Cryptococcus-Related Immune Reconstitution Inflammatory Syndrome (IRIS): Pathogenesis and its Clinical Implications

Genomics and Pathogenesis (Shmuel Shoham, Section Editor)


This review provides an overview of Cryptococcus neoformans immunology and focuses on the pathogenesis of Cryptococcus-related paradoxical immune reconstitution inflammatory syndrome (IRIS). Cryptococcal IRIS has three phases: (1) before antiretroviral therapy (ART), with a paucity of cerebrospinal fluid (CSF) inflammation and defects in antigen clearance; (2) during initial ART immune recovery, with pro-inflammatory signaling by antigen-presenting cells without an effector response; and (3) at IRIS, a cytokine storm with a predominant type-1 helper T-cell (Th1) interferon-gamma (IFN-γ) response. Understanding IRIS pathogenesis allows for risk stratification and customization of HIV/AIDS care. In brief, persons at high IRIS risk may benefit from enhancing microbiologic clearance by use of adjunctive agents in combination with amphotericin, prolonging initial induction therapy, and/or increasing the initial consolidation antifungal therapy dose to at least 800 mg of fluconazole daily until the 2-week CSF culture is known to be sterile. Prophylactic anti-inflammatory therapies or undue delay of ART initiation in an attempt to prevent IRIS is unwarranted and may be dangerous.


HIV AIDS Cryptococcal meningitis CM-IRIS Immune reconstitution inflammatory syndrome Pathogenesis Review Antiretroviral therapy Immunology Risk stratification Biomarkers Antifungal therapy Anti-inflammatory therapy 



Financial support is received from National Institutes of Health (K23AI073192-02: DRB; U01AI089244-01; DLW). Dr. Boulware thanks collaboration with Drs. Paul Bohjanen, David Meya, Andrew Kambugu, Edward Janoff, Tihana Bicanic, and the Infectious Disease Institute of Makerere University, Kampala, Uganda. We thank Dr. Bicanic for critical review of the manuscript.


Conflicts of Interest: D. Wiesner: none; D. Boulware: research support from GlaxoSmithKline’s HIV Collaborative Investigator Research Award and Merck’s Investigator-Initiated Studies Program; both of these firms manufacture HIV antiretroviral medications.


