Mycopathologia

, Volume 182, Issue 5–6, pp 495–504 | Cite as

Risk Factors and Outcomes of Invasive Fungal Infections in Allogeneic Hematopoietic Cell Transplant Recipients

  • Marisa H. Miceli
  • Tracey Churay
  • Thomas Braun
  • Carol A. Kauffman
  • Daniel R. Couriel
Article

Abstract

Allogeneic hematopoietic cell transplant (HCT) recipients are at increased risk of invasive fungal infections (IFI), which are associated with a high mortality rate. We evaluated the impact of IFI in allogeneic HCT patients. In total, 541 consecutive allogeneic HCT recipients were included. The cumulative incidence of any IFI and mold infections at 1-year post-HCT was 10 and 7%, respectively. Median times to IFI and mold infection were 200 and 210 days, respectively. There was a trend toward fewer IFI and mold infections in the last several years. Both acute graft-versus-host disease (GVHD) (OR 1.83, p = 0.05) and corticosteroid duration (OR 1.0, p = 0.026) were significantly associated with increased risk of IFI, acute GVHD (OR 2.3, p = 0.027) emerged as the most important association with mold infections. Any IFI [HR 4.1 (2.79–6.07), p < 0.0001] and mold infections [HR 3.34 (2.1–5.1), p < 0.0001] were independently associated with non-relapse mortality (NRM). This association persisted in the setting of both acute and chronic GVHD. Corticosteroid treatment for >90 days was also significantly associated with higher NRM [HR 1.9 (1.3–2.6), p < 0.0001]. This study highlights the impact of IFI on NRM among HCT patients. The decrease in number of IFI and mold infections over the last several years may reflect the benefit of prophylaxis with mold-active antifungal agents.

Keywords

Invasive fungal infections Hematopoietic cell transplantation Aspergillosis Mold infections Candidiasis 

