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Cryptococcosis Today: It Is Not All About HIV Infection

  • Mycology (J Perfect, Section Editor)
  • Published:
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Abstract

Purpose of the Review

Cryptococcal disease is most often thought of in the context of HIV infection. Much of our knowledge of the disease originates from its management in the HIV-positive population over the last 30 years. While the majority of cases globally continue to occur in the setting of advanced HIV, Cryptococcus species is increasingly responsible for disease in HIV-negative populations including those considered normal hosts and these HIV-negative populations will be the focus of this review.

Recent Findings

Currently available data indicated that significant differences exist in epidemiology, clinical presentation, management and outcomes of cryptococcal disease in HIV-negative populations when compared to those living with HIV.

Summary

Further research is required to improve our knowledge of cryptococcal disease in particular in HIV-negative cohorts so as to optimise management of the disease in the future.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Maziarz EK, Perfect JR. Cryptococcosis. Infect Dis Clin N Am. 2016;30(1):179–206.

    Article  Google Scholar 

  2. Antinori S. New insights into HIV/AIDS-associated Cryptococcosis. ISRN AIDS. 2013;2013:471363.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Pappas PG. Cryptococcal infections in non-HIV-infected patients. Trans Am Clin Climatol Assoc. 2013;124:61–79.

    PubMed  PubMed Central  Google Scholar 

  4. Knight FR, Mackenzie DW, Evans BG, Porter K, Barrett NJ, White GC. Increasing incidence of cryptococcosis in the United Kingdom. J Inf Secur. 1993;27(2):185–91.

    CAS  Google Scholar 

  5. Currie BP, Casadevall A. Estimation of the prevalence of cryptococcal infection among patients infected with the human immunodeficiency virus in New York City. Clin Infect Dis. 1994;19(6):1029–33.

    Article  CAS  PubMed  Google Scholar 

  6. Lightowler JV, Cooke GS, Mutevedzi P, Lessells RJ, Newell ML, Dedicoat M. Treatment of cryptococcal meningitis in KwaZulu-Natal. South Africa PLoS One. 2010;5(1):e8630.

    Article  PubMed  Google Scholar 

  7. Adeyemi BO, Ross A. Management of cryptococcal meningitis in a district hospital in KwaZulu-Natal: a clinical audit. Afr J Prim Health Care Fam Med. 2014;6(1):E1–6.

    Article  PubMed  Google Scholar 

  8. Park BJ, Wannemuehler KA, Marston BJ, Govender N, Pappas PG, Chiller TM. Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS. AIDS. 2009;23(4):525–30.

    Article  PubMed  Google Scholar 

  9. McKenney J, Bauman S, Neary B, Detels R, French A, Margolick J, et al. Prevalence, correlates, and outcomes of cryptococcal antigen positivity among patients with AIDS, United States, 1986-2012. Clin Infect Dis. 2015;60(6):959–65.

    Article  PubMed  Google Scholar 

  10. Brizendine KD, Baddley JW, Pappas PG. Predictors of mortality and differences in clinical features among patients with Cryptococcosis according to immune status. PLoS One. 2013;8(3):e60431.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. George IA SA, Powderly WG, Santos CA. The changing epidemiology of cryptococcal disease a retrospective population-based study. Open Forum Infect Dis. 2015;2(suppl 1):1686.

  12. Spec A, Raval K, Powderly WG. End-stage liver disease is a strong predictor of early mortality in Cryptococcosis. Open Forum Infect Dis. 2016;3(1):ofv197.

    Article  PubMed  Google Scholar 

  13. Jarvis JN, Lawn SD, Vogt M, Bangani N, Wood R, Harrison TS. Screening for cryptococcal antigenemia in patients accessing an antiretroviral treatment program in South Africa. Clin Infect Dis. 2009;48(7):856–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kambugu A, Meya DB, Rhein J, O’Brien M, Janoff EN, Ronald AR, et al. Outcomes of cryptococcal meningitis in Uganda before and after the availability of highly active antiretroviral therapy. Clin Infect Dis. 2008;46(11):1694–701.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Dromer F, Mathoulin-Pelissier S, Fontanet A, Ronin O, Dupont B, Lortholary O, et al. Epidemiology of HIV-associated cryptococcosis in France (1985-2001): comparison of the pre- and post-HAART eras. AIDS. 2004;18(3):555–62.

