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1
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Mehta RS, Choe H, Saultz J, Gong Z, Sharma P, Al-Juhaishi T, Petitto GS, Lazaryan A, Singh A, Xue E, Dimitrova D, Hyder M, McCurdy S, Im A, Huber B, Aljawai YM, Kanakry J, Milano F, Kanakry CG. Impact of Donor Age and Donor Cytomegalovirus Serostatus on Outcomes After Related Donor Allogeneic Hematopoietic Stem Cell Transplantation. Am J Hematol 2025; 100:987-997. [PMID: 40071498 DOI: 10.1002/ajh.27662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2025] [Revised: 02/27/2025] [Accepted: 03/02/2025] [Indexed: 04/07/2025]
Abstract
Cytomegalovirus (CMV) infection post-hematopoietic cell transplantation (HCT) remains a significant cause of morbidity and mortality. While letermovir prophylaxis is available for CMV-seropositive recipients, optimal donor selection for CMV-seronegative recipients remains unclear, with donor age often prioritized over CMV serostatus. We investigated the relative impact of donor age and CMV serostatus in CMV-seronegative recipients (n = 1013) with either CMV-seropositive (n = 318) or CMV-seronegative donors (n = 695), who underwent HCT with HLA-matched sibling donors with calcineurin inhibitor-based or post-transplant cyclophosphamide (PTCy)-based graft-versus-host disease prophylaxis, or haploidentical donors with PTCy. Multiple conventional and machine-learning approaches were employed to account for confounding factors. Across all analyses, CMV-seropositive donor status was consistently associated with significantly inferior overall survival (OS) and disease-free survival, primarily driven by increased non-relapse mortality (NRM). Older donor age showed a statistically significant association with OS and DFS in some but not all models, and its effect size was small (about 1% increased hazard per year in Cox proportional hazard model) compared to the substantial impact of CMV-seropositive donors (about 27%-33% increased hazards for worse OS, approximately 50%-60% higher NRM in Cox proportional hazard model). However, our machine learning model revealed a more nuanced and complex non-linear effect of donor age, further demonstrating the adverse impact of donor CMV serostatus. Our findings suggest that prioritizing a CMV-seronegative donor may be associated with improved outcomes in CMV-seronegative recipients. Further research is needed to validate these findings and explore underlying mechanisms.
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Affiliation(s)
- Rohtesh S Mehta
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Hannah Choe
- Division of Hematology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA
| | - Jennifer Saultz
- Division of Hematology/Oncology, Oregon Health and Science University, Portland, Oregon, USA
| | - Zimu Gong
- OU Health Stephenson Cancer Center, Oklahoma City, Oklahoma, USA
| | - Prashant Sharma
- Blood and Marrow Transplant/Acute Leukemia Program, Intermountain Medical Group, Salt Lake City, Utah, USA
| | - Taha Al-Juhaishi
- OU Health Stephenson Cancer Center, Oklahoma City, Oklahoma, USA
| | - Gabriela S Petitto
- Division of Hematology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA
| | - Aleksandr Lazaryan
- Department of Blood and Marrow Transplantation and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, Florida, USA
| | - Anurag Singh
- Division of Hematologic Malignancies and Cellular Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Elisabetta Xue
- Center for Immuno-Oncology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Dimana Dimitrova
- Center for Immuno-Oncology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Mustafa Hyder
- Center for Immuno-Oncology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Shannon McCurdy
- Division of Hematology-Oncology/Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Annie Im
- Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Bryan Huber
- Blood and Marrow Transplant/Acute Leukemia Program, Intermountain Medical Group, Salt Lake City, Utah, USA
| | - Yosra M Aljawai
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Jennifer Kanakry
- Center for Immuno-Oncology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | | | - Christopher G Kanakry
- Center for Immuno-Oncology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
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Wang J, Ji X, Yang C, Xu J. Susceptibility from the immunological perspective of COVID-19-associated pulmonary aspergillosis: A literature review. Medicine (Baltimore) 2025; 104:e42363. [PMID: 40355215 PMCID: PMC12073940 DOI: 10.1097/md.0000000000042363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Accepted: 04/18/2025] [Indexed: 05/14/2025] Open
Abstract
The incidence rate of COVID-19-associated pulmonary aspergillosis (CAPA) is rising. However, the pathogenesis of CAPA remains unclear. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection disrupts pathways related to type I interferon and Toll-like receptors, key components in innate immunity, thereby elevating the incidence of CAPA. Additionally, SARS-CoV-2 infection results in T and B cell functional deficiencies or exhaustion within adaptive immunity, weakening the defense against invasive Aspergillus. Furthermore, SARS-CoV-2 infection enhances the replication of cytomegalovirus and alters the gut microbiota, factors that may aid in diagnosing CAPA. Immunosuppressive therapy in COVID-19 patients is also believed to heighten the risk of invasive aspergillosis. Therefore, this review, examines the immune response to SARS-CoV-2 infection combined with invasive aspergillosis, and explores the pathogenesis and susceptibility factors of CAPA. We propose that variations in an individual's immune response significantly determine susceptibility to CAPA. The aim of this paper is to deepen clinical understanding of CAPA's pathogenesis, thereby aiding in mitigating susceptibility risk and advancing novel treatment approaches.
