Invasive mold infections in neutropenic patients with hematologic malignancies

Main Article Content

Sophie G Carlson David Shabsovich Gary Schiller

Abstract

Invasive mold infections are a significant cause of morbidity and mortality among patients with hematologic malignancies, primarily due to the prolonged periods of profound neutropenia that characterize these diseases. As our population continues to age, the incidence of hematologic malignancies is expected to rise, further exacerbating the public health burden posed by fungal infections. Therefore, it is crucial to enhance our understanding of the landscape of invasive mold infections and the underlying mechanisms by which this patient population becomes infected. Such knowledge is essential for developing effective prevention strategies and improving the management of these infections in hematologic malignancies. This review will examine the reasons why patients with hematologic malignancies represent an at-risk population for invasive mold infections, with a particular focus on the deficiencies in the host immune system. We will also address some of the challenges associated with diagnosing these infections in a vulnerable population and review current and emerging technologies aimed at improving detection. Lastly, this review will evaluate the current literature on prophylaxis and treatment options, as well as more novel therapies under development.

Keywords: Invasive mold infections, Hematologic malignancies, Neutropenia, Fungal infections, Host immune system deficiencies, Infection diagnosis, Prophylaxis and treatment, Novel therapies, Emerging diagnostic technologies, Immunocompromised patients

Article Details

How to Cite
CARLSON, Sophie G; SHABSOVICH, David; SCHILLER, Gary. Invasive mold infections in neutropenic patients with hematologic malignancies. Medical Research Archives, [S.l.], v. 13, n. 1, jan. 2025. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/6052>. Date accessed: 10 feb. 2025. doi: https://doi.org/10.18103/mra.v13i1.6052.
Section
Research Articles

References

1. Surveillance, Epidemiology, and End Results (SEER) Program Populations. Published online October 22, 2024.

2. Mangan BL, DuMontier C, Hopkins JO, Abel GA, McCurdy SR. Tailoring Therapy in Older Adults With Hematologic Malignancies. Am Soc Clin Oncol Educ Book. 2024;44(3):e432220. doi:10. 1200/EDBK_432220

3. Zhang N, Wu J, Wang Q, et al. Global burden of hematologic malignancies and evolution patterns over the past 30 years. Blood Cancer J. 2023; 13(1):82. doi:10.1038/s41408-023-00853-3

4. An ZY, Fu H, He Y, et al. Projected Global Trends in Hematological Malignancies: Incidence, Mortality, and Disability-Adjusted Life Years from 2020 to 2030. Blood. 2023;142(Supplement 1):381 0-3810. doi:10.1182/blood-2023-187856

5. Duarte RF, Sánchez-Ortega I. HSCT in Elderly Patients. In: Carreras E, Dufour C, Mohty M, Kröger N, eds. The EBMT Handbook. Springer International Publishing; 2019:499-503. doi:10.100 7/978-3-030-02278-5_68

6. Tigner A, Ibrahim SA, Murray IV. Histology, White Blood Cell. In: StatPearls. StatPearls Publishing; 2024. Accessed September 24, 2024. http://www.ncbi.nlm.nih.gov/books/NBK563148/

7. Witter AR, Okunnu BM, Berg RE. The Essential Role of Neutrophils During Infection with the Intracellular Bacterial Pathogen Listeria monocytogenes. J Immunol Baltim Md 1950. 2016; 197(5):1557-1565. doi:10.4049/jimmunol.1600599

8. Keng MK, Sekeres MA. Febrile Neutropenia in Hematologic Malignancies. Curr Hematol Malig Rep. 2013;8(4):370-378. doi:10.1007/s11899-013-0171-4

9. Baluch A, Shewayish S. Neutropenic Fever. Infect Neutropenic Cancer Patients. Published online August 11, 2019:105-117. doi:10.1007/978-3-030-21859-1_8

10. Dotson JL, Lebowicz Y. Myelodysplastic Syndrome. In: StatPearls. StatPearls Publishing; 2024. Accessed September 24, 2024. http://www.ncbi.nlm.nih.gov/books/NBK534126/

11. Hansen BA, Wendelbo Ø, Bruserud Ø, Hemsing AL, Mosevoll KA, Reikvam H. Febrile Neutropenia in Acute Leukemia. Epidemiology, Etiology, Pathophysiology and Treatment. Mediterr J Hematol Infect Dis. 2019;12(1):e202000 9. doi:10.4084/MJHID.2020.009

12. Wijeratne DT, Wright K, Gyawali B. Risk-Stratifying Treatment Strategies for Febrile Neutropenia—Tools, Tools Everywhere, and Not a Single One That Works? JCO Oncol Pract. 2021;17(11):651-654. doi:10.1200/OP.21.00148

