Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Cryptococcal meningitis: epidemiology, immunology, diagnosis and therapy

Key Points

  • In most clinical centres in Africa, despite access to antiretroviral therapies, cases of HIV-associated cryptococcal meningitis (CM) are not decreasing owing to challenges with retention and adherence to HIV care

  • CM in HIV-negative individuals is relatively rare, but carries a mortality at least as high as in HIV-associated disease; therefore, CM must be considered in all cases of lymphocytic meningitis — even in the apparently immunocompetent

  • A point-of-care, lateral flow 'dipstick' test to detect cryptococcal antigen in the blood or cerebrospinal fluid (CSF) is a significant advance: it is highly specific, sensitive, and easy to use

  • Amphotericin B (in conventional or liposomal formulation) combined with flucytosine remains the induction therapy of choice, and is associated with a survival advantage over amphotericin B alone

  • Measurement of CSF opening pressure and appropriate management of raised CSF pressure can reduce mortality

  • Any future attempts at adjunctive immunotherapies will need to be closely guided by the specific immune status of the host at the time of any intervention

Abstract

HIV-associated cryptococcal meningitis is by far the most common cause of adult meningitis in many areas of the world that have high HIV seroprevalence. In most areas in Sub-Saharan Africa, the incidence of cryptococcal meningitis is not decreasing despite availability of antiretroviral therapy, because of issues of adherence and retention in HIV care. In addition, cryptococcal meningitis in HIV-seronegative individuals is a substantial problem: the risk of cryptococcal infection is increased in transplant recipients and other individuals with defects in cell-mediated immunity, and cryptococcosis is also reported in the apparently immunocompetent. Despite therapy, mortality rates in these groups are high. Over the past 5 years, advances have been made in rapid point-of-care diagnosis and early detection of cryptococcal antigen in the blood. These advances have enabled development of screening and pre-emptive treatment strategies aimed at preventing the development of clinical infection in patients with late-stage HIV infection. Progress in optimizing antifungal combinations has been aided by evaluation of the clearance rate of infection by using serial quantitative cultures of cerebrospinal fluid (CSF). Measurement and management of raised CSF pressure, a common complication, is a vital component of care. In addition, we now better understand protective immune responses in HIV-associated cases, immunogenetic predisposition to infection, and the role of immune-mediated pathology in patients with non-HIV associated infection and in the context of HIV-associated immune reconstitution reactions.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Associations between baseline cerebrospinal fluid immune response profiles and clinical outcome in HIV-associated CM.
Figure 2: Systemic immune responses to cryptococcal antigen are associated with survival in HIV-associated cryptococcal meningitis.
Figure 3: Raised cerebrospinal fluid pressure in a patient with HIV-associated cryptococcal meningitis.
Figure 4: Host damage from infection-related inflammatory syndromes in HIV-positive and in HIV-negative cryptococcal meningitis.
Figure 5: Corticosteroid treatment can reduce brain oedema in patients with HIV-negative cryptococcal meningitis.

References

  1. 1

    Durski, K. N. et al. Cost-effective diagnostic checklists for meningitis in resource-limited settings. J. Acquir. Immune Defic. Syndr. 63, e101–e108 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  2. 2

    Rajasingham, R. et al. Epidemiology of meningitis in an HIV-infected Ugandan cohort. Am. J. Trop. Med. Hyg. 92, 274–279 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. 3

    Jarvis, J. N. et al. Adult meningitis in a setting of high HIV and TB prevalence: findings from 4961 suspected cases. BMC Infect. Dis. 10, 67 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

    Zhu, L. P. et al. Cryptococcal meningitis in non-HIV-infected patients in a Chinese tertiary care hospital, 1997–2007. Med. Mycol. 48, 570–579 (2010).

    Article  PubMed  Google Scholar 

  5. 5

    Pyrgos, V. et al. Epidemiology of cryptococcal meningitis in the US: 1997–2009. PLoS ONE 8, e56269 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6

    Phillips, P. et al. Longitudinal clinical findings and outcome among patients with Cryptococcus gattii infection in British Columbia. Clin. Infect. Dis. 60, 1368–1376 (2015).

    PubMed  Google Scholar 

  7. 7

    May, R. C. et al. Cryptococcus: from environmental saprophyte to global pathogen. Nat. Rev. Microbiol. 14, 106–117 (2016).

    CAS  Article  PubMed  Google Scholar 

  8. 8

    Alanio, A. et al. Cryptococcus neoformans host adaptation: toward biological evidence of dormancy. mBio 6, e02580-14 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Fisher, M. C. et al. Emerging fungal threats to animal, plant and ecosystem health. Nature 484, 186–194 (2012).

    CAS  Article  PubMed  Google Scholar 

  10. 10

    Park, B. J. et al. Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS. AIDS 23, 525–530 (2009).