    Article  PubMed  Google Scholar 

  16. Pyrgos V, Seitz AE, Steiner CA, Prevots DR, Williamson PR. Epidemiology of cryptococcal meningitis in the US: 1997-2009. PLoS One. 2013;8(2):e56269.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bratton EW, El Husseini N, Chastain CA, Lee MS, Poole C, Sturmer T, 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(8):e43582.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. • Spec A, Olsen MA, Raval K, Powderly WG. Impact of infectious diseases consultation on mortality of cryptococcal infection in patients without HIV. Clin Infect Dis. 2016. doi:10.1093/cid/ciw786. Highlights the importance of expert input into the management of patient with cryptococcosis to optimise outcomes.

  19. Rosen LB, Freeman AF, Yang LM, Jutivorakool K, Olivier KN, Angkasekwinai N, et al. Anti-GM-CSF autoantibodies in patients with cryptococcal meningitis. J Immunol. 2013;190(8):3959–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Neofytos D, Fishman JA, Horn D, Anaissie E, Chang CH, Olyaei A, et al. Epidemiology and outcome of invasive fungal infections in solid organ transplant recipients. Transpl Infect Dis. 2010;12(3):220–9.

    Article  CAS  PubMed  Google Scholar 

  21. Henao-Martinez AF, Beckham JD. Cryptococcosis in solid organ transplant recipients. Curr Opin Infect Dis. 2015;28(4):300–7.

    Article  PubMed  Google Scholar 

  22. Pappas PG, Alexander BD, Andes DR, Hadley S, Kauffman CA, Freifeld A, et al. Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET). Clin Infect Dis. 2010;50(8):1101–11.

    Article  PubMed  Google Scholar 

  23. Husain S, Wagener MM, Singh N. Cryptococcus neoformans infection in organ transplant recipients: variables influencing clinical characteristics and outcome. Emerg Infect Dis. 2001;7(3):375–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Chang CM, Tsai CC, Tseng CE, Tseng CW, Tseng KC, Lin CW, et al. Donor-derived Cryptococcus infection in liver transplant: case report and literature review. Exp Clin Transplant. 2014;12(1):74–7.

    Article  PubMed  Google Scholar 

  25. Kaul DR, Covington S, Taranto S, Green M, Lyon GM, Kusne S, et al. Solid organ transplant donors with central nervous system infection. Transplantation. 2014;98(6):666–70.

    Article  PubMed  Google Scholar 

  26. Sun HY, Alexander BD, Lortholary O, Dromer F, Forrest GN, Lyon GM, et al. Unrecognized pretransplant and donor-derived cryptococcal disease in organ transplant recipients. Clin Infect Dis. 2010;51(9):1062–9.

    Article  PubMed  Google Scholar 

  27. Singh N, Sifri CD, Silveira FP, Miller R, Gregg KS, Huprikar S, et al. Cryptococcosis in patients with cirrhosis of the liver and posttransplant outcomes. Transplantation. 2015;99(10):2132–41.

    Article  PubMed  Google Scholar 

  28. Brizendine KD, Baddley JW, Pappas PG. Pulmonary cryptococcosis. Semin Respir Crit Care Med. 2011;32(6):727–34.

    Article  PubMed  Google Scholar 

  29. Singh N, Alexander BD, Lortholary O, Dromer F, Gupta KL, John GT, et al. Pulmonary cryptococcosis in solid organ transplant recipients: clinical relevance of serum cryptococcal antigen. Clin Infect Dis. 2008;46(2):e12–8.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Silveira FP, Husain S, Kwak EJ, Linden PK, Marcos A, Shapiro R, et al. Cryptococcosis in liver and kidney transplant recipients receiving anti-thymocyte globulin or alemtuzumab. Transpl Infect Dis. 2007;9(1):22–7.

