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Evaluation of the risk factors for BK virus-associated hemorrhagic cystitis in pediatric bone marrow transplantation patients: Does post-transplantation cyclophosphamide increase the frequency?
Ersoy, G. Z., Bozkurt, C., Aksoy, B. A., Öner Ö, B., Aydoğdu, S., Çipe, F., Sütçü, M., Özkaya, O., Fışgın, T.
Pediatric transplantation. 2023;27(1):e14364
Abstract
BACKGROUND BKV-HC is one of the most significant complications of HSCT. This retrospective study aimed to determine the frequency of BKV-HC in pediatric patients undergoing HSCT, detect the associated risk factors for the development of BKV-HC, and explore the effects of post-transplantation Cy use. METHODS Three hundred twenty-seven patients (girls: 121, boys: 206) were analyzed according to sex, conditioning regimen, transplantation type, donor relatedness, stem cell source, the presence and grade of aGVHD, CMV co-existence, and Cy use. RESULTS Multivariate analysis confirmed the prognostic importance of age (OR: 4.865), TBI use, the presence of aGVHD (OR: 2.794), CMV coinfection (OR: 2.261), and Cy use (OR: 27.353). A statistically significant difference was found between the mean BKV-HC follow-up times compared with post-transplantation Cy intake (p < .001). The BKV-HC rate increased as the number of risk factors of the patient increased. CONCLUSION BKV-HC is an essential complication of HSCT primarily associated with Cy use, the presence of aGVHD, and donor relatedness. The present study shows that the use of Cy in the post-transplantation period further increases BKV-HC risk in pediatric patients, regardless of dose.
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Adjuvanted recombinant zoster vaccine decreases herpes zoster-associated pain and the use of pain medication across 3 randomized, placebo-controlled trials
Kim, J. H., Johnson, R., Kovac, M., Cunningham, A. L., Amakrane, M., Sullivan, K. M., Dagnew, A. F., Curran, D., Schuind, A.
Pain. 2023;164(4):741-748
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Abstract
Herpes zoster (HZ) and HZ-associated pain greatly affect patients' quality of life, particularly in older and immunocompromised adults, for whom comorbidities and polypharmacy are often reported. Three phase III, randomized, placebo-controlled clinical trials have reported the adjuvanted recombinant zoster vaccine (RZV) as highly efficacious in preventing HZ and reducing pain severity in healthy adults ≥50 years old (Zoster Efficacy Study [ZOE]-50 study, NCT01165177) and ≥70 years old (ZOE-70; NCT01165229) and in immunocompromised adults ≥18 years old undergoing autologous hematopoietic stem cell transplantation (ZOE-HSCT; NCT01610414). Here, we investigated efficacy of RZV in reducing (i) the duration of clinically significant pain (Zoster Brief Pain Inventory pain score ≥3) and (ii) HZ-associated pain medication use and duration of use in participants with confirmed HZ ("breakthrough cases") from the 3 studies. Recombinant zoster vaccine effectively reduced the duration of clinically significant HZ-associated pain during HZ episodes by 38.5% ( P -value: 0.010) in the ZOE-HSCT study. Although a similar trend was observed in the ZOE-50 and ZOE-70 studies, the results were not statistically significant because of the high vaccine efficacy (VE) against HZ resulting in rare breakthrough cases. VE in reducing pain medication use (39.6%; P -value: 0.008) and duration of medication use (49.3%, P -value: 0.040) was reported in the ZOE-70 study; corresponding positive VE estimates were observed in the ZOE-50 and ZOE-HSCT studies but were not statistically significant. Data reported here demonstrate efficacy of RZV in reducing HZ-associated pain duration and pain medication use in breakthrough cases, thereby improving quality of life of those with HZ.
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[Clinical analysis of the efficacies of ganciclovir plus foscarnet and a single antiviral drug for the treatment of cytomegalovirus infection after haploidentical stem cell transplantation]
Ma, R., He, Y., Xu, L. P., Zhang, X. H., Wang, Y., Liu, K. Y., Huang, X. J., Sun, Y. Q.
