Breakthrough Mucormycosis After Hematopoietic Stem Cell Transplantation: A Retrospective Multiyear Cohort Study in Eastern China

Breakthrough Mucormycosis After Hematopoietic Stem Cell Transplantation: A Retrospective Multiyear Cohort Study in Eastern China | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Breakthrough Mucormycosis After Hematopoietic Stem Cell Transplantation: A Retrospective Multiyear Cohort Study in Eastern China Junjie Luo, Kaidi Song, Baoling Tang, Xiang Wan, Wen Yao, Guangyu Sun, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8122974/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Background This study aimed to update the epidemiology and clinical characteristics of mucormycosis, a rare but life-threatening invasive fungal infection in hematopoietic stem cell transplantation (HSCT) recipients. Methods We conducted a retrospective, single-center observational study including all consecutive HSCT recipients from November 2020 to October 2024, with follow-up through May 2025. Results Among 1,224 HSCT recipients receiving antifungal prophylaxis, mucormycosis occurred at an incidence density of 3.40 per 100 person-years, with a median onset of 73 days post-transplant (interquartile range, 30–223 days). Pulmonary involvement was present in 75.5% of cases. Rhizopus spp. accounted for the highest proportion (37.3%) among the isolated fungal genera. Multivariate analysis identified myelodysplastic syndrome (adjusted hazard ratio [aHR] = 2.65), prior fungal infection (aHR = 2.33), and severe acute graft-versus-host disease (aGvHD) (aHR = 2.97) as independent risk factors. Among 43 patients treated with antifungals, the 84-day survival rate was 46.5%. Severe aGvHD was an independent predictor of mortality. Combination therapy with amphotericin B plus posaconazole or isavuconazole tended to reduce treatment failure compared to amphotericin B alone (42.3% vs. 80.0%; P = 0.172). Conclusions Mucormycosis poses a serious risk post-HSCT; early identification and optimized treatment are critical to improving outcomes. Mucormycosis Hematopoietic stem cell transplantation Breakthrough infection Risk factors Antifungal prophylaxis Figures Figure 1 Figure 2 Introduction Despite substantial advances in antifungal therapies, mucormycosis, once considered rare, has increasingly emerged as a significant clinical challenge among hematopoietic stem cell transplantation (HSCT) recipients, with mortality frequently exceeding 40% despite intensive antifungal treatment and surgical interventions [ 1 – 3 ]. The rising incidence of mucormycosis can be attributed to several interrelated factors. These include the expanding population of HSCT recipients and other immunocompromised individuals, the extensive use of antifungal prophylaxis with limited efficacy against Mucorales , and the growing utilization of advanced diagnostic modalities, such as metagenomic next-generation sequencing (mNGS) [ 4 – 6 ]. Moreover, the COVID-19 pandemic, along with its widespread application of immunosuppressive therapies, has further contributed to the escalation of this trend [ 7 , 8 ]. The 2017 ECIL-6 and 2019 global guidelines underscore the critical role of early diagnosis, individualized management strategies, and multidisciplinary care in improving mucormycosis outcomes for this high-risk patient population [ 9 , 10 ]. The clinical manifestations of mucormycosis in HSCT recipients are frequently atypical and rapidly progressive, posing major challenges for timely recognition. Conventional diagnostic approaches—histopathology, microscopy, and culture—are often limited by suboptimal sensitivity, prolonged turnaround times, and the need for invasive tissue sampling, which is particularly challenging in hematologic patients. In recent years, mNGS has emerged as a valuable, noninvasive diagnostic adjunct, enabling unbiased detection of Mucorales DNA directly from clinical specimens. In China, mNGS has been increasingly applied in clinical practice and has demonstrated substantial utility for pathogen identification. Although not yet incorporated into the EORTC/MSGERC criteria, multiple studies support its diagnostic value and recommend its use as a supplementary microbiological tool for invasive fungal infections [ 11 – 13 ]. Despite growing awareness, large-scale epidemiological data on mucormycosis in HSCT recipients remain limited, particularly in Asian populations. Moreover, the impact of emerging risk factors—such as novel immunosuppressive regimens—as well as the clinical efficacy of newer antifungal agents, such as isavuconazole (ISA), has not been systematically evaluated.This study provides a comprehensive evaluation of the epidemiological characteristics, risk factors, pathogen distribution, and treatment outcomes of mucormycosis among HSCT recipients. The findings aim to inform optimized management strategies and improve clinical outcomes in this high-risk population. Methods Patients and data collection This study was designed as a retrospective, observational, single-center analysis. Between November 1, 2020, and October 31, 2024, all consecutive patients who were hospitalized and underwent HSCT at the First Hospital of the University of Science and Technology of China (USTC) were included to assess the occurrence of mucormycosis. For each HSCT recipient, clinical and treatment-related data were extracted from electronic medical records. Collected variables included demographic characteristics (age and sex), primary disease, disease remission status at transplantation, pre-existing comorbidities, graft type, incidence and management of graft-versus-host disease (GvHD), post-transplant disease progression, antifungal prophylaxis, antifungal treatment, survival status, and cause of death. Follow-up continued through May 1, 2025. During this period, 221 patients died, and the remainder were alive. The median follow-up time for survivors was 18.0 months (interquartile range [IQR], 16.7–18.0 months), with a minimum follow-up of 6.0 months and a maximum of 18.0 months post-transplantation. Among the 221 patients who died, the median time to death was 3.7 months (IQR, 2.0–6.2 months). Diagnosis The diagnosis of mucormycosis was established through a combination of clinical, radiological, and microbiological findings. Cases were categorized as proven or probable according to the revised EORTC/MSGERC criteria, while possible cases were excluded. In this study, mNGS was additionally accepted as a supplementary microbiological criterion for probable cases, provided contamination was rigorously excluded [1 4- 1 6 ] . (A) Proven mucormycosis: A definitive diagnosis requires confirmation by histopathology, direct microscopy, and/or culture of Mucorale s from a sterile site. (B) Probable mucormycosis: This category is based on a combination of host factors, clinical manifestations, radiological features, and microbiological evidence. Microbiological evidence: Criteria include (1) detection of Mucorales by culture or direct microscopy from non-sterile specimens (e.g., sputum, pus) with strong clinical correlation and strict exclusion of contamination, or (2) identification of Mucorales by mNGS from sterile or non-sterile fluids (e.g., bronchoalveolar lavage fluid [BALF], plasma, cerebrospinal fluid [CSF]) after rigorous exclusion of contamination. Antifungal Prophylaxis All HSCT recipients received antifungal prophylaxis, including both primary and secondary regimens, for at least 3 months after transplantation. Additionally, allogeneic HSCT (allo-HSCT) recipients received universal prophylaxis against Pneumocystis jirovecii pneumonia with oral sulfamethoxazole/trimethoprim. allo-HSCT: Primary antifungal prophylaxis for allo-HSCT recipients was implemented using mold-active azoles, mainly voriconazole (VCZ) or posaconazole (POS). Three POS formulations were used—oral suspension, delayed-release tablets, and intravenous injection. Serum POS levels remain stable with the latter two formulations, whereas therapeutic drug monitoring (TDM) is recommended for the oral suspension, with at least one serum concentration measurement targeting ≥0.5 mg/L. Similarly, VCZ dosing was personalized through routine TDM to achieve and sustain trough concentrations within an optimal target range of 1–5 μg/mL.The choice of antifungal agent and administration route was determined by the attending physician based on clinical condition and financial considerations. Autologous HSCT (auto-HSCT): Primary antifungal prophylaxis for auto-HSCT recipients was administered using fluconazole (FLU) or VCZ. Secondary anti‑fungal prophylaxis: for HSCT recipients requiring secondary antifungal prophylaxis due to a prior invasive fungal disease, the selection of an antifungal agent is dictated by the prior therapeutic response. The preferred choice is the specific drug, or its drug class, that demonstrated clinical efficacy during the initial treatment course. GVHD prophylaxis in allo-HSCT recipients 1. Cord blood transplantation (CBT): Patients undergoing CBT received a combination of cyclosporine A (CsA) and mycophenolate molate (MMF), administered intravenously or orally, without anti-thymocyte globulin (ATG). The target trough level for CsA was maintained between 250 and 350 μg/L. For patients with malignant hematological diseases and without manifestations of GVHD, CsA tapering was initiated at 2 months post-transplant, with complete discontinuation targeted between 3 and 6 months. In contrast, for recipients with non-malignant diseases, such as aplastic anemia, the CsA course was extended, with tapering beginning after 6 months and aiming for cessation within one year post-transplant. 2. Matched sibling donor HSCT (MSD-HSCT) and haploidentical donor HSCT (haplo-HSCT): For patients undergoing MSD-HSCT or haplo-HSCT, the base GVHD prophylaxis regimen consisted of CsA and MMF. At the physician's discretion, this backbone regimen could be supplemented with an additional agent, such as rabbit anti-thymocyte globulin, post-transplant cyclophosphamide, or a short-course of methotrexate. Definitions Breakthrough infection was defined as the occurrence of proven or probable mucormycosis during systemic antifungal exposure, irrespective of the prophylactic agent’s activity against Mucorales . Disseminated infection was defined as mucormycosis involving 2 or more non-contiguous sites. Unclassified Mucorales were defined as Mucorales isolates for which species-level identification was not possible; in such cases, the isolates were assigned to the genus level or designated as “unclassified Mucorales ”. Steroid-refractory acute graft-versus-host disease (SR-aGVHD) was defined as acute graft-versus-host disease that fails to respond to adequate systemic corticosteroid therapy. Specifically, it includes: primary SR-aGVHD, characterized by progression of aGVHD after 3–5 days of treatment with methylprednisolone at ≥2 mg/kg/day (or equivalent), or lack of improvement after 5–7 days of therapy; and secondary SR-aGVHD, characterized by recurrence or flare of aGVHD during steroid taper, indicating resistance despite initial response [ 17 ] . Statistical analysis Statistical analyses were conducted using R, SPSS, or SAS, in accordance with STROBE guidelines. Continuous variables were presented as mean ± standard deviation or median with interquartile range (IQR), depending on the results of normality testing (Shapiro–Wilk test). Group comparisons were performed using Welch’s t-test for normally distributed data or the Mann–Whitney U test for non-parametric distributions. Categorical variables were summarized as frequencies and percentages, and compared using the chi-square or Fisher’s exact test, with statistical significance defined as P < 0.05. Cohorts with fewer than five events per variable were excluded from multivariable models to maintain model robustness. The incidence of mucormycosis was calculated as the number of events per 100 patient-years. Cumulative incidence estimates were generated using Fine–Gray subdistribution hazard models to account for competing risks, including non-mucormycosis-related mortality and loss to follow-up. Temporal patterns of infection were stratified by post-transplantation intervals and compared using Gray’s test. Cox proportional hazards models were applied to identify potential risk factors using both univariable and multivariable competing risks analyses. Variables that reached statistical significance in the univariable analysis ( P < 0.05) were subsequently included in the final multivariable model. Time-dependent covariates were incorporated through landmark analysis, with day 100 post-transplantation designated as the reference time point. Logistic regression was performed to evaluate factors associated with long-term (12-week) mortality. Results 1. Sample collection and patient baseline characteristics Between November 2020 and October 2024, a total of 1,224 consecutive patients underwent 1,248 HSCTs at our center, including 24 patients who received a second transplant. The median age at transplantation was 32 years (IQR, 13.3–48.4; range, 0–69 years), with a predominance of male patients (729/1,224, 59.5%). The distribution of underlying hematologic diseases was as follows: acute myeloid leukemia (30.1%, 368/1,224), acute lymphoblastic leukemia (17.0%, 208/1,224), aplastic anemia (14.5%, 177/1,224), lymphoma (11.5%, 141/1,224), multiple myeloma (MM, 10.5%, 129/1,224), myelodysplastic syndrome (MDS, 10.4%, 127/1,224), and other primary disease (6.0%, 74/1,224). Notably, the incidence of mucormycosis differed significantly across disease subgroups, with a higher rate observed in patients with MDS and lower rates among those with MM and lymphoma compared with other hematologic disorders ( P < 0.05). Allo-HSCT constituted the majority of procedures (990/1,224, 80.9%), with CBT employed in 795 (80.3%) of these cases. During the observation period, mucormycosis was diagnosed in 49 patients (4.0%), including 4 (8.2%) proven and 45 (91.8%) probable cases. The baseline characteristics of HSCT recipients with and without mucormycosis are detailed in Table 1 (to be placed at the end of the manuscript). 