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Affiliation(s)
- Jiayin Wang
- Department of Laboratory, The First Hospital of Jilin University, Changchun, China
| | - Xufeng Ji
- Department of Laboratory, The First Hospital of Jilin University, Changchun, China
| | - Chun Yang
- Department of Laboratory, The First Hospital of Jilin University, Changchun, China
| | - Jiancheng Xu
- Department of Laboratory, The First Hospital of Jilin University, Changchun, China
- Center of Infectious Diseases and Pathogen Biology, The First Hospital of Jilin University, Changchun, China
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Girmenia C, Chiusolo P, Marsili G, Piciocchi A, Micò MC, Greco R, Porto G, Galaverna F, Bonifazi F, Cutini I, Malagola M, Bramanti S, Busca A, Carella AM, Carotti A, Iori AP, Onida F, Bono R, Terruzzi E, Vacca A, Rinaldi A, Cavattoni IM, Picardi A, Faraci M, Lazzarotto T, Baldanti F, Clerici P, Castagna L, Martino M, Ciceri F. The Changing Impact of Human Cytomegalovirus Serology and Infection on Patient Outcome After Allogeneic Hematopoietic Stem Cell Transplantation: An Italian Prospective Multicenter Survey in the Era of Letermovir Prophylaxis. Open Forum Infect Dis 2025; 12:ofaf233. [PMID: 40322267 PMCID: PMC12048776 DOI: 10.1093/ofid/ofaf233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2024] [Accepted: 04/16/2025] [Indexed: 05/08/2025] Open
Abstract
Background In the letermovir primary prophylaxis (LET-PP) era, the epidemiology of human cytomegalovirus infection (HCMV-i) in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients has changed. Methods We prospectively evaluated incidence and risk factors for clinically significant (CS) HCMV-i at 180 days from transplant and 1-year overall survival in 1310 allo-HSCTs performed from January 2021 to March 2022 according to LET-PP use. Results The cumulative incidence of CS-HCMV-i at 100 and 180 days from transplant was 3.8% and 16%, respectively, in patients who received LET-PP, and 14% and 17% in patients who did not. Variables associated with increased risk of CS-HCMV-i in patients who received LET-PP included transplant from an HCMV-seronegative donor, transplant from a donor other than matched related, >20 days to engraftment, and acute graft-versus-host disease (GVHD). Transplant in HCMV-seropositive recipients was associated with increased risk of CS-HCMV-i in patients who did not receive LET-PP. One-year overall survival after transplant was 81.1%. Acute leukemia, disease not in remission at transplant, Eastern Cooperative Oncology Group performance status >1, >20 days to engraftment, acute GVHD, CS Epstein-Barr virus DNAemia, gram-negative bacteremia, and invasive fungal disease were associated with increased mortality in patients who received LET-PP. HCMV recipient seropositivity, Hematopoietic Cell Transplantation Comorbidity Index score ≥3, and gram-negative bacteremia were associated with increased mortality in patients who did not receive LET-PP. Conclusions In patients who received LET-PP, recipient/donor serology no longer correlates with early CS-HCMV-i whereas it still predicts late CS-HCMV-i as well as risk of CS-HCMV-i in patients who did not receive LET-PP. Donor serology, CS-HCMV-i and HCMV disease no longer impact survival in allo-HSCT recipients who receive LET-PP. Clinical Trials Registration. NCT04412811.
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Affiliation(s)
- Corrado Girmenia
- Dipartimento di Ematologia, Oncologia, e Dermatologia, Azienda Ospedaliera Universitaria Policlinico Umberto I, Sapienza University of Rome, Rome, Italy
| | - Patrizia Chiusolo
- Sezione di Ematologia, Dipartimento di Scienze Radiologiche ed Ematologiche, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Giovanni Marsili
- Fondazione Gruppo Italiano Malattie EMatologiche dell’Adulto, Rome, Italy
| | - Alfonso Piciocchi
- Fondazione Gruppo Italiano Malattie EMatologiche dell’Adulto, Rome, Italy
| | - Maria Caterina Micò
- Dipartimento di Oncologia ed Ematologia, Ospedale Papa Giovanni XXIII, Bergamo, Italy
| | - Raffaella Greco
- Hematology and Bone Marrow Transplant Unit, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Hospital, Milan, Italy
- University Vita-Salute San Raffaele, Milano, Italy
| | - Gaetana Porto
- Hematology and Stem Cell Transplantation and Cellular Therapies Unit, Department of Hemato-Oncology and Radiotherapy, Grande Ospedale Metropolitano “Bianchi-Melacrino-Morelli,” Reggio Calabria, Italy
| | - Federica Galaverna
- Department of Pediatric Hematology/Oncology, Cell and Gene Therapy, Istituto di Ricovero e Cura a Carattere Scientifico Bambino Gesù Children's Hospital, Rome, Italy
| | - Francesca Bonifazi
- Istituto di Ematologia “Seràgnoli,” Istituto di Ricovero e Cura a Carattere Scientifico Azienda Ospedaliero–Universitaria di Bologna, Bologna, Italy
| | - Ilaria Cutini
- Struttura Organizzativa Dipartimentale Terapie Cellulari e Medicina Trasfusionale, Azienda Ospedaliera–Universitaria Careggi, Florence, Italy
| | - Michele Malagola
- Hematology, University of Brescia and Program of Cellular Therapies and Research in Hematology, Azienda Socio Sanitaria Territoriale Spedali Civili, Brescia, Italy
| | - Stefania Bramanti
- Department of Oncology/Hematology, Istituto di Ricovero e Cura a Carattere Scientifico Humanitas Research Hospital, Milan, Italy
| | - Alessandro Busca
- Struttura Semplice Trapianto Allogenico Cellule Staminali, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin, Italy
| | - Angelo Michele Carella
- Unità Operativa Complessa Ematologia e Centro Trapianti, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Alessandra Carotti
- Programma Trapianto, Struttura Complessa Ematologia, Azienda Ospedale Università di Perugia, Perugia, Italy
| | - Anna Paola Iori
- Dipartimento di Ematologia, Oncologia, e Dermatologia, Azienda Ospedaliera Universitaria Policlinico Umberto I, Sapienza University of Rome, Rome, Italy
| | - Francesco Onida
- Struttura Complessa Ematologia, Ospedale Fatebenefratelli Sacco, Milan, Italy
- Centro Trapianti di Midollo, Fondazione Istituto di Ricovero e Cura a carattere Scientifico Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy
| | - Roberto Bono
- Bone Marrow Transplant Unit, Azienda Ospedaliera Ospedali Riuniti Villa Sofia Cervello, Palermo, Italy
| | - Elisabetta Terruzzi
- Hematology Division, Fondazione Istituto di Ricovero e Cura a carattere Scientifico San Gerardo dei Tintori, Monza, Italy
| | - Adriana Vacca
- Struttura Complessa Ematologia e Centro Trapianto di Midollo Osseo Presidio Ospedaliero, Presidio Ospedaliero Armando Businco, Azienda di Rilievo Nazionale ed Alta Specializzazione G Brotzu, Cagliari, Italy
| | - Amelia Rinaldi
- Ematologia e Centro Trapianto di Midollo Osseo, Azienda Ospedaliero–Universitaria di Parma, Parma, Italy
| | - Irene Maria Cavattoni
- Ematologia e Centro Trapianti di Midollo, Comprensorio Sanitario di Bolzano, Azienda Sanitaria Alto Adige, Bolzano, Italy
| | - Alessandra Picardi
- Transplant Program Azienda Ospedaliera di Rilievo Nazionale Cardarelli, Naples, Italy
- Dipartimento di Biomedicina e Prevenzione, Università di Roma Tor Vergata, Rome, Italy
| | - Maura Faraci
- Hematopoietic Stem Cell Transplantation Unit, Department of Hemato-Oncology, Istituto di Ricovero e Cura a Carattere Scientifico Istituto G. Gaslini, Genoa, Italy
| | - Tiziana Lazzarotto
