Aspergillus calidoustus and Talaromyces columbinus infections in chronic graft-versus-host disease.

Advancements in allogeneic haematopoietic stem cell transplant (alloHSCT) procedures have improved patient outcomes over the last two decades, though invasive fungal infections (IFIs) remain a significant risk. The incidence of IFIs in alloHSCT recipients is estimated at 6%, with a mortality rate of 13%, and Aspergillus species are the most common pathogens involved. Posaconazole is effective in preventing IFIs post-transplant and is standard care during neutropenia or when managing graft-versus-host disease (GvHD) with high-dose steroids. However, azole prophylaxis may cause resistant Aspergillus species like A. calidoustus, which are difficult to treat. We report a case from our institution where a patient developed a dual infection with Aspergillus calidoustus and Talaromyces columbinus after alloHSCT and posaconazole prophylaxis. While A. calidoustus is known to cause IFIs in HSCT recipients, T. columbinus represents a previously unreported occurrence in medical literature. This case underscores the importance of a multifaceted diagnostic strategy, integrating BAL diagnosis, mycological cultures, direct microscopy, fungal speciation, susceptibility testing, and biomarkers. These comprehensive approaches are indispensable for accurate pathogen identification and effective management of IFIs with appropriate antifungal agents.

Disseminated Mucormycosis and T-Cell-Depleted Allogeneic Stem Cell Transplantation: An Unusual Case Study.

INTRODUCTION: Invasive fungal infections are a primary cause of morbidity and mortality in patients with haematological malignancies. CASE PRESENTATION: We describe an unusual clinical and radiological presentation of invasive mucormycosis (IM) in a 69-year-old patient with relapsed acute myeloid leukaemia. The patient was diagnosed with disseminated IM with involvement of the central nervous system in an atypical location, lung, spleen, muscle, bone, and heart, after having completed induction and bridging chemotherapy to allogeneic haematopoietic stem cell transplant (HSCT). Her clinical presentation was atypical with mild neurological symptoms slowly progressing over 2 months and without appropriate signs of systemic inflammation. Mucorales was eventually confirmed from bronchoalveolar lavage and subdural collection. CONCLUSION: This report highlights the difficult challenges of managing disseminated IM in an immunocompromised patient, where close multidisciplinary specialist care enabled successful treatment, followed by T-cell-depleted allogeneic HSCT for a high-risk haematological malignancy.

A rapidly expanding cutaneous tumour in the context of a Janus kinase inhibitor agent following allogeneic stem cell transplant.

Ruxolitinib is a selective, Janus kinase (JAK)1 and JAK2 inhibitor, which is effective in management of chronic graft-versus-host disease (cGvHD). However, the ensuing immunosuppressive effects can give rise to aggressive cutaneous tumours, including Merkel cell carcinoma. We present this case to highlight the development of cutaneous tumours with ruxolitinib, an increasingly used therapy, and the challenge of managing such tumours in the context of refractory cGvHD. Click here for the corresponding questions to this CME article.

Early and late-onset veno-occlusive disease/sinusoidal syndrome post allogeneic stem cell transplantation - a real-world UK experience.

Classical veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a serious complication post allogeneic hematopoietic stem cell transplantation (HSCT). Before the recently revised EBMT criteria, the Baltimore and modified Seattle criteria failed to recognize the syndrome of late-onset VOD. We present real-world experience from a large UK transplant center reporting on VOD/SOS in consecutive HSCT adult patients (n = 530), transplanted for hematological cancers. We identified 27 patients treated with Defibrotide for VOD/SOS diagnosis, where detailed data were available for final analysis. Using standard definitions including EBMT criteria, around 30% (n = 8/27) of cases classified as late-onset VOD presenting at median of 46 (22-93) days but with D100 survival (63% vs 58%, Log-rank; P = 0.81) comparable to classical VOD. Hazard ratio for D100 mortality was 2.82 (95% CI: 1.74-4.56, P < .001, Gray test) with all VOD/SOS events. Twenty percent (n = 2/8) of late-onset VOD patients were anicteric and 42% (n = 8) classical VOD patients presented with refractory thrombocytopenia, while less than half met EBMT criteria for classical VOD in adults, highlighting gaps in real-world diagnostic limitations using EBMT criteria. However, challenges remain about underrecognition and difficulties related to early defibrotide access for treatment of late-onset VOD in current treatment guidelines. Our report strongly supports early Defibrotide for the treatment of severe VOD/SOS in adults regardless of time of onset.

