Cryptococcosis is an invasive fungal infection, most commonly caused by Cryptococcus
neoformans. Infection begins in the lungs; meningoencephalitis is the most frequently
encountered manifestation of cryptococcosis in HIV-infected patients. (See 'Introduction' above.)
●The incidence of cryptococcal meningoencephalitis has declined in patients who have access to
antiretroviral therapy (ART). However, cryptococcal disease remains a leading cause of mortality
in the developing world. (See 'Epidemiology' above.)
●Symptoms typically begin indolently over a period of one to two weeks. The most common
symptoms are fever, malaise, and headache. Other symptoms, suggesting disseminated disease,
may be present including cough, dyspnea, and skin rash. (See 'Clinical manifestations' above.)
●The definitive diagnosis of cryptococcal meningoencephalitis is made by culture of the organism
from the cerebrospinal fluid (CSF). A positive cryptococcal polysaccharide antigen in the CSF or
serum strongly suggests the presence of infection well before the cultures become positive.
(See 'Diagnosis' above.)
●Radiographic imaging of the brain must be performed prior to lumbar puncture if there is a
concern for increased intracranial pressure (ICP) and/or other space-occupying lesions.
(See 'Importance of neuroimaging' above.)
●The significant clinical and laboratory predictors of death during initial therapy include an
abnormal mental status, a CSF antigen titer of 1:1024, and a pleocytosis of <20 cells/microL.
(See 'Prognostic factors' above.)
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REFERENCES
1. Bamba S, Lortholary O, Sawadogo A, et al. Decreasing incidence of cryptococcal meningitis in West Africa in the era of highly active antiretroviral therapy. AIDS 2012; 26:1039.
2. Cox GM, Perfect JR. Cryptococcus neoformans var neoformans and gattii and Trichosporon species. In: Topley and Wilson's Microbiology and Microbial Infections, 9th Ed, Edward LA (Ed), Arnold Press, London 1997.
3. Lee SC, Dickson DW, Casadevall A. Pathology of cryptococcal meningoencephalitis: analysis of 27 patients with pathogenetic implications. Hum Pathol 1996; 27:839.
4. Park BJ, Wannemuehler KA, Marston BJ, et al. Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS. AIDS 2009; 23:525.
5. Desalermos A, Kourkoumpetis TK, Mylonakis E. Update on the epidemiology and management of cryptococcal meningitis. Expert Opin Pharmacother 2012; 13:783.
6. Mirza SA, 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.
7. Jarvis JN, Harrison TS. HIV-associated cryptococcal meningitis. AIDS 2007; 21:2119. 8. World Health Organization. Rapid advice: diagnosis, prevention and management of cryptococcal
disease in HIV-infected adults, adolescents, and children. http://whqlibdoc.who.int/publications/2011/9789241502979_eng.pdf?ua=1 (Accessed on March 03, 2014).
9. McKenney J, Bauman S, Neary B, et al. Prevalence, correlates, and outcomes of cryptococcal antigen positivity among patients with AIDS, United States, 1986-2012. Clin Infect Dis 2015; 60:959.
10. Meya DB, Manabe YC, Castelnuovo B, et al. Cost-effectiveness of serum cryptococcal antigen screening to prevent deaths among HIV-infected persons with a CD4+ cell count < or = 100 cells/microL who start HIV therapy in resource-limited settings. Clin Infect Dis 2010; 51:448.
11. Murakawa GJ, Kerschmann R, Berger T. Cutaneous Cryptococcus infection and AIDS. Report of 12 cases and review of the literature. Arch Dermatol 1996; 132:545.
12. Rex JH, Larsen RA, Dismukes WE, et al. Catastrophic visual loss due to Cryptococcus neoformans meningitis. Medicine (Baltimore) 1993; 72:207.
13. Graybill JR, Sobel J, Saag M, et al. Diagnosis and management of increased intracranial pressure in patients with AIDS and cryptococcal meningitis. The NIAID Mycoses Study Group and AIDS Cooperative Treatment Groups. Clin Infect Dis 2000; 30:47.
