Skip to main content

Advertisement

SpringerLink
Log in

Cryptococcosis in Patients with Hematologic Diseases

  • Current Management of Fungal Infections (J Maertens, Section Editor)
  • Published:
Current Fungal Infection Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

In this paper, we reviewed the epidemiology, diagnosis, and treatment of cryptococcosis in patients with hematologic malignancies. We reviewed all case series of cryptococcosis in different hematologic conditions, and looked at epidemiologic trends considering the new antineoplastic drugs introduced in the treatment of hematologic malignancies.

Recent Findings

Case series of cryptococcosis in patients with hematologic malignancies are scarce. We identified an increase in the proportion of cases of cryptococcosis occurring in patients with hematologic malignancies, and many case reports of cryptococcosis in patients receiving ibrutinib, a Bruton kinase inhibitor used in the treatment of chronic lymphoproliferative diseases.

Summary

Cryptococcosis is uncommon in patients with hematologic malignancies, but its occurrence may be associated with poor outcome. Hematologists should be aware of this complication if patients develop neurologic symptoms or present with pulmonary infiltrates that do not improve with antibiotics.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

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

  1. •• Maziarz EK, Perfect JR. Cryptococcosis. Infect Dis Clin N Am. 2016;30(1):179–206 Comprehensive review paper on cryptococcosis.

    Article  Google Scholar 

  2. •• Elsegeiny W, Marr KA, Williamson PR. Immunology of cryptococcal infections: developing a rational approach to patient therapy. Front Immunol. 2018;9:651 This study reviews the interactions between host defenses and Cryptococcus and the patterns of clinical presentation and evolution based on these interactions.

    Article  Google Scholar 

  3. Torrey FA. Cutaneous torulosis in a patient with Hodgkin’s disease. Arch Dermatol Syphilol. 1947;55(5):738.

    CAS  Google Scholar 

  4. Gendel BR, Ende M, Norman SL. Cryptococcosis; a review with special reference to apparent association with Hodgkin’s disease. Am J Med. 1950;9(3):343–55.

    Article  CAS  Google Scholar 

  5. Rodger RC, Terry LL, Binford CH. Histoplasmosis, cryptococcosis and tuberculosis complicating Hodgkin’s disease; report of a case. Am J Clin Pathol. 1951;21(2):153–7.

    Article  CAS  Google Scholar 

  6. Zelman S, O'Neil RH, Plaut A. Disseminated visceral torulosis without nervous system involvement with clinical appearance of granulocytic leukemia. Am J Med. 1951;11(5):658–64.

    Article  CAS  Google Scholar 

  7. Holmes SJ, Hawks GH. Torulosis of the central nervous system. Can Med Assoc J. 1953;68(2):143–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Symmers WS. Torulosis; a case mimicking Hodgkin's disease and rodent ulcer and a presumed case of pulmonary torulosis with acute dissemination. Lancet. 1953;265(6795):1068–74.

    Article  CAS  Google Scholar 

  9. Levene M, Michaels L. Acute disseminated torulosis associated with Hodgkin’s disease. J Clin Pathol. 1955;8(3):201–6.

    Article  CAS  Google Scholar 

  10. Misch KA. Torulosis associated with Hodgkin’s disease. J Clin Pathol. 1955;8(3):207–10.

    Article  CAS  Google Scholar 

  11. Goodman HL. Cryptococcosis associated with Hodgkin’s disease. N Y State J Med. 1956;56(9):1493–7.

    CAS  PubMed  Google Scholar 

  12. Burrows B, Barclay WR. Combined cryptococcal and tuberculous meningitis complicating reticulum cell sarcoma. Am Rev Tuberc. 1958;78(5):760–8.

    CAS  PubMed  Google Scholar 

  13. Gowing NF. Observations on a case of torulosis associated with Hodgkin’s disease. Proc R Soc Med. 1958;51(7):494–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Gruhn JG, Sanson J. Mycotic infections in leukemic patients at autopsy. Cancer. 1963;16:61–73.