    Article  PubMed  Google Scholar 

  11. 11

    French, N. et al. Cryptococcal infection in a cohort of HIV-1-infected Ugandan adults. AIDS 16, 1031–1038 (2002).

    Article  PubMed  Google Scholar 

  12. 12

    Boulware, D. R. et al. Update on the global burden of disease of HIV-associated cryptococcal meningitis. Oral Abstract presented at: 9th International Conference on Cryptococcus and Cryptococcosis; 2014 May; Amsterdam.

  13. 13

    National Institute of Communicable Diseases. RapidGerms South Africa Annual Report 2014. [online] http://www.nicd.ac.za/assets/files/GERMS-SA%20AR%202014.pdf pages 8–11 (2014).

  14. 14

    Wall, E. C. et al. Bacterial meningitis in Malawian adults, adolescents, and children during the era of antiretroviral scale-up and Haemophilus influenzae type b vaccination, 2000–2012. Clin. Infect. Dis. 58, e137–e145 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  15. 15

    Tenforde, M. et al. HIV-associated cryptococcal meningitis in Botswana: national incidence and temporal trends following ART rollout. [online] http://www.aids2016.org/Portals/0/File/AIDS2016_Abstracts_LOW.pdf?ver=2016-08-10-154247-087 Abstract presented at: 21st International AIDS Conference; July 2016; Durban.

  16. 16

    Beardsley, J. et al. Adjunctive dexamethasone in HIV-associated cryptococcal meningitis. N. Engl. J. Med. 374, 542–554 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17

    Rhein, J. et al. Efficacy of adjunctive sertraline for the treatment of HIV-associated cryptococcal meningitis: an open-label dose-ranging study. Lancet Infect. Dis. 16, 809–818 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18

    Pappas, P. G. et al. Cryptococcosis in human immunodeficiency virus-negative patients in the era of effective azole therapy. Clin. Infect. Dis. 33, 690–699 (2001).

    CAS  Article  PubMed  Google Scholar 

  19. 19

    Bernard, C. et al. Cryptococcosis in sarcoidosis: cryptOsarc, a comparative study of 18 cases. QJM 106, 523–539 (2013).

    CAS  Article  PubMed  Google Scholar 

  20. 20

    Jarvis, J. N. et al. Is HIV-associated tuberculosis a risk factor for the development of cryptococcal disease? AIDS 24, 612–614 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  21. 21

    Speed, B. & Dunt, D. Clinical and host differences between infections with the two varieties of Cryptococcus neoformans. Clin. Infect. Dis. 21, 28–34 (1995).

    CAS  Article  PubMed  Google Scholar 

  22. 22

    Ahmad, D. S., Esmadi, M. & Steinmann, W. C. Idiopathic CD4 lymphocytopenia: spectrum of opportunistic infections, malignancies, and autoimmune diseases. Avicenna J. Med. 3, 37–47 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  23. 23

    Gorska, M. M. & Alam, R. A mutation in the human Uncoordinated 119 gene impairs TCR signaling and is associated with CD4 lymphopenia. Blood 119, 1399–1406 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24

    Lee, Y. C., Chew, G. T. & Robinson, B. W. Pulmonary & meningeal cryptococcosis in pulmonary alveolar proteinosis. Aust. N. Z. J. Med. 29, 843–844 (1999).

    CAS  Article  PubMed  Google Scholar 

  25. 25

    Rosen, L. B. et al. Anti-GM-CSF autoantibodies in patients with cryptococcal meningitis. J. Immunol. 190, 3959–3966 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26

    Saijo, T. et al. Anti-granulocyte-macrophage colony-stimulating factor autoantibodies are a risk factor for central nervous system infection by Cryptococcus gattii in otherwise immunocompetent patients. mBio 5, e00912-14 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Browne, S. K. et al. Adult-onset immunodeficiency in Thailand and Taiwan. N. Engl. J. Med. 367, 725–734 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28

    Vinh, D. C. et al. Autosomal dominant and sporadic monocytopenia with susceptibility to mycobacteria, fungi, papillomaviruses, and myelodysplasia. Blood 115, 1519–1529 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29

    Hsu, A. P. et al. Mutations in GATA2 are associated with the autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome. Blood 118, 2653–2655 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30

    Spinner, M. A. et al. GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity. Blood 123, 809–821 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31

    Jacobs, D. H. et al. Esophageal cryptococcosis in a patient with the hyperimmunoglobulin E-recurrent infection (Job's) syndrome. Gastroenterology 87, 201–203 (1984).

    CAS  Article  PubMed  Google Scholar 

  32. 32

    Holland, S. M. et al. STAT3 mutations in the hyper-IgE syndrome. N. Engl. J. Med. 357, 1608–1619 (2007).

    CAS  Article  PubMed  Google Scholar 

  33. 33

    Winkelstein, J. A. et al. The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients. Medicine (Baltimore) 82, 373–384 (2003).