13. Makhani SS, Abro C, Ketineni S, et al. Inpatient Burden and Clinical Outcomes of Febrile Neutropenia in Cancer Patients: A National Inpatient Sample Database Analysis. Blood. 2022; 140(Supplement 1):5154-5155. doi:10.1182/blood -2022-165527

14. Stohs EJ, Abbas A, Freifeld A. Approach to febrile neutropenia in patients undergoing treatments for hematologic malignancies. Transpl Infect Dis. 2024;26(2):e14236. doi:10.1111/tid.14236

15. Shafiee F, Soltani R, Meidani M. Invasive fungal infections in hematologic malignancies: Incidence, management, and antifungal therapy. J Res Med Sci Off J Isfahan Univ Med Sci. 2023; 28:73. doi:10.4103/jrms.jrms_1072_21

16. Pagano L, Caira M, Candoni A, et al. The epidemiology of fungal infections in patients with hematologic malignancies: the SEIFEM-2004 study. Haematologica. 2006;91(8):1068-1075.

17. Rayens E, Norris KA. Prevalence and Healthcare Burden of Fungal Infections in the United States, 2018. Open Forum Infect Dis. 2022;9(1): ofab593. doi:10.1093/ofid/ofab593

18. Kobayashi G. Medical Microbiology. 4th Edition. Vol Disease Mechanisms of Fungi.

19. Ruchti F, LeibundGut-Landmann S. New insights into immunity to skin fungi shape our understanding of health and disease. Parasite Immunol. 2023; 45(2):e12948. doi:10.1111/pim.12948

20. Reddy GKK, Padmavathi AR, Nancharaiah YV. Fungal infections: Pathogenesis, antifungals and alternate treatment approaches. Curr Res Microb Sci. 2022;3:100137. doi:10.1016/j.crmicr.2022.100137

21. Desai JV, Lionakis MS. The role of neutrophils in host defense against invasive fungal infections. Curr Clin Microbiol Rep. 2018;5(3):181-189. doi:10. 1007/s40588-018-0098-6

22. Diamond RD, Krzesicki R, Epstein B, Jao W. Damage to hyphal forms of fungi by human leukocytes in vitro. A possible host defense mechanism in aspergillosis and mucormycosis. Am J Pathol. 1978;91(2):313-328.

23. Feldmesser M. Role of neutrophils in invasive aspergillosis. Infect Immun. 2006;74(12):6514-6516. doi:10.1128/IAI.01551-06

24. Ghuman H, Voelz K. Innate and Adaptive Immunity to Mucorales. J Fungi. 2017;3(3):48. doi:10.3390/jof3030048

25. Campuzano A, Wormley FL. Innate Immunity against Cryptococcus, from Recognition to Elimination. J Fungi Basel Switz. 2018;4(1):33. doi: 10.3390/jof4010033

26. Pinzan CF, Valero C, De Castro PA, et al. Aspergillus fumigatus conidial surface-associated proteome reveals factors for fungal evasion and host immunity modulation. Nat Microbiol. 2024;9 (10):2710-2726. doi:10.1038/s41564-024-01782-y

27. Lausch KR, Søgaard M, Rosenvinge FS, et al. High incidence of candidaemia in a nationwide cohort: Underlying diseases, risk factors and mortality. Int J Infect Dis. 2018;76:58-63. doi:10. 1016/j.ijid.2018.08.010

28. Gong Y, Li C, Wang C, et al. Epidemiology and Mortality-Associated Factors of Invasive Fungal Disease in Elderly Patients: A 20-Year Retrospective Study from Southern China. Infect Drug Resist. 2020;Volume 13:711-723. doi:10.214 7/IDR.S242187

29. Hou S, Wang X, Yu Y, et al. Invasive fungal infection is associated with antibiotic exposure in preterm infants: a multi-centre prospective case–control study. J Hosp Infect. 2023;134:43-49. doi: 10.1016/j.jhin.2023.01.002

30. Drummond RA, Desai JV, Ricotta EE, et al. Long-term antibiotic exposure promotes mortality after systemic fungal infection by driving lymphocyte dysfunction and systemic escape of commensal bacteria. Cell Host Microbe. 2022;30(7) :1020-1033.e6. doi:10.1016/j.chom.2022.04.013

31. Denning DW. Global incidence and mortality of severe fungal disease. Lancet Infect Dis. 2024;24 (7):e428-e438. doi:10.1016/S1473-3099(23)00692-8

32. Lee SO. Diagnosis and Treatment of Invasive Mold Diseases. Infect Chemother. 2023;55(1):10. doi:10.3947/ic.2022.0151

33. Webb BJ, Ferraro JP, Rea S, Kaufusi S, Goodman BE, Spalding J. Epidemiology and Clinical Features of Invasive Fungal Infection in a US Health Care Network. Open Forum Infect Dis. 2018;5(8):ofy187. doi:10.1093/ofid/ofy187

34. Bergamasco MD. Epidemiology of Invasive Fungal Diseases in Patients with Hematologic Malignancies and Hematopoietic Cell Transplantation Recipients Managed with an Antifungal Diagnostic Driven Approach. J Fungi. 7(8):588.