References

  1. 1.
    Neofytos D, Horn D, Anaissie E, Steinbach W, Olyaei A, Fishman J, et al. Epidemiology and outcome of invasive fungal infection in adult hematopoietic stem cell transplant recipients: analysis of Multicenter Prospective Antifungal Therapy (PATH) Alliance registry. Clin Infect Dis. 2009;48:265–73.CrossRefPubMedGoogle Scholar
  2. 2.
    Kontoyiannis DP, Marr KA, Park BJ, Alexander BD, Anaissie EJ, Walsh TJ, et al. Prospective surveillance for invasive fungal infections in hematopoietic stem cell transplant recipients, 2001–2006: overview of the Transplant-Associated Infection Surveillance Network (TRANSNET) Database. Clin Infect Dis. 2010;50:1091–100.CrossRefPubMedGoogle Scholar
  3. 3.
    Ullmann AJ, Lipton JH, Vesole DH, Chandrasekar P, Langston A, Tarantolo SR, et al. Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N Engl J Med. 2007;356:335–47.CrossRefPubMedGoogle Scholar
  4. 4.
    Malani AN, Kerr LE, Kauffman CA. Voriconazole: How to use this antifungal agent and What to expect. Semin Respir Crit Care Med. 2015;36:786–95.CrossRefPubMedGoogle Scholar
  5. 5.
    Clark NM, Grim SA, Lynch JP 3rd. Posaconazole: use in the prophylaxis and treatment of fungal infections. Semin Respir Crit Care Med. 2015;36:767–85.CrossRefPubMedGoogle Scholar
  6. 6.
    De Pauw B, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, Calandra T, 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 Off Publ Infect Dis Soc Am. 2008;46:1813–21.CrossRefGoogle Scholar
  7. 7.
    Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, et al. 1994 Consensus conference on acute GVHD grading. Bone Marrow Transplant. 1995;15:825–8.PubMedGoogle Scholar
  8. 8.
    Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005;11:945–56.CrossRefPubMedGoogle Scholar
  9. 9.
    Akan H, Antia VP, Kouba M, Sinko J, Tanase AD, Vrhovac R, et al. Preventing invasive fungal disease in patients with haematological malignancies and the recipients of haematopoietic stem cell transplantation: practical aspects. J Antimicrob Chemother. 2013;68:iii5–16.CrossRefPubMedGoogle Scholar
  10. 10.
    Bow EJ. Invasive fungal infection in haematopoietic stem cell transplant recipients: epidemiology from the transplant physician’s viewpoint. Mycopathologia. 2009;168:283–97.CrossRefPubMedGoogle Scholar
  11. 11.
    Omer AK, Ziakas PD, Anagnostou T, Coughlin E, Kourkoumpetis T, McAfee SL, et al. Risk factors for invasive fungal disease after allogeneic hematopoietic stem cell transplantation: a single center experience. Biol Blood Marrow Transplant. 2013;19:1190–6.CrossRefPubMedGoogle Scholar
  12. 12.
    Slavin S, Naparstek E, Nagler A, Ackerstein A, Kapelushnik J, Or R. Allogeneic cell therapy for relapsed leukemia after bone marrow transplantation with donor peripheral blood lymphocytes. Exp Hematol. 1995;23:1553–62.PubMedGoogle Scholar
  13. 13.
    Baddley JW, Stroud TP, Salzman D, Pappas PG. Invasive mold infections in allogeneic bone marrow transplant recipients. Clin Infect Dis. 2001;32:1319–24.CrossRefPubMedGoogle Scholar
  14. 14.
    Marr KA, Carter RA, Crippa F, Wald A, Corey L. Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients. Clin Infect Dis. 2002;34:909–17.CrossRefPubMedGoogle Scholar
  15. 15.
    Jantunen E, Ruutu P, Niskanen L, Volin L, Parkkali T, Koukila-Kahkola P, et al. Incidence and risk factors for invasive fungal infections in allogeneic BMT recipients. Bone Marrow Transplant. 1997;19:801–8.CrossRefPubMedGoogle Scholar
  16. 16.
    Martino R, Bautista G, Parody R, Garcia I, Esquirol A, Rovira M, et al. Severe infections after single umbilical cord blood transplantation in adults with or without the co-infusion of CD34+ cells from a third-party donor: results of a multicenter study from the Grupo Espanol de Trasplante Hematopoyetico (GETH). Transpl Infect Dis. 2015;17:221–33.CrossRefPubMedGoogle Scholar
  17. 17.
    Junghanss C, Marr KA, Carter RA, Sandmaier BM, Maris MB, Maloney DG, et al. Incidence and outcome of bacterial and fungal infections following nonmyeloablative compared with myeloablative allogeneic hematopoietic stem cell transplantation: a matched control study. Biol Blood Marrow Transplant. 2002;8:512–20.CrossRefPubMedGoogle Scholar
  18. 18.
    Mikulska M, Raiola AM, Bruno B, Furfaro E, Van Lint MT, Bregante S, et al. Risk factors for invasive aspergillosis and related mortality in recipients of allogeneic SCT from alternative donors: an analysis of 306 patients. Bone Marrow Transplant. 2009;44:361–70.CrossRefPubMedGoogle Scholar
  19. 19.
    Miceli MH, Diaz JA, Lee SA. Emerging opportunistic yeast infections. Lancet Infect Dis. 2011;11:142–51.CrossRefPubMedGoogle Scholar
  20. 20.
    Miceli MH, Lee SA. Emerging moulds: epidemiological trends and antifungal resistance. Mycoses. 2011;54:e666–78.CrossRefPubMedGoogle Scholar
  21. 21.
    Kauffman CA. Zygomycosis: reemergence of an old pathogen. Clin Infect Dis. 2004;39:588–90.CrossRefPubMedGoogle Scholar
  22. 22.