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

  1. 1.
    Chayakulkeeree M, Perfect JR. Cryptococcosis. Infect Dis Clin North Am. 2006;20:507–44. v–vi.PubMedCrossRefGoogle Scholar
  2. 2.
    Perfect JR. Cryptococcus neoformans: a sugar-coated killer with designer genes. FEMS Immunol Med Microbiol. 2005;45:395–404.PubMedCrossRefGoogle Scholar
  3. 3.
    Vecchiarelli A. Immunoregulation by capsular components of Cryptococcus neoformans. Med Mycol. 2000;38:407–17.PubMedGoogle Scholar
  4. 4.
    Chaka W, Verheul AF, Vaishnav VV, Cherniak R, Scharringa J, Verhoef J, et al. Cryptococcus neoformans and cryptococcal glucuronoxylomannan, galactoxylomannan, and mannoprotein induce different levels of tumor necrosis factor alpha in human peripheral blood mononuclear cells. Infect Immun. 1997;65:272–8.PubMedGoogle Scholar
  5. 5.
    Kwon-Chung KJ, Rhodes JC. Encapsulation and melanin formation as indicators of virulence in Cryptococcus neoformans. Infect Immun. 1986;51:218–23.PubMedGoogle Scholar
  6. 6.
    Cherniak R, Sundstrom JB. Polysaccharide antigens of the capsule of Cryptococcus neoformans. Infect Immun. 1994;62:1507–12.PubMedGoogle Scholar
  7. 7.
    Pietrella D, Cherniak R, Strappini C, Perito S, Mosci P, Bistoni F, et al. Role of mannoprotein in induction and regulation of immunity to Cryptococcus neoformans. Infect Immun. 2001;69:2808–14.PubMedCrossRefGoogle Scholar
  8. 8.
    Frases S, Nimrichter L, Viana NB, Nakouzi A, Casadevall A. Cryptococcus neoformans capsular polysaccharide and exopolysaccharide fractions manifest physical, chemical, and antigenic differences. Eukaryot Cell. 2008;7:319–27.PubMedCrossRefGoogle Scholar
  9. 9.
    Yauch LE, Mansour MK, Shoham S, Rottman JB, Levitz SM. Involvement of CD14, toll-like receptors 2 and 4, and MyD88 in the host response to the fungal pathogen Cryptococcus neoformans in vivo. Infect Immun. 2004;72:5373–82.PubMedCrossRefGoogle Scholar
  10. 10.
    Yauch LE, Mansour MK, Levitz SM. Receptor-mediated clearance of Cryptococcus neoformans capsular polysaccharide in vivo. Infect Immun. 2005;73:8429–32.PubMedCrossRefGoogle Scholar
  11. 11.
    Shoham S, Huang C, Chen JM, Golenbock DT, Levitz SM. Toll-like receptor 4 mediates intracellular signaling without TNF-alpha release in response to Cryptococcus neoformans polysaccharide capsule. J Immunol. 2001;166:4620–6.PubMedGoogle Scholar
  12. 12.
    Levitz SM, Specht CA. The molecular basis for the immunogenicity of Cryptococcus neoformans mannoproteins. FEMS Yeast Res. 2006;6:513–24.PubMedCrossRefGoogle Scholar
  13. 13.
    Kozel TR, Wilson MA, Pfrommer GS, Schlageter AM. Activation and binding of opsonic fragments of C3 on encapsulated Cryptococcus neoformans by using an alternative complement pathway reconstituted from six isolated proteins. Infect Immun. 1989;57:1922–7.PubMedGoogle Scholar
  14. 14.
    van Asbeck EC, Hoepelman AI, Scharringa J, Herpers BL, Verhoef J. Mannose binding lectin plays a crucial role in innate immunity against yeast by enhanced complement activation and enhanced uptake of polymorphonuclear cells. BMC Microbiol. 2008;8:229.PubMedCrossRefGoogle Scholar
  15. 15.
    Sallusto F, Cella M, Danieli C, Lanzavecchia A. Dendritic cells use macropinocytosis and the mannose receptor to concentrate macromolecules in the major histocompatibility complex class II compartment: downregulation by cytokines and bacterial products. J Exp Med. 1995;182:389–400.PubMedCrossRefGoogle Scholar
  16. 16.
    Wozniak KL, Levitz SM. Cryptococcus neoformans enters the endolysosomal pathway of dendritic cells and is killed by lysosomal components. Infect Immun. 2008;76:4764–71.PubMedCrossRefGoogle Scholar
  17. 17.
    • Bicanic T, Muzoora C, Brouwer AE, Meintjes G, Longley N, Taseera K, 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. 2009;49:702–9. This article reports on the important association between survival and the quantitative rate of cryptococcal clearance from the CSF. PubMedCrossRefGoogle Scholar
  18. 18.
    Siddiqui AA, Brouwer AE, Wuthiekanun V, Jaffar S, Shattock R, Irving D, et al. IFN-gamma at the site of infection determines rate of clearance of infection in cryptococcal meningitis. J Immunol. 2005;174:1746–50.PubMedGoogle Scholar
  19. 19.
