Bone Marrow Iron Stores Are Not Associated with Increased Risk for Invasive Fungal Infections in Patients with Newly Diagnosed Acute Leukemia or Myelodysplastic Syndrome in Transformation: Is There a Relationship?
Abstract
:1. Introduction
2. Materials and Methods
3. Results
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
References
- Lionakis, M.S.; Lewis, R.E.; Kontoyiannis, D.P. Breakthrough Invasive Mold Infections in the Hematology Patient: Current Concepts and Future Directions. Clin. Infect. Dis. 2018, 67, 1621–1630. [Google Scholar] [CrossRef] [PubMed]
- Pagano, L.; Caira, M.; Nosari, A.; Van Lint, M.T.; Candoni, A.; Offidani, M.; Aloisi, T.; Irrera, G.; Bonini, A.; Picardi, M.; et al. Fungal infections in recipients of hematopoietic stem cell transplants: Results of the SEIFEM B-2004 study—Sorveglianza Epidemiologica Infezioni Fungine Nelle Emopatie Maligne. Clin. Infect. Dis. 2007, 45, 1161–1170. [Google Scholar] [CrossRef] [PubMed]
- Jenks, J.D.; Cornely, O.A.; Chen, S.C.; Thompson, G.R., 3rd; Hoenigl, M. Breakthrough invasive fungal infections: Who is at risk? Mycoses 2020, 63, 1021–1032. [Google Scholar] [CrossRef] [PubMed]
- Aldoss, I.; Dadwal, S.; Zhang, J.; Tegtmeier, B.; Mei, M.; Arslan, S.; Al Malki, M.M.; Salhotra, A.; Ali, H.; Aribi, A.; et al. Invasive fungal infections in acute myeloid leukemia treated with venetoclax and hypomethylating agents. Blood Adv. 2019, 3, 4043–4049. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chamilos, G.; Lionakis, M.S.; Kontoyiannis, D.P. Call for Action: Invasive Fungal Infections Associated with Ibrutinib and Other Small Molecule Kinase Inhibitors Targeting Immune Signaling Pathways. Clin. Infect. Dis. 2018, 66, 140–148. [Google Scholar] [CrossRef] [Green Version]
- Little, J.S.; Weiss, Z.F.; Hammond, S.P. Invasive Fungal Infections and Targeted Therapies in Hematological Malignancies. J. Fungi 2021, 7, 1058. [Google Scholar] [CrossRef]
- Kontoyiannis, D.P.; Chamilos, G.; Lewis, R.E.; Giralt, S.; Cortes, J.; Raad, I.I.; Manning, J.T.; Han, X. Increased bone marrow iron stores is an independent risk factor for invasive aspergillosis in patients with high-risk hematologic malignancies and recipients of allogeneic hematopoietic stem cell transplantation. Cancer 2007, 110, 1303–1306. [Google Scholar] [CrossRef]
- Kontoyiannis, D.P.; Bodey, G.P. Invasive aspergillosis in 2002: An update. Eur. J. Clin. Microbiol. Infect. Dis. 2002, 21, 161–172. [Google Scholar] [CrossRef]
- Marr, K.A.; Carter, R.A.; Boeckh, M.; Martin, P.; Corey, L. Invasive aspergillosis in allogeneic stem cell transplant recipients: Changes in epidemiology and risk factors. Blood 2002, 100, 4358–4366. [Google Scholar] [CrossRef] [Green Version]
- Braun, V. Iron uptake mechanisms and their regulation in pathogenic bacteria. Int. J. Med. Microbiol. 2001, 291, 67–79. [Google Scholar] [CrossRef]
- Nairz, M.; Weiss, G. Iron in infection and immunity. Mol. Asp. Med. 2020, 75, 100864. [Google Scholar] [CrossRef] [PubMed]