    CAS  Article  Google Scholar 

  34. 34

    Iseki, M. et al. Hyper-IgM immunodeficiency with disseminated cryptococcosis. Acta Paediatr. 83, 780–782 (1994).

    CAS  Article  PubMed  Google Scholar 

  35. 35

    Hu, X. P. et al. Association of Fcγ receptor IIB polymorphism with cryptococcal meningitis in HIV-uninfected Chinese patients. PLoS ONE 7, e42439 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 36

    Coelho, C., Bocca, A. L. & Casadevall, A. The tools for virulence of Cryptococcus neoformans. Adv. Appl. Microbiol. 87, 1–41 (2014). This review discusses virulence factors specific to Cryptococcus.

    CAS  Article  PubMed  Google Scholar 

  37. 37

    Moodley, A. et al. Early clinical and subclinical visual evoked potential and Humphrey's visual field defects in cryptococcal meningitis. PLoS ONE 7, e52895 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38

    Jarvis, J. N. et al. Pulmonary cryptococcosis misdiagnosed as smear-negative pulmonary tuberculosis with fatal consequences. Int. J. Infect. Dis. 14 (Suppl. 3), e310–e312 (2010).

    Article  PubMed  Google Scholar 

  39. 39

    Sun, H. Y. et al. Predictors of immune reconstitution syndrome in organ transplant recipients with cryptococcosis: implications for the management of immunosuppression. Clin. Infect. Dis. 60, 36–44 (2015).

    Article  PubMed  Google Scholar 

  40. 40

    Mitchell, D. H. et al. Cryptococcal disease of the CNS in immunocompetent hosts: influence of cryptococcal variety on clinical manifestations and outcome. Clin. Infect. Dis. 20, 611–616 (1995).

    CAS  Article  PubMed  Google Scholar 

  41. 41

    Schoffelen, T. et al. Cryptococcus gattii induces a cytokine pattern that is distinct from other cryptococcal species. PLoS ONE 8, e55579 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42

    Lee, S. C., Dickson, D. W. & Casadevall, A. Pathology of cryptococcal meningoencephalitis: analysis of 27 patients with pathogenetic implications. Hum. Pathol. 27, 839–847 (1996).

    CAS  Article  PubMed  Google Scholar 

  43. 43

    Panackal, A. A. et al. Paradoxical immune responses in non-HIV cryptococcal meningitis. PLoS Pathog. 11, e1004884 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Lee, S. C., Casadevall, A. & Dickson, D. W. Immunohistochemical localization of capsular polysaccharide antigen in the central nervous system cells in cryptococcal meningoencephalitis. Am. J. Pathol. 148, 1267–1274 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Loyse, A. et al. Neurological, visual, and MRI brain scan findings in 87 South African patients with HIV-associated cryptococcal meningoencephalitis. J. Infect. 70, 668–675 (2015).

    CAS  Article  PubMed  Google Scholar 

  46. 46

    Charlier, C. et al. Cryptococcal neuroradiological lesions correlate with severity during cryptococcal meningoencephalitis in HIV-positive patients in the HAART era. PLoS ONE 3, e1950 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Rothe, C. et al. A prospective longitudinal study of the clinical outcomes from cryptococcal meningitis following treatment induction with 800 mg oral fluconazole in Blantyre, Malawi. PLoS ONE 8, e67311 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. 48

    Gaskell, K. M. et al. A prospective study of mortality from cryptococcal meningitis following treatment induction with 1200 mg oral fluconazole in Blantyre, Malawi. PLoS ONE 9, e110285 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Longley, N. et al. Dose response effect of high-dose fluconazole for HIV-associated cryptococcal meningitis in southwestern Uganda. Clin. Infect. Dis. 47, 1556–1561 (2008).

    CAS  Article  PubMed  Google Scholar 

  50. 50

    Loyse, A. et al. Comparison of the early fungicidal activity of high-dose fluconazole, voriconazole, and flucytosine as second-line drugs given in combination with amphotericin B for the treatment of HIV-associated cryptococcal meningitis. Clin. Infect. Dis. 54, 121–128 (2012).

    CAS  Article  PubMed  Google Scholar 

  51. 51

    Bicanic, T. et al. High-dose amphotericin B with flucytosine for the treatment of cryptococcal meningitis in HIV-infected patients: a randomized trial. Clin. Infect. Dis. 47, 123–130 (2008).

    CAS  Article  PubMed  Google Scholar 

  52. 52

    Jarvis, J. N. et al. Adjunctive interferon-γ immunotherapy for the treatment of HIV-associated cryptococcal meningitis: a randomized controlled trial. AIDS 26, 1105–1113 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. 53

    Dromer, F. et al. Determinants of disease presentation and outcome during cryptococcosis: the CryptoA/D study. PLoS Med. 4, e21 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  54. 54

    Lortholary, O. et al. Long-term outcome of AIDS-associated cryptococcosis in the era of combination antiretroviral therapy. AIDS 20, 2183–2191 (2006).