    Jarvis J, Meintjes G, Rebe K, Williams N, Bicanic T, Williams A, et al. Adjunctive IFN-γ immunotherapy for the treatment of HIV-associated cryptococcal meningitis: a randomized controlled trial [Abstract 40]. Presented at the Conference on Retroviruses and Opportunistic Infections (CROI). Boston, MA; Feb 28, 2011.Google Scholar
  20. 20.
    Voelz K, Lammas DA, May RC. Cytokine signaling regulates the outcome of intracellular macrophage parasitism by Cryptococcus neoformans. Infect Immun. 2009;77:3450–7.PubMedCrossRefGoogle Scholar
  21. 21.
    Muller U, Stenzel W, Kohler G, Werner C, Polte T, Hansen G, et al. IL-13 induces disease-promoting type 2 cytokines, alternatively activated macrophages and allergic inflammation during pulmonary infection of mice with Cryptococcus neoformans. J Immunol. 2007;179:5367–77.PubMedGoogle Scholar
  22. 22.
    • Stenzel W, Muller U, Kohler G, Heppner FL, Blessing M, McKenzie AN, et al. IL-4/IL-13-dependent alternative activation of macrophages but not microglial cells is associated with uncontrolled cerebral cryptococcosis. Am J Pathol. 2009;174:486–96. Using an in vivo murine model, this article demonstrates that Th 2 responses are nonprotective in cryptococcosis. PubMedCrossRefGoogle Scholar
  23. 23.
    Conti HR, Shen F, Nayyar N, Stocum E, Sun JN, Lindemann MJ, et al. Th17 cells and IL-17 receptor signaling are essential for mucosal host defense against oral candidiasis. J Exp Med. 2009;206:299–311.PubMedCrossRefGoogle Scholar
  24. 24.
    Zelante T, De Luca A, D’Angelo C, Moretti S, Romani L. IL-17/Th17 in anti-fungal immunity: what’s new? Eur J Immunol. 2009;39:645–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Hardison SE, Wozniak KL, Kolls JK, Wormley Jr FL. Interleukin-17 is not required for classical macrophage activation in a pulmonary mouse model of Cryptococcus neoformans infection. Infect Immun. 2010;78:5341–51.PubMedCrossRefGoogle Scholar
  26. 26.
    Wozniak KL, Hardison SE, Kolls JK, Wormley FL. Role of IL-17A on resolution of pulmonary C. neoformans infection. PLoS One. 2011;6:e17204.PubMedCrossRefGoogle Scholar
  27. 27.
    Zelante T, De Luca A, Bonifazi P, Montagnoli C, Bozza S, Moretti S, et al. IL-23 and the Th17 pathway promote inflammation and impair antifungal immune resistance. Eur J Immunol. 2007;37:2695–706.PubMedCrossRefGoogle Scholar
  28. 28.
    • Boulware DR, Meya DB, Bergemann TL, Wiesner DL, Rhein J, Musubire A, et al. Clinical features and serum biomarkers in HIV immune reconstitution inflammatory syndrome after cryptococcal meningitis: a prospective cohort study. PLoS Med. 2010;7:e1000384. This article details a prospective Ugandan cohort and the evolving pattern of serum cytokines and chemokines over time that are associated with IRIS. PubMedCrossRefGoogle Scholar
  29. 29.
    • Boulware DR, Bonham SC, Meya DB, Wiesner DL, Park GS, Kambugu A, et al. Paucity of initial cerebrospinal fluid inflammation in cryptococcal meningitis is associated with subsequent immune reconstitution inflammatory syndrome. J Infect Dis. 2010;202:962–70. This article reports on the inflammatory cytokines and chemokines present in the CSF of persons with and without IRIS at the time of their initial infection and at the time of IRIS. PubMedCrossRefGoogle Scholar
  30. 30.
    • Jarvis J. CSF cytokine profiles in patients with HIV-associated cryptococcal meningitis: correlates with clinical outcome. Presented at the 8th International Conference on Cryptococcus and Cryptococcosis. Charleston, SC; May 4, 2011. This abstract presents confirmatory data on CSF cytokine profiles; an initial paucity of inflammation was associated with later IRIS. Google Scholar
  31. 31.
    Stone SF, Price P, Keane NM, Murray RJ, French MA. Levels of IL-6 and soluble IL-6 receptor are increased in HIV patients with a history of immune restoration disease after HAART. HIV Med. 2002;3:21–7.PubMedCrossRefGoogle Scholar
  32. 32.
    Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008;8:958–69.PubMedCrossRefGoogle Scholar
  33. 33.
    Almeida GM, Andrade RM, Bento CA. The capsular polysaccharides of Cryptococcus neoformans activate normal CD4(+) T cells in a dominant Th2 pattern. J Immunol. 2001;167:5845–51.PubMedGoogle Scholar
  34. 34.
    Hoag KA, Lipscomb MF, Izzo AA, Street NE. IL-12 and IFN-gamma are required for initiating the protective Th1 response to pulmonary cryptococcosis in resistant C.B-17 mice. Am J Respir Cell Mol Biol. 1997;17:733–9.PubMedGoogle Scholar