- Walker, E.M., Jr.; Walker, S.M. Effects of iron overload on the immune system. Ann. Clin. Lab. Sci. 2000, 30, 354–365. [Google Scholar] [PubMed]
- Ward, R.J.; Crichton, R.R.; Taylor, D.L.; Della Corte, L.; Srai, S.K.; Dexter, D.T. Iron and the immune system. J. Neural Transm. 2011, 118, 315–328. [Google Scholar] [CrossRef]
- Hissen, A.H.; Wan, A.N.; Warwas, M.L.; Pinto, L.J.; Moore, M.M. The Aspergillus fumigatus siderophore biosynthetic gene sidA, encoding L-ornithine N5-oxygenase, is required for virulence. Infect. Immun. 2005, 73, 5493–5503. [Google Scholar] [CrossRef] [Green Version]
- Caza, M.; Kronstad, J.W. Shared and distinct mechanisms of iron acquisition by bacterial and fungal pathogens of humans. Front. Cell. Infect. Microbiol. 2013, 3, 80. [Google Scholar] [CrossRef] [PubMed]
- Valkovic, T.; Damic, M.S. Role of Iron and Iron Overload in the Pathogenesis of Invasive Fungal Infections in Patients with Hematological Malignancies. J. Clin. Med. 2022, 11, 4457. [Google Scholar] [CrossRef] [PubMed]
- Fourie, R.; Kuloyo, O.O.; Mochochoko, B.M.; Albertyn, J.; Pohl, C.H. Iron at the Centre of Candida albicans Interactions. Front. Cell. Infect. Microbiol. 2018, 8, 185. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Iglesias-Osma, C.; Gonzalez-Villaron, L.; San Miguel, J.F.; Caballero, M.D.; Vazquez, L.; de Castro, S. Iron metabolism and fungal infections in patients with haematological malignancies. J. Clin. Pathol. 1995, 48, 223–225. [Google Scholar] [CrossRef] [Green Version]
- Ibrahim, A.S.; Gebermariam, T.; Fu, Y.; Lin, L.; Husseiny, M.I.; French, S.W.; Schwartz, J.; Skory, C.D.; Edwards, J.E., Jr.; Spellberg, B.J. The iron chelator deferasirox protects mice from mucormycosis through iron starvation. J. Clin. Investig. 2007, 117, 2649–2657. [Google Scholar] [CrossRef] [Green Version]
- Shirazi, F.; Kontoyiannis, D.P.; Ibrahim, A.S. Iron starvation induces apoptosis in Rhizopus oryzae in vitro. Virulence 2015, 6, 121–126. [Google Scholar] [CrossRef] [Green Version]
- Pagano, L.; Akova, M.; Dimopoulos, G.; Herbrecht, R.; Drgona, L.; Blijlevens, N. Risk assessment and prognostic factors for mould-related diseases in immunocompromised patients. J. Antimicrob. Chemother. 2011, 66 (Suppl. S1), i5–i14. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Karp, J.E.; Merz, W.G. Association of reduced total iron binding capacity and fungal infections in leukemic granulocytopenic patients. J. Clin. Oncol. 1986, 4, 216–220. [Google Scholar] [CrossRef] [PubMed]
- Dadwal, S.S.; Tegtmeier, B.; Liu, X.; Frankel, P.; Ito, J.; Forman, S.J.; Pullarkat, V. Impact of pretransplant serum ferritin level on risk of invasive mold infection after allogeneic hematopoietic stem cell transplantation. Eur. J. Haematol. 2015, 94, 235–242. [Google Scholar] [CrossRef] [PubMed]
- Takkunen, H. Iron deficiency in the Finnish adult population. Scand. J. Haematol. Suppl. 1976, 25, 1–91. [Google Scholar]