35. Afhami S, Adibimehr A, Mousavi SA, et al. Rate, Risk Factors, and Outcomes of Invasive Fungal Infections in Patients with Hematologic Malignancies. Int J Hematol-Oncol Stem Cell Res. 2024;18(1):75-82. doi:10.18502/ijhoscr.v18i1.14746

36. Oh SM, Byun JM, Chang E, et al. Incidence of invasive fungal infection in acute lymphoblastic and acute myelogenous leukemia in the era of antimold prophylaxis. Sci Rep. 2021;11(1):22160. doi:10.103 8/s41598-021-01716-2

37. Ruhnke M, Böhme A, Buchheidt D, et al. Diagnosis of invasive fungal infections in hematology and oncology—guidelines from the Infectious Diseases Working Party in Haematology and Oncology of the German Society for Haematology and Oncology (AGIHO). Ann Oncol. 2012;23(4):823-833. doi:10.1093/annonc/mdr407

38. Donnelly JP, Chen SC, Kauffman CA, 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(6):1367-1376. doi:10.1093/cid/ciz1008

39. Asiimwe DD, Ravi M, Isache C. Fusariosis: An Invasive Fungal Disease in a Neutropenic Patient With Acute Myeloid Leukemia. Cureus. Published online September 18, 2022. doi:10.7759/cureus.29303

40. El Omri H, Padmanabhan R, Taha RY, et al. Dissecting bloodstream infections in febrile neutropenic patients with hematological malignancies, a decade-long single center retrospective observational study (2009-2019). J Infect Public Health. 2024;17( 1):152-162. doi:10.1016/j.jiph.2023.11.017

41. Leeflang MM, Debets-Ossenkopp YJ, Wang J, et al. Galactomannan detection for invasive aspergillosis in immunocompromised patients. Cochrane Airways Group, ed. Cochrane Database Syst Rev. 2015;2017(9). doi:10.1002/14651858.CD007394.pub2

42. Cordonnier C, Botterel F, Ben Amor R, et al. Correlation between galactomannan antigen levels in serum and neutrophil counts in haematological patients with invasive aspergillosis. Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis. 2009;15(1):81-86. doi:10.1111/j.1469-0691.2008.02122.x

43. White SK, Walker BS, Hanson KE, Schmidt RL. Diagnostic Accuracy of β-d-Glucan (Fungitell) Testing Among Patients With Hematologic Malignancies or Solid Organ Tumors: A Systematic Review and Meta-Analysis. Am J Clin Pathol. 2019; 151(3):275-285. doi:10.1093/ajcp/aqy135

44. Hill JA, Dalai SC, Hong DK, et al. Liquid Biopsy for Invasive Mold Infections in Hematopoietic Cell Transplant Recipients With Pneumonia Through Next-Generation Sequencing of Microbial Cell-Free DNA in Plasma. Clin Infect Dis Off Publ Infect Dis Soc Am. 2021;73(11):e3876-e3883. doi:10.10 93/cid/ciaa1639

45. Huygens S, Schauwvlieghe A, Wlazlo N, et al. Diagnostic Value of Microbial Cell-free DNA Sequencing for Suspected Invasive Fungal Infections: A Retrospective Multicenter Cohort Study. Open Forum Infect Dis. 2024;11(6):ofae252. doi:10.1093/ofid/ofae252

46. Sassi C, Stanzani M, Lewis RE, et al. The utility of contrast-enhanced hypodense sign for the diagnosis of pulmonary invasive mould disease in patients with haematological malignancies. Br J Radiol. 2018;91(1083):20170220. doi:10.1259/bjr. 20170220

47. Douglas A, Thursky K, Spelman T, et al. [18F] FDG-PET-CT compared with CT for persistent or recurrent neutropenic fever in high-risk patients (PIPPIN): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Haematol. 2022;9(8): e573-e584. doi:10.1016/S2352-3026 (22)00166-1

48. Stemler J, Mellinghoff S, Khodamaoradi Y. Primary prophylaxis of invasive fungal diseases in patients with haematological malignancies: 2022 update of the recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society for Haematology and Medical Oncology (DGHO). J Antimicrob Chemother. 2023;78(8):181 3-1826. doi:10.1093/jac/dkad143

