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Blood Res 2022; 57(1):

Published online March 31, 2022

https://doi.org/10.5045/br.2021.2021127

© The Korean Society of Hematology

Prophylaxis for invasive fungal infection in pediatric patients with allogeneic hematopoietic stem cell transplantation

Paola Perez1,2, Jaime Patiño1,2, Alexis A. Franco1,3, Fernando Rosso1,4, Estefania Beltran4, Eliana Manzi1,4, Andrés Castro4, Mayra Estacio1,4, Diego Medina Valencia1,3

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1Universidad Icesi, Facultad de Ciencias de la Salud, 2Fundación Valle del Lili, Departamento Materno-infantil, Servicio de Infectología Pediátrica, 3Fundación Valle del Lili, Departamento Materno-infantil, Unidad de Trasplante de Médula Ósea, 4Fundación Valle del Lili, Centro de Investigaciones Clínicas (CIC), Cali, Colombia

Correspondence to : Diego Medina Valencia, M.D.
Fundación Valle del Lili, Departamento Materno-infantil, Unidad de Trasplante de Médula Ósea, Cra 98 No. 18-49, Cali 760032, Colombia
E-mail: diego.medina@fvl.org.co

Received: July 14, 2021; Revised: January 21, 2022; Accepted: February 9, 2022

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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Background
Antifungal prophylaxis is recommended for hematopoietic stem cell transplantation (HSCT) to decrease the incidence of invasive fungal infections (IFI). This study aimed to compare the two groups of antifungal prophylaxis in pediatric patients undergoing allogeneic HSCT.
Methods
This observational, analytic, retrospective cohort study compared the incidence of IFI with antifungal prophylaxis with voriconazole vs. other antifungals in the first 100 days after allogeneic HSCT in patients aged <18 years between 2012 and 2018. The statistical analysis included univariate and multivariate analyses and determination of the cumulative incidence of invasive fungal infection by the Kaplan‒Meier method using STATA 14 statistical software.
Results
A total of 139 allogeneic HSCT were performed. The principal diagnosis was acute leukemia (63%). The 75% had haploidentical donors, and 50% used an antifungal in the month before transplantation. Voriconazole (69%) was the most frequently administered antifungal prophylaxis. The cumulative incidence of IFI was 5% (7 cases). Of the patients with IFIs, four began prophylaxis with voriconazole, one with caspofungin, and one with fluconazole. Additionally, six were possible cases, one was proven (Candida parapsilosis), and 1/7 died.
Conclusion
There were no differences in the incidence of IFI between patients who received prophylaxis with voriconazole and other antifungal agents.

Keywords Invasive fungal infections, Antifungal agents, Pediatrics, Hematopoietic stem cell transplantation, Mortality

Article

Original Article

Blood Res 2022; 57(1): 34-40

Published online March 31, 2022 https://doi.org/10.5045/br.2021.2021127

Copyright © The Korean Society of Hematology.

Prophylaxis for invasive fungal infection in pediatric patients with allogeneic hematopoietic stem cell transplantation

Paola Perez1,2, Jaime Patiño1,2, Alexis A. Franco1,3, Fernando Rosso1,4, Estefania Beltran4, Eliana Manzi1,4, Andrés Castro4, Mayra Estacio1,4, Diego Medina Valencia1,3

1Universidad Icesi, Facultad de Ciencias de la Salud, 2Fundación Valle del Lili, Departamento Materno-infantil, Servicio de Infectología Pediátrica, 3Fundación Valle del Lili, Departamento Materno-infantil, Unidad de Trasplante de Médula Ósea, 4Fundación Valle del Lili, Centro de Investigaciones Clínicas (CIC), Cali, Colombia

Correspondence to:Diego Medina Valencia, M.D.
Fundación Valle del Lili, Departamento Materno-infantil, Unidad de Trasplante de Médula Ósea, Cra 98 No. 18-49, Cali 760032, Colombia
E-mail: diego.medina@fvl.org.co