- Donnelly, J.P.; Chen, S.C.; Kauffman, C.A.; Steinbach, W.J.; Baddley, J.W.; Verweij, P.E.; Clancy, C.J.; Wingard, J.R.; Lockhart, S.R.; Groll, A.H.; 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. Dis. 2020, 71, 1367–1376. [Google Scholar] [CrossRef] [Green Version]
- Peng, H.; Sun, M.; Hu, X.; Han, H.; Su, J.; Peng, E.; Wiley, J.; Lommel, L.; Chen, J.L. Prevalence, awareness, and associated factors of high blood pressure among female migrant workers in Central South China. PeerJ 2022, 10, e13365. [Google Scholar] [CrossRef]
- Miceli, M.H.; Dong, L.; Grazziutti, M.L.; Fassas, A.; Thertulien, R.; Van Rhee, F.; Barlogie, B.; Anaissie, E.J. Iron overload is a major risk factor for severe infection after autologous stem cell transplantation: A study of 367 myeloma patients. Bone Marrow Transplant. 2006, 37, 857–864. [Google Scholar] [CrossRef]
- Maertens, J.; Demuynck, H.; Verbeken, E.K.; Zachee, P.; Verhoef, G.E.; Vandenberghe, P.; Boogaerts, M.A. Mucormycosis in allogeneic bone marrow transplant recipients: Report of five cases and review of the role of iron overload in the pathogenesis. Bone Marrow Transplant. 1999, 24, 307–312. [Google Scholar] [CrossRef] [Green Version]
- Sipsas, N.V.; Pagoni, M.N.; Kofteridis, D.P.; Meletiadis, J.; Vrioni, G.; Papaioannou, M.; Antoniadou, A.; Petrikkos, G.; Samonis, G. Management of Invasive Fungal Infections in Adult Patients with Hematological Malignancies in Greece during the Financial Crisis: Challenges and Recommendations. J. Fungi 2018, 4, 94. [Google Scholar] [CrossRef] [Green Version]
- Moafi, A.; Ziaie, M.; Abedi, M.; Rahgozar, S.; Reisi, N.; Nematollahi, P.; Moafi, H. The relationship between iron bone marrow stores and response to treatment in pediatric acute lymphoblastic leukemia. Medicine 2017, 96, e8511. [Google Scholar] [CrossRef]
- Lasry, A.; Nadorp, B.; Fornerod, M.; Nicolet, D.; Wu, H.; Walker, C.J.; Sun, Z.; Witkowski, M.T.; Tikhonova, A.N.; Guillamot-Ruano, M.; et al. An inflammatory state remodels the immune microenvironment and improves risk stratification in acute myeloid leukemia. Nat. Cancer 2023, 4, 27–42. [Google Scholar] [CrossRef] [PubMed]
- Styczynski, J.; Slomka, A.; Lecka, M.; Albrecht, K.; Romiszewski, M.; Pogorzala, M.; Kubicka, M.; Kurylo-Rafinska, B.; Tejza, B.; Gadomska, G.; et al. Soluble Hemojuvelin and Ferritin: Potential Prognostic Markers in Pediatric Hematopoietic Cell Transplantation. Cancers 2023, 15, 1041. [Google Scholar] [CrossRef] [PubMed]
- Burns, E.R.; Goldberg, S.N.; Lawrence, C.; Wenz, B. Clinical utility of serum tests for iron deficiency in hospitalized patients. Am. J. Clin. Pathol. 1990, 93, 240–245. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Characteristics at Diagnosis of Hematological Malignancy | No IFI (n = 76) | Patients with IFI (n = 22) | Univariate Analysis | Multivariate Analysis | ||
---|---|---|---|---|---|---|
OR (95% CI) | p | OR (95% CI) | p | |||