- Microbiologia, Istituto di Ricovero e Cura a Carattere Scientifico Azienda Ospedaliero–Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Fausto Baldanti
- Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy
- Microbiology and Virology Unit, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia, Italy
| | - Pierangelo Clerici
- Microbiology Unit, Azienda Socio Sanitaria Territoriale Ovest Milanese, Hospital of Legnano, Milan, Italy
| | - Luca Castagna
- Bone Marrow Transplant Unit, Azienda Ospedaliera Ospedali Riuniti Villa Sofia Cervello, Palermo, Italy
| | - Massimo Martino
- Hematology and Stem Cell Transplantation and Cellular Therapies Unit, Department of Hemato-Oncology and Radiotherapy, Grande Ospedale Metropolitano “Bianchi-Melacrino-Morelli,” Reggio Calabria, Italy
| | - Fabio Ciceri
- Hematology and Bone Marrow Transplant Unit, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Hospital, Milan, Italy
- University Vita-Salute San Raffaele, Milano, Italy
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Boquett JA, Sauter J, Schmidt AH, Maiers M, Hollenbach JA. Human leukocyte antigen variation is associated with cytomegalovirus serostatus in healthy individuals. Am J Hum Genet 2025; 112:913-926. [PMID: 40049169 DOI: 10.1016/j.ajhg.2025.02.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 02/05/2025] [Accepted: 02/07/2025] [Indexed: 03/12/2025] Open
Abstract
Cytomegalovirus (CMV) is a common β-herpes virus worldwide with an estimated seroprevalence among the general population of 83%. Primary infection is usually benign; however, CMV can cause severe morbidity in newborns in whom it is acquired congenitally, as well as immunocompromised individuals. Understanding the role of immunogenetic variation in risk for CMV infection can provide insight into the immune control of this ubiquitous pathogen. Here, we evaluated the association of human leukocyte antigen (HLA) genetic variation with CMV seropositivity in more than 518,000 individuals from two independent cohorts. We found three HLA class II alleles (HLA-DRB1∗04:03 with risk; HLA-DRB1∗01:03 and HLA-DRB1∗07:01 with protection) to be significantly associated with CMV serostatus across both cohorts and in multiple population subgroups. Interestingly, HLA-DRB1∗04:03 and HLA-DRB1∗01:03, the alleles with the strongest observed effect, are relatively rare, while common homologous alleles show no association with CMV. We show that these differences are mediated by changes in charge and volume to two key pockets in the peptide-binding groove of the HLA molecule, providing a structural basis for the observed association. Our results provide population-scale evidence for the role of HLA in mediating infection with this ubiquitous human virus and a framework for understanding immunological conditions necessary for efficient viral control.
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Affiliation(s)
- Juliano A Boquett
- Department of Neurology, University of California, San Francisco, San Francisco, CA, USA
| | | | | | - Martin Maiers
- CIBMTR (Center for International Blood and Marrow Transplant Research), NMDP, Minneapolis, MN, USA
| | - Jill A Hollenbach
- Department of Neurology, University of California, San Francisco, San Francisco, CA, USA; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA.
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5
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Lin R, Wu J, Liu Q. Epidemiology, clinical outcomes, and treatment patterns of cytomegalovirus infection after allogeneic hematopoietic stem cell transplantation in China: a scoping review and meta-analysis. Front Microbiol 2025; 16:1518275. [PMID: 40248426 PMCID: PMC12003426 DOI: 10.3389/fmicb.2025.1518275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Accepted: 03/10/2025] [Indexed: 04/19/2025] Open
Abstract
Introduction Cytomegalovirus (CMV) infection poses a significant threat to individuals undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), potentially resulting in substantial morbidity and mortality. This review summarized the epidemiology, clinical outcomes, and treatment patterns of CMV infection among allo-HSCT recipients in China. Methods PubMed, EMBASE, the Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), Wanfang and Chinese Biomedical Literature Database (CBM) were systematically searched from 2013 to March 2023. All analyses were performed using R 4.1.1 software with a random effects model. Results Fifty-six studies, which included 13,882 patients, were reviewed. The pooled overall incidence of CMV infection was 49.99% [95% confidence interval (CI) 43.72-56.26%]. Among post allo-HSCT recipients with CMV infection, 32.03% (95% CI 22.93-41.12%) developed refractory CMV infection. The overall incidence of CMV disease was 13.30% (95% CI 8.99-19.66%). The pooled all-cause mortality rate was 29.25% (95% CI 17.96-40.55%) and the CMV-related mortality rate was 3.46% (95% CI 1.19-5.73%). Results demonstrate that management of CMV has mainly focused on pre-emptive therapy due to the treatment-limiting toxicity of anti-CMV agents. Additionally, CMV infection is continuing to occur after the discontinuation of prophylaxis, highlighting the unmet need for a more effective treatment without treatment-limiting toxicities. Conclusion This review underscores the urgent need for improved therapeutic strategies to effectively manage cytomegalovirus infection in allo-HSCT recipients, particularly in light of the high incidence and associated morbidity, as well as the limitations of current treatment options. Systematic review registration https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024513908, identifier: CRD42024513908.
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Affiliation(s)
- Ren Lin
- Department of Hematology, Nanfang Hospital, Southern Medical University, Clinical Medical Research Center of Hematological Diseases of Guangdong Province, Guangzhou, China
| | - Jingyi Wu
- Medical Affairs, Takeda (China) International Trading Company, Shanghai, China
| | - Qifa Liu
- Department of Hematology, Nanfang Hospital, Southern Medical University, Clinical Medical Research Center of Hematological Diseases of Guangdong Province, Guangzhou, China
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6
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Mir M, Faiz S, Bommakanti AG, Sheshadri A. Pulmonary Immunocompromise in Stem Cell Transplantation and Cellular Therapy. Clin Chest Med 2025; 46:129-147. [PMID: 39890284 DOI: 10.1016/j.ccm.2024.10.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2025]
Abstract
Hematopoietic cell transplantation (HCT) and cellular therapies, such as chimeric-antigen receptor T-cell (CAR-T) treatments, are potentially curative treatments for certain hematologic malignancies and some nonmalignant disorders. However, pulmonary complications, both infectious and noninfectious, remain a significant cause of morbidity and mortality in patients who receive cellular therapies. This review article provides an overview of pulmonary complications encountered in the context of HCT and CAR-T. The authors discuss mechanisms of underlying immunocompromise that lead to a rise in infections. Additionally, they highlight key noninfectious complications of HCT that can mimic acute infections and suggest diagnostic approaches and preventive strategies to distinguish these entities promptly.