Epstein-Barr Virus and Monoclonal Gammopathy of Clinical Significance in Autologous Stem Cell Transplantation for Multiple Sclerosis.

INTRODUCTION: Autologous hematopoietic stem cell transplantation (AHSCT) with anti-thymocyte globulin (ATG) conditioning as treatment of active multiple sclerosis (MS) is rapidly increasing across Europe (EBMT registry data 2017). Clinically significant Epstein-Barr virus reactivation (EBV-R) following AHSCT with ATG for severe autoimmune conditions is an underrecognized complication relative to T-cell deplete transplants performed for hematological diseases. This retrospective study reports EBV-R associated significant clinical sequelae in MS patients undergoing AHSCT with rabbit ATG. METHODS: Retrospective data were analyzed for 36 consecutive MS-AHSCT patients at Kings College Hospital, London. All patients routinely underwent weekly EBV DNA polymerase chain reaction monitoring and serum electrophoresis for monoclonal gammopathy (MG or M-protein). EBV-R with rising Epstein-Barr viral load, M-protein, and associated clinical sequelae were captured from clinical records. RESULTS: All patients had evidence of rising EBV DNA-emia, including 7 who were lost to long-term follow-up, with a number of them developing high EBV viral load and associated lymphoproliferative disorder (LPD). Nearly 72% (n = 18/29) developed de novo MG, some with significant neurological consequences with high M-protein and EBV-R. Six patients required anti-CD20 therapy (rituximab) with complete resolution of EBV related symptoms. Receiver operating characteristics estimated a peak EBV viremia of >500 000 DNA copies/mL correlated with high sensitivity (85.5%) and specificity (82.5%) (area under the curve: 0.87; P = .004) in predicting EBV-R related significant clinical events. CONCLUSION: Symptomatic EBV reactivation increases risk of neurological sequelae and LPD in MS-AHSCT. We recommend regular monitoring for EBV and serum electrophoresis for MG in MS patients in the first 3 months post-AHSCT.

Mesenchymal stromal cells for acute graft-versus-host disease: response at 1 week predicts probability of survival.

Mesenchymal stromal cells (MSCs) have been successfully used for the treatment of steroid-resistant graft-versus-host-disease (GvHD). However, the lack of early predictors of clinical responses impacts on the time at which to add further treatment and consequently the design of informative clinical trials. Here, we present the UK experience of one of the largest cohorts of GvHD patients undergoing MSC infusions so far reported. We show that clinical responses assessed as early as 1 week after MSC infusion predict patients' overall survival. In our cohort, cell dose, patients' age and type of organ involvement are crucial factors associated with clinical responses.

Guidelines for the management of Toxoplasma gondii infection and disease in patients with haematological malignancies and after haematopoietic stem-cell transplantation: guidelines from the 9th European Conference on Infections in Leukaemia, 2022.

Patients with haematological malignancies might develop life-threatening toxoplasmosis, especially after allogeneic haematopoietic stem-cell transplantation (HSCT). Reactivation of latent cysts is the primary mechanism of toxoplasmosis following HSCT; hence, patients at high risk are those who were seropositive before transplantation. The lack of trimethoprim-sulfamethoxazole prophylaxis and various immune status parameters of the patient are other associated risk factors. The mortality of toxoplasma disease-eg, with organ involvement-can be particularly high in this setting. We have developed guidelines for managing toxoplasmosis in haematology patients, through a literature review and consultation with experts. In allogeneic HSCT recipients seropositive for Toxoplasma gondii before transplant, because T gondii infection mostly precedes toxoplasma disease, we propose weekly blood screening by use of quantitative PCR (qPCR) to identify infection early as a pre-emptive strategy. As trimethoprim-sulfamethoxazole prophylaxis might fail, prophylaxis and qPCR screening should be combined. However, PCR in blood can be negative even in toxoplasma disease. The duration of prophylaxis should be a least 6 months and extended during treatment-induced immunosuppression or severe CD4 lymphopenia. If a positive qPCR test occurs, treatment with trimethoprim-sulfamethoxazole, pyrimethamine-sulfadiazine, or pyrimethamine-clindamycin should be started, and a new sample taken. If the second qPCR test is negative, clinical judgement is recommended to either continue or stop therapy and restart prophylaxis. Therapy must be continued until a minimum of two negative PCRs for infection, or for at least 6 weeks for disease. The pre-emptive approach is not indicated in seronegative HSCT recipients, after autologous transplantation, or in non-transplant haematology patients, but PCR should be performed with a high level of clinical suspicion.