    Article  CAS  Google Scholar 

  15. Bodey GP. Fungal infections complicating acute leukemia. J Chronic Dis. 1966;19(6):667–87.

    Article  CAS  Google Scholar 

  16. Casazza AR, Duvall CP, Carbone PP. Infection in lymphoma. Histology, treatment, and duration in relation to incidence and survival. JAMA. 1966;197(9):710–6.

    Article  CAS  Google Scholar 

  17. Kaplan MH, Rosen PP, Armstrong D. Cryptococcosis in a cancer hospital: clinical and pathological correlates in forty-six patients. Cancer. 1977;39(5):2265–74.

    Article  CAS  Google Scholar 

  18. Kontoyiannis DP, Peitsch WK, Reddy BT, Whimbey EE, Han XY, Bodey GP, et al. Cryptococcosis in patients with cancer. Clin Infect Dis. 2001;32(11):E145–50.

    Article  CAS  Google Scholar 

  19. Pappas PG, Perfect JR, Cloud GA, Larsen RA, Pankey GA, Lancaster DJ, et al. Cryptococcosis in human immunodeficiency virus-negative patients in the era of effective azole therapy. Clin Infect Dis. 2001;33(5):690–9.

    Article  CAS  Google Scholar 

  20. Pagano L, Fianchi L, Caramatti C, D'Antonio D, Melillo L, Caira M, et al. Cryptococcosis in patients with hematologic malignancies. A report from GIMEMA-infection. Haematologica. 2004;89(7):852–6.

    PubMed  Google Scholar 

  21. Pagano L, Caira M, Candoni A, Offidani M, Fianchi L, Martino B, et al. The epidemiology of fungal infections in patients with hematologic malignancies: the SEIFEM-2004 study. Haematologica. 2006;91(8):1068–75.

    PubMed  Google Scholar 

  22. Schmalzle SA, Buchwald UK, Gilliam BL, Riedel DJ. Cryptococcus neoformans infection in malignancy. Mycoses. 2016;59(9):542–52.

    Article  Google Scholar 

  23. • Wang RY, Chen YQ, Wu JQ, et al. Cryptococcosis in patients with hematological diseases: a 14-year retrospective clinical analysis in a Chinese tertiary hospital. BMC Infect Dis. 2017;17(1):463 This is a case series of 33 patients with hematologic diseases who developed cryptococcosis. The authors provide a comparison between patients with neoplastic and non-neoplastic hematologic diseases.

    Article  Google Scholar 

  24. • Cogliati M, Prigitano A, Esposto MC, et al. Epidemiological trends of cryptococcosis in Italy: molecular typing and susceptibility pattern of Cryptococcus neoformans isolates collected during a 20-year period. Med Mycol 2018. The authors describe epidemiologic trends of cryptococcosis in Italy, and show that the proprotion of patients with hematologic diseases has increased over time.

  25. Benetatos L, Hatzimichael E, Vassou A, Bourantas KL. Cryptococcus lung infection complicating fludarabine treatment in a chronic lymphocytic leukemia patient. Leuk Res. 2007;31(1):119–20.

    Article  Google Scholar 

  26. Chim CS, Liang R, Wong SS, Yuen KY. Cryptococcal infection associated with fludarabine therapy. Am J Med. 2000;108(6):523–4.

    Article  CAS  Google Scholar 

  27. Costa P, Luzzati R, Nicolato A, Perboni G, Scalzini A, Lazzarini L, et al. Cryptococcal meningitis and intracranial tuberculoma in a patient with Waldenstrom’s macroglobulinemia treated with fludarabine. Leuk Lymphoma. 1998;28(5–6):617–20.

    Article  CAS  Google Scholar 

  28. Leenders A, Sonneveld P, de MS. Cryptococcal meningitis following fludarabine treatment for chronic lymphocytic leukemia. Eur J Clin Microbiol Infect Dis. 1995;14(9):826–8.

    Article  CAS  Google Scholar 

  29. Marchand T, Revest M, Tattevin P, Chevrier S, Poullot E, Lamy T, et al. Early cryptococcal meningitis following treatment with rituximab, fludarabine and cyclophosphamide in a patient with chronic lymphocytic leukemia. Leuk Lymphoma. 2013;54(3):643–5.