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Affiliation(s)
- Mahnoor Mir
- Divisions of Critical Care, Pulmonary and Sleep Medicine, McGovern Medical School at UTHealth, Houston, TX 77030, USA; Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Saadia Faiz
- Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Anuradha G Bommakanti
- Divisions of Critical Care, Pulmonary and Sleep Medicine, McGovern Medical School at UTHealth, Houston, TX 77030, USA; Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Ajay Sheshadri
- Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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Salwender H, Weinhold N, Benner A, Miah K, Merz M, Haenel M, Jehn C, Mai E, Menis E, Blau I, Scheid C, Hose D, Seckinger A, Luntz S, Besemer B, Munder M, Brossart P, Glass B, Lindemann HW, Weisel K, Hanoun C, Schnitzler P, Klemm S, Goldschmidt H, Raab M, Elmaagacli A. Cytomegalovirus immunoglobulin serology prevalence in patients with newly diagnosed multiple myeloma treated within the GMMG-MM5 phase III trial. Hematology 2024; 29:2320006. [PMID: 38407192 DOI: 10.1080/16078454.2024.2320006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Accepted: 02/07/2024] [Indexed: 02/27/2024] Open
Abstract
OBJECTIVES The seroprevalence of antibodies against Cytomegalovirus (CMV) is an established poor prognostic factor for patients receiving an allogeneic stem cell transplantation. However, the impact of CMV serology on outcome after autologous stem cell transplantation remains unknown. METHODS Here, we analyzed the CMV immunoglobulin (Ig) serology of 446 newly-diagnosed multiple myeloma (MM) patients of the GMMG-MM5 phase III trial with a median follow-up of 58 months. RESULTS CMV IgG and IgM positivity was seen in 51% and 6% of the patients, respectively. In multivariate analysis CMV IgG and CMV IgM serology show an age-depending effect for PFS. We identified positive CMV IgG/positive CMV IgM serology as an age-depending beneficial factor on PFS. DISCUSSION Younger patients with a positive CMV IgG/positive CMV IgM serology experienced a favorable effect on PFS, whereas a positive CMV IgG/positive CMV IgM serology at older age has a disadvantageous effect on PFS.
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Affiliation(s)
- Hans Salwender
- Department of Oncology and Hematology, Asklepios Hospital Hamburg Altona, Hamburg, Germany
| | - Niels Weinhold
- Department of Oncology and Hematology, Medizinische Klinik Heidelberg, Heidelberg, Germany
| | - Axel Benner
- Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany
| | - Kaya Miah
- Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany
| | - Maximilian Merz
- Department of Hematology and Cell Therapy, University Hospital Leipzig, Leipzig, Germany
| | - Mathias Haenel
- Department of Oncology and Hematology, Klinikum Chemnitz, Chemnitz, Germany
| | - Christian Jehn
- Department of Hematology/Oncology and Stem Cell Transplantation, AK St. Georg, Hamburg, Germany
| | - Elias Mai
- Department of Oncology and Hematology, Medizinische Klinik Heidelberg, Heidelberg, Germany
| | - Ekaterina Menis
- Department of Oncology and Hematology, Medizinische Klinik Heidelberg, Heidelberg, Germany
| | - Igor Blau
- Department of Oncology and Hematology, Charité Universitätsmedizin, Berlin, Germany
| | - Christof Scheid
- Department of Oncology and Hematology, University Hospital Cologne, Cologne, Germany
| | - Dirk Hose
- Laboratory of Hematology and Immunology & Labor für Myelomforschung, Vrije Universiteit Brussel (VUB), Jette, Belgium
| | - Anja Seckinger
- Laboratory of Hematology and Immunology & Labor für Myelomforschung, Vrije Universiteit Brussel (VUB), Jette, Belgium
| | - Steffen Luntz
- Department of Oncology and Hematology, Coordination Centre for Clinical Trials (KKS), Heidelberg, Germany
| | - Britta Besemer
- Department of Oncology and Hematology, University Hospital Tubingen, Tubingen, Germany
| | - Markus Munder
- Department of Oncology and Hematology, University Medical Center Mainz, Mainz, Germany
| | - Peter Brossart
- Department of Oncology and Hematology, University Hospital Bonn, Bonn, Germany
| | - Bertram Glass
- Department of Oncology and Hematology, Helios Hospital Berlin Buch, Buch, Germany
| | | | - Katja Weisel
- Department of Oncology and Hematology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christine Hanoun
- Department of Oncology and Hematology, University Hospital Essen, Essen, Germany
| | - Paul Schnitzler
- Zentrum für Infektiologie, Virologie Universitätsklinikum Heidelberg, Heidelberg, Germany
| | - Sarah Klemm
- Zentrum für Infektiologie, Virologie Universitätsklinikum Heidelberg, Heidelberg, Germany
| | - Hartmut Goldschmidt
- Department of Oncology and Hematology, Medizinische Klinik Heidelberg, Heidelberg, Germany
- Department of Oncology and Hematology, National Center for Tumor Diseases (NCT), Heidelberg, Germany
| | - Marc Raab
- Department of Oncology and Hematology, Medizinische Klinik Heidelberg, Heidelberg, Germany
| | - Ahmet Elmaagacli
- Department of Hematology/Oncology and Stem Cell Transplantation, AK St. Georg, Hamburg, Germany
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Kampouri E, Reynolds G, Teh BW, Hill JA. Chimeric antigen receptor-T-cell therapies going viral: latent and incidental viral infections. Curr Opin Infect Dis 2024; 37:526-535. [PMID: 39361275 PMCID: PMC11932447 DOI: 10.1097/qco.0000000000001066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2024]
Abstract
PURPOSE OF REVIEW Infections are the leading cause of non-relapse mortality following chimeric antigen receptor (CAR)-T-cell therapy, with viral infections being frequent both in the early and late phases post-infusion. We review the epidemiology of viral infections and discuss critical approaches to prevention and management strategies in this setting. RECENT FINDINGS Herpesviruses dominate the early period. herpes simplex virus and varicella zoster virus infections are rare due to widespread antiviral prophylaxis, but cytomegalovirus (CMV) reactivation is increasingly observed, particularly in high-risk groups including B cell maturation antigen (BCMA)-CAR-T-cell therapy recipients and patients receiving corticosteroids. While CMV end-organ disease is rare, CMV is associated with increased mortality, emphasizing the need to evaluate the broader impact of CMV on long-term hematological, infection, and survival outcomes. Human herpesvirus-6 (HHV-6) has also emerged as a concern, with its diagnosis complicated by overlapping symptoms with neurotoxicity, underscoring the importance of considering viral encephalitis in differential diagnoses. Respiratory viruses are the most common late infections with a higher incidence after BCMA CAR-T-cell therapy. Vaccination remains a critical preventive measure against respiratory viruses but may be less immunogenic following CAR-T-cell therapy. The optimal timing, type of vaccine, and dosing schedule require further investigation. SUMMARY A better understanding of viral epidemiology and preventive trials are needed to improve infection prevention practices and outcomes following CAR-T-cell therapies.