The Impact of the Fungal Priority Pathogens List on Medical Mycology: A Northern European Perspective.

Fungal diseases represent a considerable global health concern, affecting >1 billion people annually. In response to this growing challenge, the World Health Organization introduced the pivotal fungal priority pathogens list (FPPL) in late 2022. The FPPL highlights the challenges in estimating the global burden of fungal diseases and antifungal resistance (AFR), as well as limited surveillance capabilities and lack of routine AFR testing. Furthermore, training programs should incorporate sufficient information on fungal diseases, necessitating global advocacy to educate health care professionals and scientists. Established international guidelines and the FPPL are vital in strengthening local guidance on tackling fungal diseases. Future iterations of the FPPL have the potential to refine the list further, addressing its limitations and advancing our collective ability to combat fungal diseases effectively. Napp Pharmaceuticals Limited (Mundipharma UK) organized a workshop with key experts from Northern Europe to discuss the impact of the FPPL on regional clinical practice.

[68Ga]Ga-Schizokinen, a Potential Radiotracer for Selective Bacterial Infection Imaging.

Gallium-68-labeled siderophores as radiotracers have gained interest for the development of in situ infection-specific imaging diagnostics. Here, we report radiolabeling, in vitro screening, and in vivo pharmacokinetics (PK) of gallium-68-labeled schizokinen ([68Ga]Ga-SKN) as a new potential radiotracer for imaging bacterial infections. We radiolabeled SKN with ≥95% radiochemical purity. Our in vitro studies demonstrated its hydrophilic characteristics, neutral pH stability, and short-term stability in human serum and toward transchelation. In vitro uptake of [68Ga]Ga-SKN by Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and S. epidermidis, but no uptake by Candida glabrata, C. albicans, or Aspergillus fumigatus, demonstrated its specificity to bacterial species. Whole-body [68Ga]Ga-SKN positron emission tomography (PET) combined with computerized tomography (CT) in healthy mice showed rapid renal excretion with no or minimal organ uptake. The subsequent ex vivo biodistribution resembled this fast PK with rapid renal excretion with minimal blood retention and no major organ uptake and showed some dissociation of the tracer in the urine after 60 min postinjection. These findings warrant further evaluation of [68Ga]Ga-SKN as a bacteria-specific radiotracer for infection imaging.

Radiotracers for in situ infection imaging: Experimental considerations for in vitro microbial uptake of gallium-68-labeled siderophores.

In vitro screening of gallium-68(68Ga)-siderophores in pathogens relevant to infections is valuable for determining species specificity, their effect on cell viability, and potential clinical applications. As the recognition and internalization of siderophores relies on the presence of receptor- and/or siderophore-binding proteins, the level of uptake can vary between species. Here, we report in vitro uptake validation in Escherichia coli with its native siderophore, enterobactin (ENT) ([68Ga]Ga-ENT), considering different experimental factors. Compared with other reporting methods of uptake, '% Added dose/109 CFU/mL (% AD/109 CFU/mL),' considering the total viable count, showed a better comparison among microbial species. Later, in vitro screening with [68Ga]Ga-desferrioxamine B (DFO-B) showed high uptake by Staphylococcus aureus and S. epidermidis; moderate uptake by Pseudomonas aeruginosa; poor uptake by E. coli, Candida albicans, and Aspergillus fumigatus; and no uptake by Enterococcus faecalis and C. glabrata. Except for S. epidermidis, [68Ga]Ga-DFO-B did not reduce the cell viability.

