Current Fungal Infection Reports

, Volume 6, Issue 1, pp 1–10 | Cite as

IRIS and Fungal Infections: What Have We Learned?

Current Management of Fungal Infections (L Ostrosky-Zeichner, Section Editor)
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Abstract

Restoration of pathogen-specific immunity as a result of highly active antiretroviral therapy or reduction of immunosuppression in solid-organ transplant recipients can result in a destructive inflammatory response known as the immune reconstitution inflammatory syndrome (IRIS). Though immune reconstitution disorders can occur in the context of a number of infectious and neoplastic processes, IRIS associated with invasive mycoses, in particular cryptococcosis, is a highly prevalent and morbid entity worldwide. Recent consensus definitions and prospective analyses of cryptococcal IRIS, with particular attention to baseline clinical features, serum and cerebrospinal fluid biomarkers, and the evolution of these over time in individual patients have provided critical insights into pathogenesis. This review focuses on the current understanding of IRIS in the context of opportunistic mycoses, with particular attention to Cryptococcus infection, and discusses the basis for this understanding, including biomarkers as clues to pathogenesis and aids in diagnosis and novel approaches to prevention and management.

Keywords

IRIS Immune reconstitution inflammatory syndrome Immune restoration disease Cryptococcosis Cryptococcal meningitis Opportunistic mycoses HIV/AIDS Antiretroviral therapy ART Pathogenesis Diagnostic criteria Case definition Biomarkers Transplantation Immunosuppression Prevention Management 

Notes

Disclosure

Conflicts of Interest: E. Maziarz: none; J. Perfect: Research grants, consulting and honorariums from Merck, Astellas, Enzon, Schering-Plough, and Pfizer.