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Affiliation(s)
- Eleftheria Kampouri
- Infectious Diseases Service, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Gemma Reynolds
- Department of Infectious Diseases, Peter MacCallum Cancer Centre, Melbourne
| | - Benjamin W. Teh
- Department of Infectious Diseases, Peter MacCallum Cancer Centre, Melbourne
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville
- National Centre for Infections in Cancer, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Joshua A. Hill
- Vaccine and Infectious Disease Division
- Clinical Research Division, Fred Hutchinson Cancer Center
- Department of Medicine, University of Washington, Seattle, Washington, USA
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9
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Kampouri E, Boeckh MJ, Hill JA. Understanding the Clinical Significance of Cytomegalovirus Viremia After Chimeric Antigen Receptor T-Cell Therapy: Should We be Treating a Value? Clin Infect Dis 2024; 79:1319-1320. [PMID: 38306247 PMCID: PMC11581692 DOI: 10.1093/cid/ciae030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Accepted: 01/24/2024] [Indexed: 02/04/2024] Open
Affiliation(s)
- Eleftheria Kampouri
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Infectious Diseases Service, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Michael J Boeckh
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Department of Medicine, University of Washington, Seattle, Washington, USA
| | - Joshua A Hill
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Department of Medicine, University of Washington, Seattle, Washington, USA
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10
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Huang JP, Yeh CM, Gong YW, Tsai MH, Lin YT, Tsai CK, Liu CJ. Risk and impact of cytomegalovirus infection in lymphoma patients treated with bendamustine. Ann Hematol 2024; 103:4099-4109. [PMID: 39158713 DOI: 10.1007/s00277-024-05839-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Accepted: 06/06/2024] [Indexed: 08/20/2024]
Abstract
Bendamustine is used to treat lymphoma with excellent efficacy but is known for its immunosuppressive effect. Cytomegalovirus (CMV) reactivation after bendamustine use has been reported. We aim to address the impact of CMV infection in lymphoma patients treated with bendamustine-containing regimens. We retrospectively analyzed lymphoma patients at Taipei Veterans General Hospital in Taiwan between September 1, 2010, and April 30, 2022. Clinically significant CMV infection (CS-CMVi) was defined as the first CMV reactivation after bendamustine use necessitating CMV therapy. Patients' baseline characteristics and laboratory data were recorded. The primary endpoint of the study was CS-CMVi. A time-dependent covariate Cox regression model was used to estimate the risk factors of CS-CMVi and mortality. A total of 211 lymphoma patients treated with bendamustine were enrolled. Twenty-seven (12.8%) had CS-CMVi. The cumulative incidence was 10.1 per 100 person-years during the three-year follow-up period. In the multivariate analysis, lines of therapy before bendamustine ≥ 1 (95% CI 1.10-24.76), serum albumin < 3.5 g/dL (95% CI 2.63-52.93), and liver disease (95% CI 1.51-28.61) were risk factors for CS-CMVi. In conclusion, CS-CMVi (95% confidence interval [CI] 1.23-10.73) was one of the major independent risk factors of mortality. Lines of therapy before bendamustine ≥ 1, hypoalbuminemia, and liver disease were risk factors for CS-CMVi in lymphoma patients treated with bendamustine.
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Affiliation(s)
- Jen-Pei Huang
- Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou Dist, Taipei, 112201, Taiwan
| | - Chiu-Mei Yeh
- Division of Transfusion Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Institute of Public Health, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Ya-Wen Gong
- Department of Nursing, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou Dist, Taipei, 112201, Taiwan
| | - Ming-Hsuan Tsai
- Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou Dist, Taipei, 112201, Taiwan
| | - Yi-Tsung Lin
- Institute of Emergency and Critical Care Medicine, National Yang-Ming Chiao Tung University, No. 155, Section 2, Linong Street, Beitou District, Taipei, 112201, Taiwan
- Division of Infectious Diseases, Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou Dist, Taipei, 112201, Taiwan
| | - Chun-Kuang Tsai
- Division of Hematology, Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou Dist, Taipei, 112201, Taiwan.
- School of Medicine, National Yang Ming Chiao Tung University, No. 155, Section 2, Linong Street, Beitou District, Taipei, 112201, Taiwan.
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, No. 155, Section 2, Linong Street, Beitou District, Taipei, 112201, Taiwan.
- Division of Hematology, Taipei Veterans General Hospital, No. 201 Shipai Road, Sec. 2, Taipei, 11217, Taiwan.
| | - Chia-Jen Liu
- Institute of Emergency and Critical Care Medicine, National Yang-Ming Chiao Tung University, No. 155, Section 2, Linong Street, Beitou District, Taipei, 112201, Taiwan.
- Division of Transfusion Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
- Division of Transfusion Medicine, Taipei Veterans General Hospital, No. 201 Shipai Road, Sec. 2, Taipei, 11217, Taiwan.