Zhonghua Nei Ke Za Zhi. 2023;62(1):76-83
Abstract
Objective: To evaluate and compare the efficacies of ganciclovir plus foscarnet and a single agent for the treatment of cytomegalovirus (CMV) infection after haploidentical hematopoietic stem cell transplantation. Methods: This study was a non-randomized clinical controlled trial. The data of patients who underwent haploidentical transplantation and developed CMV infection between January 1, 2021, and June 30, 2021, were retrospectively analyzed. Follow-up was conducted through telephone, inpatient consultations, and the review of outpatient medical records. The observed indicators included the incidence of CMV infection (including CMV disease), rate of recurrence of CMV infection, overall survival (OS), and disease-free survival (DFS). Results: A total of 242 patients were diagnosed with post-transplantation CMV infection; 116 patients tested positive for CMV DNA for more than 14 days (P=0.011). Of the 242 patients with CMV infection, 65 were treated with ganciclovir plus foscarnet, and 156 patients were treated with a single antiviral drug; the median durations of CMV seroconversion were 21 (3-60) and 14 (3-32) days for the combination and single-drug groups, respectively. There were no significant differences between their incidence of CMV infections and 1-year OS and DFS. Of the patients with refractory CMV infections, 53 (45.7%) were treated with ganciclovir plus foscarnet, and 63 (54.3%) were treated with a single antiviral agent. The median durations of CMV seroconversion for the combination and single-drug groups were 21 (15-60) days and 20 (15-45) days, respectively (P=0.472). Two patients in each group progressed to CMV disease (P=0.860). During follow-up, 12 patients (22.6%) in the combination group and 8 patients (12.7%) in the single-drug group experienced recurrent episode(s) of CMV infection (P=0.158). The 1-year OS of the combination and single-drug groups were 92.0% and 87.1%, respectively (P=0.543); the 1-year DFS were 90.3% and 85.7%, respectively (P=0.665). Univariate analysis revealed no associations between the antiviral agents used and OS and DFS (OS: HR=0.644, P=0.547; DFS: HR=0.757, P=0.666). Conclusions: There were no significant differences in the duration of CMV infection, incidence of CMV disease, rate of recurrence of CMV infection, and survival of the patients treated with the combination of antiviral drugs and a single antiviral drug.
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Predicted Bezlotoxumab Exposure in Patients Who Have Received a Hematopoietic Stem Cell Transplant
de Almeida, C., Wong, M., Kleijn, H. J., Wrishko, R. E.
Clinical therapeutics. 2023
Abstract
PURPOSE Bezlotoxumab is approved for prevention of recurrent Clostridioides (Clostridium) difficile infection (CDI) in adults receiving antibacterial treatment for CDI who are at high risk for recurrent CDI. Previous studies have shown that although serum albumin levels are an important predictor for bezlotoxumab exposure, this has no clinically meaningful impact on efficacy. This pharmacokinetic modeling study assessed whether hematopoietic stem cell transplant (HSCT) recipients, at increased risk of CDI and exhibiting decreased albumin levels within the first month posttransplant, are at risk of clinically relevant reductions in bezlotoxumab exposure. METHODS Observed bezlotoxumab concentration-time data pooled from participants in Phase III trials MODIFY I and II (ClinicalTrials.gov identifiers NCT01241552/NCT01513239) and three Phase I studies (PN004, PN005, and PN006) were used to predict bezlotoxumab exposures in two adult post-HSCT populations: A Phase Ib study of posaconazole including allogeneic HSCT recipients (ClinicalTrials.gov identifier NCT01777763; posaconazole-HSCT population); and a Phase III study of fidaxomicin for CDI prophylaxis (ClinicalTrials.gov identifier NCT01691248; fidaxomicin-HSCT population). The bezlotoxumab PK model used the minimum albumin level for each individual in post-HSCT populations to mimic a "worst-case scenario." FINDINGS Predicted worst-case bezlotoxumab exposures for the posaconazole-HSCT population (N = 87) were decreased by 10.8% versus bezlotoxumab exposures observed in the pooled Phase III/Phase I data set (N = 1587). No further decrease was predicted for the fidaxomicin-HSCT population (N = 350). IMPLICATIONS Based on published population pharmacokinetic data, the predicted decrease in bezlotoxumab exposure in the post-HSCT populations is not expected to have a clinically meaningful effect on bezlotoxumab efficacy at the recommended 10 mg/kg dose. Dose modification is therefore not required in the hypoalbuminemia setting expected post-HSCT. (Clin Ther. 2023;45:XXX-XXX) © 2023 Elsevier HS Journals, Inc.
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Exposure-Response Analyses of Letermovir Following Oral and Intravenous Administration in Allogeneic Hematopoietic Cell Transplantation Recipients
Prohn, M., Cho, C. R., Viberg, A., Dykstra, K., Davis, C., Sabato, P., Stone, J., Badshah, C., Murata, Y., Leavitt, R., et al
Clinical Pharmacology and Therapeutics. 2022;111(2):485-495
Abstract
The cytomegalovirus (CMV) viral terminase inhibitor letermovir is approved for prophylaxis of CMV infection and disease in adult CMV-seropositive allogeneic hematopoietic stem cell transplantation recipients. In a phase III trial (NCT02137772), letermovir significantly reduced clinically significant CMV infection (CS-CMVi) rate vs. placebo through Week 24 (primary end point) and Week 14 (secondary end point) post transplantation. Here, exposure-response relationships were investigated using efficacy and selected safety end points from the phase III trial to inform the proposed clinical dose. Post hoc exposure estimates were derived from a population pharmacokinetic model. No significant exposure dependencies were found for CS-CMVi through Week 24 or Week 14 among letermovir-treated participants. Evaluated covariates had no impact on exposure-efficacy relationships and letermovir plasma exposure did not affect time of CS-CMVi onset. There was no dependence between adverse event incidence and letermovir exposure. These results support current dosing recommendations in several countries and regions, including the United States and European Union.