    Park BJ, Pappas PG, Wannemuehler KA, Alexander BD, Anaissie EJ, Andes DR, et al. Invasive non-Aspergillus mold infections in transplant recipients, United States, 2001–2006. Emerg Infect Dis. 2011;17:1855–64.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Horn DL, Freifeld AG, Schuster MG, Azie NE, Franks B, Kauffman CA. Treatment and outcomes of invasive fusariosis: review of 65 cases from the PATH Alliance registry. Mycoses. 2014;57:652–8.CrossRefPubMedGoogle Scholar
  24. 24.
    Rowley S, Friedman TM, Korngold R. Hematopoietic stem cell transplantation for malignant diseases. In: Rich R, editor. Clinical immunology principles and practice. 3rd ed. Philadelphia: Mosby-Elsevier; 2008. p. 1223–36.Google Scholar
  25. 25.
    Buttgereit F, Seibel MJH, Bijlsma JWJ. Glucocorticoids. In: Rich R, editor. Clinical immunology principles and practice. 3rd ed. Philadelphia: Mosby-Elsevier; 2008. p. 1293–305.Google Scholar
  26. 26.
    Gyetvai A, Emri T, Fekete A, Varga Z, Gazdag Z, Pesti M, et al. High-dose methylprednisolone influences the physiology and virulence of Candida albicans ambiguously and enhances the candidacidal activity of the polyene antibiotic amphotericin B and the superoxide-generating agent menadione. FEMS Yeast Res. 2007;7:265–75.CrossRefPubMedGoogle Scholar
  27. 27.
    Farmakiotis D, Shirazi F, Zhao Y, Saad PJ, Albert ND, Roilides E, et al. Methylprednisolone enhances the growth of Exserohilum rostratum in vitro, attenuates spontaneous apoptosis, and increases mortality rates in immunocompetent Drosophila flies. J Infect Dis. 2014;210:1471–5.CrossRefPubMedGoogle Scholar
  28. 28.
    Cordonnier C, Ribaud P, Herbrecht R, Milpied N, Valteau-Couanet D, Morgan C, et al. Prognostic factors for death due to invasive aspergillosis after hematopoietic stem cell transplantation: a 1-year retrospective study of consecutive patients at French transplantation centers. Clin Infect Dis. 2006;42:955–63.CrossRefPubMedGoogle Scholar
  29. 29.
    Marr KA, Carter RA, Boeckh M, Martin P, Corey L. Invasive aspergillosis in allogeneic stem cell transplant recipients: changes in epidemiology and risk factors. Blood. 2002;100:4358–66.CrossRefPubMedGoogle Scholar
  30. 30.
    Bhatti Z, Shaukat A, Almyroudis NG, Segal BH. Review of epidemiology, diagnosis, and treatment of invasive mould infections in allogeneic hematopoietic stem cell transplant recipients. Mycopathologia. 2006;162:1–15.CrossRefPubMedGoogle Scholar
  31. 31.
    Girmenia C, Raiola AM, Piciocchi A, Algarotti A, Stanzani M, Cudillo L, et al. Incidence and outcome of invasive fungal diseases after allogeneic stem cell transplantation: a prospective study of the Gruppo Italiano Trapianto Midollo Osseo (GITMO). Biol Blood Marrow Transplant. 2014;20:872–80.CrossRefPubMedGoogle Scholar
  32. 32.
    Hou CY, Xu LL, Chen H, Liu N, Jiang M, Wang GQ, et al. Intestinal aGVHD and infection after hematopoietic stem cell transplantation. Med Sci Monit. 2013;19:802–6.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Henden AS, Hill GR. Cytokines in graft-versus-host disease. J Immunol. 2015;194:4604–12.CrossRefPubMedGoogle Scholar
  34. 34.
    Shoham S, Levitz SM. The immune response to fungal infections. Br J Haematol. 2005;129:569–82.CrossRefPubMedGoogle Scholar
  35. 35.
    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.CrossRefPubMedGoogle Scholar
  36. 36.
    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.CrossRefPubMedGoogle Scholar
  37. 37.
    Malard F, Bossard C, Brissot E, Chevallier P, Guillaume T, Delaunay J, et al. Increased Th17/Treg ratio in chronic liver GVHD. Bone Marrow Transplant. 2014;49:539–44.CrossRefPubMedGoogle Scholar
  38. 38.
    Serody JS, Hill GR. The IL-17 differentiation pathway and its role in transplant outcome. Biol Blood Marrow Transplant. 2012;18:S56–61.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Gregg KS, Kauffman CA. Invasive aspergillosis: epidemiology, clinical aspects, and treatment. Semin Respir Crit Care Med. 2015;36:662–72.CrossRefPubMedGoogle Scholar
  40. 40.
    Upton A, Kirby KA, Carpenter P, Boeckh M, Marr KA. Invasive aspergillosis following hematopoietic cell transplantation: outcomes and prognostic factors associated with mortality. Clin Infect Dis. 2007;44:531–40.CrossRefPubMedGoogle Scholar
  41. 41.
    Baddley JW, Andes DR, Marr KA, Kontoyiannis DP, Alexander BD, Kauffman CA, et al. Factors associated with mortality in transplant patients with invasive aspergillosis. Clin Infect Dis. 2010;50:1559–67.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2017

Authors and Affiliations

  1. 1.Division of Infectious Diseases, Department of Internal MedicineUniversity of Michigan Health SystemAnn ArborUSA
  2. 2.Adult Blood and Marrow Transplantation ProgramAnn ArborUSA
  3. 3.Department of BiostatisticsUniversity of Michigan Health SystemAnn ArborUSA
  4. 4.Division of Infectious Diseases, Department of Internal Medicine, Veterans Affairs Ann Arbor Healthcare SystemAnn ArborUSA
  5. 5.Huntsman Cancer CenterUniversity of UtahSalt Lake CityUSA

Personalised recommendations