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11
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Bangolo A, Dey S, Nagesh VK, Gumer K, Avetisyan L, Islam S, Sahotra M, Millett M, Alqinai B, Pender S, Dunraj Y, Syeda H, Tasneem B, Duran M, Deugd ND, Thakur P, Weissman S, Cho C. Role of Endoscopic Techniques in the Diagnosis of Complications of Allogeneic Hematopoietic Stem Cell Transplantation: A Review of the Literature. J Clin Med 2024; 13:4343. [DOI: 17.bangolo, a.; dey, s.; nagesh, v.k.; gumer, k.; avetisyan, l.; islam, s.; sahotra, m.; millett, m.; alqinai, b.; pender, s.; et al.role of endoscopic techniques in the diagnosis of complications of allogeneic hematopoietic stem cell transplantation: a review of the literature.j.clin.med.2024, 13, 4343.https:/doi.org/10.3390/jcm13154343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/12/2025] Open
Abstract
Allogeneic stem cell transplantation (Allo-SCT) implies that a donor and a recipient are not genetically identical. Allo-SCT is used to cure a variety of conditions, including hematologic malignancies using the graft versus tumor effect, nonmalignant hematologic, immune deficiencies, and, more recently, genetic disorders and inborn errors of metabolism. Given the immunosuppressive and myeloablative nature of some of the conditioning chemotherapy regimens used during the Allo-SCT, patients are often at high risk of infection, including viral infections affecting the gastrointestinal tract, following the transplant. Furthermore, other complications such as hepatic sinusoidal obstruction syndrome (SOS) or graft-versus-host disease may occur post-transplant and may require endoscopy to assist in the diagnosis. This review will provide newer insights into the importance of endoscopic techniques in the diagnosis of post-Allo-SCT complications with a focus on safety and timing.
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Affiliation(s)
- Ayrton Bangolo
- Department of Internal Medicine, HMH Palisades Medical Center, North Bergen, NJ 07047, USA
| | - Shraboni Dey
- Department of Internal Medicine, HMH Palisades Medical Center, North Bergen, NJ 07047, USA
| | | | - Kabir Gumer
- Department of Internal Medicine, HMH Palisades Medical Center, North Bergen, NJ 07047, USA
| | - Lida Avetisyan
- Department of Internal Medicine, HMH Palisades Medical Center, North Bergen, NJ 07047, USA
| | - Saima Islam
- Department of Internal Medicine, HMH Palisades Medical Center, North Bergen, NJ 07047, USA
| | - Monika Sahotra
- Department of Internal Medicine, HMH Palisades Medical Center, North Bergen, NJ 07047, USA
| | - Melissa Millett
- Department of Internal Medicine, HMH Palisades Medical Center, North Bergen, NJ 07047, USA
| | - Budoor Alqinai
- Department of Internal Medicine, HMH Palisades Medical Center, North Bergen, NJ 07047, USA
| | - Silvanna Pender
- Department of Internal Medicine, HMH Palisades Medical Center, North Bergen, NJ 07047, USA
| | - Yazmika Dunraj
- Department of Internal Medicine, HMH Palisades Medical Center, North Bergen, NJ 07047, USA
| | - Habiba Syeda
- Department of Internal Medicine, HMH Palisades Medical Center, North Bergen, NJ 07047, USA
| | - Beegum Tasneem
- Department of Internal Medicine, HMH Palisades Medical Center, North Bergen, NJ 07047, USA
| | - Mikel Duran
- Department of Internal Medicine, HMH Palisades Medical Center, North Bergen, NJ 07047, USA
| | - Nicoleta De Deugd
- Department of Internal Medicine, HMH Palisades Medical Center, North Bergen, NJ 07047, USA
| | - Prasad Thakur
- Department of Internal Medicine, HMH Palisades Medical Center, North Bergen, NJ 07047, USA
| | - Simcha Weissman
- Department of Internal Medicine, HMH Palisades Medical Center, North Bergen, NJ 07047, USA
| | - Christina Cho
- Division of Bone Marrow Transplant and Cellular Therapy, John Theurer Cancer Center, Hackensack, NJ 07601, USA
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12
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Bangolo A, Dey S, Nagesh VK, Gumer K, Avetisyan L, Islam S, Sahotra M, Millett M, Alqinai B, Pender S, Dunraj Y, Syeda H, Tasneem B, Duran M, Deugd ND, Thakur P, Weissman S, Cho C. Role of Endoscopic Techniques in the Diagnosis of Complications of Allogeneic Hematopoietic Stem Cell Transplantation: A Review of the Literature. J Clin Med 2024; 13:4343. [PMID: 39124609 PMCID: PMC11313381 DOI: 10.3390/jcm13154343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 07/19/2024] [Accepted: 07/22/2024] [Indexed: 08/12/2024] Open
Abstract
Allogeneic stem cell transplantation (Allo-SCT) implies that a donor and a recipient are not genetically identical. Allo-SCT is used to cure a variety of conditions, including hematologic malignancies using the graft versus tumor effect, nonmalignant hematologic, immune deficiencies, and, more recently, genetic disorders and inborn errors of metabolism. Given the immunosuppressive and myeloablative nature of some of the conditioning chemotherapy regimens used during the Allo-SCT, patients are often at high risk of infection, including viral infections affecting the gastrointestinal tract, following the transplant. Furthermore, other complications such as hepatic sinusoidal obstruction syndrome (SOS) or graft-versus-host disease may occur post-transplant and may require endoscopy to assist in the diagnosis. This review will provide newer insights into the importance of endoscopic techniques in the diagnosis of post-Allo-SCT complications with a focus on safety and timing.
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Affiliation(s)
- Ayrton Bangolo
- Department of Internal Medicine, HMH Palisades Medical Center, North Bergen, NJ 07047, USA; (A.B.)
| | - Shraboni Dey
- Department of Internal Medicine, HMH Palisades Medical Center, North Bergen, NJ 07047, USA; (A.B.)
| | - Vignesh Krishnan Nagesh
- Department of Internal Medicine, HMH Palisades Medical Center, North Bergen, NJ 07047, USA; (A.B.)
| | - Kabir Gumer
- Department of Internal Medicine, HMH Palisades Medical Center, North Bergen, NJ 07047, USA; (A.B.)
| | - Lida Avetisyan
- Department of Internal Medicine, HMH Palisades Medical Center, North Bergen, NJ 07047, USA; (A.B.)
| | - Saima Islam
- Department of Internal Medicine, HMH Palisades Medical Center, North Bergen, NJ 07047, USA; (A.B.)
| | - Monika Sahotra
- Department of Internal Medicine, HMH Palisades Medical Center, North Bergen, NJ 07047, USA; (A.B.)
| | - Melissa Millett
- Department of Internal Medicine, HMH Palisades Medical Center, North Bergen, NJ 07047, USA; (A.B.)
| | - Budoor Alqinai
- Department of Internal Medicine, HMH Palisades Medical Center, North Bergen, NJ 07047, USA; (A.B.)