References

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

  1. 1.
    Casadevall A, Pirofski LA. The damage-response framework of microbial pathogenesis. Nat Rev Microbiol. 2003;1(1):17–24.PubMedCrossRefGoogle Scholar
  2. 2.
    Shelburne 3rd SA, Hamill RJ, Rodriguez-Barradas MC, et al. Immune reconstitution inflammatory syndrome: emergence of a unique syndrome during highly active antiretroviral therapy. Medicine. 2002;81(3):213–27.PubMedCrossRefGoogle Scholar
  3. 3.
    Singh N, Lortholary O, Alexander BD, et al. An immune reconstitution syndrome-like illness associated with Cryptococcus neoformans infection in organ transplant recipients. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America, 2005; 40(12):1756–61.Google Scholar
  4. 4.
    Jenny-Avital ER, Abadi M. Immune reconstitution cryptococcosis after initiation of successful highly active antiretroviral therapy. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2002;35(12):e128-33.Google Scholar
  5. 5.
    Blanche P, Gombert B, Ginsburg C, et al. HIV combination therapy: immune restitution causing cryptococcal lymphadenitis dramatically improved by anti-inflammatory therapy. Scand J Infect Dis. 1998;30(6):615–6.PubMedCrossRefGoogle Scholar
  6. 6.
    French MA, Price P, Stone SF. Immune restoration disease after antiretroviral therapy. AIDS. 2004;18(12):1615–27.PubMedCrossRefGoogle Scholar
  7. 7.
    Price P, Murdoch DM, Agarwal U, et al. Immune restoration diseases reflect diverse immunopathological mechanisms. Clin Microbiol Rev. 2009;22(4):651–63.PubMedCrossRefGoogle Scholar
  8. 8.
    Muller M, Wandel S, Colebunders R, et al. Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic review and meta-analysis. Lancet Infect Dis. 2010;10(4):251–61.PubMedCrossRefGoogle Scholar
  9. 9.
    Meintjes G, Lawn SD, Scano F, et al. Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings. Lancet Infect Dis. 2008;8(8):516–23.PubMedCrossRefGoogle Scholar
  10. 10.
    • Haddow LJ, Easterbrook PJ, Mosam A, et al. Defining immune reconstitution inflammatory syndrome: evaluation of expert opinion versus 2 case definitions in a South African cohort. Clin Infect Dis. 2009;49(9):1424–32. This paper measures the level of agreement in the classification of IRIS between two published case definitions and consensus expert opinion and provides a revised case definition for IRIS, with different criteria for paradoxical versus unmasking IRIS. PubMedCrossRefGoogle Scholar
  11. 11.
    French MA. HIV/AIDS: immune reconstitution inflammatory syndrome: a reappraisal. Clin Infect Dis. 2009;48(1):101–7.PubMedCrossRefGoogle Scholar
  12. 12.
    • Haddow LJ, Colebunders R, Meintjes G, et al. Cryptococcal immune reconstitution inflammatory syndrome in HIV-1-infected individuals: proposed clinical case definitions. Lancet Infect Dis. 2010;10(11):791–802. This systematic review of HIV-associated cryptococcal IRIS provides standardized consensus case definitions for paradoxical IRIS and ART-associated cryptococcosis, with clarification of the term “unmasking IRIS,” to improve precision of future prospective studies. PubMedCrossRefGoogle Scholar
  13. 13.
    Miceli MH, Maertens J, Buve K, et al. Immune reconstitution inflammatory syndrome in cancer patients with pulmonary aspergillosis recovering from neutropenia: Proof of principle, description, and clinical and research implications. Cancer. 2007;110(1):112–20.PubMedCrossRefGoogle Scholar
  14. 14.
    Koval CE, Gigliotti F, Nevins D, Demeter LM. Immune reconstitution syndrome after successful treatment of Pneumocystis carinii pneumonia in a man with human immunodeficiency virus type 1 infection. Clin Infect Dis. 2002;35(4):491–3.PubMedCrossRefGoogle Scholar
  15. 15.
    Wislez M, Bergot E, Antoine M, et al. Acute respiratory failure following HAART introduction in patients treated for Pneumocystis carinii pneumonia. Am J Respir Crit Care Med. 2001;164(5):847–51.PubMedGoogle Scholar
  16. 16.
    Jagannathan P, Davis E, Jacobson M, Huang L. Life-threatening immune reconstitution inflammatory syndrome after Pneumocystis pneumonia: a cautionary case series. AIDS. 2009;23(13):1794–6.PubMedCrossRefGoogle Scholar
  17. 17.
    Mori S, Polatino S, Estrada-Y-Martin RM. Pneumocystis-associated organizing pneumonia as a manifestation of immune reconstitution inflammatory syndrome in an HIV-infected individual with a normal CD4(+) T-cell count following antiretroviral therapy. Int J STD AIDS. 2009;20(9):662–5.PubMedCrossRefGoogle Scholar