Received: July 14, 2021; Revised: January 21, 2022; Accepted: February 9, 2022

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background
Antifungal prophylaxis is recommended for hematopoietic stem cell transplantation (HSCT) to decrease the incidence of invasive fungal infections (IFI). This study aimed to compare the two groups of antifungal prophylaxis in pediatric patients undergoing allogeneic HSCT.
Methods
This observational, analytic, retrospective cohort study compared the incidence of IFI with antifungal prophylaxis with voriconazole vs. other antifungals in the first 100 days after allogeneic HSCT in patients aged <18 years between 2012 and 2018. The statistical analysis included univariate and multivariate analyses and determination of the cumulative incidence of invasive fungal infection by the Kaplan‒Meier method using STATA 14 statistical software.
Results
A total of 139 allogeneic HSCT were performed. The principal diagnosis was acute leukemia (63%). The 75% had haploidentical donors, and 50% used an antifungal in the month before transplantation. Voriconazole (69%) was the most frequently administered antifungal prophylaxis. The cumulative incidence of IFI was 5% (7 cases). Of the patients with IFIs, four began prophylaxis with voriconazole, one with caspofungin, and one with fluconazole. Additionally, six were possible cases, one was proven (Candida parapsilosis), and 1/7 died.
Conclusion
There were no differences in the incidence of IFI between patients who received prophylaxis with voriconazole and other antifungal agents.

Keywords: Invasive fungal infections, Antifungal agents, Pediatrics, Hematopoietic stem cell transplantation, Mortality

Fig 1.

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Figure 1.100-days overall survival was 81% (A), the 100-day cumulative incidence of invasive fungal infection was 5.3% (B), and incidence of invasive fungal infection according to prophylaxis with voriconazole (4.4%) or another (7.4%) antifungal (C) at 100 days post-allogeneic hematopoietic stem cell trans-plantation.
Blood Research 2022; 57: 34-40https://doi.org/10.5045/br.2021.2021127

Table 1 . Demographic and clinical characteristics..

VariableOverall (N=139)Voriconazole (N=96)Other (N=43)P
Age, years median (IQR)9.7 (4.7–13)8.9 (3–14)10.7 (6–13)0.712
Min-max0.5–190.5–190.5–17
Female gender, N (%)57 (41)39 (41)18 (42)0.891
Transplant indication, N (%)0.002
Acute lymphoblastic leukemia58 (42)38 (40)20 (46)
Acute myeloid leukemia29 (21)28 (29)1 (2.3)
Marrow failure syndrome16 (11)7 (7)9 (21)
Immunodeficiency12 (9)8 (8.3)4 (9.3)
Hemoglobinopathies12 (8.6)4 (4.2)8 (19)
Myelodysplastic/myeloproliferative5 (3.6)4 (4.2)1 (2.3)
syndrome
Chronic myeloid leukemia2 (1.4)2 (2)0 (0)
Non-Hodgkin’s lymphoma2 (1.4)2 (2)0 (0)
Hodgkin’s lymphoma1 (0.7)1 (1)0 (0)
Others2 (1.4)2 (2)0 (0)
Type of transplant, N (%)<0.001
Haploidentical104 (75)82 (85)22 (51)
Matched related32 (23)11 (11.5)21 (49)
Cord3 (2)3 (3.1)0 (0)
Stem cell source, N (%)0.646
Bone marrow90 (65)61 (64)29 (67)
Peripheral blood41 (29.5)29 (30)12 (28)
Marrow and blood5 (3.5)3 (3.1)2 (4.6)
Cord3 (2)3 (3.1)0 (0)
Retransplantation, N (%)3 (2.1)2 (2)1 (2.3)0.928
Use of clofarabine, N (%)46 (33)36 (37)10 (23)0.099
Previous steroid use, N (%)34 (24)28 (29)6 (14)0.054
Myeloablative conditioning, N (%)77 (55)63 (65)14 (33)<0.001
Use of ATG in conditioning, N (%)47 (34)21 (22)26 (60)<0.001
Type of GVHD prophylaxis, N (%)0.005
Posttransplant cyclophosphamide-based108 (78)81 (84)27 (63)
Cyclosporine-based31 (23)15 (16)16 (37)
Use of TLI/TBI radiotherapy103 (74)70 (73)33 (77)0.634
CMV DNAemia59 (42)47 (49)12 (28)0.020

Abbreviations: ATG, antithymocyte globulin; CMV, cytomegalovirus; GVHD, graft-versus-host disease; IQR, interquartile range; TBI, total body irradiation; TLI, total lymphoid irradiation..

Table 2 . Previous antifungal/antimicrobial therapies and IFI cases..