    Article  CAS  Google Scholar 

  30. Audeh YM, Gruszecki AC, Cherrington A, Reddy VV. Hairy cell leukemia with concurrent cryptococcus infection. Am J Hematol. 2003;72(3):223–4.

    Article  CAS  Google Scholar 

  31. Dincol G, Kahraman R. Cryptococcus neoformans meningitis in a patient with hairy cell leukemia. Am J Hematol. 2006;81(5):387.

    Article  Google Scholar 

  32. Ikpeazu EV, Kaplon MK. Cryptococcal meningitis occurring at 19 months after cladribine therapy for hairy cell leukemia. Eur J Haematol. 1998;61(4):286–7.

    Article  CAS  Google Scholar 

  33. Cruz D, Costa P, Sagues M. Meningeal cryptococcosis in a patient with angioimmunoblastic lymphoma treated with alemtuzumab. Med Clin (Barc ). 2018.

  34. Henn A, Mellon G, Benoit H, et al. Disseminated cryptococcosis, invasive aspergillosis, and mucormycosis in a patient treated with alemtuzumab for chronic lymphocytic leukaemia. Scand J Infect Dis. 2014;46(3):231–4.

    Article  Google Scholar 

  35. Hotz C, Ingen-Housz-Oro S, Tran Van NJ, et al. Pulmonary cryptococcoma in a patient with Sezary syndrome treated with alemtuzumab. Eur J Dermatol 2011; 21(6):1018–1020.

  36. Bassetti M, Repetto E, Mikulska M, Miglino M, Clavio M, Gobbi M, et al. Cryptococcus neoformans fatal sepsis in a chronic lymphocytic leukemia patient treated with alemtuzumab: case report and review of the literature. J Chemother. 2009;21(2):211–4.

    Article  CAS  Google Scholar 

  37. Liu J, Mouhayar E, Tarrand JJ, Kontoyiannis DP. Fulminant Cryptococcus neoformans infection with fatal pericardial tamponade in a patient with chronic myelomonocytic leukaemia who was treated with ruxolitinib: case report and review of fungal pericarditis. Mycoses. 2018;61(4):245–55.

    Article  Google Scholar 

  38. Hirano A, Yamasaki M, Saito N, Iwato K, Daido W, Funaishi K, et al. Pulmonary cryptococcosis in a ruxolitinib-treated patient with primary myelofibrosis. Respir Med Case Rep. 2017;22:87–90.

    PubMed  PubMed Central  Google Scholar 

  39. Chen CC, Chen YY, Huang CE. Cryptococcal meningoencephalitis associated with the long-term use of ruxolitinib. Ann Hematol. 2016;95(2):361–2.

    Article  Google Scholar 

  40. Wysham NG, Sullivan DR, Allada G. An opportunistic infection associated with ruxolitinib, a novel janus kinase 1,2 inhibitor. Chest. 2013;143(5):1478–9.

    Article  Google Scholar 

  41. Stankowicz M, Banaszynski M, Crawford R. Cryptococcal infections in two patients receiving ibrutinib therapy for chronic lymphocytic leukemia. J Oncol Pharm Pract 2018;1078155217752078, 107815521775207.

  42. Baron M, Zini JM, Challan BT, et al. Fungal infections in patients treated with ibrutinib: two unusual cases of invasive aspergillosis and cryptococcal meningoencephalitis. Leuk Lymphoma. 2017;58(12):2981–2.

    Article  Google Scholar 

  43. Okamoto K, Proia LA, Demarais PL. Disseminated Cryptococcal disease in a patient with chronic lymphocytic leukemia on ibrutinib. Case Rep Infect Dis. 2016;2016:4642831.

    PubMed  PubMed Central  Google Scholar 

  44. Sudhakaran S, Bashoura L, Stewart J, Balachandran DD, Faiz SA. Pulmonary Cryptococcus presenting as a solitary pulmonary nodule. Am J Respir Crit Care Med. 2017;196(9):1217–8.

    Article  Google Scholar 

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

  46. Swan CD, Gottlieb T. Cryptococcus neoformans empyema in a patient receiving ibrutinib for diffuse large B-cell lymphoma and a review of the literature. BMJ Case Rep. 2018;2018.