    Article  CAS  PubMed  Google Scholar 

  31. Shaariah W, Morad Z, Suleiman AB. Cryptococcosis in renal transplant recipients. Transplant Proc. 1992;24(5):1898–9.

    CAS  PubMed  Google Scholar 

  32. Bittinger K, Charlson ES, Loy E, Shirley DJ, Haas AR, Laughlin A, et al. Improved characterization of medically relevant fungi in the human respiratory tract using next-generation sequencing. Genome Biol. 2014;15(10):487.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Jongwutiwes U, Sungkanuparph S, Kiertiburanakul S. Comparison of clinical features and survival between cryptococcosis in human immunodeficiency virus (HIV)-positive and HIV-negative patients. Jpn J Infect Dis. 2008;61(2):111–5.

    PubMed  Google Scholar 

  34. Davis JA, Horn DL, Marr KA, Fishman JA. Central nervous system involvement in cryptococcal infection in individuals after solid organ transplantation or with AIDS. Transpl Infect Dis. 2009;11(5):432–7.

    Article  CAS  PubMed  Google Scholar 

  35. Messina J, Maziarz EK, Spec A, Kontoyiannis D, Perfect J. Disseminated cryptococcosis with brain involvement in patients with chronic lymphoid malignancies on ibrutinib. Open Forum Infect Dis. 2017;4(1):ofw261.

  36. Christianson JC, Engber W, Andes D. Primary cutaneous cryptococcosis in immunocompetent and immunocompromised hosts. Med Mycol. 2003;41(3):177–88.

    Article  PubMed  Google Scholar 

  37. Odom A, Muir S, Lim E, Toffaletti DL, Perfect J, Heitman J. Calcineurin is required for virulence of Cryptococcus neoformans. EMBO J. 1997;16(10):2576–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Medaris LA, Ponce B, Hyde Z, Delgado D, Ennis D, Lapidus W, et al. Cryptococcal osteomyelitis: a report of 5 cases and a review of the recent literature. Mycoses. 2016.Jun;59(6):334–42.

  39. Nguyen MH, Husain S, Clancy CJ, Peacock JE, Hung CC, Kontoyiannis DP, et al. Outcomes of central nervous system cryptococcosis vary with host immune function: results from a multi-center, prospective study. J Inf Secur. 2010;61(5):419–26.

    Google Scholar 

  40. Ecevit IZ, Clancy CJ, Schmalfuss IM, Nguyen MH. The poor prognosis of central nervous system cryptococcosis among nonimmunosuppressed patients: a call for better disease recognition and evaluation of adjuncts to antifungal therapy. Clin Infect Dis. 2006;42(10):1443–7.

    Article  PubMed  Google Scholar 

  41. • Spec A, Panackal A, Williamson P, Bennett JE, Garcia-Diaz J, Ostrander D, et al. Cryptococcus Infection Network in non-HIV Cohort (CINCH) study: initial report of treatment and outcomes. ID Week. 2016; P122. Here the authors report outcomes from a cohort specifically established to address gaps in our knowledge of non-HIV associated cryptococcal disease.

  42. Singh N, Husain S, De Vera M, Gayowski T, Cacciarelli TV. Cryptococcus neoformans infection in patients with cirrhosis, including liver transplant candidates. Medicine (Baltimore). 2004;83(3):188–92.

    Article  Google Scholar 

  43. Baddley JW, Perfect JR, Oster RA, Larsen RA, Pankey GA, Henderson H, et al. Pulmonary cryptococcosis in patients without HIV infection: factors associated with disseminated disease. Eur J Clin Microbiol Infect Dis. 2008;27(10):937–43.

    Article  CAS  PubMed  Google Scholar 

  44. Bal CK, Bhatia V, Khillan V, Rathor N, Saini D, Daman R, et al. Spontaneous cryptococcal peritonitis with fungemia in patients with decompensated cirrhosis: report of two cases. Indian J Crit Care Med. 2014;18(8):536–9.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Singh DK, Tyagi I, Saran RK, Gondal R. Fatal spontaneous Cryptococcal peritonitis in a woman with decompensated liver cirrhosis. Acta Cytol. 2010;54(5 Suppl):1087–9.

    PubMed  Google Scholar 

  46. Sungkanuparph S, Vibhagool A, Pracharktam R. Spontaneous cryptococcal peritonitis in cirrhotic patients. J Postgrad Med. 2002;48(3):201–2.

    CAS  PubMed  Google Scholar 

  47. Hwang SY, Yu SJ, Lee JH, Kim JS, Yoon JW, Kim YJ, et al. Spontaneous fungal peritonitis: a severe complication in patients with advanced liver cirrhosis. Eur J Clin Microbiol Infect Dis. 2014;33(2):259–64.