  18. 18.
    Singh N, Perfect JR. Immune reconstitution syndrome associated with opportunistic mycoses. Lancet Infect Dis. 2007;7(6):395–401.PubMedCrossRefGoogle Scholar
  19. 19.
    Antinori S, Corbellino M, Necchi A, et al. Immune reconstitution inflammatory syndrome associated with Aspergillus terreus pulmonary infection in an autologous stem cell transplant recipient. Transpl Infect Dis. 2010;12(1):64–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Breton G, Adle-Biassette H, Therby A, et al. Immune reconstitution inflammatory syndrome in HIV-infected patients with disseminated histoplasmosis. AIDS. 2006;20(1):119–21.PubMedCrossRefGoogle Scholar
  21. 21.
    De Lavaissiere M, Manceron V, Bouree P, et al. Reconstitution inflammatory syndrome related to histoplasmosis, with a hemophagocytic syndrome in HIV infection. J Infect. 2009;58(3):245–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Jazwinski A, Naggie S, Perfect J. Immune reconstitution syndrome in a patient with disseminated histoplasmosis and steroid taper: maintaining the perfect balance. Mycoses. 2011;54(3):270–2.PubMedCrossRefGoogle Scholar
  23. 23.
    Shelburne SA, Visnegarwala F, Darcourt J, et al. Incidence and risk factors for immune reconstitution inflammatory syndrome during highly active antiretroviral therapy. AIDS. 2005;19(4):399–406.PubMedCrossRefGoogle Scholar
  24. 24.
    Shelburne 3rd SA, Darcourt J, White Jr AC, et al. The role of immune reconstitution inflammatory syndrome in AIDS-related Cryptococcus neoformans disease in the era of highly active antiretroviral therapy. Clin Infect Dis. 2005;40(7):1049–52.PubMedCrossRefGoogle Scholar
  25. 25.
    Lortholary O, Fontanet A, Memain N, et al. Incidence and risk factors of immune reconstitution inflammatory syndrome complicating HIV-associated cryptococcosis in France. AIDS. 2005;19(10):1043–9.PubMedCrossRefGoogle Scholar
  26. 26.
    • Bicanic T, Meintjes G, Rebe K, et al. Immune reconstitution inflammatory syndrome in HIV-associated cryptococcal meningitis: a prospective study. J Acquir Immune Defic Syndr. 2009;51(2):130–4. This first prospective cohort study of cryptococcal IRIS found an incidence of 17% in a South African cohort and (unlike reports from earlier retrospective cohorts) did not demonstrate any baseline factors predictive of future IRIS. PubMedCrossRefGoogle Scholar
  27. 27.
    Sungkanuparph S, Jongwutiwes U, Kiertiburanakul S. Timing of cryptococcal immune reconstitution inflammatory syndrome after antiretroviral therapy in patients with AIDS and cryptococcal meningitis. J Acquir Immune Defic Syndr. 2007;45(5):595–6.PubMedCrossRefGoogle Scholar
  28. 28.
    • Kambugu A, Meya DB, Rhein J, 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. This article reports findings of two prospective Ugandan cohorts of HIV-infected ART-naïve patients with cryptococcosis, in which probable IRIS events occurred in 42% of patients, with an estimated attributable mortality rate of 40–50%. PubMedCrossRefGoogle Scholar
  29. 29.
    • Boulware DR, Bonham SC, Meya DB, et al. Paucity of initial cerebrospinal fluid inflammation in cryptococcal meningitis is associated with subsequent immune reconstitution inflammatory syndrome. J Infect Dis. 2010;202(6):962–70. This prospective study of a Ugandan cohort with cryptococcal meningitis compares the CSF cellular and cytokine profiles of patients with and without IRIS, both at baseline and at the time of the IRIS event. This study finds that initial CSF in patients who develop IRIS is marked by less inflammation, and that changes in inflammatory cytokines at the time of the event are useful in distinguishing IRIS cases from culture-positive disease relapse. PubMedCrossRefGoogle Scholar
  30. 30.
    • Sungkanuparph S, Filler SG, Chetchotisakd P, et al. Cryptococcal immune reconstitution inflammatory syndrome after antiretroviral therapy in AIDS patients with cryptococcal meningitis: a prospective multicenter study. Clin Infect Dis. 2009;49(6):931–4. This prospective study of cryptococcal IRIS provides further evidence that CSF parameters at the time of the IRIS event (compared with baseline) can be used to distinguish IRIS from relapse and finds no association between time to ART initiation and risk of subsequent IRIS. PubMedCrossRefGoogle Scholar