14. Sánchez-Portocarrero J, Pérez-Cecilia E. Intracerebral mass lesions in patients with human immunodeficiency virus infection and cryptococcal meningitis. Diagn Microbiol Infect Dis 1997; 29:193.
15. Troncoso A, Fumagalli J, Shinzato R, et al. CNS cryptococcoma in an HIV-positive patient. J Int Assoc Physicians AIDS Care (Chic) 2002; 1:131.
16. Brouwer AE, Rajanuwong A, Chierakul W, et al. Combination antifungal therapies for HIV-associated cryptococcal meningitis: a randomised trial. Lancet 2004; 363:1764.
17. Darras-Joly C, Chevret S, Wolff M, et al. Cryptococcus neoformans infection in France: epidemiologic features of and early prognostic parameters for 76 patients who were infected with human immunodeficiency virus. Clin Infect Dis 1996; 23:369.
18. Garlipp CR, Rossi CL, Bottini PV. Cerebrospinal fluid profiles in acquired immunodeficiency syndrome with and without neurocryptococcosis. Rev Inst Med Trop Sao Paulo 1997; 39:323.
19. Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: Recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf (Accessed on October 20, 2015).
20. Jarvis JN, Percival A, Bauman S, et al. Evaluation of a novel point-of-care cryptococcal antigen test on serum, plasma, and urine from patients with HIV-associated cryptococcal meningitis. Clin Infect Dis 2011; 53:1019.
21. Boulware DR, Rolfes MA, Rajasingham R, et al. Multisite validation of cryptococcal antigen lateral flow assay and quantification by laser thermal contrast. Emerg Infect Dis 2014; 20:45.
22. Tanner DC, Weinstein MP, Fedorciw B, et al. Comparison of commercial kits for detection of cryptococcal antigen. J Clin Microbiol 1994; 32:1680.
23. Chanock SJ, Toltzis P, Wilson C. Cross-reactivity between Stomatococcus mucilaginosus and latex agglutination for cryptococcal antigen. Lancet 1993; 342:1119.
24. McManus EJ, Jones JM. Detection of a Trichosporon beigelii antigen cross-reactive with Cryptococcus neoformans capsular polysaccharide in serum from a patient with disseminated Trichosporon infection. J Clin Microbiol 1985; 21:681.
25. Westerink MA, Amsterdam D, Petell RJ, et al. Septicemia due to DF-2. Cause of a false-positive cryptococcal latex agglutination result. Am J Med 1987; 83:155.
26. Blevins LB, Fenn J, Segal H, et al. False-positive cryptococcal antigen latex agglutination caused by disinfectants and soaps. J Clin Microbiol 1995; 33:1674.
27. Boom WH, Piper DJ, Ruoff KL, Ferraro MJ. New cause for false-positive results with the cryptococcal antigen test by latex agglutination. J Clin Microbiol 1985; 22:856.
28. Wilson DA, Sholtis M, Parshall S, et al. False-positive cryptococcal antigen test associated with use of BBL Port-a-Cul transport vials. J Clin Microbiol 2011; 49:702.
29. Asawavichienjinda T, Sitthi-Amorn C, Tanyanont V. Serum cyrptococcal antigen: diagnostic value in the diagnosis of AIDS-related cryptococcal meningitis. J Med Assoc Thai 1999; 82:65.
30. Micol R, Lortholary O, Sar B, et al. Prevalence, determinants of positivity, and clinical utility of cryptococcal antigenemia in Cambodian HIV-infected patients. J Acquir Immune Defic Syndr 2007; 45:555.
31. Powderly WG, Cloud GA, Dismukes WE, Saag MS. Measurement of cryptococcal antigen in serum and cerebrospinal fluid: value in the management of AIDS-associated cryptococcal meningitis. Clin Infect Dis 1994; 18:789.
32. Aberg JA, Watson J, Segal M, Chang LW. Clinical utility of monitoring serum cryptococcal antigen (sCRAG) titers in patients with AIDS-related cryptococcal disease. HIV Clin Trials 2000; 1:1.