    Article  CAS  PubMed  Google Scholar 

  48. Haddow LJ, Colebunders R, Meintjes G, Lawn SD, Elliott JH, Manabe YC, et al. Cryptococcal immune reconstitution inflammatory syndrome in HIV-1-infected individuals: proposed clinical case definitions. Lancet Infect Dis. 2010;10(11):791–802.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Panackal AA, Wuest SC, Lin YC, Wu T, Zhang N, Kosa P, et al. Paradoxical immune responses in non-HIV cryptococcal meningitis. PLoS Pathog. 2015;11(5):e1004884.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Kwon-Chung KJ, Bennett JE. High prevalence of Cryptococcus neoformans var. gattii in tropical and subtropical regions. Zentralbl Bakteriol Mikrobiol Hyg A. 1984;257(2):213–8.

    CAS  PubMed  Google Scholar 

  51. Kidd SE, Hagen F, Tscharke RL, Huynh M, Bartlett KH, Fyfe M, et al. A rare genotype of Cryptococcus gattii caused the cryptococcosis outbreak on Vancouver Island (British Columbia, Canada). Proc Natl Acad Sci U S A. 2004;101(49):17258–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Chowdhary A, Randhawa HS, Boekhout T, Hagen F, Klaassen CH, Meis JF. Temperate climate niche for Cryptococcus gattii in Northern Europe. Emerg Infect Dis. 2012;18(1):172–4.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Speed B, Dunt D. Clinical and host differences between infections with the two varieties of Cryptococcus neoformans. Clin Infect Dis. 1995;21(1):28–34; discussion 5–6.

  54. Mitchell DH, Sorrell TC, Allworth AM, Heath CH, McGregor AR, Papanaoum K, et al. Cryptococcal disease of the CNS in immunocompetent hosts: influence of cryptococcal variety on clinical manifestations and outcome. Clin Infect Dis. 1995;20(3):611–6.

    Article  CAS  PubMed  Google Scholar 

  55. Chen S, Sorrell T, Nimmo G, Speed B, Currie B, Ellis D, et al. Epidemiology and host- and variety-dependent characteristics of infection due to Cryptococcus neoformans in Australia and New Zealand. Australasian Cryptococcal Study Group. Clin Infect Dis. 2000;31(2):499–508.

    Article  CAS  PubMed  Google Scholar 

  56. MacDougall L, Fyfe M, Romney M, Starr M, Galanis E. Risk factors for Cryptococcus gattii infection, British Columbia, Canada. Emerg Infect Dis. 2011;17(2):193–9.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Chen SC, Meyer W, Sorrell TC. Cryptococcus gattii infections. Clin Microbiol Rev. 2014;27(4):980–1024.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Ngamskulrungroj P, Price J, Sorrell T, Perfect JR, Meyer W. Cryptococcus gattii virulence composite: candidate genes revealed by microarray analysis of high and less virulent Vancouver island outbreak strains. PLoS One. 2011;6(1):e16076.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Phillips P, Galanis E, MacDougall L, Chong MY, Balshaw R, Cook VJ, et al. Longitudinal clinical findings and outcome among patients with Cryptococcus gattii infection in British Columbia. Clin Infect Dis. 2015;60(9):1368–76.

    PubMed  Google Scholar 

  60. Liu Y, Ma S, Wang X, Xu W, Tang J. Cryptococcus albidus encephalitis in newly diagnosed HIV-patient and literature review. Med Mycol Case Rep. 2014;3:8–10.

    Article  CAS  PubMed  Google Scholar 

  61. Shankar EM, Kumarasamy N, Bella D, Renuka S, Kownhar H, Suniti S, et al. Pneumonia and pleural effusion due to Cryptococcus laurentii in a clinically proven case of AIDS. Can Respir J. 2006;13(5):275–8.