    Article  PubMed  Google Scholar 

  55. 55

    Robinson, P. A. et al. Early mycological treatment failure in AIDS-associated cryptococcal meningitis. Clin. Infect. Dis. 28, 82–92 (1999).

    CAS  Article  PubMed  Google Scholar 

  56. 56

    Brizendine, K. D., Baddley, J. W. & Pappas, J. W. Predictors of mortality and differences in clinical features among patients with Cryptococcosis according to immune status. PLoS ONE 8, e60431 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. 57

    Panackal, A. A. et al. Fighting the monster: applying the host damage framework to human central nervous system infections. mBio 7, e01906-15 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Chen, S. C. et al. Clinical manifestations of Cryptococcus gattii infection: determinants of neurological sequelae and death. Clin. Infect. Dis. 55, 789–798 (2012).

    Article  PubMed  Google Scholar 

  59. 59

    Steele, K. T. et al. In-hospital mortality of HIV-infected cryptococcal meningitis patients with C. gattii and C. neoformans infection in Gaborone, Botswana. Med. Mycol. 48, 1112–1115 (2010).

    Article  PubMed  Google Scholar 

  60. 60

    Jarvis, J. N. et al. Determinants of mortality in a combined cohort of 501 patients with HIV-associated cryptococcal meningitis: implications for improving outcomes. Clin. Infect. Dis. 58, 736–745 (2014).

    Article  PubMed  Google Scholar 

  61. 61

    Bicanic, T. et al. Independent association between rate of clearance of infection and clinical outcome of HIV-associated cryptococcal meningitis: analysis of a combined cohort of 262 patients. Clin. Infect. Dis. 49, 702–709 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  62. 62

    Diamond, R. D. & Bennett, J. E. Prognostic factors in cryptococcal meningitis: a study in 111 cases. Ann. Intern. Med. 80, 176–181 (1974).

    CAS  Article  PubMed  Google Scholar 

  63. 63

    Dismukes, W. E. et al. Treatment of cryptococcal meningitis with combination amphotericin B and flucytosine for four as compared with six weeks. N. Engl. J. Med. 317, 334–341 (1987).

    CAS  Article  PubMed  Google Scholar 

  64. 64

    Jarvis, J. N. et al. The phenotype of the Cryptococcus-specific CD4+ memory T-cell response is associated with disease severity and outcome in HIV-associated cryptococcal meningitis. J. Infect. Dis. 207, 1817–1828 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  65. 65

    Jarvis, J. N. et al. Cerebrospinal fluid cytokine profiles predict risk of early mortality and immune reconstitution inflammatory syndrome in HIV-associated cryptococcal meningitis. PLoS Pathog. 11, e1004754 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Siddiqui, A. A. et al. IFN-γ at the site of infection determines rate of clearance of infection in cryptococcal meningitis. J. Immunol. 174, 1746–1750 (2005).

    CAS  Article  PubMed  Google Scholar 

  67. 67

    Scriven, J. E. et al. A glucuronoxylomannan-associated immune signature, characterized by monocyte deactivation and an increased interleukin 10 level, is a predictor of death in cryptococcal meningitis. J. Infect. Dis. 213, 1725–1734 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. 68

    Peeling, R. W. et al. Rapid tests for sexually transmitted infections (STIs): the way forward. Sex. Transm. Infect. 82 (Suppl. 5). v1–v6 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  69. 69

    Jarvis, J. N. 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. 53, 1019–1023 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  70. 70

    Percival, A., Thorkildson, P. & Kozel, T. R. Monoclonal antibodies specific for immunorecessive epitopes of glucuronoxylomannan, the major capsular polysaccharide of Cryptococcus neoformans, reduce serotype bias in an immunoassay for cryptococcal antigen. Clin. Vaccine Immunol. 18, 1292–1296 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  71. 71

    Williams, D. A. et al. Evaluation of fingerstick cryptococcal antigen lateral flow assay in HIV-infected persons: a diagnostic accuracy study. Clin. Infect. Dis. 61, 464–467 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  72. 72

    Tenforde, M. W. et al. Poor specificity of urinary cryptococcal antigen testing: Reply to Drain et al. Prevalence of cryptococcal antigenuria at initial HIV diagnosis in KwaZulu-Natal. HIV Med. http://dx.doi.org/10.1111/hiv.12319 (2015).

  73. 73

    Longley, N. et al. Cryptococcal antigen screening in patients initiating ART in South Africa: a prospective cohort study. Clin. Infect. Dis. 62, 581–587 (2016).

    CAS  Article  PubMed  Google Scholar 

  74. 74

    Berlin, L. & Pincus, J. H. Cryptococcal meningitis. False-negative antigen test results and cultures in nonimmunosuppressed patients. Arch. Neurol. 46, 1312–1316 (1989).