  31. 31.
    da Cunha Colombo ER, Mora DJ, Silva-Vergara ML. Immune reconstitution inflammatory syndrome (IRIS) associated with Cryptococcus neoformans infection in AIDS patients. Mycoses. 2011;54(4):e178–82.PubMedCrossRefGoogle Scholar
  32. 32.
    Rambeloarisoa J, Batisse D, Thiebaut JB, et al. Intramedullary abscess resulting from disseminated cryptococcosis despite immune restoration in a patient with AIDS. J Infect. 2002;44(3):185–8.PubMedCrossRefGoogle Scholar
  33. 33.
    Skiest DJ, Hester LJ, Hardy RD. Cryptococcal immune reconstitution inflammatory syndrome: report of four cases in three patients and review of the literature. J Infect. 2005;51(5):e289–97.PubMedCrossRefGoogle Scholar
  34. 34.
    • Boulware DR, Meya DB, Bergemann TL, et al. Clinical features and serum biomarkers in HIV immune reconstitution inflammatory syndrome after cryptococcal meningitis: a prospective cohort study. PLoS Medicine 2010;7(12):e1000384. This article details serum cytokine profiles in a prospective cohort of HIV-infected persons with recent cryptococcal meningitis and the change in these over time among patients with and without IRIS; it provides a predictive risk score for future IRIS based on baseline serum cytokines. PubMedCrossRefGoogle Scholar
  35. 35.
    Bicanic T, Harrison T, Niepieklo A, et al. Symptomatic relapse of HIV-associated cryptococcal meningitis after initial fluconazole monotherapy: the role of fluconazole resistance and immune reconstitution. Clin Infect Dis. 2006;43(8):1069–73.PubMedCrossRefGoogle Scholar
  36. 36.
    • Tan DB, Yong YK, Tan HY, et al. Immunological profiles of immune restoration disease presenting as mycobacterial lymphadenitis and cryptococcal meningitis. HIV Med. 2008:9(5):307–16. Using peripheral blood mononuclear cells collected over a year in patients initiating ART, these authors report findings that pathogen-specific IFN-γ and IgG responses to C neoformans are elevated and peak at the time of IRIS events, as do the proportion of activated T cells, without an associated decrease in the proportion of regulatory T cells. PubMedCrossRefGoogle Scholar
  37. 37.
    Vecchiarelli A. Immunoregulation by capsular components of Cryptococcus neoformans. Med Mycol. 2000;38(6):407–17.PubMedGoogle Scholar
  38. 38.
    Shoham S, Levitz SM. The immune response to fungal infections. Br J Haematol. 2005;129(5):569–82.PubMedCrossRefGoogle Scholar
  39. 39.
    Osterholzer JJ, Milam JE, Chen GH, et al. Role of dendritic cells and alveolar macrophages in regulating early host defense against pulmonary infection with Cryptococcus neoformans. Infect Immun. 2009;77(9):3749–58.PubMedCrossRefGoogle Scholar
  40. 40.
    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(2):389–400.PubMedCrossRefGoogle Scholar
  41. 41.
    Wozniak KL, Levitz SM. Cryptococcus neoformans enters the endolysosomal pathway of dendritic cells and is killed by lysosomal components. Infect Immun. 2008;76(10):4764–71.PubMedCrossRefGoogle Scholar
  42. 42.
    Parkin J, Cohen B. An overview of the immune system. Lancet. 2001;357(9270):1777–89.PubMedCrossRefGoogle Scholar
  43. 43.
    Wormley Jr FL, Perfect JR, Steele C, Cox GM. Protection against cryptococcosis by using a murine gamma interferon-producing Cryptococcus neoformans strain. Infect Immun. 2007;75(3):1453–62.PubMedCrossRefGoogle Scholar
  44. 44.
    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(6):733–9.PubMedGoogle Scholar
  45. 45.
    Siddiqui AA, Brouwer AE, Wuthiekanun V, et al. IFN-gamma at the site of infection determines rate of clearance of infection in cryptococcal meningitis. J Immunol. 2005;174(3):1746–50.PubMedGoogle Scholar
  46. 46.
    Voelz K, Lammas DA, May RC. Cytokine signaling regulates the outcome of intracellular macrophage parasitism by Cryptococcus neoformans. Infect Immun. 2009;77(8):3450–7.PubMedCrossRefGoogle Scholar
  47. 47.
    Bettelli E, Carrier Y, Gao W, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006;441(7090):235–8.PubMedCrossRefGoogle Scholar
  48. 48.
    Bonham S, Meya DB, Bohjanen PR, Boulware DR. Biomarkers of HIV immune reconstitution inflammatory syndrome. Biomark Med. 2008;2(4):349–61.PubMedCrossRefGoogle Scholar
  49. 49.
    Stockinger B, Veldhoen M. Differentiation and function of Th17 T cells. Curr Opin Immunol. 2007;19(3):281–6.PubMedCrossRefGoogle Scholar