VariableOverall (N=139)Voriconazole (N=96)Other (N=43)P
Previous antifungal therapies, N (%)69 (50)47 (49)22 (51)0.810
Fluconazole, N (%)432914
Voriconazole, N (%)271611
Caspofungin, N (%)16133
Amphotericin B, N (%)541
Posaconazole, N (%)330
Previous antimicrobial therapy for, N (%)67 (48)52 (54)15 (35)0.035
Cefepime972
Meropenem433310
Vancomycin35269
Piperacilin-tazobactam31238
IFI, N (%)7 (5)4 (4)3 (7)0.321
Proven1/70/41/3
Candida parapsilosis101
Possible6/74/42/3

Abbreviation: IFI, invasive fungal infection..

Table 3 . Characteristics of patients with IFI..

Case1234567
Age (yr)0.591217121613
Underlying diseaseMFSALLALLHodgkin’s LALLALLHemoglobinopathy
Type of initial prophylaxisVoriconazoleVoriconazoleCaspofunginVoriconazolePosaconazoleVoriconazoleFluconazole
Change of prophylaxisNoNoVoriconazolePosaconazoleCaspofunginNoPosaconazole
Days of initial prophylaxis448251841539
Days between HSCT/IFI4482724181544
IFI diagnosisPossiblePossibleProvenPossiblePossiblePossiblePossible
Acute GVHDG IIG IVNANAG INAG III
Infection with CMVNoYesYesYesNoNoYes
DeathNoNoNoNoNoYesNo

Abbreviations: CMV, cytomegalovirus; F, female; G, grade; GVHD, graft-versus-host disease; HL, acute lymphoblastic leukemia; HSCT, hematopoietic stem cell transplantation; IFI, invasive fungal infection; M, male; MFS, marrow failure syndrome; NA, not applicable..

Table 4 . Posttransplant outcomes and complications..

VariableOverall (N=139)Voriconazole (N=96)Other (N=43)P
Acute GVHD grade III-Iva), N (%)15 (11)9 (10)6 (15)0.440
ARDS, N (%)11 (8)10 (10.4)1 (2.3)0.102
Hemorrhagic cystitis, N (%)39 (28)30 (31)9 (21)0.211
Veno-occlusive disease, N (%)8 (6)6 (6)2 (4.6)0.708
Moderate to severe mucositis, N (%)60 (43)45 (47)15 (35)0.187
Infection, N (%)71 (51)53 (55)18 (42)0.146
Catheter infection, N (%)5 (7)5 (9)0 (0)0.177
Primary graft failureb), N (%)6 (4.5)5 (5.5)1 (2.4)0.415
Deaths, N (%)24 (17)19 (20)5 (12)0.239
Disease-related, N3/242/191/5
Transplant related, N21/2417/194/5
GVHD321
Bacterial infections, N440
P. aeruginosa, N(2)(2)0
K. pneumoniae, N(1)(1)0
S. epidermidis, N(1)(1)0
Viral infections532
Adenovirus(2)(1)(1)
CMV(3)(2)(1)
Bleeding110
Multiple organ110
Failure, N871

a)Of 131 neutrophil-grafted and alive patients. b)Of 132 patients that survived at least 28 days..

Abbreviations: ARDS, acute respiratory distress syndrome; GVHD, graft-versus-host disease..

Table 5 . Risk factors for the development of IFI in the total group: a univariate and multivariate analysis..

VariablesOverall, NIFI, N (%)RR (95% CI)POR adjusted (95% CI)P
Voriconazole prophylaxis964 (4.2)0.58 (0.12–2.7)0.4880.31 (0.06–1.5)0.152
Moderate to severe mucositis605 (8.3)3.5 (0.63–19)0.1433.47 (0.63–19.1)0.152
Malignant-based disease1005 (5)1.05 (0.19–5.6)0.956--
Acute GVHD grade III-IV152 (13)3.1 (0.65–14)0.144--
Myeloablative conditioning regimen773 (3.9)0.6 (0.14– 2.6)0.493--

Table 6 . Risk factors for the development of IFI in the subgroup: a univariate and multivariate analysis..

VariablesOverall, NIFI, N (%)RR (95% CI)POR adjusted (95% CI)P
Voriconazole prophylaxis964 (4.2)0.95 (0.10 – 8.98)0.9690.97 (0.98–9.67)0.982
Moderate to severe mucositis513 (5.9)3.5 (0.65–18.70)0.143--
Malignant-based disease873 (3.4)1.04 (0.19–5.63)0.956--
Acute GVHD grade III-IV112 (18.2)3.41 (0.60–19.41)0.1667.33 (1.08–49)0.041
Myeloablative conditioning regimen732 (2.7)0.58 (0.12–2.73)0.498--
Previous steroid use301 (3.3)1.25 (0.23–6.75)0.786--

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