33. Larsen RA, Bozzette S, McCutchan JA, et al. Persistent Cryptococcus neoformans infection of the prostate after successful treatment of meningitis. California Collaborative Treatment Group. Ann Intern Med 1989; 111:125.
34. Lortholary O, Poizat G, Zeller V, et al. Long-term outcome of AIDS-associated cryptococcosis in the era of combination antiretroviral therapy. AIDS 2006; 20:2183.
35. Lanoy E, Guiguet M, Bentata M, et al. Survival after neuroAIDS: association with antiretroviral CNS Penetration-Effectiveness score. Neurology 2011; 76:644.
36. Saag 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.
37. Robinson PA, Bauer M, Leal MA, et al. Early mycological treatment failure in AIDS-associated cryptococcal meningitis. Clin Infect Dis 1999; 28:82.
38. Bratton EW, El Husseini N, Chastain CA, et al. Comparison and temporal trends of three groups with cryptococcosis: HIV-infected, solid organ transplant, and HIV-negative/non-transplant. PLoS One 2012; 7:e43582.
Topic 3757 Version 13.0
GRAPHICS
Disseminated cryptococcosis
Multiple umbilicated papules are present on the face of this patient with cryptococcosis. The
Treatment of Cryptococcus neoformans meningoencephalitis in HIV-infected patients Authors Gary M Cox, MD John R Perfect, MD Section Editor John G Bartlett, MD Deputy Editor Jennifer Mitty, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Aug 2016. | This topic last updated: Feb 26, 2016.
INTRODUCTION — Cryptococcus neoformans meningoencephalitis is one of the leading opportunistic
infections seen in patients with untreated AIDS [1]. Management of these severely
immunocompromised patients includes antifungal therapy combined with antiretroviral therapy (ART),
with careful monitoring for complications related to the invasive fungal infection and the inflammatory
syndromes secondary to immune recovery [2].
This topic is devoted to the treatment of the HIV-infected host with C. neoformans meningitis. The
epidemiology, clinical manifestations, diagnosis, treatment and management of complications of
disease are discussed elsewhere. C. neoformans infection outside the central nervous system, C.
neoformans infection in HIV seronegative patients, and Cryptococcus gattii infection are also
discussed separately. (See "Epidemiology, clinical manifestations, and diagnosis of Cryptococcus
neoformans meningoencephalitis in HIV-infected patients" and "Microbiology and epidemiology of
Cryptococcus neoformans infection" and "Immune reconstitution inflammatory syndrome" and "Clinical
management and monitoring during antifungal therapy of the HIV-infected patient with cryptococcal
meningoencephalitis" and"Cryptococcus neoformans infection outside the central nervous
system" and "Clinical manifestations and diagnosis of Cryptococcus neoformans meningoencephalitis
in HIV-seronegative patients" and "Treatment of Cryptococcus neoformans meningoencephalitis and
disseminated infection in HIV seronegative patients" and "Cryptococcus gattii infection: Microbiology,
epidemiology, and pathogenesis" and "Cryptococcus gattii infection: Clinical features and
diagnosis" and "Cryptococcus gattii infection: Treatment".)
ANTIFUNGAL AGENTS — The primary antifungal agents used for the treatment of cryptococcal
meningoencephalitis include intravenous amphotericin B deoxycholate or its lipid formulations,
oral flucytosine, and oral fluconazole. For most patients, liposomal preparations of amphotericin B are
preferred to minimize the risk of toxicity and improve the ability to give an uninterrupted induction
period of treatment. Echinocandin antifungals do not have significant activity against C.
neoformans and should not be used to treat this infection [3]. (See "Pharmacology of
azoles" and "Pharmacology of amphotericin B".)
Combination therapy with amphotericin B and flucytosine is fungicidal (inhibition leads to cell death),
while fluconazole alone is only fungistatic (ie, inhibits without killing). Importantly, the use of a
fungicidal regimen during the initial phase of therapy has been associated with better clinical outcomes
[4]. (See 'Induction and consolidation therapy' below.)