    Article  PubMed  PubMed Central  Google Scholar 

  62. McCurdy LH, Morrow JD. Ventriculitis due to Cryptococcus uniguttulatus. South Med J. 2001;94(1):65–6.

    Article  CAS  PubMed  Google Scholar 

  63. Animalu C, Mazumder S, Cleveland KO, Gelfand MS. Cryptococcus uniguttulatus meningitis. Am J Med Sci. 2015.Nov;350(5):421–2

  64. Shibuya K, Coulson WF, Wollman JS, Wakayama M, Ando T, Oharaseki T, et al. Histopathology of cryptococcosis and other fungal infections in patients with acquired immunodeficiency syndrome. Int J Infect Dis. 2001;5(2):78–85.

    Article  CAS  PubMed  Google Scholar 

  65. Nalintya E, Kiggundu R, Meya D. Evolution of cryptococcal antigen testing: what is new? Curr Fungal Infect Rep. 2016;2016:1–6.

    PubMed  PubMed Central  Google Scholar 

  66. Huang HR, Fan LC, Rajbanshi B, Xu JF. Evaluation of a new cryptococcal antigen lateral flow immunoassay in serum, cerebrospinal fluid and urine for the diagnosis of cryptococcosis: a meta-analysis and systematic review. PLoS One. 2015;10(5):e0127117.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Perfect JR, Dismukes WE, Dromer F, Goldman DL, Graybill JR, Hamill RJ, 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(3):291–322.

    Article  PubMed  Google Scholar 

  68. Beardsley J, Wolbers M, Kibengo FM, Ggayi AB, Kamali A, Cuc NT, et al. Adjunctive dexamethasone in HIV-associated cryptococcal meningitis. N Engl J Med. 2016;374(6):542–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Sun HY, Alexander BD, Huprikar S, Forrest GN, Bruno D, Lyon GM, et al. Predictors of immune reconstitution syndrome in organ transplant recipients with cryptococcosis: implications for the management of immunosuppression. Clin Infect Dis. 2015;60(1):36–44.

    Article  PubMed  Google Scholar 

  70. Rossato L, Loreto ES, Zanette RA, Chassot F, Santurio JM, Alves SH. In vitro synergistic effects of chlorpromazine and sertraline in combination with amphotericin B against Cryptococcus neoformans var. grubii. Folia Microbiol (Praha).2016. Sep;61(5):399–403.

  71. Rhein J, Morawski BM, Hullsiek KH, Nabeta HW, Kiggundu R, Tugume L, et al. Efficacy of adjunctive sertraline for the treatment of HIV-associated cryptococcal meningitis: an open-label dose-ranging study. Lancet Infect Dis. 2016.Jul;16(7):809–18.

  72. • Lockhart SR, Fothergill AW, Iqbal N, Bolden CB, Grossman NT, Garvey EP, et al. The investigational fungal Cyp51 inhibitor VT-1129 demonstrates potent in vitro activity against Cryptococcus neoformans and Cryptococcus gattii. Antimicrob Agents Chemother. 2016;60(4):2528–31. Given the limited arsenal of drugs available to treat cryptococcal disease, the development of novel pharmacological therapies in is of importance.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Cutshaw D, Premji A, Pagadala P, Giamberardino C, Mccabe A, Lad SP, et al. A novel therapeutic approach for cryptococcal meningitis. Open Forum Infectious Diseases. 2016;3(suppl 1). 1643.

  74. Rolfes MA, Hullsiek KH, Rhein J, Nabeta HW, Taseera K, Schutz C, et al. The effect of therapeutic lumbar punctures on acute mortality from cryptococcal meningitis. Clin Infect Dis. 2014;59(11):1607–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, 4523 Clayton Ave, Campus Box 8051, St. Louis, MO, 63110, USA

    Jane A. O’Halloran, William G. Powderly & Andrej Spec

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  1. Jane A. O’Halloran
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  2. William G. Powderly
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  3. Andrej Spec
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Correspondence to Andrej Spec.

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Conflict of Interest

Dr. O’Halloran has nothing to disclose. Dr. Spec has received research funding from Astellas. Dr. Powderly reports grants and personal fees from Merck labs, grants from Astellas and MiraVista Laboratories, and personal fees from Gilead Sciences, outside the submitted work.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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This article is part of the Topical Collection on Mycology

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O’Halloran, J.A., Powderly, W.G. & Spec, A. Cryptococcosis Today: It Is Not All About HIV Infection. Curr Clin Micro Rpt 4, 88–95 (2017). https://doi.org/10.1007/s40588-017-0064-8

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