  47. Sun K, Kasparian S, Iyer S, Pingali SR. Cryptococcal meningoencephalitis in patients with mantle cell lymphoma on ibrutinib. Ecancermedicalscience. 2018;12:836.

    PubMed  PubMed Central  Google Scholar 

  48. •• Varughese T, Taur Y, Cohen N, et al. Serious infections in patients receiving ibrutinib for treatment of lymphoid cancer. Clin Infect Dis. 2018;67(5):687–92 In this study, the authors characterize 43 patients who developed serious infections while on ibrutinib. Etiology and risk factors for infection are described.

    Article  Google Scholar 

  49. •• Ghez D, Calleja A, Protin C, et al. Early-onset invasive aspergillosis and other fungal infections in patients treated with ibrutinib. Blood. 2018;131(17):1955–9 The authors present the characteristics of 33 patients receivinb ibrutinib who developed invasive fungal disease.

    Article  CAS  Google Scholar 

  50. Ajam T, Hyun G, Blue BJ, Rajeh N. Primary cutaneous cryptococcosis in a patient with chronic lymphocytic leukemia: a case report 3 ed 2016:1–3.

  51. Abid MB, Stromich J, Gundacker ND. Is ibrutinib associated with disseminated cryptococcosis with CNS involvement? Cancer Biol Ther. 2018:1–3.

  52. Parampalli YS, Stubig T, Cornez I, et al. JAK1/2 inhibition impairs T cell function in vitro and in patients with myeloproliferative neoplasms. Br J Haematol. 2015;169(6):824–33.

    Article  Google Scholar 

  53. Heine A, Brossart P, Wolf D. Ruxolitinib is a potent immunosuppressive compound: is it time for anti-infective prophylaxis? Blood. 2013;122(23):3843–4.

    Article  CAS  Google Scholar 

  54. Badar T, Burger JA, Wierda WG, O’Brien S. Ibrutinib: a paradigm shift in management of CLL. Expert Rev Hematol. 2014;7(6):705–17.

    Article  CAS  Google Scholar 

  55. •• Rogers K. Ibrutinib and fungus: an invasive concern. Blood. 2018;131(17):1882–4 In this editorial, the author speculates on what mechanisms are involved in the possible increased risk of invasive fungal disease in patients receiving ibrutinib.

    Article  CAS  Google Scholar 

  56. Pagano L, Caira M, Fianchi L. Pulmonary fungal infection with yeasts and pneumocystis in patients with hematological malignancy. Ann Med. 2005;37(4):259–69.

    Article  Google Scholar 

  57. Zinck SE, Leung AN, Frost M, Berry GJ, Muller NL. Pulmonary cryptococcosis: CT and pathologic findings. J Comput Assist Tomogr. 2002;26(3):330–4.

    Article  Google Scholar 

  58. Yamada W, Yamada H, Murata K, Kosugi H, Asano Y, Mochizuki K, et al. Case of cryptococcal choroiditis in adult with T-cell leukemia/lymphoma. J Infect Chemother. 2018.

  59. De Pauw B, Walsh TJ, Donnelly JP, et al. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis. 2008;46(12):1813–21.

    Article  Google Scholar 

  60. Boulware DR, Rolfes MA, Rajasingham R, von Hohenberg M, Qin Z, Taseera K, et al. Multisite validation of cryptococcal antigen lateral flow assay and quantification by laser thermal contrast. Emerg Infect Dis. 2014;20(1):45–53.

    Article  Google Scholar 

  61. Sato Y, Osabe S, Kuno H, Kaji M, Oizumi K. Rapid diagnosis of cryptococcal meningitis by microscopic examination of centrifuged cerebrospinal fluid sediment. J Neurol Sci. 1999;164(1):72–5.

    Article  CAS  Google Scholar 

  62. Antinori S. New insights into HIV/AIDS-associated cryptococcosis. ISRN AIDS 2013; 2013:471363, 1, 22.

  63. Arendrup MC, Bille J, Dannaoui E, Ruhnke M, Heussel CP, Kibbler C. ECIL-3 classical diagnostic procedures for the diagnosis of invasive fungal diseases in patients with leukaemia. Bone Marrow Transplant. 2012;47(8):1030–45.

