{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T08:39:18Z","timestamp":1769589558062,"version":"3.49.0"},"reference-count":36,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,8,26]],"date-time":"2025-08-26T00:00:00Z","timestamp":1756166400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Robert C. Hickey Chair in Clinical Care endowment","award":["n\/a"],"award-info":[{"award-number":["n\/a"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JoF"],"abstract":"<jats:p>Mold-active prophylaxis has reduced the incidence of invasive pulmonary aspergillosis (IPA) in patients with hematological malignancies (HMs), but breakthrough IPA (Bt-IPA) is increasingly encountered. Therefore, we studied determinants of Bt-IPA risk and its prognostic significance. We retrospectively reviewed culture-positive proven\/probable IPA cases in HM patients at MD Anderson Cancer Center (2016\u20132021). Bt-IPA and non-Bt-IPA cases were compared to characterize risk factors, clinical presentation, and outcomes. Independent predictors of 42-day all-cause mortality were assessed using propensity score-adjusted Cox regression. Among 118 IPA cases, 50 (42.4%) were Bt-IPA. Bt-IPA was associated with acute leukemia\/myelodysplastic syndrome, active HM, severe neutropenia (&lt;100\/mm3), and graft-versus-host diseases. Uncommon Aspergillus species (non-fumigatus, flavus, terreus, or niger) were more frequent in Bt-IPA than non-Bt-IPA (20.4% vs. 4.8%, p = 0.010). Forty-two-day mortality was higher in Bt-IPA (65.3% vs. 37.3%, p = 0.003), but Bt-IPA itself was not an independent predictor or mortality (p = 0.064), which was instead driven by neutropenia (p = 0.020) and hypoalbuminemia (p = 0.002). In conclusion, Bt-IPA accounted for nearly half of contemporary IPA cases and was linked to host-related risk factors and the recovery of uncommon Aspergillus species. Although not an independent prognostic predictor, Bt-IPA reflected poor host status. Thus, early diagnosis, immune enhancement strategies, and effective first-in-class antifungals may improve outcomes.<\/jats:p>","DOI":"10.3390\/jof11090623","type":"journal-article","created":{"date-parts":[[2025,8,26]],"date-time":"2025-08-26T10:35:17Z","timestamp":1756204517000},"page":"623","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["What Is the Prognostic Significance of Culture-Documented Breakthrough Invasive Pulmonary Aspergillosis in Patients with Hematological Malignancies? A Propensity Score-Adjusted Analysis"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5392-3405","authenticated-orcid":false,"given":"Sung-Yeon","family":"Cho","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA"},{"name":"Division of Infectious Diseases, Department of Internal Medicine, Vaccine Bio Research Institute, Catholic Hematology Hospital, Seoul St. Mary\u2019s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7784-7256","authenticated-orcid":false,"given":"Sebastian","family":"Wurster","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9389-0628","authenticated-orcid":false,"given":"Takahiro","family":"Matsuo","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey","family":"Tarrand","sequence":"additional","affiliation":[{"name":"Section of Clinical Microbiology and Virology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8051-2940","authenticated-orcid":false,"given":"Dimitrios P.","family":"Kontoyiannis","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1086\/651263","article-title":"Prospective surveillance for invasive fungal infections in hematopoietic stem cell transplant recipients, 2001\u20132006: Overview of the Transplant-Associated Infection Surveillance Network (TRANSNET) Database","volume":"50","author":"Kontoyiannis","year":"2010","journal-title":"Clin. Infect. Dis."},{"key":"ref_2","first-page":"1068","article-title":"The epidemiology of fungal infections in patients with hematologic malignancies: The SEIFEM-2004 study","volume":"91","author":"Pagano","year":"2006","journal-title":"Haematologica"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e428","DOI":"10.1016\/S1473-3099(23)00692-8","article-title":"Global incidence and mortality of severe fungal disease","volume":"24","author":"Denning","year":"2024","journal-title":"Lancet Infect. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/j.idc.2021.03.008","article-title":"Aspergillosis: Epidemiology, diagnosis, and treatment","volume":"35","author":"Cadena","year":"2021","journal-title":"Infect. Dis. Clin. N. Am."