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Epidemiology, antimicrobial resistance, and mortality risk factors of carbapenem resistant gram-negative bacteria in hematopoietic stem cell transplantation recipients
Jia, Y., Li, Y., Liu, Y., Yang, Z., Chen, X., Liu, Y.
Frontiers in cellular and infection microbiology. 2022;12:1098856
Abstract
INTRODUCTION Carbapenem resistant gram-negative bacteria (CRGNB) infection is more and more frequent in patients after hematopoietic stem cell transplantation (HSCT), and the prognosis is very poor. The purpose of this study was to investigate the clinical characteristics and risk factors for mortality with CRGNB infection in HSCT recipients, and to provide useful information for guiding the application of antibiotics and improving the prognosis in the future. METHODS Electronic medical records of CRGNB infected patients who underwent HSCT in Xiangya Hospital from January 1, 2015 to June 30, 2022 were collected. At the same time, 1:1 case-control matching was performed according to gender, age and disease type. The epidemiological characteristics and drug resistance of patients with CRGNB infection and non-CRGNB infection were compared. Logistic regression and Cox regression analysis were used to determine the risk factors for CRGNB acquisition and death respectively, and a prediction model of overall survival was constructed by R language. RESULTS AND DISCUSSION The crude infection rate of CRGNB in HSCT recipients was 7.42%, and the mortality rate was 47.1%. CRGNB was resistant to most commonly used antibiotics. Time interval from diagnosis to transplantation >180 days (HR=7.886, 95% CI 2.624-23.703, P=0.000), septic shock (HR=6.182, 95% CI 2.605-14.671, P=0.000), platelet count < 20 × 10(9)/L (HR=2.615, 95% CI 1.152-5.934, P=0.022) and total bilirubin > 34.2 μmol/L (HR=7.348, 95% CI 2.966-18.202, P=0.000) at the initial stage of infection were 4 independent risk factors associated with mortality. CRGNB infection has become a serious threat to HSCT recipients. Clinicians should pay high attention to it and actively seek personalized treatment strategies suitable for local medical conditions.
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Pre-exposure prophylaxis with tixagevimab/cilgavimab (AZD7442) prevents severe SARS-CoV-2 infection in recipients of allogeneic hematopoietic stem cell transplantation during the Omicron wave: a multicentric retrospective study of SFGM-TC
Jondreville, L., D'Aveni, M., Labussière-Wallet, H., Le Bourgeois, A., Villate, A., Berceanu, A., Bezsera, S. M., Thiebaut, A., Boissard-Simonet, M., Legrand, M., et al
Journal of hematology & oncology. 2022;15(1):169
Abstract
Since the emergence of the Omicron variant of SARS-CoV-2, though considered less virulent, hospitalization and death rates among immunocompromised patients remain high, especially for poor responders to vaccination. We conducted a retrospective multicentric study to evaluate pre-exposure prophylaxis with AZD7442 (tixagevimab/cilgavimab) for preventing COVID-19 in adult allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients. Among the 161 patients of our cohort, 22 (14%) contracted COVID-19 after a median follow-up of 105 days, but no severe form was observed. Only one major adverse event was reported: an acute coronary syndrome, resolved without sequelae. Pending randomized controlled trial results, our data support the use of AZD7442 as pre-exposure prophylaxis for COVID-19 during Omicron wave in allo-HSCT patients who failed to develop humoral immunity to vaccination, to prevent severe and potentially lethal forms of SARS-CoV-2 infection.
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What We Learn from Surveillance of Microbial Colonization in Recipients of Pediatric Hematopoietic Stem Cell Transplantation
Kropshofer, G., Hetzer, B., Knoll, M., Meryk, A., Salvador, C., Rabensteiner, E., Crazzolara, R.
