Blood Res 2022; 57(1):
Published online March 31, 2022
https://doi.org/10.5045/br.2021.2021127
© The Korean Society of Hematology
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
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.
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
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.
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
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.
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
Table 1 . Demographic and clinical characteristics..
Variable | Overall (N=139) | Voriconazole (N=96) | Other (N=43) | |
---|---|---|---|---|
Age, years median (IQR) | 9.7 (4.7–13) | 8.9 (3–14) | 10.7 (6–13) | 0.712 |
Min-max | 0.5–19 | 0.5–19 | 0.5–17 | |
Female gender, N (%) | 57 (41) | 39 (41) | 18 (42) | 0.891 |
Transplant indication, N (%) | 0.002 | |||
Acute lymphoblastic leukemia | 58 (42) | 38 (40) | 20 (46) | |
Acute myeloid leukemia | 29 (21) | 28 (29) | 1 (2.3) | |
Marrow failure syndrome | 16 (11) | 7 (7) | 9 (21) | |
Immunodeficiency | 12 (9) | 8 (8.3) | 4 (9.3) | |
Hemoglobinopathies | 12 (8.6) | 4 (4.2) | 8 (19) | |
Myelodysplastic/myeloproliferative | 5 (3.6) | 4 (4.2) | 1 (2.3) | |
syndrome | ||||
Chronic myeloid leukemia | 2 (1.4) | 2 (2) | 0 (0) | |
Non-Hodgkin’s lymphoma | 2 (1.4) | 2 (2) | 0 (0) | |
Hodgkin’s lymphoma | 1 (0.7) | 1 (1) | 0 (0) | |
Others | 2 (1.4) | 2 (2) | 0 (0) | |
Type of transplant, N (%) | <0.001 | |||
Haploidentical | 104 (75) | 82 (85) | 22 (51) | |
Matched related | 32 (23) | 11 (11.5) | 21 (49) | |
Cord | 3 (2) | 3 (3.1) | 0 (0) | |
Stem cell source, N (%) | 0.646 | |||
Bone marrow | 90 (65) | 61 (64) | 29 (67) | |
Peripheral blood | 41 (29.5) | 29 (30) | 12 (28) | |
Marrow and blood | 5 (3.5) | 3 (3.1) | 2 (4.6) | |
Cord | 3 (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-based | 108 (78) | 81 (84) | 27 (63) | |
Cyclosporine-based | 31 (23) | 15 (16) | 16 (37) | |
Use of TLI/TBI radiotherapy | 103 (74) | 70 (73) | 33 (77) | 0.634 |
CMV DNAemia | 59 (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..
Variable | Overall (N=139) | Voriconazole (N=96) | Other (N=43) | |
---|---|---|---|---|
Previous antifungal therapies, N (%) | 69 (50) | 47 (49) | 22 (51) | 0.810 |
Fluconazole, N (%) | 43 | 29 | 14 | |
Voriconazole, N (%) | 27 | 16 | 11 | |
Caspofungin, N (%) | 16 | 13 | 3 | |
Amphotericin B, N (%) | 5 | 4 | 1 | |
Posaconazole, N (%) | 3 | 3 | 0 | |
Previous antimicrobial therapy for, N (%) | 67 (48) | 52 (54) | 15 (35) | 0.035 |
Cefepime | 9 | 7 | 2 | |
Meropenem | 43 | 33 | 10 | |
Vancomycin | 35 | 26 | 9 | |
Piperacilin-tazobactam | 31 | 23 | 8 | |
IFI, N (%) | 7 (5) | 4 (4) | 3 (7) | 0.321 |
Proven | 1/7 | 0/4 | 1/3 | |
1 | 0 | 1 | ||
Possible | 6/7 | 4/4 | 2/3 |
Abbreviation: IFI, invasive fungal infection..
Table 3 . Characteristics of patients with IFI..
Case | 1 | 2 | 3 | 4 | 5 | 6 | 7 |
---|---|---|---|---|---|---|---|
Age (yr) | 0.5 | 9 | 12 | 17 | 12 | 16 | 13 |
Underlying disease | MFS | ALL | ALL | Hodgkin’s L | ALL | ALL | Hemoglobinopathy |
Type of initial prophylaxis | Voriconazole | Voriconazole | Caspofungin | Voriconazole | Posaconazole | Voriconazole | Fluconazole |
Change of prophylaxis | No | No | Voriconazole | Posaconazole | Caspofungin | No | Posaconazole |
Days of initial prophylaxis | 4 | 48 | 25 | 18 | 4 | 15 | 39 |
Days between HSCT/IFI | 4 | 48 | 27 | 24 | 18 | 15 | 44 |
IFI diagnosis | Possible | Possible | Proven | Possible | Possible | Possible | Possible |
Acute GVHD | G II | G IV | NA | NA | G I | NA | G III |
Infection with CMV | No | Yes | Yes | Yes | No | No | Yes |
Death | No | No | No | No | No | Yes | No |
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..
Variable | Overall (N=139) | Voriconazole (N=96) | Other (N=43) | |
---|---|---|---|---|
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, N | 3/24 | 2/19 | 1/5 | |
Transplant related, N | 21/24 | 17/19 | 4/5 | |
GVHD | 3 | 2 | 1 | |
Bacterial infections, N | 4 | 4 | 0 | |
(2) | (2) | 0 | ||
(1) | (1) | 0 | ||
(1) | (1) | 0 | ||
Viral infections | 5 | 3 | 2 | |
Adenovirus | (2) | (1) | (1) | |
CMV | (3) | (2) | (1) | |
Bleeding | 1 | 1 | 0 | |
Multiple organ | 1 | 1 | 0 | |
Failure, N | 8 | 7 | 1 |
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..
Variables | Overall, N | IFI, N (%) | RR (95% CI) | OR adjusted (95% CI) | ||
---|---|---|---|---|---|---|
Voriconazole prophylaxis | 96 | 4 (4.2) | 0.58 (0.12–2.7) | 0.488 | 0.31 (0.06–1.5) | 0.152 |
Moderate to severe mucositis | 60 | 5 (8.3) | 3.5 (0.63–19) | 0.143 | 3.47 (0.63–19.1) | 0.152 |
Malignant-based disease | 100 | 5 (5) | 1.05 (0.19–5.6) | 0.956 | - | - |
Acute GVHD grade III-IV | 15 | 2 (13) | 3.1 (0.65–14) | 0.144 | - | - |
Myeloablative conditioning regimen | 77 | 3 (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..
Variables | Overall, N | IFI, N (%) | RR (95% CI) | OR adjusted (95% CI) | ||
---|---|---|---|---|---|---|
Voriconazole prophylaxis | 96 | 4 (4.2) | 0.95 (0.10 – 8.98) | 0.969 | 0.97 (0.98–9.67) | 0.982 |
Moderate to severe mucositis | 51 | 3 (5.9) | 3.5 (0.65–18.70) | 0.143 | - | - |
Malignant-based disease | 87 | 3 (3.4) | 1.04 (0.19–5.63) | 0.956 | - | - |
Acute GVHD grade III-IV | 11 | 2 (18.2) | 3.41 (0.60–19.41) | 0.166 | 7.33 (1.08–49) | 0.041 |
Myeloablative conditioning regimen | 73 | 2 (2.7) | 0.58 (0.12–2.73) | 0.498 | - | - |
Previous steroid use | 30 | 1 (3.3) | 1.25 (0.23–6.75) | 0.786 | - | - |
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