Restricted accessResearch articleFirst published online 2022-6
Evaluation of a primary antifungal prophylaxis protocol for preventing invasive mold infections after allogeneic hematopoietic stem cell transplantation
Invasive mold infections contribute to morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplantation. The optimal strategy for primary antifungal prophylaxis in this patient population remains uncertain.
Methods
Medical records of patients who underwent allogeneic hematopoietic stem cell transplantation between 1 January 2013 and 31 December 2017 were retrospectively reviewed. Adult patients were included if they received micafungin followed by fluconazole, with the option to escalate to voriconazole, for antifungal prophylaxis. The primary outcome was the incidence rate of proven or probable invasive mold infection. Secondary outcomes were time to invasive mold infection diagnosis, invasive mold infection-related mortality, and risk factors associated with invasive mold infection.
Results
Two hundred patients were included in the study, a majority of whom underwent matched unrelated (46%) or matched related (33%) donor transplants. The incidence rate of proven or probable invasive mold infection was 18.4 cases per 100 patient-years, with a one-year cumulative incidence of 14%. Median time to proven or probable invasive mold infection was 94 days post-transplant (IQR 26–178), with invasive mold infection-related mortality occurring in 18 (64%) of 28 patients diagnosed with invasive mold infection. Comparison of invasive mold infection-free survival by potential risk factors failed to show any significant differences.
Conclusions
In this real-life cohort of allogeneic hematopoietic stem cell transplantation recipients, the incidence of proven or probable invasive mold infection was higher than expected based on previous literature. In the absence of standard guidance on anti-mold prophylaxis in this patient population and given that unique risk factors for invasive mold infection may differ between institutions, it is essential that centers performing allogeneic hematopoietic stem cell transplantation routinely monitor their antifungal prophylaxis strategies for effectiveness.
WingardJRHsuJHiemenzJW.Hematopoietic stem cell transplantation: an overview of infection risks and epidemiology. Hematol Oncol Clin North Am2011;
25: 101–116.
3.
RubinsteinSMCulosKASavaniB, et al.
Foiling fungal disease post hematopoietic cell transplant: review of prophylactic strategies. Bone Marrow Transplant2018;
53: 123–128.
4.
SchusterMGClevelandAADubberkeER, et al.
Infections in hematopoietic cell transplant recipients: results from the organ transplant infection project, a multicenter, prospective, cohort study. Open Forum Infect Dis2017;
4: 1–7.
5.
De La CruzOSilveiraFP.Respiratory fungal infections in solid organ and hematopoietic stem cell transplantation. Clin Chest Med2017;
38: 727–739.
6.
CordonnierCRibaudPHerbrechtR, et al.; Societe Francaise de Greffe de Moelle et de Therapie Cellulaire.
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 Dis2006;
42: 955–963.
7.
NeofytosDHornDAnaissieE, 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 Dis2009;
48: 265–273.
8.
KontoyiannisDPMarrKAParkBJ, 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 Dis2010;
50: 1091–1100.
9.
NucciMMarrKAQueiroz-TellesF, et al.
Fusarium infection in hematopoietic stem cell transplant recipients. Clin Infect Dis2004;
38: 1237–1242.
10.
RosilloCAvilaAMHuangYT, et al.
Sequential systematic anti-mold prophylaxis with micafungin and voriconazole results in very low incidence of invasive mold infections in patients undergoing allogeneic hematopoietic stem cell transplantation. Transpl Infect Dis2018;
20: e12897.
11.
Garcia‐VidalCUptonAKirbyKA, et al.
Epidemiology of invasive mold infections in allogeneic stem cell transplant recipients: biological risk factors for infection according to time after transplantation. Clin Infect Dis2008;
47: 1041–1050.
12.
TomblynMChillerTEinseleH, et al.; Centers for Disease Control and Prevention.
Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant2009;
15: 1143–1238.
13.
UllmannAJLiptonJHVesoleDH, et al.
Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N Engl J Med2007;
356: 335–347.
14.
WingardJRCarterSLWalshTJ, et al.; Blood and Marrow Transplant Clinical Trials Network.
Randomized, double-blind trial of fluconazole versus voriconazole for prevention of invasive fungal infection after allogeneic hematopoietic cell transplantation. Blood2010;
116: 5111–5118.
15.
BacigalupoABallenKRizzoD, et al.
Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transplant2009;
15: 1628–1633.
16.
BitanMOrRShapiraMY, et al.
Time to engraftment following allogeneic stem cell transplantation is significantly longer in patients with myelodysplastic syndrome than with acute myeloid leukemia. Bone Marrow Transplant2008;
41: 69–78.
17.
DonnellyJPChenSCKauffmanCA, et al.