  35. 35.
    Gilliet M, Liu YJ. Human plasmacytoid-derived dendritic cells and the induction of T-regulatory cells. Hum Immunol. 2002;63:1149–55.PubMedCrossRefGoogle Scholar
  36. 36.
    McKenna K, Beignon AS, Bhardwaj N. Plasmacytoid dendritic cells: linking innate and adaptive immunity. J Virol. 2005;79:17–27.PubMedCrossRefGoogle Scholar
  37. 37.
    Dale DC, Liles WC, Llewellyn C, Price TH. Effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) on neutrophil kinetics and function in normal human volunteers. Am J Hematol. 1998;57:7–15.PubMedCrossRefGoogle Scholar
  38. 38.
    van Pelt LJ, Huisman MV, Weening RS, von dem Borne AE, Roos D, van Oers RH. A single dose of granulocyte-macrophage colony-stimulating factor induces systemic interleukin-8 release and neutrophil activation in healthy volunteers. Blood. 1996;87:5305–13.PubMedGoogle Scholar
  39. 39.
    Chen G-H, Olszewski MA, McDonald RA, Wells JC, Paine III R, Huffnagle GB, et al. Role of granulocyte macrophage colony-stimulating factor in host defense against pulmonary Cryptococcus neoformans infection during murine allergic bronchopulmonary mycosis. Am J Pathol. 2007;170:1028–40.PubMedCrossRefGoogle Scholar
  40. 40.
    Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006;441:235–8.PubMedCrossRefGoogle Scholar
  41. 41.
    Diehl S, Rincon M. The two faces of IL-6 on Th1/Th2 differentiation. Mol Immunol. 2002;39:531–6.PubMedCrossRefGoogle Scholar
  42. 42.
    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;46:1694–701.PubMedCrossRefGoogle Scholar
  43. 43.
    Bicanic T, Meintjes G, Wood R, Hayes M, Rebe K, Bekker LG, et al. Fungal burden, early fungicidal activity, and outcome in cryptococcal meningitis in antiretroviral-naive or antiretroviral-experienced patients treated with amphotericin B or fluconazole. Clin Infect Dis. 2007;45:76–80.PubMedCrossRefGoogle Scholar
  44. 44.
    • Chang CC. Patients with cryptococcal meningitis who attain CSF sterility pre-ART commencement experience improved outcomes in the first 6 months. Presented at the 8th International Conference on Cryptococcus and Cryptococcosis. Charleston, SC; May 5, 2011. This abstract presents convincing data from a prospective cohort on the importance of CSF culture sterility before ART initiation and/or before fluconazole dosing is reduced to fungistatic levels. Google Scholar
  45. 45.
    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;50:291–322.PubMedCrossRefGoogle Scholar
  46. 46.
    Bicanic T, Jarvis J, Loyse A, Jackson A, Muzoora C, Wilson D, et al. Determinants of acute outcome and long-term survival in HIV-associated cryptococcal meningitis: Results from a combined cohort of 523 patients [Abstract 892]. Presented at the Conference on Retroviruses and Opportunistic Infections (CROI). Boston, MA; March 3, 2011.Google Scholar
  47. 47.
    Bahr N, Rolfes MAR, Musubire A, Nabeta H, Lo M, Meya DB, et al. The impact of routine electrolyte supplementation during amphotericin induction therapy in resource-limited settings. Presented at the 8th International Conference on Cryptococcus and Cryptococcosis. Charleston, SC; May 4, 2011.Google Scholar
  48. 48.
    Longley N, Muzoora C, Taseera K, Mwesigye J, Rwebembera J, Chakera A, et al. Dose response effect of high-dose fluconazole for HIV-associated cryptococcal meningitis in southwestern Uganda. Clin Infect Dis. 2008;47:1556–61.PubMedCrossRefGoogle Scholar
  49. 49.
    Grant PM, Komarow L, Andersen J, Sereti I, Pahwa S, Lederman MM, et al. Risk factor analyses for immune reconstitution inflammatory syndrome in a randomized study of early vs. deferred ART during an opportunistic infection. PLoS One. 2010;5:e11416.PubMedCrossRefGoogle Scholar
  50. 50.
    • Bicanic T, Meintjes G, Rebe K, Williams A, Loyse A, Wood R, et al. Immune reconstitution inflammatory syndrome in HIV-associated cryptococcal meningitis: a prospective study. J Acquir Immune Defic Syndr. 2009;51:130–4. This cohort is the first prospective study to detail the incidence of Cryptococcus-related IRIS in sub-Saharan Africa. PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Division of Infectious Disease & International Medicine, Department of MedicineUniversity of MinnesotaMinneapolisUSA

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