    CAS  Article  PubMed  Google Scholar 

  75. 75

    Jitmuang, A. et al. Performance of the cryptococcal antigen lateral flow assay in non-HIV-related cryptococcosis. J. Clin. Microbiol. 54, 460–463 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  76. 76

    Tintelnot, K. et al. Pitfalls in serological diagnosis of Cryptococcus gattii infections. Med. Mycol. 53, 874–879 (2015).

    CAS  Article  PubMed  Google Scholar 

  77. 77

    World Health Organization. Rapid Advice: Diagnosis, Prevention and Management of Cryptococcal Disease in HIV-Infected Adults, Adolescents and Children. http://apps.who.int/iris/bitstream/10665/44786/1/9789241502979_eng.pdf (2011)

  78. 78

    Perfect, J. R. et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin. Infect. Dis. 50, 291–322 (2010).

    PubMed  PubMed Central  Article  Google Scholar 

  79. 79

    Govender, N. P. et al. Guideline for the prevention, diagnosis and management of cryptococcal meningitis among HIV-infected persons: 2013 update. South Afr. J. HIV Med. 14, 76–86 (2013).

    Article  Google Scholar 

  80. 80

    van der Horst, C. M. et al. Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. N. Engl. J. Med. 337, 15–21 (1997).

    CAS  Article  PubMed  Google Scholar 

  81. 81

    Brouwer, A. E. et al. Combination antifungal therapies for HIV-associated cryptococcal meningitis: a randomised trial. Lancet 363, 1764–1767 (2004).

    CAS  Article  PubMed  Google Scholar 

  82. 82

    Day, J. N. et al. Combination antifungal therapy for cryptococcal meningitis. N. Engl. J. Med. 368, 1291–1302 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  83. 83

    Loyse, A. et al. Flucytosine and cryptococcosis: time to urgently address the worldwide accessibility of a 50-year-old antifungal. J. Antimicrob. Chemother. 68, 2435–2444 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  84. 84

    Bicanic, T. et al. Toxicity of amphotericin B deoxycholate-based induction therapy in patients with HIV-associated cryptococcal meningitis. Antimicrob. Agents Chemother. 59, 7224–7231 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  85. 85

    Brouwer, A. E. et al. Oral versus intravenous flucytosine in patients with human immunodeficiency virus-associated cryptococcal meningitis. Antimicrob. Agents Chemother. 51, 1038–1042 (2007).

    CAS  Article  PubMed  Google Scholar 

  86. 86

    Girmenia, C. et al. Effects of hydration with salt repletion on renal toxicity of conventional amphotericin B empirical therapy: a prospective study in patients with hematological malignancies. Support. Care Cancer 13, 987–992 (2005).

    Article  PubMed  Google Scholar 

  87. 87

    Thakur, C. P. et al. Improving outcome of treatment of kala-azar by supplementation of amphotericin B with physiologic saline and potassium chloride. Am. J. Trop. Med. Hyg. 83, 1040–1043 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  88. 88

    Hamill, R. J. et al. Comparison of 2 doses of liposomal amphotericin B and conventional amphotericin B deoxycholate for treatment of AIDS-associated acute cryptococcal meningitis: a randomized, double-blind clinical trial of efficacy and safety. Clin. Infect. Dis. 51, 225–232 (2010).

    CAS  Article  PubMed  Google Scholar 

  89. 89

    Molefi, M. et al. AMBITION-cm: intermittent high dose AmBisome on a high dose fluconazole backbone for cryptococcal meningitis induction therapy in sub-Saharan Africa: study protocol for a randomized controlled trial. Trials 16, 276 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Nussbaum, J. C. et al. Combination flucytosine and high-dose fluconazole compared with fluconazole monotherapy for the treatment of cryptococcal meningitis: a randomized trial in Malawi. Clin. Infect. Dis. 50, 338–344 (2009).

    Article  CAS  Google Scholar 

  91. 91

    Jackson, A. et al. A phase II randomised controlled trial adding oral flucytosine to high dose fluconazole, with short-course amphotericin B, for cryptococcal meningitis in Malawi. AIDS 26, 1363–1370 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  92. 92

    Muzoora, C. K. et al. Short course amphotericin B with high dose fluconazole for HIV-associated cryptococcal meningitis. J. Infect. 64, 76–81 (2011).

    Article  PubMed  Google Scholar 

  93. 93

    Livermore, J. et al. Efficacy of an abbreviated induction regimen of amphotericin B deoxycholate for cryptococcal meningoencephalitis: 3 days of therapy is equivalent to 14 days. mBio 5, e00725-13 (2013).

    Article  CAS  Google Scholar 

  94. 94

    ISRCTN registry. ISRCTN.com [online] http://www.isrctn.com/ISRCTN45035509, (2015).

  95. 95

    US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT01802385 (2016).