    Article  CAS  Google Scholar 

  64. Makadzange AT, McHugh G. New approaches to the diagnosis and treatment of cryptococcal meningitis. Semin Neurol. 2014;34(1):47–60.

    Article  Google Scholar 

  65. Tanner DC, Weinstein MP, Fedorciw B, Joho KL, Thorpe JJ, Reller L. Comparison of commercial kits for detection of cryptococcal antigen. J Clin Microbiol. 1994;32(7):1680–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Jitmuang A, Panackal AA, Williamson PR, Bennett JE, Dekker JP, Zelazny AM. Performance of the cryptococcal antigen lateral flow assay in non-HIV-related cryptococcosis. J Clin Microbiol. 2016;54(2):460–3.

    Article  CAS  Google Scholar 

  67. Vidal JE, Boulware DR. Lateral flow assay for cryptococcal antigen: an important advance to improve the continuum of HIV care and reduce cryptococcal meningitis-related mortality. Rev Inst Med Trop Sao Paulo. 2015;57(Suppl 19):38–45.

    Article  CAS  Google Scholar 

  68. Jarvis JN, Harrison TS. Pulmonary cryptococcosis. Semin Respir Crit Care Med. 2008;29(2):141–50.

    Article  Google Scholar 

  69. Baughman RP, Rhodes JC, Dohn MN, Henderson H, Frame PT. Detection of cryptococcal antigen in bronchoalveolar lavage fluid: a prospective study of diagnostic utility. Am Rev Respir Dis. 1992;145(5):1226–9.

    Article  CAS  Google Scholar 

  70. 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  Google Scholar 

  71. 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  Google Scholar 

  72. Henao-Martinez AF, Chastain DB, Franco-Paredes C. Treatment of cryptococcosis in non-HIV immunocompromised patients. Curr Opin Infect Dis. 2018;31(4):278–85.

    CAS  PubMed  Google Scholar 

  73. Tenforde MW, Shapiro AE, Rouse B, et al. Treatment for HIV-associated cryptococcal meningitis. Cochrane Database Syst Rev. 2018;7:CD005647.

    PubMed  Google Scholar 

  74. Vidal JE, Penalva de Oliveira AC, Dauar RF, Boulware DR. Strategies to reduce mortality and morbidity due to AIDS-related cryptococcal meningitis in Latin America. Braz J Infect Dis. 2013;17(3):353–62.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Instituto Estadual de Hematologia Arthur de Siqueira Cavalcante, Hemorio, Rio de Janeiro, Brazil

    Mariana Guarana

  2. Serviço de Neurologia, Instituto de Infectologia Emilio Ribas, São Paulo, Brazil

    Jose Ernesto Vidal

  3. Departamento de Molestias Infecciosas e Parasitárias, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil

    Jose Ernesto Vidal

  4. Department of Internal Medicine, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

    Marcio Nucci

  5. Hospital Universitário Clementino Fraga Filho, Rua Prof. Rodolpho Paulo Rocco 255 Sala 4A 12, Rio de Janeiro, 21941-913, Brazil

    Marcio Nucci

Authors
  1. Mariana Guarana
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jose Ernesto Vidal
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marcio Nucci
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marcio Nucci.

Ethics declarations

Conflict of Interest

Mariana Guarana declares no conflict of interest.

Jose Ernesto Vidal has received personal fees from Gilead, United Medical, Janssen, Merck, Roche, and Glaxo.

Marcio Nucci has received a grant and personal fees from Pfizer, and personal fees from Merck, Teva, United Medical, Gilead, and Janssen.

Human and Animal Rights and Informed Consent

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

Additional information

This article is part of the Topical Collection on Current Management of Fungal Infections

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Guarana, M., Vidal, J.E. & Nucci, M. Cryptococcosis in Patients with Hematologic Diseases. Curr Fungal Infect Rep 12, 187–194 (2018). https://doi.org/10.1007/s12281-018-0332-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12281-018-0332-y

Keywords

Search

Navigation