Age (median, 25–75th percentile, years) | 67.5 (53.5–75.0) | 58 (47–65) | - | - | - | - |
Male sex | 44/76 (57.9%) | 14/22 (63.6%) | - | - | - | - |
AML | 56/76 (73.7%) | 21/22 (95.5%) | 7.40 (1.05–325.42) | 0.037 | 7.96 (0.94–67.34) | 0.057 |
Neutropenia at diagnosis (<500 cells/mm3) | 18/76 (23.7%) | 9/22 (40.9%) | 2.21 (0.71–6.72) | 0.174 | 1.97 (0.68–5.74) | 0.214 |
Profound neutropenia at diagnosis (<100 cells/mm3) | 10/76 (13.2%) | 6/22 (27.3%) | 2.45 (0.63–8.83) | 0.186 | - | - |
Corticosteroid use | 17/76 (22.4%) | 5/22 (22.7%) | 1.02 (0.26–3.47) | >0.999 | 1.11 (0.32–3.82) | 0.874 |
Diabetes mellitus | 7/76 (9.2%) | 2/22 (9.1%) | 0.99 (0.09–5.76) | >0.999 | 1.01 (0.17–6.06) | 0.995 |
Malnutrition (albumin < 3 mg/dL) | 25/76 (32.9%) | 7/22 (31.8%) | 0.95 (0.29–2.88) | >0.999 | 1.13 (0.37–3.46) | 0.828 |
BMIS ≥ 3 | 31/76 (40.8%) | 8/22 (36.4%) | 0.83 (0.27–2.43) | 0.807 | 0.88 (0.31–2.50) | 0.805 |
Baseline serum iron levels (median, 25–75th percentile, mg/dL) | 125.5 (79.5–170.5) | 114.0 (92.0–156.0) | 1.00 (0.98–1.00) | 0.334 | 1.00 (0.99–1.00) | 0.346 |
Baseline serum ferritin levels (median, 25–75th percentile, mg/dL) | 678.2 (233.4–1012.0) (n = 75) | 873.3 (386.1–1225.6) | 1.00 (0.99–1.00) | 0.911 | 1.00 (0.99–1.00) | 0.519 |
Invasive Fungal Infection | Proven * | Probable * | Total |
---|---|---|---|
Invasive candidiasis/candidemia | 5 | 0 | 5 |
Invasive aspergillosis | 4 | 12 | 16 |
Mucormycosis | 1 | 0 | 1 |
Total | 10 | 12 | 22 |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Apostolidi, E.A.; Gamaletsou, M.N.; Arapaki, M.; Asimakopoulos, J.V.; Diamantopoulos, P.; Zafeiratou, S.; Kofteridis, D.; Pagoni, M.; Kotsopoulou, M.; Voulgarelis, M.; et al. Bone Marrow Iron Stores Are Not Associated with Increased Risk for Invasive Fungal Infections in Patients with Newly Diagnosed Acute Leukemia or Myelodysplastic Syndrome in Transformation: Is There a Relationship? J. Fungi 2023, 9, 748. https://doi.org/10.3390/jof9070748
Apostolidi EA, Gamaletsou MN, Arapaki M, Asimakopoulos JV, Diamantopoulos P, Zafeiratou S, Kofteridis D, Pagoni M, Kotsopoulou M, Voulgarelis M, et al. Bone Marrow Iron Stores Are Not Associated with Increased Risk for Invasive Fungal Infections in Patients with Newly Diagnosed Acute Leukemia or Myelodysplastic Syndrome in Transformation: Is There a Relationship? Journal of Fungi. 2023; 9(7):748. https://doi.org/10.3390/jof9070748
Chicago/Turabian StyleApostolidi, Eirini A., Maria N. Gamaletsou, Maria Arapaki, John V. Asimakopoulos, Panagiotis Diamantopoulos, Sofia Zafeiratou, Diamantis Kofteridis, Maria Pagoni, Maria Kotsopoulou, Michael Voulgarelis, and et al. 2023. "Bone Marrow Iron Stores Are Not Associated with Increased Risk for Invasive Fungal Infections in Patients with Newly Diagnosed Acute Leukemia or Myelodysplastic Syndrome in Transformation: Is There a Relationship?" Journal of Fungi 9, no. 7: 748. https://doi.org/10.3390/jof9070748