  96. 96

    Butts, A. et al. Estrogen receptor antagonists are anti-cryptococcal agents that directly bind EF hand proteins and synergize with fluconazole in vivo. mBio 5, e00765-13 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

    Chen, S. C. et al. Antifungal therapy and management of complications of cryptococcosis due to Cryptococcus gattii. Clin. Infect. Dis. 57, 543–551 (2013).

    CAS  Article  PubMed  Google Scholar 

  98. 98

    Singh, N. How I treat cryptococcosis in organ transplant recipients. Transplantation 93, 17–21 (2012).

    Article  PubMed  Google Scholar 

  99. 99

    Kontoyiannis, D. P. et al. Calcineurin inhibitor agents interact synergistically with antifungal agents in vitro against Cryptococcus neoformans isolates: correlation with outcome in solid organ transplant recipients with cryptococcosis. Antimicrob. Agents Chemother. 52, 735–738 (2008).

    CAS  Article  PubMed  Google Scholar 

  100. 100

    Graybill, J. R. et al. Diagnosis and management of increased intracranial pressure in patients with AIDS and cryptococcal meningitis. Clin. Infect. Dis. 30, 47–54 (2000).

    CAS  Article  PubMed  Google Scholar 

  101. 101

    Loyse, A. et al. Histopathology of the arachnoid granulations and brain in HIV-associated cryptococcal meningitis: correlation with cerebrospinal fluid pressure. AIDS 24, 405–410 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  102. 102

    Bicanic, T. et al. Relationship of cerebrospinal fluid pressure, fungal burden and outcome in patients with cryptococcal meningitis undergoing serial lumbar punctures. AIDS 23, 701–706 (2009).

    PubMed  Google Scholar 

  103. 103

    Shoham, S. et al. Cryptococcus neoformans meningitis at hospitals in Washington, D. C.: adherence of health care providers to published practice guidelines for the management of cryptococcal disease. Clin. Infect. Dis. 40, 477–479 (2005).

    Article  PubMed  Google Scholar 

  104. 104

    Rolfes, M. A. et al. The effect of therapeutic lumbar punctures on acute mortality from cryptococcal meningitis. Clin. Infect. Dis. 59, 1607–1614 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  105. 105

    Macsween, K. F. et al. Lumbar drainage for control of raised cerebrospinal fluid pressure in cryptococcal meningitis: case report and review. J. Infect. 51, e221–e224 (2005).

    Article  PubMed  Google Scholar 

  106. 106

    Manosuthi, W. et al. Temporary external lumbar drainage for reducing elevated intracranial pressure in HIV-infected patients with cryptococcal meningitis. Int. J. STD AIDS 19, 268–271 (2008).

    Article  PubMed  Google Scholar 

  107. 107

    Park, M. K., Hospenthal, D. R. & Bennett, J. E. Treatment of hydrocephalus secondary to cryptococcal meningitis by use of shunting. Clin. Infect. Dis. 28, 629–633 (1999).

    CAS  Article  PubMed  Google Scholar 

  108. 108

    Haddow, L. J. et al. Cryptococcal immune reconstitution inflammatory syndrome in HIV-1-infected individuals: proposed clinical case definitions. Lancet Infect. Dis. 10, 791–802 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  109. 109

    Bicanic, T. et al. Immune reconstitution inflammatory syndrome in HIV-associated cryptococcal meningitis: a prospective study. J. Acquir. Immune Defic. Syndr. 51, 130–134 (2009).

    CAS  Article  PubMed  Google Scholar 

  110. 110

    Boulware, D. R. et al. Clinical features and serum biomarkers in HIV immune reconstitution inflammatory syndrome after cryptococcal meningitis: a prospective cohort study. PLoS Med. 7, e1000384 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  111. 111

    Muller, M. et al. Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic review and meta-analysis. Lancet Infect. Dis. 10, 251–261 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  112. 112

    Longley, N., Harrison, T. S. & Jarvis, J. N. Cryptococcal immune reconstitution inflammatory syndrome. Curr. Opin. Infect. Dis. 26, 26–34 (2013).

    CAS  Article  PubMed  Google Scholar 

  113. 113

    Boulware, D. R. et al. Paucity of initial cerebrospinal fluid inflammation in cryptococcal meningitis is associated with subsequent immune reconstitution inflammatory syndrome. J. Infect. Dis. 202, 962–970 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  114. 114

    Chang, C. C. et al. Cryptococcosis-IRIS is associated with lower cryptococcus-specific IFN-γ responses before antiretroviral therapy but not higher T-cell responses during therapy. J. Infect. Dis. 208, 898–906 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  115. 115

    Chang, C. C. et al. Chemokine levels and chemokine receptor expression in the blood and the cerebrospinal fluid of HIV-infected patients with cryptococcal meningitis and cryptococcosis-associated immune reconstitution inflammatory syndrome. J. Infect. Dis. 208, 1604–1612 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  116. 116

    Worsley, C. M. et al. Multi-analyte profiling of ten cytokines in South African HIV-infected patients with immune reconstitution inflammatory syndrome (IRIS). AIDS Res. Ther. 7, 36 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. 117

    Meya, D. B. et al. Cellular immune activation in cerebrospinal fluid from Ugandans with cryptococcal meningitis and immune reconstitution inflammatory syndrome. J. Infect. Dis. 211, 1597–1606 (2015).