GENERAL PRINCIPLES — The HIV-infected patient with advanced immunosuppression (CD4 cell
count <50 cells/microL) is at risk for severe cryptococcal meningoencephalitis, which is uniformly fatal
within approximately two weeks if untreated [5]. Common presenting symptoms include fever,
headache, photophobia, nausea, and vomiting; patients with fulminant disease may present with
coma. Predictors of poor outcome include high cerebrospinal fluid (CSF) cryptococcal antigen levels
(titer >1:1024), low body weight, poor CSF inflammatory response (<20 cells/ul of CSF), and altered
mental status on presentation [6]. (See "Epidemiology, clinical manifestations, and diagnosis of
orally) in addition to amphotericin B during the two-week induction phase of therapy (Grade 1B).
It is important that induction therapy not be interrupted. (See 'Induction and consolidation' above.)
•For patients with normal renal function, we suggest liposomal amphotericin B (3 to
4 mg/kg IV daily) rather than amphotericin B deoxycholate (Grade 2B). However,
amphotericin B deoxycholate (0.7 mg/kg IV daily) is a suitable alternative for such patients if
liposomal amphotericin is not available. (See 'Patients without risk of nephrotoxicity' above.)
•For patients with baseline renal dysfunction and for those at risk for renal failure (eg, those
with diabetes or uncontrolled hypertension or patients taking other nephrotoxic drugs), we
recommend liposomal amphotericin B (3 to 4 mg/kg IV daily) rather than amphotericin B
deoxycholate (Grade 1B). The incidence and severity of decreased renal function is
reduced with liposomal amphotericin B compared with amphotericin deoxycholate,
particularly among patients at increased risk of nephrotoxicity. (See 'Patients at risk of renal
insufficiency' above and 'Patients with established renal insufficiency' above.)
●If there is clinical improvement during the two-week induction therapy period, amphotericin B
and flucytosine can be discontinued and oral azole therapy initiated for the eight-week
consolidation phase of treatment. For patients who received amphotericin B plus flucytosine
during the induction phase of therapy, we recommendfluconazole (400 mg per day orally) rather
than itraconazole during the consolidation phase (Grade 1B). For patients who received
amphotericin B plus fluconazole during the induction phase of therapy, we suggest fluconazole at
a dose of 800 mg orally daily rather than itraconazole or fluconazole at a lower dose (Grade 2C).
(See 'Induction and consolidation' above.)
●After the completion of induction/consolidation phases of therapy, we
recommend fluconazole (200 mg daily) for maintenance treatment compared with no therapy
(Grade 1A). Long-term chronic suppression should be continued for a minimum of one year.
(See 'Maintenance therapy' above.)
●We discontinue maintenance fluconazole therapy in asymptomatic patients who have CD4 cell
counts >100 cells/microL, who have an undetectable viral load on antiretroviral therapy (ART) for
greater than three months and who have received a minimum of one year of azole maintenance
therapy. Close follow-up is advised, and fluconazole should be reinitiated if the CD4 cell count
declines to <100 cells/microL. (See 'Discontinuation of maintenance therapy' above.)
●We suggest not routinely administering antifungal prophylaxis for primary prevention of
cryptococcal disease (Grade 2B). However, for asymptomatic patients with a CD4 count
<100 cells/microL not receiving ART, who are from resource-limited settings where the
prevalence of cryptococcal antigenemia is >3 percent, we suggest a strategy involving serum
cryptococcal antigen screening prior to initiation of ART (Grade 2C). The management of patients
who screen positive for cryptococcal antigen is discussed above. (See 'Preventing symptomatic
disease' above.)
Use of UpToDate is subject to the Subscription and License Agreement.
REFERENCES
1. Bamba S, Lortholary O, Sawadogo A, et al. Decreasing incidence of cryptococcal meningitis in West Africa in the era of highly active antiretroviral therapy. AIDS 2012; 26:1039.
2. 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; 50:291.
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