Antibiotics (Basel, Switzerland). 2022;12(1)
Abstract
Infections in hematopoietic stem cell transplant (HSCT) remain one of the major causes for morbidity and mortality, and it is still unclear whether knowledge of microbial colonization is important. In this single-center study, we collected weekly surveillance cultures in pediatric recipients of allogenic HSCT from five different body regions and tested for bacteria and fungi. Between January 2010 and December 2021, we collected 1095 swabs from 57 recipients of allogeneic HSCTs (median age: 7.5 years, IQR 1−3: 2.5−11.9). The incidence of positive microbiological cultures (n = 220; 20.1%) differed according to the anatomic localization (p < 0.001) and was most frequent in the anal region (n = 98), followed by the genital, pharyngeal and nasal regions (n = 55, n = 37 and n = 16, respectively). Gram-positive bacteria (70.4%) were the most commonly isolated organisms, followed by fungi (18.6%), Gram-negative (5.5%), non-fermenting bacteria (1.4%), and other flora (4.1%). No association with increased risk of infection (n = 32) or septicemia (n = 7) was noted. Over time, we did not observe any increase in bacterial resistance. We conclude that there is no benefit to surveillance of microbial colonization by culture-based techniques in pediatric HSCT. Sequencing methods might enhance the detection of pathogens, but its role is still to be defined.
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Systemic antifungal strategies in allogeneic hematopoietic stem cell recipients hospitalized in french hematology units: a post-hoc analysis of the cross-sectional observational AFHEM study
Michallet, M., El Cheikh, J., Herbrecht, R., Yakoub-Agha, I., Caillot, D., Gangneux, J. P.
BMC infectious diseases. 2022;22(1):352
Abstract
BACKGROUND Invasive fungal diseases (IFD) remain a major complication of allogeneic hematopoietic stem cell transplantation (alloHSCT) and are associated with high mortality rates in patients receiving alloHSCT. Antifungal prophylaxis is increasingly being used in the management of IFDs in patients receiving alloHSCT. METHODS A post-hoc analysis of the cross-sectional observational AFHEM study was carried out to describe the use of antifungal drugs in real-life clinical practice in alloHSCT recipients hospitalized in French hematological units. RESULTS A total of 147 alloHSCT recipients were enrolled; most were adults (n = 135; 92%) and had received alloHSCT < 6 months prior to enrollment (n = 123; 84%). Overall, 119 (81%) patients received a systemic antifungal therapy; of these, 95 (80%) patients received antifungal prophylaxis. Rates of patients receiving systemic antifungal treatment were similar irrespective of transplant time, neutropenic, and graft-versus-host disease status. Among patients on systemic antifungal treatment, 83 (70%) received an azole, 22 (18%) received an echinocandin, and 16 (13%) received a polyene. CONCLUSIONS This work provides evidence of the antifungal strategies used in alloHSCT recipients hospitalized in French hematological units. Unlike earlier studies, the AFHEM study showed that prophylaxis appears to be the leading antifungal strategy used in alloHSCT recipients in France.
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Strongyloides stercoralis prevalence in solid-organ and haematopoietic stem cell transplant candidates and recipients: a systematic review and meta-analysis protocol
Barkati, S., Naeem, F., Hales, L., Quan, C., Libman, M.
BMJ open. 2022;12(8):e057649
Abstract
INTRODUCTION Strongyloides stercoralis is an intestinal helminth ubiquitous in tropical and subtropical regions worldwide. It persists in the human host for a lifetime as a result of autoinfection and if undetected and untreated, can lead to increased morbidity and high mortality in immunocompromised individuals such as the transplant population. Transplant patients, including solid-organ and haematopoietic stem cell transplants (SOT and HSCT, respectively), are at a high risk of hyperinfection and disseminated strongyloidiasis. Unfortunately screening is often not systematically performed. Prevalence estimates of Strongyloides in this high-risk population is not well studied. Through this systematic review, we aim to summarise the descriptive evidence on Strongyloides prevalence in SOT and HSCT patients, including diagnostic and screening practices alongside the cases of hyperinfection, disseminated strongyloidiasis and the mortality rate in this population. METHODS AND ANALYSES Through the use of various online library databases, we will conduct a systematic review including relevant literature on the prevalence of Strongyloides in SOT and HSCT patients as well as studies assessing hyperinfection and disseminated strongyloidiasis in this patient population. The Population, Intervention, Comparison, Outcome and Study Design strategy and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines will be used to determine a final subset of studies for analysis. Quality assessment for case series and case reports will be determined by a modified quality assessment tool developed by the National Heart, Lung, and Blood Institute (NIH), and the CARE guidelines, respectively. We will provide a narrative synthesis of the findings pertaining to the primary and secondary outcomes of interest (prevalence of Strongyloides and mortality rate in transplant population, respectively) alongside the associated 95% CI. Estimates from individual studies will be pooled using a random effects model. ETHICS AND DISSEMINATION This systematic review does not require formal ethical approval since no primary data will be collected. Findings will be disseminated through a peer-reviewed publication and relevant conferences. PROSPERO REGISTRATION NUMBER CRD42021269305.