    CAS  Article  PubMed  Google Scholar 

  118. 118

    Makadzange, A. T. et al. Early versus delayed initiation of antiretroviral therapy for concurrent HIV infection and cryptococcal meningitis in sub-saharan Africa. Clin. Infect. Dis. 50, 1532–1538 (2010).

    CAS  Article  PubMed  Google Scholar 

  119. 119

    Boulware, D. R. et al. Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis. N. Engl. J. Med. 370, 2487–2498 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. 120

    Zolopa, A. et al. Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial. PLoS ONE 4, e5575 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. 121

    Scriven, J. E. et al. Early ART after cryptococcal meningitis is associated with cerebrospinal fluid pleocytosis and macrophage activation in a multisite randomized trial. J. Infect. Dis. 212, 769–778 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  122. 122

    Scemla, A. et al. Dramatic improvement of severe cryptococcosis-induced immune reconstitution syndrome with adalimumab in a renal transplant recipient. Am. J. Transplant. 15, 560–564 (2015).

    CAS  Article  PubMed  Google Scholar 

  123. 123

    Brunel, A. S. et al. Thalidomide for steroid-dependent immune reconstitution inflammatory syndromes during AIDS. AIDS 26, 2110–2112 (2012).

    Article  PubMed  Google Scholar 

  124. 124

    Jarvis, J. N., Meintjes, G. & Harrison, T. S. Outcomes of cryptococcal meningitis in antiretroviral naive and experienced patients in South Africa. J. Infect. 60, 496–498 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  125. 125

    Hardison, S. E. et al. Pulmonary infection with an interferon-gamma-producing Cryptococcus neoformans strain results in classical macrophage activation and protection. Am. J. Pathol. 176, 774–785 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  126. 126

    Phillips, P. et al. Dexamethasone in Cryptococcus gattii central nervous system infection. Clin. Infect. Dis. 49, 591–595 (2009).

    Article  PubMed  Google Scholar 

  127. 127

    Casadevall, A. & Pirofski, L. A. The damage-response framework of microbial pathogenesis. Nat. Rev. Microbiol. 1, 17–24 (2003).

    CAS  Article  PubMed  Google Scholar 

  128. 128

    Tazawa, R. et al. Inhaled granulocyte/macrophage-colony stimulating factor as therapy for pulmonary alveolar proteinosis. Am. J. Respir. Crit. Care Med. 181, 1345–1354 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  129. 129

    Tazawa, R. et al. Duration of benefit in patients with autoimmune pulmonary alveolar proteinosis after inhaled granulocyte-macrophage colony-stimulating factor therapy. Chest 145, 729–737 (2014).

    CAS  Article  PubMed  Google Scholar 

  130. 130

    Pappas, P. G. et al. Recombinant interferon-γ1b as adjunctive therapy for AIDS-related acute cryptococcal meningitis. J. Infect. Dis. 189, 2185–2191 (2004).

    CAS  Article  PubMed  Google Scholar 

  131. 131

    Jarvis, J. N. et al. Screening for cryptococcal antigenemia in patients accessing an antiretroviral treatment program in South Africa. Clin. Infect. Dis. 48, 856–862 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  132. 132

    Jarvis, J. N. et al. Cost effectiveness of cryptococcal antigen screening as a strategy to prevent HIV-associated cryptococcal meningitis in South Africa. PLoS ONE 8, e69288 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  133. 133

    Meya, D. 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. 51, 448–455 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  134. 134

    Govender, N. P. et al. Phased implementation of screening for cryptococcal disease in South Africa. S. Afr. Med. J. 102, 914–917 (2012).

    Article  PubMed  Google Scholar 

  135. 135

    Mfinanga, S. et al. Cryptococcal meningitis screening and community-based early adherence support in people with advanced HIV infection starting antiretroviral therapy in Tanzania and Zambia: an open-label, randomised controlled trial. Lancet 385, 2173–2182 (2015).

    Article  PubMed  Google Scholar 

  136. 136

    Morawski, B. M. et al. Pre-ART cryptococcal antigen titer associated with preemptive fluconazole failure. [online] http://www.croiconference.org/sessions/pre-art-cryptococcal-antigen-titer-associated-preemptive-fluconazole-failure Abstract presented at: CROI; February 2016; Boston.

  137. 137

    Loyse, A. et al. Cryptococcal meningitis: improving access to essential antifungal medicines in resource-poor countries. Lancet Infect. Dis. 13, 629–637 (2013).