Revision and update of the consensus definitions of invasive fungal disease from the European organization for research and treatment of cancer and the mycoses study group education and research consortium. Clin Infect Dis2020;
71: 1367–1376.
18.
KaplanELMeierP.Nonparametric estimation from incomplete observations. J Am Stat Assoc1958;
53: 457–481.
19.
CoxDR.Regression models and life-tables. J R Stat Soc Series B Stat Methodol1972;
34: 187–220.
20.
EthierMCScienceMBeyeneJ, et al.
Mould-active compared with fluconazole prophylaxis to prevent invasive fungal diseases in cancer patients receiving chemotherapy or haematopoietic stem-cell transplantation: a systematic review and Meta-analysis of randomised controlled trials. Br J Cancer2012;
106: 1626–1637.
21.
SternASuYLeeYJ, et al.
A single-center, open-label trial of isavuconazole prophylaxis against invasive fungal infection in patients undergoing allogeneic hematopoietic cell transplantation: isavuconazole for antifungal prophylaxis following HCT. Biol Blood Marrow Transplant2020;
26: 1195–1202.
22.
MarrKACarterRABoeckhM, et al.
Invasive aspergillosis in allogeneic stem cell transplant recipients: changes in epidemiology and risk factors. Blood2002;
100: 4358–4366.
23.
WaldALeisenringWvan BurikJ, et al.
Epidemiology of Aspergillus infections in a large cohort of patients undergoing bone marrow transplantation. J Infect Dis1997;
175: 1459–1466.
24.
MartinoRSubiráMRoviraM, et al.; for the alloPBSCT Infectious/Non-infectious Complications Subcommittees of the Grupo Español de Trasplante Hematopoyético (GETH).
Invasive fungal infections after allogeneic peripheral blood stem cell transplantation: incidence and risk factors in 395 patients. Br J Haematol2002;
116: 475–482.
25.
De PauwBWalshTJDonnellyJP, 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 Dis2008;
46: 1813–1821.
26.
PaganoLCairaMCandoniA, et al.
The epidemiology of fungal infections in patients with hematologic malignancies: the SEIFEM-2004 study. Haematologica2006;
91: 1068–1075.
27.
CornelyOAMaertensJWinstonDJ, et al.
Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med2007;
356: 348–359.
28.
BuscaACandoniAAudisioE, et al.
Long-lasting protective effect of posaconazole prophylaxis in patients with acute myeloid leukemia receiving allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant2016;
22: 2214–2219.
29.
PattersonTFThompsonIIGDenningDW, et al.
Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis2016;
63: e1–e60.
30.
El-CheikhJVentonGCrocchioloR, et al.
Efficacy and safety of micafungin for prophylaxis of invasive fungal infections in patients undergoing haplo-identical hematopoietic SCT. Bone Marrow Transplant2013;
48: 1472–1477.
31.
van BurikJ-AHRatanatharathornVStepanDE, et al.; for the National Institute of Allergy and Infectious Diseases Mycoses Study Group.
Micafungin versus fluconazole for prophylaxis against invasive fungal infections during neutropenia in patients undergoing hematopoietic stem cell transplantation. Clin Infect Dis2004;
39: 1407–1416.
32.
ParkSKimKJangJH, et al.
Randomized trial of micafungin versus fluconazole as prophylaxis against invasive fungal infections in hematopoietic stem cell transplant recipients. J Infect2016;
73: 496–505.
33.
LangebrakeCRohdeHLellekH, et al.
Micafungin as antifungal prophylaxis in recipients of allogeneic hematopoietic stem cell transplantation: results of different dosage levels in clinical practice. Clin Transplant2014;
28: 286–291.
34.
AntachopoulosCMeletiadisJSeinT, et al.
Comparative in vitro pharmacodynamics of caspofungin, micafungin, and anidulafungin against germinated and nongerminated Aspergillus conidia. Antimicrob Agents Chemother2008;
52: 321–328.
35.
PfallerMBoykenLHollisR, et al.
In vitro susceptibility of clinical isolates of Aspergillus spp. to anidulafungin, caspofungin, and micafungin: a head-to-head comparison using the CLSI M38-A2 broth microdilution method. J Clin Microbiol2009;
47: 3323–3325.
36.
ManavathuECutrightJChandrasekarP.Organism-dependent fungicidal activities of azoles. Antimicrob Agents Chemother1998;
42: 3018–3021.
37.
CornelyOAHoeniglMLass-FlörlC, et al.; Mycoses Study Group Education and Research Consortium (MSG-ERC) and the European Confederation of Medical Mycology (ECMM).
Defining breakthrough invasive fungal infection–position paper of the mycoses study group education and research consortium and the european confederation of medical mycology. Mycoses2019;
62: 716–729.