Haploidentical Transplant with Post-Transplant Cyclophosphamide for Acute Myeloid Leukaemia and Myelodysplastic Syndromes Patients: The Role of Previous Lines of Therapy.

Background: Allogeneic haematopoietic stem-cell transplant is an option, potentially curative, for high-risk acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) patients. Post-transplant cyclophosphamide administration allows for the selection of haploidentical donors in patients who are eligible for the procedure but do not have a fully matched donor since it can overcome the HLA barrier. There is still an active debate on whether intensifying the conditioning regimen is necessary with haploidentical donors when peripheral blood stem cells are used as the graft source. Herein, we report our decennial experience of haploidentical stem-cell transplant using peripheral blood stem cells (haplo-PBSC) at King's College Hospital. Objectives: The primary objective was to evaluate overall survival (OS) following haplo-PBSC. Secondary objectives were total OS for patients with less than two previous lines of therapy, OS according to cytomegalovirus (CMV) reactivation, incidence of transplant-related mortality (TRM), graft-versus-host disease (GVHD) and GVHD-relapse-free survival (GRFS). Results: One-year and three-year total OS were 62% and 43%, respectively, with a median OS of 22 months. One-year and three-year OS for patients with ≤2 and those with >2 previous lines of therapy were 72% and 55%, and 60% and 22%, respectively (p-value=0.04). The median OS in patients with >2 previous and ≤2 lines of therapy was 16 and 49 months, respectively. Cumulative incidence (CI) of relapse was 25% with a median time to relapse of 5 months (range 1 - 38 months). Conclusions: Haploidentical haematopoietic stem-cell transplant is potentially curative in chemosensitive AML and MDS and offers a high rate of prolonged remission. Our cohort further confirms the role of consolidative haploidentical transplant in patients in complete remission and highlights that patients with heavily pre-treated disease may not benefit from this strategy.

Radiometal chelators for infection diagnostics.

Infection of native tissues or implanted devices is common, but clinical diagnosis is frequently difficult and currently available noninvasive tests perform poorly. Immunocompromised individuals (for example transplant recipients, or those with cancer) are at increased risk. No imaging test in clinical use can specifically identify infection, or accurately differentiate bacterial from fungal infections. Commonly used [18F]fluorodeoxyglucose (18FDG) positron emission computed tomography (PET/CT) is sensitive for infection, but limited by poor specificity because increased glucose uptake may also indicate inflammation or malignancy. Furthermore, this tracer provides no indication of the type of infective agent (bacterial, fungal, or parasitic). Imaging tools that directly and specifically target microbial pathogens are highly desirable to improve noninvasive infection diagnosis and localization. A growing field of research is exploring the utility of radiometals and their chelators (siderophores), which are small molecules that bind radiometals and form a stable complex allowing sequestration by microbes. This radiometal-chelator complex can be directed to a specific microbial target in vivo, facilitating anatomical localization by PET or single photon emission computed tomography. Additionally, bifunctional chelators can further conjugate therapeutic molecules (e.g., peptides, antibiotics, antibodies) while still bound to desired radiometals, combining specific imaging with highly targeted antimicrobial therapy. These novel therapeutics may prove a useful complement to the armamentarium in the global fight against antimicrobial resistance. This review will highlight current state of infection imaging diagnostics and their limitations, strategies to develop infection-specific diagnostics, recent advances in radiometal-based chelators for microbial infection imaging, challenges, and future directions to improve targeted diagnostics and/or therapeutics.

Rising incidence of Pneumocystis pneumonia: A population-level descriptive ecological study in England.