| | - Silvanna Pender
- Department of Internal Medicine, HMH Palisades Medical Center, North Bergen, NJ 07047, USA; (A.B.)
| | - Yazmika Dunraj
- Department of Internal Medicine, HMH Palisades Medical Center, North Bergen, NJ 07047, USA; (A.B.)
| | - Habiba Syeda
- Department of Internal Medicine, HMH Palisades Medical Center, North Bergen, NJ 07047, USA; (A.B.)
| | - Beegum Tasneem
- Department of Internal Medicine, HMH Palisades Medical Center, North Bergen, NJ 07047, USA; (A.B.)
| | - Mikel Duran
- Department of Internal Medicine, HMH Palisades Medical Center, North Bergen, NJ 07047, USA; (A.B.)
| | - Nicoleta De Deugd
- Department of Internal Medicine, HMH Palisades Medical Center, North Bergen, NJ 07047, USA; (A.B.)
| | - Prasad Thakur
- Department of Internal Medicine, HMH Palisades Medical Center, North Bergen, NJ 07047, USA; (A.B.)
| | - Simcha Weissman
- Department of Internal Medicine, HMH Palisades Medical Center, North Bergen, NJ 07047, USA; (A.B.)
| | - Christina Cho
- Division of Bone Marrow Transplant and Cellular Therapy, John Theurer Cancer Center, Hackensack, NJ 07601, USA
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13
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Lin RY, Anderson AD, Natori Y, Raja M, Morris MI, Jimenez AJ, Beitinjaneh A, Wang T, Goodman M, Lekakis L, Spiegel J, Holtzman NG, Pereira D, Benjamin C, Natori A, Komanduri KV, Camargo JF. Incidence and outcomes of cytomegalovirus reactivation after chimeric antigen receptor T-cell therapy. Blood Adv 2024; 8:3813-3822. [PMID: 38838226 PMCID: PMC11298821 DOI: 10.1182/bloodadvances.2024012922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Revised: 05/15/2024] [Accepted: 06/02/2024] [Indexed: 06/07/2024] Open
Abstract
ABSTRACT Cytomegalovirus (CMV) reactivation is a major complication among seropositive allogeneic hematopoietic cell transplantation recipients; however, data on CMV reactivation after chimeric antigen receptor (CAR) T-cell therapy are limited. We report the incidence and outcomes of 95 adult CMV-seropositive patients who received CAR T-cell therapy between February 2018 and February 2023. CMV outcomes were CMV reactivation (any viremia) and clinically significant CMV infection (cs-CMV). Thirty-one patients (33%) had evidence of CMV reactivation (any viremia), and 10 patients (11%) had cs-CMV. The median time from CAR T-cell infusion to CMV reactivation was 19 days (interquartile range [IQR], 9-31). The cumulative incidence of CMV (any viremia) was significantly higher among patients with grade 3 to 4 cytokine release syndrome (67 vs 28%; P = .01), and those who received corticosteroids (39 vs 21%; P = .03), anakinra (56 vs 28%; P = .02), or ≥2 immunosuppressants (41 vs 21%; P = .02). Receipt of corticosteroids (18 vs 0%; P = .004), tocilizumab (14 vs 0%; P = .04), anakinra (33 vs 7%; P = .008), and ≥2 immunosuppressants (20 vs 0%; P = .001) were all associated with cs-CMV. Receiving ≥2 immunosuppressants was associated with a twofold increase in CMV reactivation in multivariate analyses (adjusted odds ratio [aOR], 2.27; 95% confidence interval, 1.1-4.8; P = .03). Overall, the 1-year mortality was significantly higher in those with CMV reactivation (57% vs 23%; P = .001). Immunosuppression, particularly with corticosteroids, for the management of CAR T-cell toxicities, is a major risk factor for CMV reactivation.
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Affiliation(s)
- Rick Y. Lin
- Department of Medicine, University of Florida, Gainesville, FL
| | | | - Yoichiro Natori
- Division of Infectious Diseases, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL
| | - Mohammed Raja
- Division of Infectious Diseases, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL
| | - Michele I. Morris
- Division of Infectious Diseases, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL
| | - Antonio Jimenez Jimenez
- Division of Transplantation and Cellular Therapy, Sylvester Comprehensive Cancer Center, Miami, FL
| | - Amer Beitinjaneh
- Division of Transplantation and Cellular Therapy, Sylvester Comprehensive Cancer Center, Miami, FL
| | - Trent Wang
- Division of Transplantation and Cellular Therapy, Sylvester Comprehensive Cancer Center, Miami, FL
| | - Mark Goodman
- Division of Transplantation and Cellular Therapy, Sylvester Comprehensive Cancer Center, Miami, FL
| | - Lazaros Lekakis
- Division of Transplantation and Cellular Therapy, Sylvester Comprehensive Cancer Center, Miami, FL
| | - Jay Spiegel
- Division of Transplantation and Cellular Therapy, Sylvester Comprehensive Cancer Center, Miami, FL
| | - Noa G. Holtzman
- Division of Transplantation and Cellular Therapy, Sylvester Comprehensive Cancer Center, Miami, FL
| | - Denise Pereira
- Division of Transplantation and Cellular Therapy, Sylvester Comprehensive Cancer Center, Miami, FL
| | - Cara Benjamin
- Division of Transplantation and Cellular Therapy, Sylvester Comprehensive Cancer Center, Miami, FL
| | - Akina Natori
- Division of Medical Oncology, Sylvester Comprehensive Cancer Center, Miami, FL
| | - Krishna V. Komanduri
- Division of Hematology and Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA
| | - Jose F. Camargo
- Division of Infectious Diseases, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL
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14
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AlQahtani HY, AlSuhebany N, Alowais SA, AlShehri B, Althemery A, Alghanim A, Alqahtani H, Alkhathran L, Alyaqub M, Alsulimani M, AlHarbi A, Alhatmi H, Almansour S, Almohaya A, Bosaeed M. Characterization of recurrent cytomegalovirus reactivations post allogenic stem cell transplantation in a population with high seropositivity. Virol J 2024; 21:149. [PMID: 38956615 PMCID: PMC11218190 DOI: 10.1186/s12985-024-02421-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Accepted: 06/21/2024] [Indexed: 07/04/2024] Open
Abstract
OBJECTIVES This study aimed to characterize incidences of CMV reactivations within one year post-allo-SCT and identify risk factors for CMV second reactivation episode in population with high seropositivity where first CMV reactivation episode deemed to be high. METHODS This retrospective cohort study analyzed data from 359 allo-SCT patients aged 14 and older admitted to a tertiary academic hospital. Data on demographic and clinical factors, CMV serostatus, conditioning regimens, graft-versus-host disease prophylaxis, engraftment time, and CMV reactivations were collected. RESULTS First and second CMV reactivations occurred in 88.9% and 18.4% of post-allo-SCT patients respectively. Patients were stratified into two groups based on primary disease necessitating allo-SCT, patients with malignant (Group 1) and non-malignant (Group 2) hematological disease. Factors associated with the second reactivation included cord blood as a stem cell source, human leukocyte antigen mismatch, acute graft-versus-host disease, and hematological malignancies. Patients with non-malignant hematological disease displayed better outcomes, including a higher rate of spontaneous clearance of first CMV reactivation (70% versus 49.4%) and lower rates of second CMV reactivation (9.6% versus 31%) than those with malignant hematological disease. The one-year overall survival rate was 87.7% (95.5% in non-malignant hematological disease and 78.13% in malignant hematological disease). CONCLUSION Our findings are concordant with previous local study in regard to high rate of first CMV reactivation post-allo-SCT. It appears that patients with nonmalignant hematological disease had better outcomes, such as lower second CMV reactivation and higher survival rates compared to patients with malignant hematological disease. Further investigation is needed to identify other factors affecting recurrent CMV reactivations in allo-SCT in patients with malignant hematological disease.