  50. 50.
    Fossiez F, Banchereau J, Murray R, et al. Interleukin-17. Int Rev Immunol. 1998;16(5–6):541–51.PubMedCrossRefGoogle Scholar
  51. 51.
    Huang W, Na L, Fidel PL, Schwarzenberger P. Requirement of interleukin-17A for systemic anti-Candida albicans host defense in mice. J Infect Dis. 2004;190(3):624–31.PubMedCrossRefGoogle Scholar
  52. 52.
    Conti HR, Shen F, Nayyar N, et al. Th17 cells and IL-17 receptor signaling are essential for mucosal host defense against oral candidiasis. J Exp Med. 2009;206(2):299–311.PubMedCrossRefGoogle Scholar
  53. 53.
    Kleinschek MA, Muller U, Brodie SJ, et al. IL-23 enhances the inflammatory cell response in Cryptococcus neoformans infection and induces a cytokine pattern distinct from IL-12. J Immunol. 2006;176(2):1098–106.PubMedGoogle Scholar
  54. 54.
    Zelante T, De Luca A, Bonifazi P, et al. IL-23 and the Th17 pathway promote inflammation and impair antifungal immune resistance. Eur J Immunol. 2007;37(10):2695–706.PubMedCrossRefGoogle Scholar
  55. 55.
    Retini C, Casadevall A, Pietrella D, et al. Specific activated T cells regulate IL-12 production by human monocytes stimulated with Cryptococcus neoformans. J Immunol. 1999;162(3):1618–23.PubMedGoogle Scholar
  56. 56.
    Sau K, Mambula SS, Latz E, et al. The antifungal drug amphotericin B promotes inflammatory cytokine release by a Toll-like receptor- and CD14-dependent mechanism. J Biol Chem. 2003;278(39):37561–8.PubMedCrossRefGoogle Scholar
  57. 57.
    Simitsopoulou M, Roilides E, Georgiadou E, et al. Differential transcriptional profiles induced by amphotericin B formulations on human monocytes during response to hyphae of Aspergillus fumigatus. Med Mycol. 2011;49(2):176–85.PubMedCrossRefGoogle Scholar
  58. 58.
    Lanternier F, Chandesris MO, Poiree S, et al. Cellulitis revealing a cryptococcosis-related immune reconstitution inflammatory syndrome in a renal allograft recipient. Am J Transplant. 2007;7(12):2826–8.PubMedCrossRefGoogle Scholar
  59. 59.
    Sakaguchi S, Wing K, Miyara M. Regulatory T cells - a brief history and perspective. Eur J Immunol. 2007;37 Suppl 1:S116–23.PubMedCrossRefGoogle Scholar
  60. 60.
    Shankar EM, Vignesh R, Velu V, et al. Does CD4+CD25+foxp3+ cell (Treg) and IL-10 profile determine susceptibility to immune reconstitution inflammatory syndrome (IRIS) in HIV disease? J Inflamm (Lond). 2008;5:2.CrossRefGoogle Scholar
  61. 61.
    Sun HY, Singh N. Opportunistic infection-associated immune reconstitution syndrome in transplant recipients. Clin Infect Dis. 2011;53(2):168–76.PubMedCrossRefGoogle Scholar
  62. 62.
    van de Veerdonk FL, Gresnigt MS, Kullberg BJ, et al. Th17 responses and host defense against microorganisms: an overview. BMB Rep. 2009;42(12):776–87.PubMedCrossRefGoogle Scholar
  63. 63.
    Seddiki N, Sasson SC, Santner-Nanan B, et al. Proliferation of weakly suppressive regulatory CD4+ T cells is associated with over-active CD4+ T-cell responses in HIV-positive patients with mycobacterial immune restoration disease. Eur J Immunol. 2009;39(2):391–403.PubMedCrossRefGoogle Scholar
  64. 64.
    • Porter BO, Ouedraogo GL, Hodge JN, et al. d-Dimer and CRP levels are elevated prior to antiretroviral treatment in patients who develop IRIS. Clin Immunol. 2010;136(1):42–50. This article reports that levels of D-dimer and CRP prior to ART initiation are higher in patients who subsequently develop IRIS, and it offers preliminary evidence of the use of serum biomarkers in predicting risk of IRIS. PubMedCrossRefGoogle Scholar
  65. 65.
    • Zolopa A, Andersen J, Powderly W, et al. Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial. PloS One. 2009;4(5):e5575. This article reports findings of a randomized trial of a strategy of early versus deferred ART initiation in the setting of AIDS-related opportunistic infections, demonstrating no difference in rates of confirmed IRIS among patients randomized to early ART. PubMedCrossRefGoogle Scholar
  66. 66.
    Singh N, Lortholary O, Alexander BD, et al. Allograft loss in renal transplant recipients with cryptococcus neoformans associated immune reconstitution syndrome. Transplantation. 2005;80(8):1131–3.PubMedCrossRefGoogle Scholar
  67. 67.
    Crespo G, Cervera C, Michelena J, et al. Immune reconstitution syndrome after voriconazole treatment for cryptococcal meningitis in a liver transplant recipient. Liver Transplant. 2008;14(11):1671–4.CrossRefGoogle Scholar