49. Taplitz RA, Kennedy EB, Bow EJ, et al. Antimicrobial Prophylaxis for Adult Patients With Cancer-Related Immunosuppression: ASCO and IDSA Clinical Practice Guideline Update. J Clin Oncol Off J Am Soc Clin Oncol. 2018;36(30):3043-3054. doi:10.1200/JCO.18.00374

50. Ethier MC, Science M, Beyene J, Briel M, Lehrnbecher T, Sung L. 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 Cancer. 2012;106(10):1626-1637. doi:10.1038/bjc.2012.147

51. Zhao YJ, Khoo AL, Tan G, et al. Network Meta-analysis and Pharmacoeconomic Evaluation of Fluconazole, Itraconazole, Posaconazole, and Voriconazole in Invasive Fungal Infection Prophylaxis. Antimicrob Agents Chemother. 2016;60(1):376-386. doi:10.1128/AAC.01985-15

52. Fontana L, Perlin DS, Zhao Y, et al. Isavuconazole Prophylaxis in Patients With Hematologic Malignancies and Hematopoietic Cell Transplant Recipients. Clin Infect Dis Off Publ Infect Dis Soc Am. 2020;70(5):723-730. doi:10. 1093/cid/ciz282

53. Maiti A, Konopleva MY. How We Incorporate Venetoclax in Treatment Regimens for Acute Myeloid Leukemia. Cancer J Sudbury Mass. 2022; 28(1):2-13. doi:10.1097/PPO.0000000000000567

54. Rausch CR, DiNardo CD, Maiti A, et al. Duration of cytopenias with concomitant venetoclax and azole antifungals in acute myeloid leukemia. Cancer. 2021;127(14):2489-2499. doi:10 .1002/cncr.33508

55. Lerolle N, Raffoux E, Socie G, et al. Breakthrough invasive fungal disease in patients receiving posaconazole primary prophylaxis: a 4-year study. Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis. 2014;20(11):O952-959. doi:10.1111/1469-0691.12688

56. Venton G, Adam H, Colle J, et al. Micafungin as primary antifungal prophylaxis in patients presenting with acute myeloid leukemia. Med Mal Infect. 2016;46(4):226-229. doi:10.1016/j.medmal.2016.03.008

57. Maertens JA, Raad II, Marr KA, et al. Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial. Lancet Lond Engl. 2016;387(10020):760-769. doi:10.1016/S0140-6736(15)01159-9

58. Maertens JA, Rahav G, Lee DG, et al. Posaconazole versus voriconazole for primary treatment of invasive aspergillosis: a phase 3, randomised, controlled, non-inferiority trial. Lancet Lond Engl. 2021;397(10273):499-509. doi:10.1016 /S0140-6736(21)00219-1

59. Ahn H, Lee R, Cho SY, Lee DG. Advances in prophylaxis and treatment of invasive fungal infections: perspectives on hematologic diseases. Blood Res. 2022;57(S1):101-111. doi:10.5045/br. 2022.2022036

60. Marty FM, Ostrosky-Zeichner L, Cornely OA, et al. Isavuconazole treatment for mucormycosis: a single-arm open-label trial and case-control analysis. Lancet Infect Dis. 2016;16(7):828-837. doi: 10.1016/S1473-3099(16)00071-2

61. Shariati A, Moradabadi A, Chegini Z, Khoshbayan A, Didehdar M. An Overview of the Management of the Most Important Invasive Fungal Infections in Patients with Blood Malignancies. Infect Drug Resist. 2020;13:2329-2354. doi:10.2147/IDR.S254478

62. Hoenigl M, Arastehfar A, Arendrup MC, et al. Novel antifungals and treatment approaches to tackle resistance and improve outcomes of invasive fungal disease. Clin Microbiol Rev. 2024;37(2): e0007423. doi:10.1128/cmr.00074-23

63. Maertens JA, Verweij PE, Lanuza EF, et al. 870. Olorofim for the treatment of invasive mould infections in patients with limited or no treatment options: Comparison of interim results from a Phase 2B open-label study with outcomes in historical control populations (NCT03583164, FORMULA-OLS, Study 32). Open Forum Infect Dis. 2022;9(Supplement_2):ofac492.063. doi:10.1093/ofid/ofac492.063

64. Estcourt LJ, Stanworth SJ, Hopewell S, Doree C, Trivella M, Massey E. Granulocyte transfusions for treating infections in people with neutropenia or neutrophil dysfunction. Cochrane Database Syst Rev. 2016;4(4):CD005339. doi:10.1002/14651858. CD005339.pub2