A retrospective single-center observational study conducted in Eastern China has evaluated the epidemiological patterns, risk factors, microbiological distributions, and therapeutic outcomes of breakthrough mucormycosis among recipients of hematopoietic stem cell transplantation. Published in Annals of Clinical Microbiology and Antimicrobials, the multiyear investigation examined 1,224 consecutive patients who underwent a total of 1,248 transplantation procedures between November 1, 2020, and October 31, 2024, at the First Hospital of the University of Science and Technology of China, with patient follow-up maintained through May 1, 2025. Across the entire cohort of patients receiving antifungal prophylaxis, mucormycosis was diagnosed in 49 individuals, corresponding to an overall cumulative incidence of 4.0 percent and an incidence density of 3.4 cases per 100 person-years, with a 95 percent confidence interval spanning 2.52 to 4.50 cases per 100 person-years, or 0.09 cases per 1,000 patient-days. The median follow-up period for surviving patients reached 18.0 months, while the median duration from transplantation to the confirmed or probable onset of mucormycosis stood at 73.0 days, highlighting the substantial clinical burden posed by this opportunistic invasive mold infection in post-transplant hematology recipients.
The study cohort displayed distinct underlying demographic and hematologic characteristics that contextualize the emergence of invasive fungal complications. Among the 1,224 transplant recipients, the median age at transplantation was 32 years, spanning an interquartile range of 13.3 to 48.4 years and an overall range from 0 to 69 years, with a male predominance representing 59.6 percent of the participants, or 729 of the 1,224 cases. The primary underlying hematologic conditions prompting transplantation comprised acute myeloid leukemia in 30.1 percent of patients, acute lymphoblastic leukemia in 17.0 percent, aplastic anemia in 14.5 percent, lymphoma in 11.5 percent, multiple myeloma in 10.5 percent, myelodysplastic syndrome in 10.4 percent, and other primary hematologic disorders in 6.0 percent. The vast majority of the interventions were allogeneic hematopoietic stem cell transplantations, which constituted 80.9 percent of all procedures, including 795 cord blood transplantations representing 80.3 percent of the allogeneic subgroup. Autologous procedures accounted for the remaining 234 transplant recipients. The observed distribution of mucormycosis differed across primary hematologic conditions, manifesting at a higher proportion among patients with myelodysplastic syndrome and at comparatively lower proportions among individuals with multiple myeloma and lymphoma.
Tracking the temporal trajectory of fungal manifestation revealed that breakthrough mucormycosis clustered predominantly within the early weeks and months following transplantation. Using Fine-Gray subdistribution hazard models to account for competing mortality risks, the researchers documented that the cumulative incidence reached 1.0 percent by post-transplantation day 30, 2.3 percent by day 100, 2.9 percent by day 180, 3.5 percent by day 365, and 4.2 percent by day 550. Of the 49 identified proven or probable cases, 57.1 percent occurred within the initial 100 days following transplantation, while 16.3 percent emerged between days 101 and 180, 14.3 percent occurred between days 181 and 365, and 12.2 percent manifested between days 366 and 550. The authors observed that this distribution aligned with a bimodal presentation pattern, wherein early-onset cases coincided with post-transplant neutropenia and peak conditioning-related immunosuppression, whereas late-onset episodes, developing beyond one year, arose primarily among individuals undergoing sustained immunosuppression for chronic graft-versus-host disease or managing disease relapse. At the specific time of fungal diagnosis, 24 of the 49 affected patients were neutropenic, exhibiting an absolute neutrophil count below 0.5 multiplied by 10 to the ninth power per liter, with a median neutropenia duration of 8.0 days.
Diagnostic adjudication classified 4 of the 49 patients as proven mucormycosis cases and 45 as probable cases in accordance with established European Organization for Research and Treatment of Cancer and Mycoses Study Group criteria supplemented by molecular sequencing methods. The 4 proven cases obtained definitive microbiological confirmation through histopathology performed on tissue biopsies obtained during bronchoscopy. In contrast, among the 45 probable cases, 8 were documented via positive fungal culture, of which 4 received supplementary metagenomic next-generation sequencing support from bronchoalveolar lavage fluid or plasma; one case was verified by direct microscopy of skin secretion accompanied by plasma metagenomic sequencing; and the remaining 36 cases were identified solely through metagenomic next-generation sequencing, including 29 plasma samples, 6 bronchoalveolar lavage fluid specimens, and one cerebrospinal fluid sample. In total, 51 distinct Mucorales isolates were recovered across the cohort. Anatomically, pulmonary involvement represented the predominant clinical presentation, occurring in 75.5 percent of the cases, followed by disseminated disease affecting two or more non-contiguous anatomical sites in 16.3 percent, rhinocerebral infection in 6.1 percent, and primary cutaneous infection in 2.0 percent.
Taxonomic classification of the 51 recovered fungal isolates revealed considerable genus and species diversity across the cohort. At the genus level, Rhizopus species predominated, accounting for 37.3 percent of the recovered isolates, followed by Cunninghamella species at 31.4 percent, Rhizomucor species at 27.5 percent, and unclassified Mucorales isolates representing 3.9 percent. Species-level identification was successfully achieved in 46 of the 51 isolates, demonstrating that Cunninghamella elegans and Rhizomucor pusillus each represented 23.5 percent of the total, while Rhizopus microsporus constituted 21.6 percent. Notably, typical Mucor species were not identified in this cohort, diverging from earlier international reports where Mucor species frequently ranked second following Rhizopus. Furthermore, the investigators observed significant variation in patient outcomes based on genus-level taxonomy, as infections caused by Cunninghamella species demonstrated a significantly higher mortality rate of 73.3 percent compared to the 48.6 percent mortality observed among infections attributed to other Mucorales genera. Concurrent non-Mucorales infections were documented in 81.6 percent of patients, with viral pathogens detected in 59.2 percent, including human herpesvirus 6B in 26.5 percent and cytomegalovirus in 20.4 percent, while Aspergillus co-infections were verified in 6 patients.
Antifungal prophylaxis regimens administered across the center exhibited distinct prescribing patterns depending on the transplant type. Among the 990 allogeneic transplant recipients, voriconazole served as the predominant prophylactic agent in 56.7 percent of patients, followed by posaconazole in 27.0 percent, with plasma trough levels monitored to maintain defined therapeutic thresholds. In contrast, oral fluconazole was administered to 86.8 percent of the 234 autologous transplant recipients. Breakthrough mucormycosis occurred almost exclusively within the allogeneic transplantation cohort, involving 46 patients, whereas only one breakthrough episode occurred following autologous transplantation in a patient receiving fluconazole on day 7. Within the allogeneic cohort, breakthrough mucormycosis developed in 5.7 percent of patients receiving voriconazole, with a median onset of 70.5 days post-transplantation, compared with 4.1 percent of patients receiving posaconazole, with a median onset of 94 days, and 3.0 percent of recipients receiving other agents. Although breakthrough infections occurred more frequently and earlier among voriconazole recipients than among those on posaconazole, this numerical difference did not achieve statistical significance, yielding a p-value of 0.400. In addition, two patients developed delayed mucormycosis following the planned cessation of posaconazole prophylaxis at a median of 119 days post-transplantation.
Multivariate survival modeling identified specific clinical characteristics that independently increased the hazard of developing breakthrough mucormycosis among allogeneic transplant recipients. Univariable Cox proportional hazards regression initially indicated significant associations between mucormycosis and myelodysplastic syndrome, pre-existing diabetes mellitus, chronic hepatitis B infection, prior invasive fungal infection, severe acute graft-versus-host disease, and steroid-refractory acute graft-versus-host disease. However, upon incorporating these variables into the final multivariable competing risks model, independent statistical significance was retained by three primary factors: underlying myelodysplastic syndrome, which conferred an adjusted hazard ratio of 2.65 with a p-value of 0.003; a history of prior invasive fungal infection, yielding an adjusted hazard ratio of 2.33 with a p-value of 0.010; and severe acute graft-versus-host disease, which generated an adjusted hazard ratio of 2.96 with a p-value of 0.002. Borderline associations were noted for diabetes mellitus with an adjusted hazard ratio of 2.04 and steroid-refractory acute graft-versus-host disease with an adjusted hazard ratio of 1.97, whereas chronic hepatitis B and conditioning regimen intensity showed no independent statistical association in the adjusted analysis.
The biological rationale underlying these independent risk predictors highlights the convergent mechanisms of immune dysfunction and tissue barrier compromise in susceptible hosts. In patients with myelodysplastic syndrome, chronic dysregulation within the bone marrow microenvironment, frequent transfusion-related iron overload, and abnormal activation of the NLRP3 inflammasome are recognized to compromise host immune defenses while creating favorable biochemical conditions for fungal proliferation. Excess serum iron supplies essential growth factors for Mucorales hyphae and induces oxidative damage that impairs neutrophil and macrophage phagocytosis. Concurrently, severe acute graft-versus-host disease and its associated intensified immunosuppressive therapies lead to profound, sustained T-cell depletion and mucosal barrier disruption, creating opportunities for angioinvasive mold penetration. Similarly, a documented history of prior fungal disease signals pre-existing tissue vulnerability and impaired mucosal architecture, rendering patients susceptible to recurrent or breakthrough opportunistic fungal invasions when subsequent post-transplantation immunosuppression suppresses residual cellular immunity.
Therapeutic interventions for diagnosed mucormycosis relied primarily on systemic amphotericin B formulations, with survival rates tracked across standardized post-diagnosis timepoints. Among the 49 diagnosed patients, 43 received systemic antifungal therapy within 48 hours of diagnosis, achieving an overall 42-day survival rate of 60.4 percent and an 84-day survival rate of 46.5 percent. The remaining 6 patients did not receive targeted antifungal therapy due to rapid death prior to diagnosis or severe financial constraints, and all 6 died within 42 days. First-line antifungal therapy in 35 treated patients predominantly involved amphotericin B formulations, comprising amphotericin B colloidal dispersion in 48.6 percent of cases at dosages between 1.0 and 3.0 milligrams per kilogram daily, amphotericin B deoxycholate in 40.0 percent at dosages between 0.7 and 2.0 milligrams per kilogram daily, and liposomal amphotericin B in 11.4 percent at dosages between 2.0 and 6.0 milligrams per kilogram daily. Combination antifungal therapy was administered to 79.1 percent of treated patients, combining amphotericin B most frequently with isavuconazole or posaconazole for a median intravenous duration of 22.5 days. Although combination therapy with posaconazole or isavuconazole demonstrated an 84-day mortality rate of 42.3 percent compared to 80.0 percent with amphotericin B monotherapy, this difference did not reach statistical significance, yielding a p-value of 0.172. Multivariable logistic regression revealed that severe acute graft-versus-host disease independently predicted patient mortality with an odds ratio of 6.15.
The study authors highlighted several methodological considerations and clinical constraints that contextualize their findings. Histopathological verification was achieved in only 8.2 percent of cases, reflecting the clinical difficulty and bleeding risks of obtaining invasive tissue biopsies in profoundly thrombocytopenic transplant recipients. Consequently, 73.4 percent of the cases were classified as probable mucormycosis based solely on metagenomic next-generation sequencing, an approach reflecting contemporary real-world diagnostic practice in China that may contribute to differences in reported incidence compared to centers strictly adhering to standard mycological cultures. Furthermore, surgical debridement was not performed in this cohort due to severe thrombocytopenia, coagulopathy, and poor general systemic status, precluding an evaluation of combined surgical and medical intervention. Economic and availability constraints during the study period also influenced pharmacotherapy, as liposomal amphotericin B received regulatory approval in China in early 2023 and carried high costs, prompting reliance on conventional formulations and lower median dosages of 2.0 milligrams per kilogram daily. The researchers noted that these single-center retrospective observations warrant validation through future multicenter prospective investigations to refine risk-stratified prophylaxis and standardize molecular diagnostic protocols.
Subject of Research: Epidemiological and clinical characterization of breakthrough mucormycosis in post-transplant patients
Article Title: Breakthrough mucormycosis after hematopoietic stem cell transplantation: a retrospective multiyear cohort study in Eastern China
Article References: Luo, J., Song, K., Tang, B., Wan, X., Yao, W., Sun, G., Yuan, K., Qiang, P., & Zhu, X. (2026). Breakthrough mucormycosis after hematopoietic stem cell transplantation: a retrospective multiyear cohort study in Eastern China. Annals of Clinical Microbiology and Antimicrobials, 25(1), Article 27. https://doi.org/10.1186/s12941-026-00862-7
Image Credits: AI Generated
DOI: 10.1186/s12941-026-00862-7
Keywords: mucormycosis, hematopoietic stem cell transplantation, metagenomic next-generation sequencing, fungal infections, antifungal prophylaxis, graft-versus-host disease, amphotericin B, Rhizopus, Breakthrough, hematopoietic, stem, cell
News Source: Drew Townsend. (November 10, 2026). Study Analyzes Breakthrough Mucormycosis Patterns After Stem Cell Transplantation in Eastern China. Scienmag.