  68. 68.
    Singh N. Novel immune regulatory pathways and their role in immune reconstitution syndrome in organ transplant recipients with invasive mycoses. Eur J Clin Microbiol Infect Dis. 2008;27(6):403–8.PubMedCrossRefGoogle Scholar
  69. 69.
    Ingram PR, Howman R, Leahy MF, Dyer JR. Cryptococcal immune reconstitution inflammatory syndrome following alemtuzumab therapy. Clin Infect Dis. 2007;44(12):e115–7.PubMedCrossRefGoogle Scholar
  70. 70.
    Cadena J, Thompson 3rd GR, Ho TT, et al. Immune reconstitution inflammatory syndrome after cessation of the tumor necrosis factor alpha blocker adalimumab in cryptococcal pneumonia. Diagn Microbiol Infect Dis. 2009;64(3):327–30.PubMedCrossRefGoogle Scholar
  71. 71.
    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.PubMedCrossRefGoogle Scholar
  72. 72.
    Trevenzoli M, Cattelan AM, Rea F, et al. Mediastinitis due to cryptococcal infection: a new clinical entity in the HAART era. J Infect. 2002;45(3):173–9.PubMedGoogle Scholar
  73. 73.
    Cinti SK, Armstrong WS, Kauffman CA. Case report. Recurrence of increased intracranial pressure with antiretroviral therapy in an AIDS patient with cryptococcal meningitis. Mycoses. 2001;44(11–12):497–501.PubMedCrossRefGoogle Scholar
  74. 74.
    Makadzange AT, Ndhlovu CE, Takarinda K, et al. Early versus delayed initiation of antiretroviral therapy for concurrent HIV infection and cryptococcal meningitis in sub-saharan Africa. Clin Infect Dis. 2010;50(11):1532–8.PubMedCrossRefGoogle Scholar
  75. 75.
    Burgess DS, Hastings RW. A comparison of dynamic characteristics of fluconazole, itraconazole, and amphotericin B against Cryptococcus neoformans using time-kill methodology. Diagn Microbiol Infect Dis. 2000;38(2):87–93.PubMedCrossRefGoogle Scholar
  76. 76.
    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(4):448–55.PubMedCrossRefGoogle Scholar
  77. 77.
    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(3):291–322.PubMedCrossRefGoogle Scholar
  78. 78.
    • Bicanic T, Muzoora C, Brouwer AE, 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(5):702–9. This article demonstrates that a slower rate of fungal clearance in cryptococcal meningitis is independently associated with increased mortality and that higher baseline levels of IFN-γ are independently associated with more rapid fungal clearance. PubMedCrossRefGoogle Scholar
  79. 79.
    Meintjes G, Wilkinson RJ, Morroni C, et al. Randomized placebo-controlled trial of prednisone for paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome. AIDS. 2010;24(15):2381–90.PubMedGoogle Scholar
  80. 80.
    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(1):47–54.PubMedCrossRefGoogle Scholar
  81. 81.
    Brunel AS, Makinson A, de Champfleur NM, et al. HIV-related immune reconstitution cryptococcal meningoradiculitis: corticosteroid response. Neurology. 2009;73(20):1705–7.PubMedCrossRefGoogle Scholar
  82. 82.
    Biagetti C, Nicola M, Borderi M, et al. Paradoxical immune reconstitution inflammatory syndrome associated with previous Cryptococcus neoformans infection in an HIV-positive patient requiring neurosurgical intervention. New Microbiol. 2009;32(2):209–12.PubMedGoogle Scholar
  83. 83.
    Legris T, Massad M, Purgus R, et al. Immune reconstitution inflammatory syndrome mimicking relapsing cryptococcal meningitis in a renal transplant recipient. Transpl Infect Dis. 2011;13(3):303–8.PubMedCrossRefGoogle Scholar
  84. 84.
    Manfredi R, Pieri F, Pileri SA, Chiodo F. The changing face of AIDS-related opportunism: cryptococcosis in the highly active antiretroviral therapy (HAART) era. Case reports and literature review. Mycopathologia. 1999;148(2):73–8.PubMedCrossRefGoogle Scholar
  85. 85.
    Narayanan S, Banerjee C, Holt PA. Cryptococcal immune reconstitution syndrome during steroid withdrawal treated with hydroxychloroquine. Int J Infect Dis. 2011;15(1):e70–3.PubMedCrossRefGoogle Scholar
  86. 86.
    Sitapati AM, Kao CL, Cachay ER, et al. Treatment of HIV-related inflammatory cerebral cryptococcoma with adalimumab. Clin Infect Dis. 2010;50(2):e7–e10.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Division of Infectious Disease and International Health, Department of MedicineDuke University Medical CenterDurhamUSA

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