2.Infection epidemiology of mucormycosis The overall incidence density of mucormycosis was 3.40 cases per 100 person-years (95% CI: 2.52–4.50), equivalent to 0.09 cases per 1,000 patient-days. The cumulative incidence increased over time, reaching 1.0% by day 30, 2.3% by day 100, 2.9% by day 180, 3.5% by day 365, and 4.2% by day 550 (Figure 1A). The median time from transplantation to mucormycosis diagnosis was 73 days (IQR, 30–223). Among the 49 proven or probable cases, 59.2% (29/49) occurred within the first 100 days post-transplantation, followed by 16.3% (8/49) between days 101 and 180, 14.3% (7/49) between days 181 and 365, and 12.2% (6/49) between days 366 and 550. The temporal distribution of cases demonstrated a significant concentration during the early post-transplantation period, with statistically significant differences observed across the defined time intervals ( P < 0.05). 3. Diagnosis Methods and Infection Characteristics Among the 49 patients with mucormycosis, 4 were classified as proven cases based on histopathological confirmation from bronchoscopic biopsy, whereas the remaining 45 were categorized as probable cases. Of these, 8 cases were culture-positive, with additional mNGS support in 4 (3 BALF, 1 plasma); 1 case was diagnosed by direct microscopy of skin secretion supported by plasma mNGS, and the remaining 36 were identified solely by mNGS (1 CSF, 6 BALF, and 29 plasma samples). A total of 51 Mucorales isolates were recovered. At the genus level, Rhizopus spp. predominated (37.3%, 19/51), followed by Cunninghamella spp. (31.4%, 16/51) and Rhizomucor spp. (27.5%, 14/51), with 2 isolates (3.9%) unclassified (Figure 1B). At the species level, identification was achieved in 46 isolates (90.2%), with Cunninghamella elegans (23.5%, 12/51), Rhizomucor pusillus (23.5%, 12/51), and Rhizopus microsporus (21.6%, 11/51) being the most prevalent (Figure 1C). Regarding the site of infection, pulmonary mucormycosis was the most prevalent presentation (75.5%, 37/49), followed by disseminated (16.3%, 8/49), rhinocerebral (6.1%, 3/49), and cutaneous forms (2.0%, 1/49) (Figure 1D). Concurrent non- Mucorales infections occurred in 81.6% (40/49) of patients, with viral pathogens detected in 59.2% (29/49), including human herpesvirus 6B (26.5%, 13/49) and cytomegalovirus (20.4%, 10/49). Among other fungal co-infections, Aspergillus spp. were the most common, identified in 6 patients. 4.Antifungal prophylaxis and breakthrough infections Distinct antifungal prophylaxis patterns were observed across transplant types (Table 1). Among allo-HSCT recipients (n = 990), VCZ was the predominant agent (56.7%), followed by POS (27.0%), whereas FLU was administered in 86.8% of auto-HSCT recipients (n = 234). Breakthrough mucormycosis occurred in 46 allogeneic recipients, with the highest incidence observed in VCZ recipients (5.7%, 32/561; median onset 70.5 days post-transplant), followed by POS (4.1%, 11/267; median onset 94 days post-transplant) and other agents (3.0%, 3/101; median onset 67 days post-transplant); no cases were reported in the FLU group. Two patients developed delayed infection after discontinuation of POS prophylaxis (median onset, 119 days post-transplant). In contrast, only one breakthrough infection occurred in the auto-HSCT cohort (0.5%, 1/203), in a FLU recipient on day 7 post-transplantation. Within the allo-HSCT cohort, breakthrough mucormycosis tended to occur more frequently and earlier in VCZ recipients than in those receiving POS (5.7% vs. 4.1%; median onset 70.5 vs. 94 days post-transplant), although the difference did not reach statistical significance (P = 0.400). Table 1. Baseline characteristics of HSCT recipients with and without mucormycosis Variable Mucormycosis (n = 49) Non-mucormycosis (n = 1175) Total (n = 1224) Demographics Age, median (IQR), years 33 (17.5–48.3) 32 (13.0–48.6) 32 (13.3–48.4) Male sex, No. (%) 31 (63.3) 698 (59.4) 729 (59.6) Underlying disease, No. (%) AML 17 (34.7) 351 (29.9) 368 (30.1) ALL 7 (14.3) 201 (17.1) 208 (17.0) AA 8 (16.3) 169 (14.4) 177 (14.5) Lymphoma 1 (2.0) 140 (11.9) 141 (11.5) MM 1 (2.0) 128 (10.9) 129 (10.5) MDS 14 (28.6) 113 (9.6) 127 (10.4) Others 2 (4.1) 72 (6.1) 74 (6.0) Transplant Type a , No. (%) Allogeneic HSCT 48 (98.0) 942 (80.2) 990 (80.9) CBT 33 (67.3) 762 (64.9) 795 (64.9) MD-HSCT 10 (20.4) 99 (8.4) 109 (8.9) Haplo-HSCT 5 (10.2) 81 (6.9) 86 (7.0) Autologous HSCT 1 (2.0) 233 (19.8) 234 (19.1) Stem Cell Source, No. (%) Allogeneic HSCT Umbilical cord blood 34 (69.4) 761 (64.8) 795 (65.0) PBSC 14 (28.6) 178 (35.0) 192 (15.7) Other b - 3 (0.2) 3 (0.2) Autologous HSCT PBSC 1 (2.0) 233 (19.8) 234 (19.1) Neutrophil engraftment, median (IQR), days, No. (%) Allogeneic HSCT 16 (14.0–18.8) 15 (13.0–18.0) 15 (13.0–18.0) CBT 18 (14.0–20.3) 16 (14.0–19.0) 16 (14.0–19.0) MD-HSCT 15 (11.3–16.0) 12 (10.5–13.0) 12 (10.5–13.0) Haplo-HSCT 16 (15.8–16.5) 16 (14.0–18.8) 14 (13.0–16.0) Autologous HSCT 1 c 9 (10.0–11.0) 9 (10.0–11.0) Allogeneic HSCT (n = 990) Autologous HSCT (n = 234) Antifungal prophylaxis, No. (%) Mucormycosis (n = 48) Non-mucormycosis (n = 942) Mucormycosis (n = 1) Non-mucormycosis (n = 233) Posaconazole 11 (22.9) 256 (27.2) 0 (0.0) 2 (0.9) Voriconazole 32 (66.7) 529 (56.2) 0 (0.0) 27 (11.6) Fluconazole 0 (0.0) 59 (6.3) 1 (100.0) 202 (86.7) Other agents 3 (6.3) 98 (10.4) 0 (0.0) 2 (0.9) Delayed infection after prophylaxis discontinuation d 2 (4.2) – – – a For patients whose first HSCT failed engraftment and who subsequently underwent a second HSCT, the transplant type in this table is recorded according to the second transplantation. No patient underwent a third HSCT. b Combined peripheral blood stem cells (PBSC) and bone marrow (n = 1); PBSC and cord blood (n = 2). c Only one case in the autologous HSCT group; IQR not available. d Delayed infection after prophylaxis discontinuation refers to two patients who developed mucormycosis after premature discontinuation of antifungal prophylaxis (median onset, 119 days post-transplant; range, 60–178 days). Abbreviations: IQR, interquartile range; AML, acute myelocytic leukemia; ALL, acute lymphoblastic leukemia; AA, aplastic anemia; MM, multiple myeloma; MDS, myelodysplastic syndrome; HSCT, hematopoietic stem cell transplantation; MD-HSCT, matched donor HSCT (including both matched sibling donors and matched unrelated donors); Haplo-HSCT, haploidentical donor HSCT; CBT, cord blood transplantation; PBSC, peripheral blood stem cells. 5.Risk factors of mucormycosis Given the low incidence of mucormycosis among auto-HSCT recipients, the risk factor analysis was restricted to allo-HSCT recipients. In univariable Cox regression, several factors were significantly associated with mucormycosis, including: MDS (hazard ratio [HR] = 2.97, P < 0.001), diabetes mellitus (HR = 2.87, P = 0.004), chronic hepatitis B (HR = 2.88, P = 0.043), prior invasive fungal infection (HR = 2.88, P = 0.001), severe acute GvHD (HR = 4.57, P < 0.001), and SR-aGVHD (HR = 3.34, P < 0.001). In multivariable analysis, MDS (adjusted hazard ratio [aHR] = 2.65, P = 0.003), prior fungal infection (aHR = 2.33, P = 0.010), and severe acute GvHD (aHR = 2.97, P = 0.001) remained independent predictors. Diabetes mellitus (aHR = 2.05, P = 0.062) and SR-aGVHD (aHR = 1.97, P = 0.061) showed a borderline association, while chronic hepatitis B (aHR = 2.32, P = 0.122) were not statistically significant. Further analyses of additional risk factors are presented in Figure 2, with detailed results in Supplementary Table 1. 6. Treatment outcomes and prognostic factors Among the 49 patients diagnosed with mucormycosis, 43 (87.8%) received systemic antifungal therapy within 48 hours of diagnosis, achieving 42-day and 84-day survival rates of 64.6% (26/43) and 46.5% (20/43), respectively. The remaining six patients did not receive antifungal treatment and all subsequently died from the infection. First-line treatment predominantly comprised amphotericin B formulations (AmB), including amphotericin B deoxycholate (AmBD, 40.0%, 14/35; dose range: 0.7–2 mg/kg/day), liposomal amphotericin B (L- AmB, 11.4%, 4/35; dose range: 2–6 mg/kg/day), and amphotericin B colloidal dispersion (ABCD, 48.6%, 17/35; dose range: 1–3 mg/kg/day). Combination antifungal therapy was administered in 79.1% (34/43) of cases, most frequently in conjunction with ISA (35.3%, 12/34) or POS (29.4%, 10/34). Treatment regimens are detailed in Table 2. The median duration of intravenous antifungal therapy during hospitalization was 22.5 days (range, 2–90). While the differences were not statistically significant, combination therapy was associated with a reduced 84-day mortality compared to monotherapy (50.0% [17/34] vs. 66.7% [6/9]; P = 0.100). A similar non-significant trend when comparing AmB combined with POS or ISA versus AmB monotherapy (42.3% [11/26] vs. 80.0% [4/5]; P = 0.172). Multivariable logistic regression analysis identified severe acute GvHD as an independent predictor of mortality (odds ratio [OR] = 6.15, P = 0.013) (Table 3). Table 2. Antifungal treatment regimens and 84-day mortality in 49 patients with mucormycosis Treatment Number of patients (%) Deaths at 84 days (%) Monotherapy 9 (18.4%) 6 (66.7%) AmB 5 (10.2%) 4 (80.0%) ISA 2 (4.1%) 1 (50.0%) POS 2 (4.1%) 1 (50.0%) Combination therapy 34 (69.4%) 17 (50.0%) AmB + POS/ISA 26 (53.1%) 11 (42.3%) AmB + POS 10 (20.4%) 4 (40.0%) AmB + ISA 12 (24.5%) 5 (41.7%) AmB + POS/ISA (adjusted) 4 (8.2%) 2 (50.0%) Other antifungal combinations 8 (16.3%) 6 (75.0%) AmB + Voriconazole 4 (8.2%) 3 (75.0%) AmB + Caspofungin 1 (2.0%) 1 (100.0%) ISA + Caspofungin 2 (4.1%) 2 (100.0%) POS + Caspofungin 1 (2.0%) 0 (0.0%) Untreated 6 (12.2%) 6 (100.0%) AmB includes liposomal amphotericin B, amphotericin B colloidal dispersion, and amphotericin B deoxycholate. Abbreviations: AmB, amphotericin B; POS, posaconazole; ISA, isavuconazole. Table 3. Univariate and multivariable logistic regression analyses of risk factors for mortality in patients with mucormycosis Factors Univariate analysis Multivariable analysis P OR 95% CI P OR 95% CI Infection factors Infection site (disseminated vs. other) 0.118 5.73 0.64-50.97 Microbiology Cunninghamella species 0.058 4.00 0.96-16.76 Rhizopus species 0.884 0.92 0.29-2.95 Rhizomucor species 0.064 0.74 0.08-0.94 Host factors Myeloablative conditioning regimen 0.175 2.68 0.65-11.13 Delayed neutrophil recovery (>15 days )a 0.801 1.16 0.37-3.66 Severe acute GVHD ( Grade III–IV) 0.002 8.89 2.31-34.25 0.013 6.15 1.48-25.58 steroid-refractory aGVHD 0.005 6.13 1.74-21.51 0.222 2.51 0.57-10.97 Primary disease not in remission 0.644 0.76 0.24-2.40 ATG-containing regimens 0.485 1.504 0.48-4.728 Treatment factors Monotherapy 0.378 2.00 0.43-9.33 Combined antifungals therapy 0.378 0.50 0.11-2.33 a Delayed neutrophil recovery was defined as time to neutrophil engraftment exceeding the cohort median (15 days). Abbreviations: OR, odds ratio; CI, confidence interval; GvHD, graft-versus-host disease; PES, pre-engraftment syndrome; ATG, anti-thymocyte globulin. DISCUSSION In this large retrospective cohort of HSCT recipients in China,, we provide a contemporary, region-specific characterization of mucormycosis: an incidence density of 3.40 per 100 person-years, a predominance of pulmonary disease, and a concentration of cases early after transplantation. The markedly higher risk after allogeneic versus autologous transplantation (aHR = 11.75) derscores the profound impact of allogeneic immune reconstitution, conditioning-related tissue injury, and prolonged immunosuppressive therapy on host susceptibility to invasive Mucorales infection. Within this context, severe immune complications—particularly severe acute GVHD (aHR = 2.97)—together with disease-specific vulnerabilities such as MDS (aHR = 2.65) and prior invasive fungal infection (aHR = 2.33), emerged as independent predictors. These findings highlight a multifactorial interplay between cumulative immune deficits, tissue barrier disruption, and local microenvironmental alterations that collectively create a permissive niche for fungal invasion [18-20] . Although chronic hepatitis B attained significance in univariable analysis, it did not persist after multivariable adjustment; mechanistic links (for example, HBV-associated CD8 + T-cell dysfunction and PD-L1-mediated immune suppression) remain biologically plausible but require prospective validation [21, 22] . The temporal pattern of cases was bimodal: most events clustered within the first 100 days—a period characterized by neutropenia and peak immunosuppressive exposure —whereas a smaller fraction of late-onset infections (>1 year) occurred in patients with relapsed disease or prolonged immunosuppression for chronic GVHD. This distinction suggests different predominant pathogenic pathways (treatment-related vulnerability versus cumulative immune dysfunction and environmental exposure) and argues for time-adapted surveillance and prophylactic strategies. Despite widespread use of antifungal prophylaxis, breakthrough mucormycosis developed in 3.8% (47/1,224) of patients, nearly all within the allogeneic HSCT cohort. Within this cohort, breakthrough infection occurred more frequently and earlier among VCZ recipients compared with POS (5.7% vs. 4.1%; median onset, 70.5 vs. 94 days), consistent with the lack of anti- Mucorales activity of VCZ and suggesting an ecological shift that favors Mucorales colonization [23, 24] . Although POS is considered a more effective prophylactic agent, breakthrough infections still occurred, likely due to variable drug absorption, subtherapeutic serum levels, or host-related factors impairing antifungal efficacy. These findings underscore the need for individualized prophylaxis and therapeutic drug monitoring to optimize protection against mucormycosis in high-risk HSCT recipients. Furthermore, mNGS provided species-level identification within the Mucorales order, which has increasing clinical relevance [25, 26] . In our cohort, 91.8% of patients underwent mNGS in combination with conventional diagnostics. Rhizopus spp. was the most frequently detected species, followed by Cunninghamella spp. and Rhizomucor spp. , while Mucor spp. was not identified, This distribution differs from prior reports, which ranked Rhizopus spp. first and Mucor spp. second among hematologic malignancy cases [27] . The divergence may reflect genuine shifts in species prevalence, enhanced detection accuracy with mNGS, geographic variation, or reporting bias. Notably, infections caused by Cunninghamella spp. were associated with significantly higher mortality rates compared to those caused by other Mucorales species (73.3% vs. 48.6%, P < 0.05), highlighting interspecies variation in virulence and antifungal susceptibility. Additionally, mNGS revealed co-infections with bacterial, viral, or other fungal pathogens in 77.6% of cases, emphasizing its value in guiding comprehensive antimicrobial management strategies. In the treatment of mucormycosis, AmB remains the guideline-recommended first-line therapy, while POS and ISA have demonstrated promising efficacy [28, 29] . Although clinical guidelines recommend an L-AmB dosage of 5–10 mg/kg, patients in our cohort received lower doses (median 2 mg/kg), partly due to the nephrotoxicity and hypokalemia associated with AmBD, which was administered to 14 patients. This dosing approach is substantiated by meta-analyses reporting comparable efficacy with lower dosages in Chinese populations [30] . Notably, combination therapy with AmB plus POS and/or ISA was associated with a 37.7% reduction in mortality compared with AmB monotherapy, although this difference did not reach statistical significance. These findings underscore the potential benefit of combination antifungal therapy, while highlighting the need for larger prospective or randomized studies to validate its efficacy and safety. There are several important limitations to this study. First, histopathological confirmation was achieved in only a small proportion of cases (8.2%), reflecting the practical challenges of obtaining invasive tissue samples in HSCT recipients. In contrast, 73.4% of cases were classified as probable mucormycosis based solely on mNGS as the microbiological criterion, in conjunction with compatible host factors, clinical manifestations, and radiological features that fulfilled the diagnostic definition. While this approach reflects real-world diagnostic practice in China, reliance on mNGS as the sole microbiological evidence may have led to an overestimation of mucormycosis incidence compared with studies that strictly adhere to the EORTC/MSGERC criteria. Second, most patients in this cohort were managed with conservative antifungal therapy, whereas surgical resection—a critical determinant of prognosis—was infrequently performed and therefore not included in the analysis. Third, as a single-center retrospective study, the findings primarily reflect real-world experience and should be interpreted with caution. Future multicenter prospective studies are warranted to validate molecular diagnostic methods, refine case definitions, and optimize management strategies for this rare but life-threatening infection. Conclusion This study demonstrates that mucormycosis remains a rare but life-threatening complication in HSCT recipients, predominantly affecting allogeneic transplant patients. Severe aGvHD , MDS, and prior invasive fungal infection were independent risk factors, highlighting the impact of immune dysregulation and host vulnerability. Combining mNGS with conventional diagnostics enabled timely pathogen identification and revealed frequent co-infections, supporting its value in guiding targeted therapy. AMB-based regimens remain the mainstay of treatment, while combination therapy with POS or ISA showed a trend toward improved survival. These findings emphasize the need for early recognition, risk-adapted prophylaxis, and optimized antifungal management to improve outcomes in this high-risk population. Declarations Ethics approval Ethical approval for this study was obtained from the Ethics Committee of the First Affiliated Hospital of USTC (2025-RE-237), and informed consent was provided by the patients or their families. Informed consent was waived because the study involved no interventions and did not include any patient-identifiable information. Consent for publication No conflict of interest exits in the submission of this manuscript, and the manuscript is approved by all authors for publication. Declaration of Interest Statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Funding This work was supported by the National Natural Science Foundation of China (grants # U23A20453 and 82270223), USTC Research Funds of the Double First-Class Initiative (YD9110002047). Author information Authors and Affiliations The First Affiliated Hospital of University of Science and Technology of China, Blood and Cell Therapy Institute, Anhui Provincial Key Laboratory of Blood Research and Applications, Hefei, China Junjie Luo, Xiaoyu Zhu The First Affiliated Hospital of University of Science and Technology of China, Hefei, 230001, Anhui, China; Kaidi Song, Baoling Tang, Xiang Wan, Wen Yao, Guangyu Sun, Ping Qiang, BGI Genomics, Shenzhen, China Ke Yuan Author contributions: X.Z. and P.Q. conceptualized and designed the study and critically revised the manuscript. J.L. and K.S. performed the clinical data analysis and drafted the manuscript. J.L., B.T., and X.W. contributed to data collection. W.Y., G.S., and K.Y. were responsible for patient management and treatment. All authors read and approved the final version of the manuscript. Acknowlegements We sincerely thank all the participating patients for their cooperation during this study. Declaration of Interest Statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Data availability No datasets were generated or analysed during the current study. References Sipsas NV, Gamaletsou MN, Anastasopoulou A, Kontoyiannis DP, Roilides E, Walsh TJ, et al. Mucormycosis in hematopoietic stem cell transplant recipients: a systematic review. Clin Infect Dis. 2014;59:503-514. Marón GA, Inagaki K, Rodriguez A, Knapp KM, Hayden RT, Adderson EE, et al. Mucormycosis in children with cancer and hematopoietic cell transplant: a single-center cohort study. PLoS One. 2024;19:e0297590. Skiada A, Pagano L, Groll AH, Zhang J, Dannaoui E, Balajee SA, et al. Zygomycosis in Europe: analysis of 230 cases accrued by the registry of the European Confederation of Medical Mycology (ECMM) Working Group on Zygomycosis between 2005 and 2007. Clin Microbiol Infect. 2011;17:1859-1867. Puerta-Alcalde P, Garcia-Vidal C. Changing epidemiology of invasive fungal disease in allogeneic hematopoietic stem cell transplantation. J Fungi (Basel). 2021;7:848. Neofytos D, Treadway S, Ostrander D, Alonso CD, Dierberg KL, Nussenblatt V, et al. Epidemiology, outcomes and mortality predictors of invasive mold infections among transplant recipients: a 10-year, single-center experience. Transpl Infect Dis. 2013;15:233-242. Park SY, Ardura MI, Zhang SX. Diagnostic limitations and challenges in current clinical guidelines and potential application of metagenomic sequencing to manage pulmonary invasive fungal infections in patients with haematological malignancies. Clin Microbiol Infect. 2024;30:1139-1146. Chandley P, Subba P, Rohatgi S. COVID-19-Associated mucormycosis: a matter of concern amid the SARS-CoV-2 pandemic. Vaccines. 2022;10:1266. Sahu RK, Salem-Bekhit MM, Bhattacharjee B, Almoshari Y, Ikbal AMA, Alshamrani M, et al. Mucormycosis in Indian COVID-19 patients: insight into its patho-genesis, clinical manifestation, and management strategies. Antibiotics (Basel). 2021;10:1079. Tissot F, Agrawal S, Pagano L, Cornely OA, Ribaud P, Herbrecht R, et al. ECIL-6 guidelines for the treatment of invasive candidiasis, aspergillosis and mucormycosis in leukemia and hematopoietic stem cell transplant patients. Haematologica. 2017;102:433-444. Donnelly JP, Chen SC, Kauffman CA, Steinbach WJ, Baddley JW, Verweij PE, 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. Safiia J, Díaz MA, Alshaker H, Atallah CJ, Sakr P, Moshovitis DG, et al. Recent advances in diagnostic approaches for mucormycosis. J Fungi (Basel). 2024;10:727. Wang J, Liu L, Li J, Li M, Zhao L, et al. Clinical characteristics, prognosis factors and metagenomic next-generation sequencing diagnosis of mucormycosis in patients with hematologic diseases. Mycopathologia. 2024;189:71. Zhang M, Lu W, Xie D, Chen S, Li Y, et al. Metagenomic next-generation sequencing for diagnostically challenging mucormycosis in patients with hematological malignancies. Infect Drug Resist. 2022;15, 7509-7517. Cornely OA, Alastruey-Izquierdo A, Arenz D, Chen S, Dannaoui E, Hochhegger B, et al. Global guideline for the diagnosis and management of mucormycosis: an initiative of the European Confederation of Medical Mycology in cooperation with the Mycoses Study Group Education and Research Consortium. Lancet Infect Dis. 2019;9, e405-e421. Xu C, Zhang Y, Li Y, Huang X, Chen H, et al. China expert consensus on the application of metagenomic next-generation sequencing in the diagnosis of infections in patients with hematologic disorders. Blood Sci. 2025;10:1-10. Chinese Society of Laboratory Medicine Clinical Microbiology Group; Chinese Society of Microbiology and Immunology Clinical Microbiology Group; Chinese Medical Doctor Association Clinical Microbiology and Infection Group. Chinese expert consensus on metagenomics next-generation sequencing application on pathogen detection of infectious diseases. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2020;32:632-639. Westin JR, Saliba RM, De Lima M, Couriel D, Shpall EJ, Ayash L. Steroid-Refractory acute GVHD: predictors and outcomes. Adv Hematol. 2011;2011:601953. Andrianaki AM, Kyrmizi I, Thanopoulou K, Tsitsigiannis DI, Momany M, Klimko C. Iron restriction inside macrophages regulates pulmonary host defence against Rhizopus species. Nat Commun. 2018;9:2205. Briard B, Fontaine T, Samir P, Beauvais A, Latgé JP, Mouyna I.Galactosaminogalactan activates the inflammasome to provide host protection. Nature. 2020;588:688-692. Kim CH, Leitch HA. Iron overload–induced oxidative stress in myelodysplastic syndromes and its cellular sequelae. Crit Rev Oncol Hematol. 2021;166:103367. Yu X, Yang F, Shen Z, Zhang Y, Sun J, Qiu C, et al. BTLA contributes to acute-on-chronic liver failure infection and mortality through CD4+ T-cell exhaustion. Nat Commun. 2024;15:1835. Jiang D, Chen C, Yan D, Zhang X, Liu X, Yan D, et al. Exhausted phenotype of circulating CD8+ T cell subsets in hepatitis B virus carriers. BMC Immunol. 2022;23:18. Trifilio SM, Bennett CL, Yarnold PR, McKoy JM, Parada J, Mehta J, et al. Breakthrough zygomycosis after voriconazole administration among patients with hematologic malignancies who receive hematopoietic stem-cell transplants or intensive chemotherapy. Bone Marrow Transplant. 2007;39:425-429. Trifilio S, Singhal S, Williams S, Frankfurt O, Gordon L, Evens A, et al. Breakthrough fungal infections after allogeneic hematopoietic stem cell transplantation in patients on prophylactic voriconazole. Bone Marrow Transplant. 2007;40:451-456. Li J, Ge Y, Xin C, Jiang L. Rhino-orbital-cerebral mucormycosis caused by Rhizopus arrhizus diagnosis via metagenomics next-generation sequencing: a case report. Front Cell Infect Microbiol. 2024;14:1375058. Wen B, Cai L, Cai Y, Du X. Case report: metagenomics next-generation sequencing for diagnosing cerebral infarction and infection caused by haematogenous disseminated mucormycosis in a patient with acute lymphoblastic leukaemia. Front Med. 2021;8:779981. Gomes MZR, Lewis RE, Kontoyiannis DP. Mucormycosis caused by unusual mucormycetes, Non-Rhizopus, -Mucor, and -Lichtheimia Species. Clin Microbiol Rev. 2011;24:411-445. Cornely OA, Maertens J, Bresnik M, Ebrahimi R, Ullmann AJ, Bouza E, et al. Liposomal amphotericin B as initial therapy for invasive mold infection: AmBiLoad Trial. Clin Infect Dis. 2007;44:1289-1297. Marty FM, Ostrosky-Zeichner L, Cornely OA, Mullane KM, Perfect JR, Thompson GR, et al. Isavuconazole treatment for mucormycosis: a single-arm open-label trial and case-control analysis. Lancet Infect Dis. 2016;16:828-837. Wei LW, Zhu PQ, Chen XQ, Yu J. Mucormycosis in Mainland China: a systematic review of case reports. Mycopathologia. 2019;187:1-14. Additional Declarations No competing interests reported. Supplementary Files Additionalfile1.docx Additional files The following supplementary materials are available in the electronic supplementary material Supplementary Table S1. Univariable Cox regression analysis of mucormycosis risk factors in allogeneic HSCT recipients. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8122974","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":593391748,"identity":"735c6254-652a-45c9-9503-f73560adaf50","order_by":0,"name":"Junjie Luo","email":"","orcid":"","institution":"The First Affiliated Hospital of USTC: Anhui Provincial Hospital","correspondingAuthor":false,"prefix":"","firstName":"Junjie","middleName":"","lastName":"Luo","suffix":""},{"id":593391749,"identity":"8b45865c-2f5f-4c5e-aecf-ebcb16ede8a5","order_by":1,"name":"Kaidi Song","email":"","orcid":"","institution":"The First Affiliated Hospital of USTC: Anhui Provincial Hospital","correspondingAuthor":false,"prefix":"","firstName":"Kaidi","middleName":"","lastName":"Song","suffix":""},{"id":593391750,"identity":"7e9cf128-15df-48bc-933c-de32e1aadb75","order_by":2,"name":"Baoling Tang","email":"","orcid":"","institution":"The First Affiliated Hospital of USTC: Anhui Provincial Hospital","correspondingAuthor":false,"prefix":"","firstName":"Baoling","middleName":"","lastName":"Tang","suffix":""},{"id":593391753,"identity":"9075880c-65a4-402a-9cd0-21e20c436b94","order_by":3,"name":"Xiang Wan","email":"","orcid":"","institution":"The First Affiliated Hospital of USTC: Anhui Provincial Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xiang","middleName":"","lastName":"Wan","suffix":""},{"id":593391755,"identity":"2d66e111-bf8f-499d-878f-5041431aefa3","order_by":4,"name":"Wen Yao","email":"","orcid":"","institution":"The First Affiliated Hospital of USTC: Anhui Provincial Hospital","correspondingAuthor":false,"prefix":"","firstName":"Wen","middleName":"","lastName":"Yao","suffix":""},{"id":593391756,"identity":"ee8c1581-4114-4d89-947e-8a9171f351aa","order_by":5,"name":"Guangyu Sun","email":"","orcid":"","institution":"The First Affiliated Hospital of USTC: Anhui Provincial Hospital","correspondingAuthor":false,"prefix":"","firstName":"Guangyu","middleName":"","lastName":"Sun","suffix":""},{"id":593391757,"identity":"a4733cb7-17dc-42c5-ad0b-d4a1f7a4cc4a","order_by":6,"name":"Ke Yuan","email":"","orcid":"","institution":"BGI Genomics","correspondingAuthor":false,"prefix":"","firstName":"Ke","middleName":"","lastName":"Yuan","suffix":""},{"id":593391760,"identity":"04a0fc67-99ae-44ee-87c1-25b8f69efc9b","order_by":7,"name":"Ping Qiang","email":"","orcid":"","institution":"The First Affiliated Hospital of USTC: Anhui Provincial Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ping","middleName":"","lastName":"Qiang","suffix":""},{"id":593391761,"identity":"aa216ef9-56ed-4117-b587-f8fc49dbc763","order_by":8,"name":"Xiaoyu Zhu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1klEQVRIiWNgGAWjYDACZgglh8olRosxlEWMFihIbCBai8Fx5oePedvq0jecP3/wA0OFdWID+9kDeLVINrMZG/O2seVuuJHMLMFwJj2xgScvAa8WfmYGM2neNh6gFmY2Bsa2w4kNEjwGeLWwMbN/A2qRSDc4fxio5R8RWviZeUC2GCQYHEgGamkgQotkM0+x4ZxzCYYzbyQbSyQcSzdu48nBr8Xg/PGND96U1cnznT/48MOHGmvZfvYz+LWAABMPjJUA8h1B9UDA+IMYVaNgFIyCUTByAQCArjtYT2YDRAAAAABJRU5ErkJggg==","orcid":"","institution":"The First Affiliated Hospital of USTC: Anhui Provincial Hospital","correspondingAuthor":true,"prefix":"","firstName":"Xiaoyu","middleName":"","lastName":"Zhu","suffix":""}],"badges":[],"createdAt":"2025-11-15 15:23:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8122974/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8122974/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":103165400,"identity":"ce82da81-383b-4065-ba36-36cab18d6351","added_by":"auto","created_at":"2026-02-22 12:28:02","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":397327,"visible":true,"origin":"","legend":"\u003cp\u003eCumulative incidence, pathogen distribution, and infection sites of mucormycosis after hematopoietic stem cell transplantation.\u003c/p\u003e\n\u003cp\u003e(A) Line chart showing the cumulative incidence of mucormycosis after HSCT across different transplant-related groups.\u003c/p\u003e\n\u003cp\u003e(B) Pie chart showing the distribution of mucormycosis pathogens at the genus level.\u003c/p\u003e\n\u003cp\u003e(C) Pie chart showing the distribution of pathogens at the species level.\u003c/p\u003e\n\u003cp\u003e(D) Pie chart illustrating the anatomical sites of infection among mucormycosis cases.\u003c/p\u003e\n\u003cp\u003eAbbreviations: HSCT, hematopoietic stem cell transplantation; Allo-UCBT, allogeneic umbilical cord blood transplantation; Allo-PBSCT, allogeneic peripheral blood stem cell transplantation; Auto-HSCT, autologous HSCT.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-8122974/v1/fbd652faf1993b046efd3034.png"},{"id":103165402,"identity":"ff7dda47-37cd-495e-9cfe-b22d6cccea66","added_by":"auto","created_at":"2026-02-22 12:28:02","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":634996,"visible":true,"origin":"","legend":"\u003cp\u003eUnivariable and multivariable Cox regression analysis of mucormycosis risk factors in allogeneic HSCT recipients.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003eDelayed neutrophil recovery was defined as time to neutrophil engraftment exceeding the cohort median (15 days).\u003c/p\u003e\n\u003cp\u003eThis figure presents hazard ratios (HRs) and 95% confidence intervals (CIs) from univariable and multivariable Cox regression analyses. Adjusted HRs are shown as red filled squares with red error bars; a vertical line at HR = 1 indicates no effect. Exposure to time-dependent covariates (new-onset diabetes, breakthrough fungal infections, severe acute graft-versus-host disease (GvHD), and steroid-refractory acute GvHD was defined from day 100 post-transplant.\u003c/p\u003e\n\u003cp\u003eAbbreviations: HR, hazard ratio; CI, confidence interval; AML, acute myelocytic leukemia; MDS, myelodysplastic syndrome; HSCT, hematopoietic stem cell transplantation; PBSCT, peripheral blood stem cell transplantation; CBT, cord blood transplantation; HLA, human leukocyte antigen; RIC, reduced-intensity conditioning; NMA, non-myeloablative conditioning; ATG, anti-thymocyte globulin; GvHD, graft-versus-host disease; SR-aGVHD, steroid-refractory acute GvHD.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-8122974/v1/e0115e33698d4266f6df35bc.png"},{"id":103504779,"identity":"90eab3d2-4502-4d31-a072-69b406a051fd","added_by":"auto","created_at":"2026-02-26 13:21:23","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1079366,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8122974/v1/428509b2-d9eb-49ae-9d31-8cb6f66212fa.pdf"},{"id":103165403,"identity":"7496d771-a33f-46bf-9a22-1e10304946d2","added_by":"auto","created_at":"2026-02-22 12:28:02","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":32933,"visible":true,"origin":"","legend":"\u003cp\u003eAdditional files\u003c/p\u003e\n\u003cp\u003eThe following supplementary materials are available in the electronic supplementary material\u003c/p\u003e\n\u003cp\u003eSupplementary Table S1. Univariable Cox regression analysis of mucormycosis risk factors in allogeneic HSCT recipients.\u003c/p\u003e","description":"","filename":"Additionalfile1.docx","url":"https://assets-eu.researchsquare.com/files/rs-8122974/v1/6c4003f8ca2a1c879a1082c6.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Breakthrough Mucormycosis After Hematopoietic Stem Cell Transplantation: A Retrospective Multiyear Cohort Study in Eastern China","fulltext":[{"header":"Introduction","content":"\u003cp\u003eDespite substantial advances in antifungal therapies, mucormycosis, once considered rare, has increasingly emerged as a significant clinical challenge among hematopoietic stem cell transplantation (HSCT) recipients, with mortality frequently exceeding 40% despite intensive antifungal treatment and surgical interventions [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The rising incidence of mucormycosis can be attributed to several interrelated factors. These include the expanding population of HSCT recipients and other immunocompromised individuals, the extensive use of antifungal prophylaxis with limited efficacy against \u003cem\u003eMucorales\u003c/em\u003e, and the growing utilization of advanced diagnostic modalities, such as metagenomic next-generation sequencing (mNGS) [\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Moreover, the COVID-19 pandemic, along with its widespread application of immunosuppressive therapies, has further contributed to the escalation of this trend [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The 2017 ECIL-6 and 2019 global guidelines underscore the critical role of early diagnosis, individualized management strategies, and multidisciplinary care in improving mucormycosis outcomes for this high-risk patient population [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe clinical manifestations of mucormycosis in HSCT recipients are frequently atypical and rapidly progressive, posing major challenges for timely recognition. Conventional diagnostic approaches\u0026mdash;histopathology, microscopy, and culture\u0026mdash;are often limited by suboptimal sensitivity, prolonged turnaround times, and the need for invasive tissue sampling, which is particularly challenging in hematologic patients. In recent years, mNGS has emerged as a valuable, noninvasive diagnostic adjunct, enabling unbiased detection of \u003cem\u003eMucorales\u003c/em\u003e DNA directly from clinical specimens. In China, mNGS has been increasingly applied in clinical practice and has demonstrated substantial utility for pathogen identification. Although not yet incorporated into the EORTC/MSGERC criteria, multiple studies support its diagnostic value and recommend its use as a supplementary microbiological tool for invasive fungal infections [\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Despite growing awareness, large-scale epidemiological data on mucormycosis in HSCT recipients remain limited, particularly in Asian populations. Moreover, the impact of emerging risk factors\u0026mdash;such as novel immunosuppressive regimens\u0026mdash;as well as the clinical efficacy of newer antifungal agents, such as isavuconazole (ISA), has not been systematically evaluated.This study provides a comprehensive evaluation of the epidemiological characteristics, risk factors, pathogen distribution, and treatment outcomes of mucormycosis among HSCT recipients. The findings aim to inform optimized management strategies and improve clinical outcomes in this high-risk population.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003ePatients and data collection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was designed as a retrospective, observational, single-center analysis. Between November 1, 2020, and October 31, 2024, all consecutive patients who were hospitalized and underwent HSCT at the First Hospital of the University of Science and Technology of China (USTC) were included to assess the occurrence of mucormycosis. For each HSCT recipient, clinical and treatment-related data were extracted from electronic medical records. Collected variables included demographic characteristics (age and sex), primary disease, disease remission status at transplantation, pre-existing comorbidities, graft type, incidence and management of graft-versus-host disease (GvHD), post-transplant disease progression, antifungal prophylaxis, antifungal treatment, survival status, and cause of death.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFollow-up continued through May 1, 2025. During this period, 221 patients died, and the remainder were alive. The median follow-up time for survivors was 18.0 months (interquartile range [IQR], 16.7\u0026ndash;18.0 months), with a minimum follow-up of 6.0 months and a maximum of 18.0 months post-transplantation. Among the 221 patients who died, the median time to death was 3.7 months (IQR, 2.0\u0026ndash;6.2 months).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiagnosis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe diagnosis of mucormycosis was established through a combination of clinical, radiological, and microbiological findings. Cases were categorized as proven or probable according to the revised EORTC/MSGERC criteria, while possible cases were excluded. In this study, mNGS was additionally accepted as a supplementary microbiological criterion for probable cases, provided contamination was rigorously excluded \u003cstrong\u003e[1\u003c/strong\u003e\u003cstrong\u003e4-\u003c/strong\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003cstrong\u003e6\u003c/strong\u003e\u003cstrong\u003e]\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e(A) Proven mucormycosis: A definitive diagnosis requires confirmation by histopathology, direct microscopy, and/or culture of\u003cem\u003e\u0026nbsp;Mucorale\u003c/em\u003es from a sterile site.\u003c/p\u003e\n\u003cp\u003e(B) Probable mucormycosis: This category is based on a combination of host factors, clinical manifestations, radiological features, and microbiological evidence.\u003c/p\u003e\n\u003cp\u003eMicrobiological evidence: Criteria include (1) detection of \u003cem\u003eMucorales\u003c/em\u003e by culture or direct microscopy from non-sterile specimens (e.g., sputum, pus) with strong clinical correlation and strict exclusion of contamination, or (2) identification of \u003cem\u003eMucorales\u003c/em\u003e by mNGS from sterile or non-sterile fluids (e.g., bronchoalveolar lavage fluid [BALF], plasma, cerebrospinal fluid [CSF]) after rigorous exclusion of contamination.\u003c/p\u003e\n\u003cp\u003eAntifungal Prophylaxis\u003c/p\u003e\n\u003cp\u003eAll HSCT recipients received antifungal prophylaxis, including both primary and secondary regimens, for at least 3 months after transplantation. Additionally, allogeneic HSCT (allo-HSCT) recipients received universal prophylaxis against \u003cem\u003ePneumocystis jirovecii\u003c/em\u003e pneumonia with oral sulfamethoxazole/trimethoprim.\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003eallo-HSCT: Primary antifungal prophylaxis for allo-HSCT recipients was implemented using mold-active azoles, mainly voriconazole (VCZ) or posaconazole (POS). Three POS formulations were used\u0026mdash;oral suspension, delayed-release tablets, and intravenous injection. Serum POS levels remain stable with the latter two formulations, whereas therapeutic drug monitoring (TDM) is recommended for the oral suspension, with at least one serum concentration measurement targeting\u0026nbsp;\u0026ge;0.5 mg/L. Similarly, VCZ dosing was personalized through routine TDM to achieve and sustain trough concentrations within an optimal target range of 1\u0026ndash;5 \u0026mu;g/mL.The choice of antifungal agent and administration route was determined by the attending physician based on clinical condition and financial considerations.\u003c/li\u003e\n \u003cli\u003eAutologous HSCT (auto-HSCT): Primary antifungal prophylaxis for auto-HSCT recipients was administered using fluconazole (FLU) or VCZ.\u003c/li\u003e\n \u003cli\u003eSecondary anti‑fungal prophylaxis: for HSCT recipients requiring secondary antifungal prophylaxis due to a prior invasive fungal disease, the selection of an antifungal agent is dictated by the prior therapeutic response. The preferred choice is the specific drug, or its drug class, that demonstrated clinical efficacy during the initial treatment course.\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eGVHD prophylaxis in allo-HSCT recipients\u003cbr\u003e\u0026nbsp;1. Cord blood transplantation (CBT): Patients undergoing CBT received a combination of cyclosporine A (CsA) and mycophenolate molate (MMF), administered intravenously or orally, without anti-thymocyte globulin (ATG). The target trough level for CsA was maintained between 250 and 350 \u0026mu;g/L. For patients with malignant hematological diseases and without manifestations of GVHD, CsA tapering was initiated at 2 months post-transplant, with complete discontinuation targeted between 3 and 6 months. In contrast, for recipients with non-malignant diseases, such as aplastic anemia, the CsA course was extended, with tapering beginning after 6 months and aiming for cessation within one year post-transplant.\u003c/p\u003e\n\u003cp\u003e2. Matched sibling donor HSCT (MSD-HSCT) and haploidentical donor HSCT (haplo-HSCT): For patients undergoing MSD-HSCT or haplo-HSCT, the base GVHD prophylaxis regimen consisted of CsA and MMF. At the physician\u0026apos;s discretion, this backbone regimen could be supplemented with an additional agent, such as rabbit anti-thymocyte globulin, post-transplant cyclophosphamide, or a short-course of \u0026nbsp;methotrexate.\u003c/p\u003e\n\u003cp\u003eDefinitions\u003c/p\u003e\n\u003cp\u003eBreakthrough infection was defined as the occurrence of proven or probable mucormycosis during systemic antifungal exposure, irrespective of the prophylactic agent\u0026rsquo;s activity against \u003cem\u003eMucorales\u003c/em\u003e.\u003c/p\u003e\n\u003cp\u003eDisseminated infection was defined as mucormycosis involving 2 or more non-contiguous sites.\u003c/p\u003e\n\u003cp\u003eUnclassified \u003cem\u003eMucorales\u003c/em\u003e were defined as \u003cem\u003eMucorales\u003c/em\u003e isolates for which species-level identification was not possible; in such cases, the isolates were assigned to the genus level or designated as \u0026ldquo;unclassified\u003cem\u003e\u0026nbsp;Mucorales\u003c/em\u003e\u0026rdquo;.\u003c/p\u003e\n\u003cp\u003eSteroid-refractory acute graft-versus-host disease (SR-aGVHD) was defined as acute graft-versus-host disease that fails to respond to adequate systemic corticosteroid therapy. Specifically, it includes: primary SR-aGVHD, characterized by progression of aGVHD after 3\u0026ndash;5 days of treatment with methylprednisolone at \u0026ge;2 mg/kg/day (or equivalent), or lack of improvement after 5\u0026ndash;7 days of therapy; and secondary SR-aGVHD, characterized by recurrence or flare of aGVHD during steroid taper, indicating resistance despite initial response \u003cstrong\u003e[\u003c/strong\u003e\u003cstrong\u003e17\u003c/strong\u003e\u003cstrong\u003e]\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStatistical analyses were conducted using R, SPSS, or SAS, in accordance with STROBE guidelines. Continuous variables were presented as mean \u0026plusmn; standard deviation or median with interquartile range (IQR), depending on the results of normality testing (Shapiro\u0026ndash;Wilk test). Group comparisons were performed using Welch\u0026rsquo;s t-test for normally distributed data or the Mann\u0026ndash;Whitney U test for non-parametric distributions. Categorical variables were summarized as frequencies and percentages, and compared using the chi-square or Fisher\u0026rsquo;s exact test, with statistical significance defined as \u003cem\u003eP\u0026nbsp;\u003c/em\u003e\u0026lt; 0.05. Cohorts with fewer than five events per variable were excluded from multivariable models to maintain model robustness.\u003c/p\u003e\n\u003cp\u003eThe incidence of mucormycosis was calculated as the number of events per 100 patient-years. Cumulative incidence estimates were generated using Fine\u0026ndash;Gray subdistribution hazard models to account for competing risks, including non-mucormycosis-related mortality and loss to follow-up. Temporal patterns of infection were stratified by post-transplantation intervals and compared using Gray\u0026rsquo;s test.\u003c/p\u003e\n\u003cp\u003eCox proportional hazards models were applied to identify potential risk factors using both univariable and multivariable competing risks analyses. Variables that reached statistical significance in the univariable analysis (\u003cem\u003eP\u0026nbsp;\u003c/em\u003e\u0026lt; 0.05) were subsequently included in the final multivariable model. Time-dependent covariates were incorporated through landmark analysis, with day 100 post-transplantation designated as the reference time point. Logistic regression was performed to evaluate factors associated with long-term (12-week) mortality.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e1. Sample collection and patient baseline characteristics\u003c/p\u003e\n\u003cp\u003eBetween November 2020 and October 2024, a total of 1,224 consecutive patients underwent 1,248 HSCTs at our center, including 24 patients who received a second transplant. The median age at transplantation was 32 years (IQR, 13.3\u0026ndash;48.4; range, 0\u0026ndash;69 years), with a predominance of male patients (729/1,224, 59.5%). The distribution of underlying hematologic diseases was as follows: acute myeloid leukemia (30.1%, 368/1,224), acute lymphoblastic leukemia (17.0%, 208/1,224), aplastic anemia (14.5%, 177/1,224), lymphoma (11.5%, 141/1,224), multiple myeloma (MM, 10.5%, 129/1,224), myelodysplastic syndrome (MDS, 10.4%, 127/1,224), and other primary\u0026nbsp;disease\u0026nbsp;(6.0%, 74/1,224). Notably, the incidence of mucormycosis\u0026nbsp;differed significantly across disease subgroups, with a higher rate observed in patients with MDS and lower rates among those with MM and lymphoma compared with other hematologic disorders (\u003cem\u003eP\u0026nbsp;\u003c/em\u003e\u0026lt; 0.05). Allo-HSCT constituted the majority of procedures (990/1,224, 80.9%), with CBT employed in 795 (80.3%) of these cases. During the observation period, mucormycosis was diagnosed in 49 patients (4.0%), including 4 (8.2%) proven and 45 (91.8%) probable cases. The baseline characteristics of HSCT recipients with and without mucormycosis are detailed in Table 1 (to be placed at the end of the manuscript).\u003c/p\u003e\n\u003cp\u003e2.Infection epidemiology of mucormycosis\u003c/p\u003e\n\u003cp\u003eThe overall incidence density of mucormycosis was 3.40 cases per 100 person-years (95% CI: 2.52\u0026ndash;4.50), equivalent to 0.09 cases per 1,000 patient-days. The cumulative incidence increased over time, reaching 1.0% by day 30, 2.3% by day 100, 2.9% by day 180, 3.5% by day 365, and 4.2% by day 550 (Figure 1A). The median time from transplantation to mucormycosis diagnosis was 73 days (IQR, 30\u0026ndash;223). Among the 49 proven or probable cases, 59.2% (29/49) occurred within the first 100 days post-transplantation, followed by 16.3% (8/49) between days 101 and 180, 14.3% (7/49) between days 181 and 365, and 12.2% (6/49) between days 366 and 550. The temporal distribution of cases demonstrated a significant concentration during the early post-transplantation period, with statistically significant differences observed across the defined time intervals (\u003cem\u003eP \u0026lt;\u0026nbsp;\u003c/em\u003e0.05).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e3. Diagnosis Methods and Infection Characteristics\u003c/p\u003e\n\u003cp\u003eAmong the 49 patients with mucormycosis, 4 were classified as proven cases based on histopathological confirmation from bronchoscopic biopsy, whereas the remaining 45 were categorized as probable cases. Of these, 8 cases were culture-positive, with additional mNGS support in 4 (3 BALF, 1 plasma); 1 case was diagnosed by direct microscopy of skin secretion supported by plasma mNGS, and the remaining 36 were identified solely by mNGS (1 CSF, 6 BALF, and 29 plasma samples). A total of 51 \u003cem\u003eMucorales\u003c/em\u003e isolates were recovered. At the genus level, \u003cem\u003eRhizopus\u003c/em\u003e spp. predominated (37.3%, 19/51), followed by \u003cem\u003eCunninghamella\u0026nbsp;\u003c/em\u003espp. (31.4%, 16/51) and \u003cem\u003eRhizomucor\u0026nbsp;\u003c/em\u003espp. (27.5%, 14/51), with 2 isolates (3.9%) unclassified (Figure 1B). At the species level, identification was achieved in 46 isolates (90.2%), with \u003cem\u003eCunninghamella elegans\u003c/em\u003e (23.5%, 12/51), \u003cem\u003eRhizomucor pusillus\u0026nbsp;\u003c/em\u003e(23.5%, 12/51), and \u003cem\u003eRhizopus microsporus\u003c/em\u003e (21.6%, 11/51) being the most prevalent (Figure 1C).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRegarding the site of infection, pulmonary mucormycosis was the most prevalent presentation (75.5%, 37/49), followed by disseminated (16.3%, 8/49), rhinocerebral (6.1%, 3/49), and cutaneous forms (2.0%, 1/49) (Figure 1D). Concurrent non-\u003cem\u003eMucorales\u0026nbsp;\u003c/em\u003einfections occurred in 81.6% (40/49) of patients, with viral pathogens detected in 59.2% (29/49), including human herpesvirus 6B (26.5%, 13/49) and cytomegalovirus (20.4%, 10/49). Among other fungal co-infections, \u003cem\u003eAspergillus\u0026nbsp;\u003c/em\u003espp. were the most common, identified in 6 patients.\u003c/p\u003e\n\u003cp\u003e4.Antifungal prophylaxis and breakthrough infections\u003c/p\u003e\n\u003cp\u003eDistinct antifungal prophylaxis patterns were observed across transplant types (Table 1). Among allo-HSCT recipients (n = 990), VCZ was the predominant agent (56.7%), followed by POS (27.0%), whereas FLU was administered in 86.8% of auto-HSCT recipients (n = 234). Breakthrough mucormycosis occurred in 46 allogeneic recipients, with the highest incidence observed in VCZ recipients (5.7%, 32/561; median onset 70.5 days post-transplant), followed by POS (4.1%, 11/267; median onset 94 days post-transplant) and other agents (3.0%, 3/101; median onset 67 days post-transplant); no cases were reported in the FLU group. Two patients developed delayed infection after discontinuation of POS prophylaxis (median onset, 119 days post-transplant). In contrast, only one breakthrough infection occurred in the auto-HSCT cohort (0.5%, 1/203), in a FLU recipient on day 7 post-transplantation. Within the allo-HSCT cohort, breakthrough mucormycosis tended to occur more frequently and earlier in VCZ recipients than in those receiving POS (5.7% vs. 4.1%; median onset 70.5 vs. 94 days post-transplant), although the difference did not reach statistical significance (P = 0.400).\u003c/p\u003e\n\u003cp\u003eTable 1. Baseline characteristics of HSCT recipients with and without mucormycosis\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"761\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 220px;\"\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 182px;\"\u003e\n \u003cp\u003eMucormycosis (n = 49)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 173px;\"\u003e\n \u003cp\u003eNon-mucormycosis (n = 1175)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 187px;\"\u003e\n \u003cp\u003eTotal (n = 1224)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 220px;\"\u003e\n \u003cp\u003eDemographics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 182px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 173px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 187px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 220px;\"\u003e\n \u003cp\u003eAge, median (IQR), years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 182px;\"\u003e\n \u003cp\u003e33 (17.5\u0026ndash;48.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 173px;\"\u003e\n \u003cp\u003e32 (13.0\u0026ndash;48.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 187px;\"\u003e\n \u003cp\u003e32 (13.3\u0026ndash;48.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 220px;\"\u003e\n \u003cp\u003eMale sex, No. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 182px;\"\u003e\n \u003cp\u003e31 (63.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 173px;\"\u003e\n \u003cp\u003e698 (59.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 187px;\"\u003e\n \u003cp\u003e729 (59.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\" style=\"width: 761px;\"\u003e\n \u003cp\u003eUnderlying disease, No. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 220px;\"\u003e\n \u003cp\u003eAML\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 182px;\"\u003e\n \u003cp\u003e17 (34.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 173px;\"\u003e\n \u003cp\u003e351 (29.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 187px;\"\u003e\n \u003cp\u003e368 (30.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 220px;\"\u003e\n \u003cp\u003eALL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 182px;\"\u003e\n \u003cp\u003e7 (14.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 173px;\"\u003e\n \u003cp\u003e201 (17.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 187px;\"\u003e\n \u003cp\u003e208 (17.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 220px;\"\u003e\n \u003cp\u003eAA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 182px;\"\u003e\n \u003cp\u003e8 (16.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 173px;\"\u003e\n \u003cp\u003e169 (14.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 187px;\"\u003e\n \u003cp\u003e177 (14.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 220px;\"\u003e\n \u003cp\u003eLymphoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 182px;\"\u003e\n \u003cp\u003e1 (2.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 173px;\"\u003e\n \u003cp\u003e140 (11.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 187px;\"\u003e\n \u003cp\u003e141 (11.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 220px;\"\u003e\n \u003cp\u003eMM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 182px;\"\u003e\n \u003cp\u003e1 (2.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 173px;\"\u003e\n \u003cp\u003e128 (10.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 187px;\"\u003e\n \u003cp\u003e129 (10.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 220px;\"\u003e\n \u003cp\u003eMDS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 182px;\"\u003e\n \u003cp\u003e14 (28.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 173px;\"\u003e\n \u003cp\u003e113 (9.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 187px;\"\u003e\n \u003cp\u003e127 (10.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 220px;\"\u003e\n \u003cp\u003eOthers\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 182px;\"\u003e\n \u003cp\u003e2 (4.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 173px;\"\u003e\n \u003cp\u003e72 (6.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 187px;\"\u003e\n \u003cp\u003e74 (6.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\" style=\"width: 761px;\"\u003e\n \u003cp\u003eTransplant Type\u003csup\u003ea\u003c/sup\u003e, No. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 220px;\"\u003e\n \u003cp\u003eAllogeneic HSCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 182px;\"\u003e\n \u003cp\u003e48 (98.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 173px;\"\u003e\n \u003cp\u003e942 (80.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 187px;\"\u003e\n \u003cp\u003e990 (80.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 220px;\"\u003e\n \u003cp\u003eCBT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 182px;\"\u003e\n \u003cp\u003e33 (67.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 173px;\"\u003e\n \u003cp\u003e762 (64.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 187px;\"\u003e\n \u003cp\u003e795 (64.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 220px;\"\u003e\n \u003cp\u003eMD-HSCT\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 182px;\"\u003e\n \u003cp\u003e10 (20.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 173px;\"\u003e\n \u003cp\u003e99 (8.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 187px;\"\u003e\n \u003cp\u003e109 (8.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 220px;\"\u003e\n \u003cp\u003eHaplo-HSCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 182px;\"\u003e\n \u003cp\u003e5 (10.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 173px;\"\u003e\n \u003cp\u003e81 (6.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 187px;\"\u003e\n \u003cp\u003e86 (7.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 220px;\"\u003e\n \u003cp\u003eAutologous HSCT\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 182px;\"\u003e\n \u003cp\u003e1 (2.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 173px;\"\u003e\n \u003cp\u003e233 (19.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 187px;\"\u003e\n \u003cp\u003e234 (19.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\" style=\"width: 761px;\"\u003e\n \u003cp\u003eStem Cell Source, No. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 220px;\"\u003e\n \u003cp\u003eAllogeneic HSCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 182px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 173px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 187px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 220px;\"\u003e\n \u003cp\u003eUmbilical cord blood\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 182px;\"\u003e\n \u003cp\u003e34 (69.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 173px;\"\u003e\n \u003cp\u003e761 (64.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 187px;\"\u003e\n \u003cp\u003e795 (65.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 220px;\"\u003e\n \u003cp\u003ePBSC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 182px;\"\u003e\n \u003cp\u003e14 (28.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 173px;\"\u003e\n \u003cp\u003e178 (35.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 187px;\"\u003e\n \u003cp\u003e192 (15.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 220px;\"\u003e\n \u003cp\u003eOther\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 182px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 173px;\"\u003e\n \u003cp\u003e3 (0.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 187px;\"\u003e\n \u003cp\u003e3 (0.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 220px;\"\u003e\n \u003cp\u003eAutologous HSCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 182px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 173px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 187px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 220px;\"\u003e\n \u003cp\u003e\u0026nbsp;PBSC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 182px;\"\u003e\n \u003cp\u003e1 (2.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 173px;\"\u003e\n \u003cp\u003e233 (19.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 187px;\"\u003e\n \u003cp\u003e234 (19.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\" style=\"width: 761px;\"\u003e\n \u003cp\u003eNeutrophil engraftment, median (IQR), days, No. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 220px;\"\u003e\n \u003cp\u003eAllogeneic HSCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 182px;\"\u003e\n \u003cp\u003e16 (14.0\u0026ndash;18.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 173px;\"\u003e\n \u003cp\u003e15 (13.0\u0026ndash;18.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 187px;\"\u003e\n \u003cp\u003e15 (13.0\u0026ndash;18.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 220px;\"\u003e\n \u003cp\u003eCBT\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 182px;\"\u003e\n \u003cp\u003e18 (14.0\u0026ndash;20.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 173px;\"\u003e\n \u003cp\u003e16 (14.0\u0026ndash;19.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 187px;\"\u003e\n \u003cp\u003e16 (14.0\u0026ndash;19.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 220px;\"\u003e\n \u003cp\u003eMD-HSCT\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 182px;\"\u003e\n \u003cp\u003e15 (11.3\u0026ndash;16.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 173px;\"\u003e\n \u003cp\u003e12 (10.5\u0026ndash;13.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 187px;\"\u003e\n \u003cp\u003e12 (10.5\u0026ndash;13.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 220px;\"\u003e\n \u003cp\u003eHaplo-HSCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 182px;\"\u003e\n \u003cp\u003e16 (15.8\u0026ndash;16.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 173px;\"\u003e\n \u003cp\u003e16 (14.0\u0026ndash;18.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 187px;\"\u003e\n \u003cp\u003e14 (13.0\u0026ndash;16.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 220px;\"\u003e\n \u003cp\u003eAutologous HSCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 182px;\"\u003e\n \u003cp\u003e1\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 173px;\"\u003e\n \u003cp\u003e9 (10.0\u0026ndash;11.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 187px;\"\u003e\n \u003cp\u003e9 (10.0\u0026ndash;11.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 201px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" style=\"width: 282px;\"\u003e\n \u003cp\u003eAllogeneic HSCT (n\u0026nbsp;= 990)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 278px;\"\u003e\n \u003cp\u003eAutologous HSCT \u0026nbsp;(n = 234)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 201px;\"\u003e\n \u003cp\u003eAntifungal prophylaxis, No. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 141px;\"\u003e\n \u003cp\u003eMucormycosis\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(n = 48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 141px;\"\u003e\n \u003cp\u003eNon-mucormycosis\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(n = 942)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 134px;\"\u003e\n \u003cp\u003eMucormycosis\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(n = 1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 143px;\"\u003e\n \u003cp\u003eNon-mucormycosis\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(n = 233)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003ePosaconazole\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 141px;\"\u003e\n \u003cp\u003e11 (22.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 141px;\"\u003e\n \u003cp\u003e256 (27.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 134px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 143px;\"\u003e\n \u003cp\u003e2 (0.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003eVoriconazole\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 141px;\"\u003e\n \u003cp\u003e32 (66.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 141px;\"\u003e\n \u003cp\u003e529 (56.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 134px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 143px;\"\u003e\n \u003cp\u003e27 (11.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003eFluconazole\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 141px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 141px;\"\u003e\n \u003cp\u003e59 (6.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 134px;\"\u003e\n \u003cp\u003e1 (100.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 143px;\"\u003e\n \u003cp\u003e202 (86.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003eOther agents\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 141px;\"\u003e\n \u003cp\u003e3 (6.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 141px;\"\u003e\n \u003cp\u003e98 (10.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 134px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 143px;\"\u003e\n \u003cp\u003e2 (0.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003eDelayed infection after prophylaxis discontinuation\u003csup\u003ed\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 141px;\"\u003e\n \u003cp\u003e2 (4.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 141px;\"\u003e\n \u003cp\u003e\u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 134px;\"\u003e\n \u003cp\u003e\u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 143px;\"\u003e\n \u003cp\u003e\u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 99.7372%;\" colspan=\"8\"\u003e\n \u003cp\u003e\u003csup\u003ea\u003c/sup\u003e For patients whose first HSCT failed engraftment and who subsequently underwent a second HSCT, the transplant type in this table is recorded according to the second transplantation. No patient underwent a third HSCT.\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003csup\u003eb\u003c/sup\u003e Combined peripheral blood stem cells (PBSC) and bone marrow (n = 1); PBSC and cord blood (n = 2).\u003c/p\u003e\n \u003cp\u003e\u003csup\u003ec\u003c/sup\u003e Only one case in the autologous HSCT group; IQR not available.\u003c/p\u003e\n \u003cp\u003e\u003csup\u003ed\u003c/sup\u003e Delayed infection after prophylaxis discontinuation refers to two patients who developed mucormycosis after premature discontinuation of antifungal prophylaxis (median onset, 119 days post-transplant; range, 60\u0026ndash;178 days).\u003c/p\u003e\n \u003cp\u003eAbbreviations: IQR, interquartile range; AML, acute myelocytic leukemia; ALL, acute lymphoblastic leukemia; AA, aplastic anemia; MM, multiple myeloma; MDS, myelodysplastic syndrome; HSCT, hematopoietic stem cell transplantation; MD-HSCT, matched donor HSCT (including both matched sibling donors and matched unrelated donors); Haplo-HSCT, haploidentical donor HSCT; CBT, cord blood transplantation; PBSC, peripheral blood stem cells.\u003c/p\u003e\u003cbr\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e5.Risk factors of mucormycosis\u003c/p\u003e\n\u003cp\u003eGiven the low incidence of mucormycosis among auto-HSCT recipients, the risk factor analysis was restricted to allo-HSCT recipients. In univariable Cox regression, several factors were significantly associated with mucormycosis, including: MDS (hazard ratio [HR] = 2.97, P \u0026lt; 0.001), diabetes mellitus (HR = 2.87, \u003cem\u003eP\u003c/em\u003e = 0.004), chronic hepatitis B (HR = 2.88, \u003cem\u003eP\u003c/em\u003e = 0.043), prior invasive fungal infection (HR = 2.88, \u003cem\u003eP\u003c/em\u003e = 0.001), severe acute GvHD (HR = 4.57, \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.001), and SR-aGVHD (HR = 3.34, \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.001). In multivariable analysis, MDS (adjusted hazard ratio [aHR] = 2.65, \u003cem\u003eP\u003c/em\u003e = 0.003), prior fungal infection (aHR = 2.33, \u003cem\u003eP\u003c/em\u003e = 0.010), and severe acute GvHD (aHR = 2.97, \u003cem\u003eP\u003c/em\u003e = 0.001) remained independent predictors. Diabetes mellitus (aHR = 2.05, \u003cem\u003eP\u003c/em\u003e = 0.062) and SR-aGVHD (aHR = 1.97, \u003cem\u003eP\u003c/em\u003e = 0.061) showed a borderline association, while chronic hepatitis B (aHR = 2.32, \u003cem\u003eP\u003c/em\u003e = 0.122) were not statistically significant. Further analyses of additional risk factors are presented in Figure 2, with detailed results in Supplementary Table 1.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e6. Treatment outcomes and prognostic factors\u003c/p\u003e\n\u003cp\u003eAmong the 49 patients diagnosed with mucormycosis, 43 (87.8%) received systemic antifungal therapy within 48 hours of diagnosis, achieving 42-day and 84-day survival rates of 64.6% (26/43) and 46.5% (20/43), respectively. The remaining six patients did not receive antifungal treatment and all subsequently died from the infection. First-line treatment predominantly comprised amphotericin B formulations (AmB), including amphotericin B deoxycholate (AmBD, 40.0%, 14/35; dose range: 0.7\u0026ndash;2 mg/kg/day), liposomal amphotericin B (L- AmB, 11.4%, 4/35; dose range: 2\u0026ndash;6 mg/kg/day), and amphotericin B colloidal dispersion (ABCD, 48.6%, 17/35; dose range: 1\u0026ndash;3 mg/kg/day). Combination antifungal therapy was administered in 79.1% (34/43) of cases, most frequently in conjunction with ISA (35.3%, 12/34) or POS (29.4%, 10/34). Treatment regimens are detailed in Table 2. The median duration of intravenous antifungal therapy during hospitalization was 22.5 days (range, 2\u0026ndash;90). While the differences were not statistically significant, combination therapy was associated with a reduced 84-day mortality compared to monotherapy (50.0% [17/34] vs. 66.7% [6/9]; \u003cem\u003eP\u003c/em\u003e = 0.100). A similar non-significant trend when comparing AmB combined with POS or ISA versus AmB monotherapy (42.3% [11/26] vs. 80.0% [4/5]; \u003cem\u003eP\u003c/em\u003e = 0.172). Multivariable logistic regression analysis identified severe acute GvHD as an independent predictor of mortality (odds ratio [OR] = 6.15, P = 0.013) (Table 3).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 2. Antifungal treatment regimens and 84-day mortality in 49 patients with mucormycosis\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"627\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 257px;\"\u003e\n \u003cp\u003eTreatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003eNumber of patients (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 186px;\"\u003e\n \u003cp\u003eDeaths at 84 days (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 257px;\"\u003e\n \u003cp\u003eMonotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003e9 (18.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 186px;\"\u003e\n \u003cp\u003e6 (66.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 257px;\"\u003e\n \u003cp\u003eAmB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003e5 (10.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 186px;\"\u003e\n \u003cp\u003e4 (80.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 257px;\"\u003e\n \u003cp\u003eISA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003e2 (4.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 186px;\"\u003e\n \u003cp\u003e1 (50.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 257px;\"\u003e\n \u003cp\u003ePOS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003e2 (4.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 186px;\"\u003e\n \u003cp\u003e1 (50.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 257px;\"\u003e\n \u003cp\u003eCombination therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003e34 (69.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 186px;\"\u003e\n \u003cp\u003e17 (50.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 257px;\"\u003e\n \u003cp\u003eAmB\u0026nbsp;+\u0026nbsp;POS/ISA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003e26 (53.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 186px;\"\u003e\n \u003cp\u003e11 (42.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 257px;\"\u003e\n \u003cp\u003eAmB\u0026nbsp;+\u0026nbsp;POS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003e10 (20.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 186px;\"\u003e\n \u003cp\u003e4 (40.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 257px;\"\u003e\n \u003cp\u003eAmB\u0026nbsp;+\u0026nbsp;ISA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003e12 (24.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 186px;\"\u003e\n \u003cp\u003e5 (41.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 257px;\"\u003e\n \u003cp\u003eAmB\u0026nbsp;+ POS/ISA (adjusted)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003e4 (8.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 186px;\"\u003e\n \u003cp\u003e2 (50.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 257px;\"\u003e\n \u003cp\u003eOther antifungal combinations\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003e8 (16.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 186px;\"\u003e\n \u003cp\u003e6 (75.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 257px;\"\u003e\n \u003cp\u003eAmB\u0026nbsp;+\u0026nbsp;Voriconazole\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003e4 (8.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 186px;\"\u003e\n \u003cp\u003e3 (75.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 257px;\"\u003e\n \u003cp\u003eAmB\u0026nbsp;+\u0026nbsp;Caspofungin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003e1 (2.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 186px;\"\u003e\n \u003cp\u003e1 (100.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 257px;\"\u003e\n \u003cp\u003eISA\u0026nbsp;+\u0026nbsp;Caspofungin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003e2 (4.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 186px;\"\u003e\n \u003cp\u003e2 (100.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 257px;\"\u003e\n \u003cp\u003ePOS\u0026nbsp;+\u0026nbsp;Caspofungin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003e1 (2.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 186px;\"\u003e\n \u003cp\u003e0 (0.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 257px;\"\u003e\n \u003cp\u003eUntreated\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 183px;\"\u003e\n \u003cp\u003e6 (12.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 186px;\"\u003e\n \u003cp\u003e6 (100.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAmB includes liposomal amphotericin B, amphotericin B colloidal dispersion, and amphotericin B deoxycholate. Abbreviations: AmB, amphotericin B; POS, posaconazole; ISA, isavuconazole.\u003c/p\u003e\n\u003cp\u003eTable 3. Univariate and multivariable logistic regression analyses of risk factors for mortality in patients with mucormycosis\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"695\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 245px;\"\u003e\n \u003cp\u003eFactors\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 231px;\"\u003e\n \u003cp\u003eUnivariate analysis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 219px;\"\u003e\n \u003cp\u003eMultivariable analysis\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003eOR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003eOR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003eInfection factors\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003e\u0026nbsp; Infection site (disseminated vs. other)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.118\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003e5.73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e0.64-50.97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003eMicrobiology\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003eCunninghamella species\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.058\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003e4.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e0.96-16.76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003e\u0026emsp;Rhizopus species\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.884\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003e0.92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e0.29-2.95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003e\u0026emsp;Rhizomucor species\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.064\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003e0.74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e0.08-0.94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003eHost factors\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003eMyeloablative conditioning regimen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.175\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003e2.68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e0.65-11.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003eDelayed neutrophil recovery (\u0026gt;15 days )a\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.801\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003e1.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e0.37-3.66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003eSevere acute GVHD (\u0026nbsp;Grade III\u0026ndash;IV)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003e8.89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e2.31-34.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e0.013\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e6.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e1.48-25.58\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003esteroid-refractory aGVHD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.005\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003e6.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e1.74-21.51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e0.222\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e2.51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.57-10.97\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003ePrimary disease not in remission\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.644\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003e0.76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e0.24-2.40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003eATG-containing regimens\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.485\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003e1.504\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e0.48-4.728\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003eTreatment factors\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003e\u0026emsp;Monotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.378\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003e\u0026nbsp;2.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e0.43-9.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 245px;\"\u003e\n \u003cp\u003eCombined antifungals therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.378\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003e0.50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e0.11-2.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003eDelayed neutrophil recovery was defined as time to neutrophil engraftment exceeding the cohort median (15 days).\u003c/p\u003e\n\u003cp\u003eAbbreviations: OR, odds ratio; CI, confidence interval; GvHD, graft-versus-host disease; PES, pre-engraftment syndrome; ATG, anti-thymocyte globulin.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eIn this large retrospective cohort of HSCT recipients in China,, we provide a contemporary, region-specific characterization of mucormycosis: an incidence density of 3.40 per 100 person-years, a predominance of pulmonary disease, and a concentration of cases early after transplantation. The markedly higher risk after allogeneic versus autologous transplantation (aHR = 11.75) derscores the profound impact of allogeneic immune reconstitution, conditioning-related tissue injury, and prolonged immunosuppressive therapy on host susceptibility to invasive Mucorales infection. Within this context, severe immune complications\u0026mdash;particularly severe acute GVHD (aHR = 2.97)\u0026mdash;together with disease-specific vulnerabilities such as MDS (aHR = 2.65) and prior invasive fungal infection (aHR = 2.33), emerged as independent predictors. These findings highlight a multifactorial interplay between cumulative immune deficits, tissue barrier disruption, and local microenvironmental alterations that collectively create a permissive niche for fungal invasion \u003cstrong\u003e[18-20]\u003c/strong\u003e. Although chronic hepatitis B attained significance in univariable analysis, it did not persist after multivariable adjustment; mechanistic links (for example, HBV-associated CD8\u003csup\u003e+\u003c/sup\u003e T-cell dysfunction and PD-L1-mediated immune suppression) remain biologically plausible but require prospective validation \u003cstrong\u003e[21, 22]\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eThe temporal pattern of cases was bimodal: most events clustered within the first 100 days\u0026mdash;a period characterized by neutropenia and peak immunosuppressive exposure \u0026mdash;whereas a smaller fraction of late-onset infections (\u0026gt;1 year) occurred in patients with relapsed disease or prolonged immunosuppression for chronic GVHD. This distinction suggests different predominant pathogenic pathways (treatment-related vulnerability versus cumulative immune dysfunction and environmental exposure) and argues for time-adapted surveillance and prophylactic strategies.\u003c/p\u003e\n\u003cp\u003eDespite widespread use of antifungal prophylaxis, breakthrough mucormycosis developed in 3.8% (47/1,224) of patients, nearly all within the allogeneic HSCT cohort. Within this cohort, breakthrough infection occurred more frequently and earlier among VCZ recipients compared with POS (5.7% vs. 4.1%; median onset, 70.5 vs. 94 days), consistent with the lack of anti-\u003cem\u003eMucorales\u003c/em\u003e activity of VCZ and suggesting an ecological shift that favors \u003cem\u003eMucorales\u003c/em\u003e colonization \u003cstrong\u003e[23, 24]\u003c/strong\u003e. Although POS is considered a more effective prophylactic agent, breakthrough infections still occurred, likely due to variable drug absorption, subtherapeutic serum levels, or host-related factors impairing antifungal efficacy. These findings underscore the need for individualized prophylaxis and therapeutic drug monitoring to optimize protection against mucormycosis in high-risk HSCT recipients.\u003c/p\u003e\n\u003cp\u003eFurthermore, mNGS provided species-level identification within the Mucorales order, which has increasing clinical relevance \u003cstrong\u003e[25, 26]\u003c/strong\u003e. In our cohort, 91.8% of patients underwent mNGS in combination with conventional diagnostics. \u003cem\u003eRhizopus\u0026nbsp;\u003c/em\u003espp.\u003cem\u003e\u0026nbsp;\u003c/em\u003ewas the most frequently detected species, followed by \u003cem\u003eCunninghamella\u0026nbsp;\u003c/em\u003espp. and \u003cem\u003eRhizomucor\u0026nbsp;\u003c/em\u003espp.\u003cem\u003e,\u003c/em\u003e while\u003cem\u003e\u0026nbsp;Mucor\u0026nbsp;\u003c/em\u003espp. was not identified, This distribution differs from prior reports, which ranked \u003cem\u003eRhizopus\u0026nbsp;\u003c/em\u003espp. first and \u003cem\u003eMucor\u003c/em\u003e spp. second among hematologic malignancy cases \u003cstrong\u003e[27]\u003c/strong\u003e. The divergence may reflect genuine shifts in species prevalence, enhanced detection accuracy with mNGS, geographic variation, or reporting bias. Notably, infections caused by \u003cem\u003eCunninghamella\u003c/em\u003e spp. were associated with significantly higher mortality rates compared to those caused by other \u003cem\u003eMucorales\u003c/em\u003e species (73.3% vs. 48.6%, \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05), highlighting interspecies variation in virulence and antifungal susceptibility. Additionally, mNGS revealed co-infections with bacterial, viral, or other fungal pathogens in 77.6% of cases, emphasizing its value in guiding comprehensive antimicrobial management strategies.\u003c/p\u003e\n\u003cp\u003eIn the treatment of mucormycosis, AmB remains the guideline-recommended first-line therapy, while POS and ISA have demonstrated promising efficacy\u003cstrong\u003e[28, 29]\u003c/strong\u003e. Although clinical guidelines recommend an L-AmB dosage of 5\u0026ndash;10 mg/kg, patients in our cohort received lower doses (median 2 mg/kg), partly due to the nephrotoxicity and hypokalemia associated with AmBD, which was administered to 14 patients. This dosing approach is substantiated by meta-analyses reporting comparable efficacy with lower dosages in Chinese populations \u003cstrong\u003e[30]\u003c/strong\u003e. Notably, combination therapy with AmB plus POS and/or ISA was associated with a 37.7% reduction in mortality compared with AmB monotherapy, although this difference did not reach statistical significance. These findings underscore the potential benefit of combination antifungal therapy, while highlighting the need for larger prospective or randomized studies to validate its efficacy and safety.\u003c/p\u003e\n\u003cp\u003eThere are several important limitations to this study. First, histopathological confirmation was achieved in only a small proportion of cases (8.2%), reflecting the practical challenges of obtaining invasive tissue samples in HSCT recipients. In contrast, 73.4% of cases were classified as probable mucormycosis based solely on mNGS as the microbiological criterion, in conjunction with compatible host factors, clinical manifestations, and radiological features that fulfilled the diagnostic definition. While this approach reflects real-world diagnostic practice in China, reliance on mNGS as the sole microbiological evidence may have led to an overestimation of mucormycosis incidence compared with studies that strictly adhere to the EORTC/MSGERC criteria. Second, most patients in this cohort were managed with conservative antifungal therapy, whereas surgical resection\u0026mdash;a critical determinant of prognosis\u0026mdash;was infrequently performed and therefore not included in the analysis. Third, as a single-center retrospective study, the findings primarily reflect real-world experience and should be interpreted with caution. Future multicenter prospective studies are warranted to validate molecular diagnostic methods, refine case definitions, and optimize management strategies for this rare but life-threatening infection.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study demonstrates that mucormycosis remains a rare but life-threatening complication in HSCT recipients, predominantly affecting allogeneic transplant patients. Severe aGvHD , MDS, and prior invasive fungal infection were independent risk factors, highlighting the impact of immune dysregulation and host vulnerability. Combining mNGS with conventional diagnostics enabled timely pathogen identification and revealed frequent co-infections, supporting its value in guiding targeted therapy. AMB-based regimens remain the mainstay of treatment, while combination therapy with POS or ISA showed a trend toward improved survival. These findings emphasize the need for early recognition, risk-adapted prophylaxis, and optimized antifungal management to improve outcomes in this high-risk population.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval\u003c/p\u003e\n\u003cp\u003eEthical approval for this study was obtained from the Ethics Committee of the First Affiliated Hospital of USTC (2025-RE-237), and informed consent was provided by the patients or their families. Informed consent was waived because the study involved no interventions and did not include any patient-identifiable information.\u003c/p\u003e\n\u003cp\u003eConsent for publication\u003c/p\u003e\n\u003cp\u003eNo conflict of interest exits in the submission of this manuscript, and the manuscript is approved by all authors for publication.\u003c/p\u003e\n\u003cp\u003eDeclaration of Interest Statement\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no known competing financial interests or personal\u003c/p\u003e\n\u003cp\u003erelationships that could have appeared to influence the work reported in this paper.\u003c/p\u003e\n\u003cp skip=\"true\"\u003eFunding\u003c/p\u003e\n\u003cp skip=\"true\"\u003eThis work was supported by the National Natural Science Foundation of China (grants # U23A20453 and 82270223), USTC Research Funds of the Double First-Class Initiative (YD9110002047).\u003c/p\u003e\n\u003cp\u003eAuthor information\u003c/p\u003e\n\u003cp\u003eAuthors and Affiliations\u003c/p\u003e\n\u003cp\u003eThe First Affiliated Hospital of University of Science and Technology of China, Blood and Cell Therapy Institute, Anhui Provincial Key Laboratory of Blood Research and Applications, Hefei, China\u003c/p\u003e\n\u003cp\u003eJunjie Luo, Xiaoyu Zhu\u003c/p\u003e\n\u003cp\u003eThe First Affiliated Hospital of University of Science and Technology of China, Hefei, 230001, Anhui, China;\u003c/p\u003e\n\u003cp\u003eKaidi Song, Baoling Tang, Xiang Wan, Wen Yao, Guangyu Sun, Ping Qiang,\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBGI Genomics, Shenzhen, China\u003c/p\u003e\n\u003cp\u003eKe Yuan\u003c/p\u003e\n\u003cp\u003eAuthor contributions:\u003c/p\u003e\n\u003cp\u003eX.Z. and P.Q. conceptualized and designed the study and critically revised the manuscript. J.L. and K.S. performed the clinical data analysis and drafted the manuscript. J.L., B.T., and X.W. contributed to data collection. W.Y., G.S., and K.Y. were responsible for patient management and treatment. All authors read and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003eAcknowlegements\u003c/p\u003e\n\u003cp\u003eWe sincerely thank all the participating patients for their cooperation during this study.\u003c/p\u003e\n\u003cp\u003eDeclaration of Interest Statement\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\u003c/p\u003e\n\u003cp\u003eData availability\u003c/p\u003e\n\u003cp\u003eNo datasets were generated or analysed during the current study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSipsas NV, Gamaletsou MN, Anastasopoulou A, Kontoyiannis DP, Roilides E, Walsh TJ, et al. Mucormycosis in hematopoietic stem cell transplant recipients: a systematic review. Clin Infect Dis. 2014;59:503-514.\u003c/li\u003e\n\u003cli\u003eMar\u0026oacute;n GA, Inagaki K, Rodriguez A, Knapp KM, Hayden RT, Adderson EE, et al. Mucormycosis in children with cancer and hematopoietic cell transplant: a single-center cohort study. PLoS One. 2024;19:e0297590.\u003c/li\u003e\n\u003cli\u003eSkiada A, Pagano L, Groll AH, Zhang J, Dannaoui E, Balajee SA, et al. Zygomycosis in Europe: analysis of 230 cases accrued by the registry of the European Confederation of Medical Mycology (ECMM) Working Group on Zygomycosis between 2005 and 2007. Clin Microbiol Infect. 2011;17:1859-1867.\u003c/li\u003e\n\u003cli\u003ePuerta-Alcalde P, Garcia-Vidal C. Changing epidemiology of invasive fungal disease in allogeneic hematopoietic stem cell transplantation. J Fungi (Basel). 2021;7:848.\u003c/li\u003e\n\u003cli\u003eNeofytos D, Treadway S, Ostrander D, Alonso CD, Dierberg KL, Nussenblatt V, et al. Epidemiology, outcomes and mortality predictors of invasive mold infections among transplant recipients: a 10-year, single-center experience. Transpl Infect Dis. 2013;15:233-242.\u003c/li\u003e\n\u003cli\u003ePark SY, Ardura MI, Zhang SX. Diagnostic limitations and challenges in current clinical guidelines and potential application of metagenomic sequencing to manage pulmonary invasive fungal infections in patients with haematological malignancies. Clin Microbiol Infect. 2024;30:1139-1146.\u003c/li\u003e\n\u003cli\u003eChandley P, Subba P, Rohatgi S. COVID-19-Associated mucormycosis: a matter of concern amid the SARS-CoV-2 pandemic. Vaccines. 2022;10:1266.\u003c/li\u003e\n\u003cli\u003eSahu RK, Salem-Bekhit MM, Bhattacharjee B, Almoshari Y, Ikbal AMA, Alshamrani M, et al. Mucormycosis in Indian COVID-19 patients: insight into its patho-genesis, clinical manifestation, and management strategies. Antibiotics (Basel). 2021;10:1079.\u003c/li\u003e\n\u003cli\u003eTissot F, Agrawal S, Pagano L, Cornely OA, Ribaud P, Herbrecht R, et al. ECIL-6 guidelines for the treatment of invasive candidiasis, aspergillosis and mucormycosis in leukemia and hematopoietic stem cell transplant patients. Haematologica. 2017;102:433-444.\u003c/li\u003e\n\u003cli\u003eDonnelly JP, Chen SC, Kauffman CA, Steinbach WJ, Baddley JW, Verweij PE, 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.\u003c/li\u003e\n\u003cli\u003eSafiia J, D\u0026iacute;az MA, Alshaker H, Atallah CJ, Sakr P, Moshovitis DG, et al. Recent advances in diagnostic approaches for mucormycosis. J Fungi (Basel). 2024;10:727.\u003c/li\u003e\n\u003cli\u003eWang J, Liu L, Li J, Li M, Zhao L, et al. Clinical characteristics, prognosis factors and metagenomic next-generation sequencing diagnosis of mucormycosis in patients with hematologic diseases. Mycopathologia. 2024;189:71.\u003c/li\u003e\n\u003cli\u003eZhang M, Lu W, Xie D, Chen S, Li Y, et al. Metagenomic next-generation sequencing for diagnostically challenging mucormycosis in patients with hematological malignancies. Infect Drug Resist. 2022;15, 7509-7517.\u003c/li\u003e\n\u003cli\u003eCornely OA, Alastruey-Izquierdo A, Arenz D, Chen S, Dannaoui E, Hochhegger B, et al. Global guideline for the diagnosis and management of mucormycosis: an initiative of the European Confederation of Medical Mycology in cooperation with the Mycoses Study Group Education and Research Consortium. Lancet Infect Dis. 2019;9, e405-e421.\u003c/li\u003e\n\u003cli\u003eXu C, Zhang Y, Li Y, Huang X, Chen H, et al. China expert consensus on the application of metagenomic next-generation sequencing in the diagnosis of infections in patients with hematologic disorders. Blood Sci. 2025;10:1-10.\u003c/li\u003e\n\u003cli\u003eChinese Society of Laboratory Medicine Clinical Microbiology Group; Chinese Society of Microbiology and Immunology Clinical Microbiology Group; Chinese Medical Doctor Association Clinical Microbiology and Infection Group. Chinese expert consensus on metagenomics next-generation sequencing application on pathogen detection of infectious diseases. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2020;32:632-639.\u003c/li\u003e\n\u003cli\u003eWestin JR, Saliba RM, De Lima M, Couriel D, Shpall EJ, Ayash L. Steroid-Refractory acute GVHD: predictors and outcomes. Adv Hematol. 2011;2011:601953.\u003c/li\u003e\n\u003cli\u003eAndrianaki AM, Kyrmizi I, Thanopoulou K, Tsitsigiannis DI, Momany M, Klimko C. Iron restriction inside macrophages regulates pulmonary host defence against Rhizopus species. Nat Commun. 2018;9:2205.\u003c/li\u003e\n\u003cli\u003eBriard B, Fontaine T, Samir P, Beauvais A, Latg\u0026eacute; JP, Mouyna I.Galactosaminogalactan activates the inflammasome to provide host protection. Nature. 2020;588:688-692.\u003c/li\u003e\n\u003cli\u003eKim CH, Leitch HA. Iron overload\u0026ndash;induced oxidative stress in myelodysplastic syndromes and its cellular sequelae. Crit Rev Oncol Hematol. 2021;166:103367.\u003c/li\u003e\n\u003cli\u003eYu X, Yang F, Shen Z, Zhang Y, Sun J, Qiu C, et al. BTLA contributes to acute-on-chronic liver failure infection and mortality through CD4+ T-cell exhaustion. Nat Commun. 2024;15:1835.\u003c/li\u003e\n\u003cli\u003eJiang D, Chen C, Yan D, Zhang X, Liu X, Yan D, et al. Exhausted phenotype of circulating CD8+ T cell subsets in hepatitis B virus carriers. BMC Immunol. 2022;23:18.\u003c/li\u003e\n\u003cli\u003eTrifilio SM, Bennett CL, Yarnold PR, McKoy JM, Parada J, Mehta J, et al. Breakthrough zygomycosis after voriconazole administration among patients with hematologic malignancies who receive hematopoietic stem-cell transplants or intensive chemotherapy. Bone Marrow Transplant. 2007;39:425-429.\u003c/li\u003e\n\u003cli\u003eTrifilio S, Singhal S, Williams S, Frankfurt O, Gordon L, Evens A, et al. Breakthrough fungal infections after allogeneic hematopoietic stem cell transplantation in patients on prophylactic voriconazole. Bone Marrow Transplant. 2007;40:451-456.\u003c/li\u003e\n\u003cli\u003eLi J, Ge Y, Xin C, Jiang L. Rhino-orbital-cerebral mucormycosis caused by Rhizopus arrhizus diagnosis via metagenomics next-generation sequencing: a case report. Front Cell Infect Microbiol. 2024;14:1375058.\u003c/li\u003e\n\u003cli\u003eWen B, Cai L, Cai Y, Du X. Case report: metagenomics next-generation sequencing for diagnosing cerebral infarction and infection caused by haematogenous disseminated mucormycosis in a patient with acute lymphoblastic leukaemia. Front Med. 2021;8:779981.\u003c/li\u003e\n\u003cli\u003eGomes MZR, Lewis RE, Kontoyiannis DP. Mucormycosis caused by unusual mucormycetes, Non-Rhizopus, -Mucor, and -Lichtheimia Species. Clin Microbiol Rev. 2011;24:411-445.\u003c/li\u003e\n\u003cli\u003eCornely OA, Maertens J, Bresnik M, Ebrahimi R, Ullmann AJ, Bouza E, et al. Liposomal amphotericin B as initial therapy for invasive mold infection: AmBiLoad Trial. Clin Infect Dis. 2007;44:1289-1297.\u003c/li\u003e\n\u003cli\u003eMarty FM, Ostrosky-Zeichner L, Cornely OA, Mullane KM, Perfect JR, Thompson GR, et al. Isavuconazole treatment for mucormycosis: a single-arm open-label trial and case-control analysis. Lancet Infect Dis. 2016;16:828-837.\u003c/li\u003e\n\u003cli\u003eWei LW, Zhu PQ, Chen XQ, Yu J. Mucormycosis in Mainland China: a systematic review of case reports. Mycopathologia. 2019;187:1-14.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"annals-of-clinical-microbiology-and-antimicrobials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cmam","sideBox":"Learn more about [Annals of Clinical Microbiology and Antimicrobials](http://ann-clinmicrob.biomedcentral.com/)","snPcode":"12941","submissionUrl":"https://submission.nature.com/new-submission/12941/3","title":"Annals of Clinical Microbiology and Antimicrobials","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Mucormycosis, Hematopoietic stem cell transplantation, Breakthrough infection, Risk factors, Antifungal prophylaxis","lastPublishedDoi":"10.21203/rs.3.rs-8122974/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8122974/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThis study aimed to update the epidemiology and clinical characteristics of mucormycosis, a rare but life-threatening invasive fungal infection in hematopoietic stem cell transplantation (HSCT) recipients.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe conducted a retrospective, single-center observational study including all consecutive HSCT recipients from November 2020 to October 2024, with follow-up through May 2025.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eAmong 1,224 HSCT recipients receiving antifungal prophylaxis, mucormycosis occurred at an incidence density of 3.40 per 100 person-years, with a median onset of 73 days post-transplant (interquartile range, 30\u0026ndash;223 days). Pulmonary involvement was present in 75.5% of cases. Rhizopus spp. accounted for the highest proportion (37.3%) among the isolated fungal genera. Multivariate analysis identified myelodysplastic syndrome (adjusted hazard ratio [aHR]\u0026thinsp;=\u0026thinsp;2.65), prior fungal infection (aHR\u0026thinsp;=\u0026thinsp;2.33), and severe acute graft-versus-host disease (aGvHD) (aHR\u0026thinsp;=\u0026thinsp;2.97) as independent risk factors. Among 43 patients treated with antifungals, the 84-day survival rate was 46.5%. Severe aGvHD was an independent predictor of mortality. Combination therapy with amphotericin B plus posaconazole or isavuconazole tended to reduce treatment failure compared to amphotericin B alone (42.3% vs. 80.0%; P\u0026thinsp;=\u0026thinsp;0.172).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eMucormycosis poses a serious risk post-HSCT; early identification and optimized treatment are critical to improving outcomes.\u003c/p\u003e","manuscriptTitle":"Breakthrough Mucormycosis After Hematopoietic Stem Cell Transplantation: A Retrospective Multiyear Cohort Study in Eastern China","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-22 12:27:57","doi":"10.21203/rs.3.rs-8122974/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-04-02T20:06:26+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-31T16:30:30+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-26T13:16:56+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"93696066742588403102927913161342694374","date":"2026-03-03T10:07:08+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"2287219573203768587834283589767128482","date":"2026-02-26T14:05:37+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"61081001118506363992903088036191307726","date":"2026-02-24T19:08:21+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-13T13:56:09+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-13T07:16:10+00:00","index":"","fulltext":""},{"type":"submitted","content":"Annals of Clinical Microbiology and Antimicrobials","date":"2026-02-12T08:41:47+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"annals-of-clinical-microbiology-and-antimicrobials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cmam","sideBox":"Learn more about [Annals of Clinical Microbiology and Antimicrobials](http://ann-clinmicrob.biomedcentral.com/)","snPcode":"12941","submissionUrl":"https://submission.nature.com/new-submission/12941/3","title":"Annals of Clinical Microbiology and Antimicrobials","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"509b2578-b667-4208-9908-0fc09b952ca6","owner":[],"postedDate":"February 22nd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-17T16:53:10+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-22 12:27:57","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8122974","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8122974","identity":"rs-8122974","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}