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1056\/NEJMoa061094","article-title":"Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia","volume":"356","author":"Cornely","year":"2007","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1093\/cid\/ciae203","article-title":"Breakthrough invasive fungal infections in patients with high-risk hematological disorders receiving voriconazole and posaconazole prophylaxis: A systematic review","volume":"79","author":"Boutin","year":"2024","journal-title":"Clin. Infect. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1610","DOI":"10.1093\/cid\/ciy406","article-title":"Breakthrough fungal infections in patients with leukemia receiving isavuconazole","volume":"67","author":"Rausch","year":"2018","journal-title":"Clin. Infect. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Axell-House, D.B., Wurster, S., Jiang, Y., Kyvernitakis, A., Lewis, R.E., Tarrand, J.J., Raad, I.I., and Kontoyiannis, D.P. (2021). Breakthrough Mucormycosis Developing on Mucorales-active antifungals portrays a poor prognosis in patients with hematologic cancer. J. Fungi, 7.","DOI":"10.3390\/jof7030217"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1755","DOI":"10.1093\/cid\/ciaa358","article-title":"Isavuconazole as primary antifungal prophylaxis in patients with acute myeloid leukemia or myelodysplastic syndrome: An open-label, prospective, phase 2 study","volume":"72","author":"Bose","year":"2021","journal-title":"Clin. Infect. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2775","DOI":"10.1128\/AAC.01527-13","article-title":"Effectiveness of primary anti-Aspergillus prophylaxis during remission induction chemotherapy of acute myeloid leukemia","volume":"58","author":"Gomes","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1093\/cid\/ciz1008","article-title":"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","volume":"71","author":"Donnelly","year":"2020","journal-title":"Clin. Infect. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1093\/cid\/cix297","article-title":"Changes in In Vitro Susceptibility Patterns of Aspergillus to Triazoles and Correlation with Aspergillosis Outcome in a Tertiary Care Cancer Center, 1999\u20132015","volume":"65","author":"Heo","year":"2017","journal-title":"Clin. Infect. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1111\/myc.12960","article-title":"Defining breakthrough invasive fungal infection-position paper of the mycoses study group education and research consortium (MSG-ERC) and the European Confederation of Medical Mycology (ECMM)","volume":"62","author":"Cornely","year":"2019","journal-title":"Mycoses"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e00188-17","DOI":"10.1128\/AAC.00188-17","article-title":"Real-life assessment of the safety and effectiveness of the new tablet and intravenous formulations of posaconazole in the prophylaxis of invasive fungal infections via analysis of 343 courses","volume":"61","author":"Tverdek","year":"2017","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1401","DOI":"10.1038\/s41409-018-0204-7","article-title":"EBMT-NIH-CIBMTR Task Force position statement on standardized terminology & guidance for graft-versus-host disease assessment","volume":"53","author":"Schoemans","year":"2018","journal-title":"Bone Marrow Transplant."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"S117","DOI":"10.1016\/j.kint.2023.10.018","article-title":"Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease","volume":"105","author":"Stevens","year":"2024","journal-title":"Kidney Int."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1136\/gutjnl-2019-318813","article-title":"Epidemiology of chronic liver diseases in the USA in the past three decades","volume":"69","author":"Younossi","year":"2020","journal-title":"Gut"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.jinf.2023.05.005","article-title":"Breakthrough invasive fungal infection among patients with haematologic malignancies: A national, prospective, and multicenter study","volume":"87","author":"Ramos","year":"2023","journal-title":"J. Infect."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1426","DOI":"10.1086\/587101","article-title":"When primary antifungal therapy fails","volume":"46","author":"Nucci","year":"2008","journal-title":"Clin. Infect. Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1621","DOI":"10.1093\/cid\/ciy473","article-title":"Breakthrough Invasive Mold Infections in the Hematology Patient: Current Concepts and Future Directions","volume":"67","author":"Lionakis","year":"2018","journal-title":"Clin. Infect. Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1093\/jac\/dkx423","article-title":"Impact of unresolved neutropenia in patients with neutropenia and invasive aspergillosis: A post hoc analysis of the SECURE trial","volume":"73","author":"Kontoyiannis","year":"2018","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Wiedermann, C.J. (2021). Hypoalbuminemia as Surrogate and Culprit of Infections. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22094496"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Austermeier, S., Pekmezovi\u0107, M., Porschitz, P., Lee, S., Kichik, N., Moyes, D.L., Ho, J., Kotowicz, N.K., Naglik, J.R., and Hube, B. (2021). Albumin Neutralizes Hydrophobic Toxins and Modulates Candida albicans Pathogenicity. mBio, 12.","DOI":"10.1128\/mBio.00531-21"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Pikoulas, A., Morianos, I., Nidris, V.N., Hamdy, R., L\u00f3pez-L\u00f3pez, A., Moran-Garrido, M., Halabalaki, M.M., Papadovasilaki, M., Irene, K., and Gu, Y. (2024). Albumin orchestrates a natural host defense mechanism against mucormycosis. Res. Sq., rs.3.rs-5441197.","DOI":"10.21203\/rs.3.rs-5441197\/v1"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"6782","DOI":"10.1128\/AAC.03641-14","article-title":"Impact of Hypoalbuminemia on Voriconazole Pharmacokinetics in Critically Ill Adult Patients","volume":"58","author":"Vanstraelen","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1955","DOI":"10.1182\/blood-2017-11-818286","article-title":"Early-onset invasive aspergillosis and other fungal infections in patients treated with ibrutinib","volume":"131","author":"Ghez","year":"2018","journal-title":"Blood"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Little, J.S., Weiss, Z.F., and Hammond, S.P. (2021). Invasive fungal infections and targeted therapies in hematological malignancies. J. Fungi, 7.","DOI":"10.3390\/jof7121058"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"ofac112","DOI":"10.1093\/ofid\/ofac112","article-title":"Noninvasive Testing and Surrogate Markers in Invasive Fungal Diseases","volume":"9","author":"Thompson","year":"2022","journal-title":"Open Forum Infect. Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1619","DOI":"10.1093\/cid\/cix130","article-title":"Changing Epidemiology of Invasive Mold Infections in Patients Receiving Azole Prophylaxis","volume":"64","author":"Lamoth","year":"2017","journal-title":"Clin. Infect. Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1093\/cid\/ciy260","article-title":"Breakthrough Invasive Fungal Infections on Isavuconazole Prophylaxis and Treatment: What Is Happening in the Real-World Setting?","volume":"67","author":"Fung","year":"2018","journal-title":"Clin. Infect. Dis."},{"key":"ref_31","first-page":"237","article-title":"Breakthrough invasive fungal diseases during voriconazole treatment for aspergillosis: A 5-year retrospective cohort study","volume":"55","author":"Kim","year":"2017","journal-title":"Med. Mycol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"O952","DOI":"10.1111\/1469-0691.12688","article-title":"Breakthrough invasive fungal disease in patients receiving posaconazole primary prophylaxis: A 4-year study","volume":"20","author":"Lerolle","year":"2014","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Lamoth, F., Lewis, R.E., and Kontoyiannis, D.P. (2020). Role and Interpretation of Antifungal Susceptibility Testing for the Management of Invasive Fungal Infections. J. Fungi, 7.","DOI":"10.3390\/jof7010017"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1086\/322970","article-title":"Counterpoint: Invasive aspergillosis and the environment--rethinking our approach to prevention","volume":"33","author":"Hajjeh","year":"2001","journal-title":"Clin. Infect. Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1007\/s15010-008-8129-5","article-title":"Occupation, lifestyle, diet, and invasive fungal infections","volume":"36","author":"Sipsas","year":"2008","journal-title":"Infection"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1023\/A:1020363010465","article-title":"Using Propensity Scores to Help Design Observational Studies: Application to the Tobacco Litigation","volume":"2","author":"Rubin","year":"2001","journal-title":"Health Serv. Outcomes Res. Methodol."}],"container-title":["Journal of Fungi"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2309-608X\/11\/9\/623\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:32:48Z","timestamp":1760034768000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2309-608X\/11\/9\/623"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,26]]},"references-count":36,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["jof11090623"],"URL":"https:\/\/doi.org\/10.3390\/jof11090623","relation":{},"ISSN":["2309-608X"],"issn-type":[{"value":"2309-608X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,26]]}}}