    Article  PubMed  Google Scholar 

  138. 138

    Kuris, A. M., Lafferty, K. D. & Sokolow, S. H. Sapronosis: a distinctive type of infectious agent. Trends Parasitol. 30, 386–393 (2014).

    Article  PubMed  Google Scholar 

  139. 139

    Casadevall, A. Evolution of intracellular pathogens. Annu. Rev. Microbiol. 62, 19–33 (2008).

    CAS  Article  PubMed  Google Scholar 

  140. 140

    McDonald, T., Wiesner, D. L. & Nielsen, K. Cryptococcus. Curr. Biol. 22, R554–R555 (2012).

    CAS  Article  PubMed  Google Scholar 

  141. 141

    Casadevall, A., Steenbergen, J. N. & Nosanchuk, J. D. 'Ready made' virulence and 'dual use' virulence factors in pathogenic environmental fungi — the Cryptococcus neoformans paradigm. Curr. Opin. Microbiol. 6, 332–337 (2003).

    Article  PubMed  Google Scholar 

  142. 142

    Zaragoza, O. et al. The capsule of the fungal pathogen Cryptococcus neoformans. Adv. Appl. Microbiol. 68, 133–216 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  143. 143

    Xu, J. Fundamentals of fungal molecular population genetic analyses. Curr. Issues Mol. Biol. 8, 75–89 (2006).

    CAS  PubMed  Google Scholar 

  144. 144

    Hagen, F. et al. Recognition of seven species in the Cryptococcus gattii/Cryptococcus neoformans species complex. Fungal Genet. Biol. 78, 16–48 (2015).

    CAS  Article  PubMed  Google Scholar 

  145. 145

    Farrer, R. A. et al. Genome evolution and innovation across the four major lineages of Cryptococcus gattii. mBio 6, e00868-15 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. 146

    Engelthaler, D. M. et al. Cryptococcus gattii in North American Pacific Northwest: whole-population genome analysis provides insights into species evolution and dispersal. mBio 5, e01464–14 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Affiliations

Authors

Contributions

P.R.W., J.N.J., A.A.P., M.C.F. and T.S.H. wrote the article. All authors participated in researching data for article, provided substantial contribution to discussion of content, and reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Thomas S. Harrison.

Ethics declarations

Competing interests

P.W. has a CRADA (cooperative research and development agreement) with Matinas BioPharma regarding an oral amphotericin formulation. J.J. has received an Investigator Award (to institution) from Gilead Sciences. T.H. has received an Investigator Award (to institution) from Gilead Sciences and has received a donation of cryptococcosis test kits for research purposes from Immuno-Mycologics, received honoraria from Pfizer, and is on the advisory board for Viamet.

Related links

PowerPoint slides

Glossary

Idiopathic CD4+ lymphopenia

Repeated presence of a CD4+ T lymphocyte count of <300 cells/ml without a predisposing cause.

Hyperimmunoglobulin E recurrent infection syndrome

This syndrome, also known as Job syndrome, is caused by mutations in the signal transducer and activator of transcription (STAT3). Patients typically have eosinophilia, eczema, and recurrent skin and pulmonary infections.

Colony forming unit

A measure to quantify viable fungal cells on the basis of the cells' ability to grow to form visible colonies on an agar plate.

Rate of infection clearance

The rate of decrease in viable organisms in the cerebrospinal fluid (CSF) during treatment, derived from quantitative cultures of the CSF obtained from serial lumbar punctures done over the first 14 days of treatment. For a particular drug regimen, the early fungicidal activity is the mean rate of infection clearance for patients on that regimen.

ASSURED criteria

Originally developed by the WHO Sexually Transmitted Diseases Diagnostics Initiative as a benchmark to determine whether new diagnostic tests addressed the needs of their disease control programmes in resource-limited settings: the ASSURED criteria include the test being affordable, sensitive, specific, user-friendly, rapid and robust, equipment-free, and deliverable to end-users.

Paradoxical IRIS

Clinical deterioration in HIV-positive patients with cryptococcal meningitis who have responded to initial antifungal therapy, but then relapse after starting antiretroviral therapy owing to the resultant immune restoration and enhanced inflammatory immune response to residual cryptococcal antigens.

Unmasking IRIS

Individuals with HIV infection can present for the first time with cryptococcal meningitis after effective antiretroviral therapy (ART) has been initiated. These patients may have a mixture of active infection and immune-mediated pathology as a result of ART-mediated immune restoration.

Macrophage–T-cell dissociation

Despite appropriate T-cell signalling, macrophages fail to become classically activated and clear infection but rather remain in an alternatively activated state that is less effective at controlling infection and clearing antigen.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Williamson, P., Jarvis, J., Panackal, A. et al. Cryptococcal meningitis: epidemiology, immunology, diagnosis and therapy. Nat Rev Neurol 13, 13–24 (2017). https://doi.org/10.1038/nrneurol.2016.167

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing