SUMMARYIatrogenic central nervous system mold infections (ICNSMIs) are rare and occur as sporadic complications of neurosurgical procedures or device insertions. However, recent outbreaks have been reported in outpatient settings, following epidural injections with contaminated medicines. We conducted a comprehensive literature review of studies published without date restrictions through July 2025 on ICNSMIs. We identified 905 cases of such infections, with 4% occurring in non-outbreak settings and 96% associated with five documented outbreaks. In both non-outbreak and outbreak settings, infections were more common after spinal/epidural injections, with contaminated medicines or supplies being the primary source. Due to their angioinvasive tendencies, ICNSMI caused by Fusarium solani and Aspergillus species had a higher frequency of stroke/intracranial hemorrhage (P = 0.011), aneurysm formation (P = 0.012), and resulted in higher mortality compared with ICNSMI caused by other molds (P < 0.001). ICNSMI, as a result of catheter-associated fungemia, was very rare (only one case). Strategies to identify ICNSMI in exposed individuals during an outbreak have included (i) symptom-driven lumbar puncture, (ii) screening lumbar puncture regardless of symptoms, and (iii) screening brain MRI regardless of symptoms. Measurement of (1→3)-β-D-glucan in cerebrospinal fluid was a valuable tool to diagnose ICNSMI preemptively. Outcomes of ICNSMI following neurosurgical procedures were poor (90-day mortality of 35%) and depended on the route of inoculation, mold species, timing of diagnosis, and prompt initiation of appropriate antifungal therapy in combination with source control. Patients with ICNSMI often suffered long-term neurologic sequelae, even with the most optimal management strategies.

Invasive aspergillosis (IA) remains a common cause of both direct and contributable mortality in patients with hematologic malignancies (HM). Given the advances in antifungal management, it would be important to assess IA-attributable mortality (AM) and contributable mortality (CM), in addition to overall mortality (OM). We retrospectively reviewed the records of 76 consecutive HM patients with proven/probable culture-positive IA (MSG/EORTC criteria) from 2015 to 2021. Death causality was adjudicated based on published criteria. AM was defined as death “due to” IA, while CM as death “due to” and “with” IA. OM encompassed death from any cause. Mortality rates and death causalities were evaluated at 2-, 4-, 6-, and 12-week intervals following IA diagnosis. A multivariate competing risk analysis was performed to identify independent risk factors for 6-week AM, with other death causalities as the competing event. To increase diagnostic accuracy, we excluded culture-negative, Aspergillus galactomannan (GM) positive cases, as GM can be produced by other hyalohyphomycetes. The median patient age was 60 years (61%). Lymphoma and multiple myeloma (L/MM) were the most common HM (40, 53%). The remaining patients had active leukemia. Twenty-nine patients (38%) had prior stem cell transplantation, and 10 (13%) had graft-versus-host disease. Aspergillus fumigatus was the most common species (47%). Six and 12-week mortality rates were 18.7% and 22.7% for AM, 42.7% and 49.3% for CM, and 45.3% and 53.3% for OM, respectively. Notably, 2-week OM was 27.6%. Lack of neutrophil recovery was the only independent risk factor for 6-week AM on multivariate analysis (OR=4.2, p=0.006). Our findings reflect the modern reality of culture-documented IA, occurring mostly in HM patients with heavily pretreated L/MM not routinely receiving mold-active prophylaxis, and in those with active leukemia. In this real-life contemporary HM population, culture-positive IA was associated with high cumulative OM and CM. Understanding AM and CM rates could lead to more accurate sample size estimations in clinical mycology trials. Such trials should be pragmatic and assess antifungal failure at an earlier time point than the traditional 4-week mark post-diagnosis. Dimitrios P. Kontoyiannis, MD, AbbVie, Inc: Advisory Board Participation|Astellas: Grant/Research Support|Basilea: Advisor/Consultant|Cidara, Inc: Advisory Board Participation|F2G, Inc: Advisor/Consultant|Gilead: Advisor/Consultant|Gilead: Grant/Research Support|Knight, Inc: Honoraria|Pfizer: Advisor/Consultant|Scynexis: Advisor/Consultant|TTF Pharmaceuticals, Inc: Advisor/Consultant|US-Israel Binational Sci Foundation: Grant/Research Support

Mucormycosis is an emerging, life-threatening human infection caused by Mucorales fungi1-3. Metabolic disorders uniquely predispose an ever-expanding group of patients to mucormycosis through poorly understood mechanisms1,2,4,5, suggesting that uncharacterized host metabolic effectors may confer protective immunity against this infection. Here we uncover a master regulatory role of albumin in host defence against Mucorales through the modulation of fungal pathogenicity. Our initial studies identified severe hypoalb uminaemia as a prominent metabolic abnormality and an independent biomarker of poor mucormycosis outcome across three distinct cohorts of patients with mucormycosis. Notably, purified albumin selectively inhibits Mucorales growth among a range of pathogens, and albumin-deficient mice display susceptibility specifically to mucormycosis. The antifungal activity of albumin is mediated by the release of bound free fatty acids (FFAs). Albumin prevents FFA oxidation, which otherwise abolishes their antifungal properties, and sera from patients with mucormycosis display high levels of oxidized FFAs. Physiologically, albumin-bound FFAs suppress the expression of key virulence factors by inhibiting protein synthesis, the reby rendering Mucorales avirulent in vivo. Overall, we identify a host defence mechanism that directs the pathogen to suppress its pathogenicity program in response to unfavourable metabolic cues regulated by albumin. These findings have major implications for the pathogenesis and management of mucormycosis.

BACKGROUND:BK virus infection is a marker of poor immune recovery, especially after kidney or allogeneic cell transplantation. Because of the challenges associated with BK virus infection and the lack of effective treatments, there is a growing interest in novel approaches, such as adoptive cellular therapy, that aim to restore antiviral immunity and promote viral clearance. METHODS:Our clinical trial assessed the feasibility, safety, and efficacy of administering third-party, BK virus-specific cytotoxic T lymphocytes (CTLs) used to treat allogeneic HCT patients and kidney transplant patients with biopsy-proven BK-virus nephropathy. Comprehensive clinical assessments and correlative studies were performed. RESULTS:The study included six patients after kidney-transplantation and five HCT recipients. Viremia declined in most evaluable patients by Day 45 after BKCTL infusion. No new instances of graft-versus-host disease, kidney-transplant rejection, graft failure, or infusion-related toxicities were attributed to the treatment. Antiviral activity (as assessed by interferon-γ secretion) did not differ between infused BKV-CTLs given to kidney-transplant versus allogeneic SCT recipients. CONCLUSION:In this study, we longitudinally tracked the in vivo persistence of adoptively transferred BKV-CTLs and demonstrated their sustained functional activity. This therapy could be promising in KT and SCT patients with recent-onset BK-virus viremia.

Vincristine (VCR) is an essential component of combination chemotherapy for patients (pts) with acute lymphoblastic leukemia (ALL). VCR neurotoxicity (NTX) which can present as peripheral neuropathy, constipation, or ileus, is a well-known dose-limiting side effect. As pts with ALL are at risk of invasive fungal infections (IFIs), azoles are often used as prophylaxis, but excess NTX is a concern due to the inhibition of VCR metabolism. Our practice is to hold the azole for 72 hours around VCR administration. There is limited data on the clinical significance of the azole-VCR interaction in the adult pts with ALL. We reviewed the records of all pts > 18 yrs with newly diagnosed ALL who received treatment with Hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone) with ofatumumab (O-Hyper-CVAD; NCT01363128) or ponatinib (NCT01424982). NTX was graded according to CTCAE v5.0 and IFIs classified according to EORTC/MSG criteria. A total of 289 VCR episodes were evaluated among 111 pts. 81 pts (73%) received azole prophylaxis, mostly voriconazole ( VOR; 53%). Forty-one pts (37%) experienced NTX. Median age, frequency of concomitant neurotoxic agents, and baseline neuropathy, diabetes, and liver function tests were similar between pts with or without NTX. Twenty-six pts (63%) who experienced NTX received O-Hyper-CVAD and 15 pts (37%) Hyper-CVAD and ponatinib (p=0.07). Median time between VCR initiation and NTX onset was 54 days (range, 1-183). NTX was typically grade 1 (54%) or 2 (39%) and included peripheral neuropathy (85%) and ileus/constipation (20%). Among all VCR episodes, azoles were administered in 58% of those with NTX reported and in 48% of those without (p=NS). VOR was administered in 50% of the VCR episodes with NTX versus 33% of the episodes without NTX (p=0.043). Concomitant VOR was the only factor significantly associated with an increased risk of NTX (OR: 2.49; 95% CI: 1.22-5.12, p=0.013). Only 2 pts (2%) developed an IFI (1 Rhizopus sinusitis; 1 probable pulmonary aspergillosis) while on VOR prophylaxis. Although severe NTX was uncommon during VCR and azole co-administration, VOR may increase the risk of NTX. The rate of breakthrough IFIs is low in contemporary adult ALL pts who are predominantly on azole prophylaxis. Elias Jabbour, MD, Abbvie: Grant/Research Support|Adaptive Biotechnologies: Grant/Research Support|Amgen Pharmaceuticals: Grant/Research Support|Ascentage: Grant/Research Support|Novartis: Grant/Research Support|Pfizer: Grant/Research Support|Takeda: Grant/Research Support Dimitrios P. Kontoyiannis, MD, AbbVie, Inc: Advisory Board Participation|Astellas: Grant/Research Support|Basilea: Advisor/Consultant|Cidara, Inc: Advisory Board Participation|F2G, Inc: Advisor/Consultant|Gilead: Advisor/Consultant|Gilead: Grant/Research Support|Knight, Inc: Honoraria|Pfizer: Advisor/Consultant|Scynexis: Advisor/Consultant|TTF Pharmaceuticals, Inc: Advisor/Consultant|US-Israel Binational Sci Foundation: Grant/Research Support

Guidelines recommend liposomal amphotericin B (L-AMB) at 5-10 mg/kg/day as first-line therapy for invasive mucormycosis, but whether doses exceeding 5-6 mg/kg/day improve outcomes enough to justify added nephrotoxicity and cost remains unclear. We critically appraised pharmacokinetic, preclinical, and clinical evidence from 58 publications, defining standard-dose L-AMB as 5-6 mg/kg/day and high-dose (HD) L-AMB as >6 mg/kg/day. Animal models show dose-dependent efficacy, but the only prospective trial (Ambizygo) examining HD-L-AMB was a single-arm pilot trial whose response rates were similar to historical 5 mg/kg/day cohorts. Retrospective studies have not found survival benefit favoring HD L-AMB, with consistently higher rates of nephrotoxicity. Saturable pharmacokinetics and altered liposome distribution at doses >10 mg/kg/day may explain this lack of benefit. Routine dose escalation beyond 5-6 mg/kg/day is not supported by current evidence; early diagnosis, surgical debridement, and reversal of immunosuppression appear more critical. However, selected cases may still warrant higher L-AMB doses based on individualized risk-benefit assessment.

Drug-resistant fungal disease must be addressed in the 2026 update to the Global Action Plan on Antimicrobial Resistance

Given competing death causalities among hematological malignancy patients with invasive aspergillosis (IA), we assessed IA-attributable, contributable, and all-cause mortalities in patients with culture-confirmed IA. Although attributable mortality decreased, contributable and all-cause mortalities remained high. Our data suggest that improving survival would require host augmentation, in addition to improved antifungals.

The treatment of invasive fungal diseases is unsatisfactory because of high morbidity and mortality despite antifungal therapy. These patients are often immunocompromised, and improvements in treatment outcome are likely to require immune therapy. To promote immune therapies against fungal diseases, the International Immunotherapy Society for Fungal Diseases was organized.

Background: As hyperbaric oxygen therapy has been sporadically used in combination with antimicrobial treatment for refractory infections in patients with hematologic malignancies, data on its efficacy and outcomes are limited. Methods: We retrospectively analyzed 55 patients with hematologic malignancies treated with hyperbaric oxygen therapy over a 10-year period at a single tertiary care center and report on patients' clinical features, infection types, treatment responses, and survival outcomes. Results: The most common underlying hematologic malignancy diagnosis was acute myeloid leukemia (30 patients, 55%). The most common hyperbaric oxygen therapy indications were invasive mold disease (IMD) (35 patients, 64%), BK virus-associated cystitis (17 patients, 31%), and bacterial cellulitis (3 patients, 5%). Patients underwent a median of 10 hyperbaric oxygen therapy sessions (range, 1-45). In total, 54 (98%) of the 55 patients were evaluable for response, of whom 32 (59%) patients demonstrated a response, defined as either resolution or stabilization of the infection. Among the 35 patients with IMDs, we found that 11 patients (31%) achieved a complete response, 5 (14%) had a partial response, 6 (17%) had stable disease, and 13 (37%) patients experienced progression of their infection. In contrast, among the 17 patients with BK virus-associated cystitis, 9 patients (53%) had persistent or worsening hematuria. The two evaluable patients with bacterial cellulitis responded with resolution of the infection. We reviewed the status of the hematologic malignancies at the time of hyperbaric oxygen therapy treatment and found that the 21 patients whose hematologic malignancies were in remission tended to have a higher response rate of their infection compared to patients whose hematologic malignancies were not in remission (73% vs. 46% p = 0.057). Despite the response of infections, 1-year mortality in these patients remained high at 76%. Conclusions: Based on our experience, hyperbaric oxygen therapy, in conjunction with appropriate anti-infective therapy and debridement surgery, could benefit selected patients with hematologic malignancies, especially those whose underlying disease is controlled but experience recalcitrant bacterial or fungal infections.

The evidence supporting the impact of global warming on the epidemiology of infectious diseases, including fungal infections, is increasing. Fungi have a remarkable ability to adapt to heat and pollution, and to disseminate via air, water ecosystems, or wildfire smoke. Their genetic plasticity can lead to thermotolerance, the ability to find new ecological niches, and fitness gains. Natural reservoirs of the fungal biomass, which are heavily affected by global warming, may serve as the environments from where new fungal diseases originate, as illustrated by the recent emergence of Candidozyma auris and Rhodosporidiobolus fluvialis. Moreover, global warming also affects human skin/mucosal integrity and local or systemic immune responses, which could increase host susceptibility to fungal infections. This review examines the impact of global warming on the complex fungi-host interactions, which can lead to new challenges in mycology, and discusses possible mitigation strategies.

Most iatrogenic central nervous system fungal infections (ICNSFIs) are caused by Candida species or molds. However, the ICNSFIs caused by non-Candida yeasts and dimorphic molds have not been evaluated. In the literature review, we identified 24 cases of potential non-Candida yeasts and dimorphic molds-related ICNSFIs, 75% were associated with CNS diversion devices, and 63% were Cryptococcus neoformans infection. The median time from the procedure to the onset of CNS symptoms was 6.5 months. These patients had mild cerebrospinal fluid pleocytosis (median WBC, 12 × 10⁶/l). The 90-day mortality rate was 17%.

Invasive pulmonary mucormycosis (IPM) is a severe opportunistic mold infection whose outcome is predominantly host driven. Preclinical proof-of-concept studies and clinical case reports in salvage therapy settings suggested a benefit of immune checkpoint inhibitors (ICIs) in IPM management. However, the kinetics of infection-induced immune paralysis and optimal timing of ICI therapy remain poorly understood. Here, we performed sequential nCounter-based transcriptomics on lung tissue of cyclophosphamide-immunosuppressed mice with IPM (Rhizopus arrhizus infection) to dynamically study the pulmonary immune environment. Within 7 d after infection, lungs of mice with IPM showed reversal of early proinflammatory signaling, impaired T cell signaling, and upregulation of exhaustion markers. Similar immune paralysis signatures were seen in mice with invasive pulmonary aspergillosis and fusariosis. For therapeutic studies, Mucorales-active antifungal therapy with isavuconazonium sulfate (ISAV) was initiated on day 3 after IPM infection, along with anti-PD-L1 or a nontargeting isotype antibody (control) given either on days 3 + 5 (early) or days 6 + 8 (late). Both early and late adjunct anti-PD-L1 therapy were well tolerated and significantly improved morbidity/mortality outcomes compared to ISAV + isotype. Notably, early adjunct anti-PD-L1 therapy promoted significantly stronger innate immune cell activation, upregulation of key cytokine pathways, reinvigoration of T-helper-cell signaling, and reversal of IPM-induced exhaustion signals than both late adjunct anti-PD-L1 and isotype control. These findings indicate that combined antifungal and early immunomodulatory therapy may be an important strategy to intercept immune paralysis and improve outcomes in immunocompromised hosts with IPM, inviting further preclinical and clinical exploration of early host-directed interventions to treat deadly mold pneumonias.

Epidemiologic trends in pulmonary mold infections were assessed. Of 227 infections, 24 were considered late-onset (>14 days) and Aspergillus less common (58.3% vs 78.3%; P = .030). For late-onset cases, Aspergillus was dramatically less frequent from 2020-2025 compared to 2014-2019 (11.1% vs 86.7%, P < .001), while Fusarium spp. increased (44.4% vs 0%, P = .012).

The prognosis of mucormycosis after hematopoietic stem cell transplantation (HSCT) is generally poor but data on post-HSCT outcomes in patients with pre-HSCT mucormycosis are limited. We reviewed patients with documented mucormycosis at MD Anderson Cancer Center (2008–2024) and identified five patients who subsequently underwent HSCT. A literature review identified 24 additional such cases. Most patients had acute myeloid leukemia (69%). The most common site of mucormycosis was pulmonary (59%), while 31% had disseminated mucormycosis. All patients received antifungals and 76% had surgery prior to HSCT. At the time of HSCT, 67% had mucormycosis responding to treatment. No patient went to transplant with progressing mucormycosis. Eighty percent of patients with ≥12 months of follow-up after HSCT were alive. Five of the twenty-nine patients (17%) had documented or suspected mucormycosis recurrence post-HSCT. Relapsed malignancy pre-HSCT was associated with increased 12-month post-HSCT mortality (p = 0.031). Furthermore, post-transplant mortality was higher in cord blood recipients (p = 0.019) and tended to be higher in patients not undergoing surgery pre-HSCT (p = 0.062). Despite publication bias, our data suggest that HSCT can be conducted safely in selected patients with pre-HSCT mucormycosis, particularly when underlying hematologic malignancy is in remission, mucormycosis is stable, and surgical source control is feasible.

Abstract Background Invasive aspergillosis (IA) is a significant cause of morbidity and mortality in patients with haematological malignancy (HM) patients and hematopoietic stem cell transplant (HSCT) recipients. A. terreus is well known to be more resistant to amphotericin B regimens and is associated with worse outcomes as compared to non-terreus Aspergillus species. After the first introduction of effective anti-mold azole in May 24,2002, there has been limited data showing the change in in etiology of culture documented IA. We retrospectively reviewed all HM and HSCT patients with a positive culture of Aspergillosis who were treated for either definite or probable IA over the past three decades (1993-2023). Methods We compared baseline characteristics, antifungal prophylaxis and treatment between patients infected with A. terreus and those infected with non-terreus Aspergillus between July 1993 and July 2023 with a follow up period of 12 weeks. We examined the rate of A. terreus across the 3 decades 1993 – 2003, 2004 – 2013, and 2014-2023. Results A total of 699 patients with culture -documented IA were analyzed, 537 with A. non-terreus species and 162 with A. terreus. Type of underlying malignancy (HM and HSCT), neutropenia as well as GVHD were similar in both groups. Anti-mold prophylaxis was similar in both groups. After the introduction of anti-mold azoles, the rate of A. terreus decreased significantly from 35.9 % between 1993-2003 to 11.2% between 2004-2013 (p< 0.0001) and from 35.9% between 1993-2003 to 16.7% between 2014-2023 (p< 0.0001). ICU stay and mechanical ventilation were more common among patients with A. terreus (p=0.002). All-cause mortality at 6 weeks and at 12 weeks was significantly higher in patients with A. terreus (p< 0.01). Similarly, IA-associated 6 weeks mortality was significantly higher among patients with A. terreus (43 % vs 29%, p< 0.01). Conclusion The rate of IA due to A. terreus decreased significantly with the introduction of anti-mold azoles. However, IA caused by A. terreus continues to have poor prognosis in HM patients. Disclosures Dimitrios P. Kontoyiannis, MD, AbbVie: Advisor/Consultant|Astellas Pharma: Advisor/Consultant|Astellas Pharma: Grant/Research Support|Astellas Pharma: Honoraria|Cidara Therapeutics: Advisor/Consultant|Gilead Sciences: Advisor/Consultant|Gilead Sciences: Grant/Research Support|Gilead Sciences: Honoraria|Knight: Advisor/Consultant|Merck: Advisor/Consultant|Scynexis: Advisor/Consultant

OBJECTIVES:Severe and prolonged neutropenia is associated with poor outcomes of invasive pulmonary aspergillosis (IPA) in leukemia patients. Given the high frequency of IPA in patients with relapsed/refractory leukemia, we studied the association of peripheral blood blast burden (blastemia), IPA outcomes, and antifungal immune failure, even without neutropenia. METHODS:We retrospectively reviewed adult patients with acute leukemia (AL) or myelodysplastic syndrome and culture-positive proven/probable IPA (2011-2022). Blast and neutropenia indices were calculated and incorporated into multi-variable prognostic models. The impact of blasts on immune cell-mediated fungal clearance was studied in vitro. RESULTS:Among 74 patients, 69% had neutropenia and 57% had blastemia at IPA diagnosis. Blast index ≥90 at IPA diagnosis and ≥3 lines of prior chemotherapies were independent predictors of 42-day mortality and early antifungal treatment failure. Leukemic blasts had minimal immune activity against Aspergillus fumigatus and impaired fungal inhibition by peripheral blood mononuclear cells. CONCLUSION:Blastemia is common in contemporary leukemia patients with IPA and is a significant risk factor for poor IPA outcomes, possibly due to interference with fungal clearance by immune cells. Therefore, blastemia should be considered as a risk stratification parameter in future mycology trials and as an experimental variable in preclinical IPA models.

Mold-active prophylaxis has reduced the incidence of invasive pulmonary aspergillosis (IPA) in patients with hematological malignancies (HMs), but breakthrough IPA (Bt-IPA) is increasingly encountered. Therefore, we studied determinants of Bt-IPA risk and its prognostic significance. We retrospectively reviewed culture-positive proven/probable IPA cases in HM patients at MD Anderson Cancer Center (2016–2021). Bt-IPA and non-Bt-IPA cases were compared to characterize risk factors, clinical presentation, and outcomes. Independent predictors of 42-day all-cause mortality were assessed using propensity score-adjusted Cox regression. Among 118 IPA cases, 50 (42.4%) were Bt-IPA. Bt-IPA was associated with acute leukemia/myelodysplastic syndrome, active HM, severe neutropenia (<100/mm3), and graft-versus-host diseases. Uncommon Aspergillus species (non-fumigatus, flavus, terreus, or niger) were more frequent in Bt-IPA than non-Bt-IPA (20.4% vs. 4.8%, p = 0.010). Forty-two-day mortality was higher in Bt-IPA (65.3% vs. 37.3%, p = 0.003), but Bt-IPA itself was not an independent predictor or mortality (p = 0.064), which was instead driven by neutropenia (p = 0.020) and hypoalbuminemia (p = 0.002). In conclusion, Bt-IPA accounted for nearly half of contemporary IPA cases and was linked to host-related risk factors and the recovery of uncommon Aspergillus species. Although not an independent prognostic predictor, Bt-IPA reflected poor host status. Thus, early diagnosis, immune enhancement strategies, and effective first-in-class antifungals may improve outcomes.