OBJECTIVES: Pneumocystis pneumonia (PCP) is an opportunistic infection that causes significant morbidity and mortality in the immunocompromised population. This population is growing and diversifying, yet contemporary epidemiology is lacking. We investigated the population-level incidence of PCP over the past decade. METHODS: We conducted a descriptive study of all hospital admissions in England from April 2012 to March 2022. PCP episodes, age, median length of stay, gender and episodes of other respiratory fungal infections were collected. Consumption of Trimethoprim-Sulfamethoxazole was obtained between January 2019 and May 2022. RESULTS: The incidence of PCP increased from 2·2-4·5/100,000 population between 2012/2013 and 2019/2020 (p < 0·0001). There was a drop in 2020/2021 to 2·7/100,000 before returning to 3.9/100,000 in 2021/2022. PCP episodes rose as a proportion of all-cause admissions as well as a proportion of episodes due to other fungal infections. The proportion of PCP patients aged 75+ increased from 14% to 26%. The median length of stay was 13.5 days. Consumption of intravenous Trimethoprim-Sulfamethoxazole increased from 0.24 × 100,000 to 0.30 × 100,000 defined daily doses. CONCLUSIONS: The incidence of PCP is rising rapidly and represents a significant burden to the healthcare system. Further study into who is at risk of PCP is needed to better determine who should be given prophylaxis.

Fludarabine-Melphalan-Campath, Followed by Unmanipulated Peripheral-Blood Haematopoietic Stem Cells, Can Still Cure Lymphoma.

Background: The second decade of this millennium was characterized by a widespread availability of chimeric antigen receptor T-cell (CAR-T) therapies to treat relapsed and refractory lymphomas. As expected, the role and indication of allogeneic haematopoietic stem cell transplant (allo-HSCT) in the management of lymphoma changed. Currently, a non-neglectable proportion of patients will be considered candidate for an allo-HSCT, and the debate of which transplant platform should be offered is still active. Objectives: to report the outcome of patients affected with relapsed/refractory lymphoma and transplanted following reduced intensity conditioning at King's College Hospital, London, between January 2009 and April 2021. Methods: Conditioning was with 150mg/m2 of fludarabine and melphalan of 140mg/m2. The graft was unmanipulated G-CSF mobilized peripheral blood haematopoietic stem cells (PBSC). Graft-versus-host disease (GVHD) prophylaxis consisted of pre-transplant Campath at the total dose of 60 mg in unrelated donors and 30 mg in fully matched sibling donors and ciclosporin. Results: One-year and five years OS were 87% and 79.9%, respectively, and median OS was not reached. The cumulative incidence of relapse was 16%. The incidence of acute GVHD was 48% (only grade I/II); no cases of grade III/IV were diagnosed. Chronic GVHD occurred in 39% of patients. TRM was 12%, with no cases developed within day 100 and 18 months after the procedure. Conclusions: The outcomes of heavily pretreated lymphoma patients are favorable, with median OS and survival not reached after a median of 49 months. In conclusion, even if some lymphoma subgroups cannot be treated (yet) with advanced cellular therapies, this study confirms the role of allo-HSCT as a safe and curative strategy.

Myeloablative Dose of Busulfan and Fludarabine Combined with In Vivo T Cell Depletion Is Safe and Effective Conditioning for Acute Myeloid Leukemia and Myelodysplastic Syndrome Patients.

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative strategy for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). The prediction of transplantation-related mortality (TRM) using the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) score and an arbitrary upper age limit of 55 years for administering myeloablative conditioning (MAC) are common strategies to ensure a safe procedure. The use of reduced-toxicity conditioning regimens is an additional approach to providing safe and effective myeloablation. Herein we report the outcome of AML and MDS patients conditioned with fludarabine and a myeloablative dose of busulfan (FB4) stratified by age and HCT-CI score. The primary objective was overall survival (OS) for patients age ≥55 years. Secondary objectives were total OS, TRM, graft-versus-host disease (GVHD), and GVHD, relapse-free survival (GRFS). The 2 year OS was 72% in patients age <55 and 51% in patients age ≥55. In patients age ≥55 with an HCT-CI <2, the estimated 2 year OS was 64%, with median OS not reached. In those with HCT-CI ≥2, the 2-year OS was 43%, with a median OS of 14 months. The total cumulative incidence of relapse was 30% regardless of age or HCT-CI score. FB4 conditioning regimen offers a high rate of prolonged remission with a relapse rate similar to that reported in previous studies. These positive outcomes suggest that this conditioning platform can be offered to patients age ≥55 years in the absence of comorbidities, and that age should not be the sole determinant of conditioning intensity.