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Affiliation(s)
- Hajar Y AlQahtani
- Department of Pharmaceutical Care, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia.
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.
- King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.
| | - Nada AlSuhebany
- Department of Pharmaceutical Care, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
- College of Pharmacy, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Shuroug A Alowais
- Department of Pharmaceutical Care, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
- College of Pharmacy, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Bashayer AlShehri
- Department of Pharmaceutical Care, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia
| | - Abdullah Althemery
- Department of Clinical Pharmacy, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, Al Riyadh Province, Saudi Arabia
| | - Amirah Alghanim
- College of Pharmacy, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Hessa Alqahtani
- College of Pharmacy, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Lama Alkhathran
- College of Pharmacy, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Majd Alyaqub
- College of Pharmacy, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Mariam Alsulimani
- College of Pharmacy, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Ahmad AlHarbi
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
- Division of Infectious Diseases, Department of Medicine, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia
- College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Hind Alhatmi
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
- Division of Infectious Diseases, Department of Medicine, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia
- College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Sarah Almansour
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
- King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
- Division of Infectious Diseases, Department of Medicine, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia
| | - Abdulellah Almohaya
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
- King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
- Division of Infectious Diseases, Department of Medicine, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia
| | - Mohammed Bosaeed
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
- Division of Infectious Diseases, Department of Medicine, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia
- College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
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15
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Konishi T, Matsuda K, Itonaga H, Doki N, Nishida T, Matsuoka KI, Ikeda T, Kanda Y, Fukuda T, Kanda J, Nakamae H, Imada K, Ueda Y, Ichinohe T, Atsuta Y, Ishiyama K. Impact of Early Cytomegalovirus Reactivation After Allogeneic Hematopoietic Stem Cell Transplantation on Relapse in Patients With Myelodysplastic Syndrome: A Nationwide Retrospective Study From Adult Myelodysplastic Syndrome Working Group of the JSTCT. Transplant Cell Ther 2024; 30:685.e1-685.e12. [PMID: 38697293 DOI: 10.1016/j.jtct.2024.04.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 04/22/2024] [Accepted: 04/25/2024] [Indexed: 05/04/2024]
Abstract
Cytomegalovirus (CMV) reactivation is a prominent complication associated with adverse outcomes in allogeneic hematopoietic stem cell transplantation (HSCT). However, CMV reactivation after allogeneic HSCT may be associated with a lower incidence of relapse in some hematological malignancies. This study analyzed the Japanese registry data from 1082 patients with myelodysplastic syndrome (MDS) who underwent their first allogeneic HSCT and survived for 100 days after transplantation without graft failure or disease relapse to investigate this association. Patients who received cord blood transplants, demonstrated in vivo T cell depletion, underwent prophylactic anti-CMV treatment, or diagnosed with secondary MDS were excluded. CMV reactivation measured by pp65 antigenemia within 100 days after allogeneic HSCT was observed in 57.5% of patients, with a median time of 46 days from transplant. The 5-yr overall survival and cumulative incidence of relapse (CIR) in the cohort were 60.5% and 15.6%, respectively. The 5-yr CIR showed no significant difference between patients with and without CMV reactivation (14.4% versus 17.2%; P = .185). Interestingly, CMV reactivation within 100 days was significantly associated with a lower 5-yr CIR (7.6% versus 16.4%; P = .002) in patients with <5% myeloblasts in the bone marrow (BM) just before HSCT. Furthermore, this relevancy confirmed even when excluding patients with Grade II to IV acute GVHD (Hazard ratio: 0.38; 95% confidential intervals: 0.18-0.801; P = .011). Our findings indicate a correlation between early CMV reactivation and MDS relapse, based on the proportion of myeloblasts in the BM. These results may contribute to the development of effective CMV prophylaxis post-HSCT.
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Affiliation(s)
- Tatsuya Konishi
- Department of Hematology, Clinical Immunology and Infectious Diseases, Ehime University Graduate School of Medicine, Ehime, Japan.
| | - Kensuke Matsuda
- Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hidehiro Itonaga
- Transfusion and Cell Therapy Unit, Nagasaki University Hospital, Nagasaki, Japan
| | - Noriko Doki
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
| | - Tetsuya Nishida
- Department of Hematology, Japanese Red Cross Aichi Medical Center Nagoya Daiichi Hospital, Aichi, Japan
| | - Ken-Ichi Matsuoka
- Department of Hematology and Oncology, Okayama University Hospital, Okayama, Japan
| | - Takashi Ikeda
- Division of Hematology and Stem Cell Transplantation, Shizuoka Cancer Center, Shizuoka, Japan
| | - Yoshinobu Kanda
- Division of Hematology, Jichi Medical University, Tochigi, Japan
| | - Takahiro Fukuda
- Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan
| | - Junya Kanda
- Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hirohisa Nakamae
- Department of Hematology, Osaka Metropolitan University Hospital, Osaka, Japan
| | - Kazunori Imada
- Department of Hematology, Japanese Red Cross Osaka Hospital, Osaka, Japan
| | - Yasunori Ueda
- Department of Hematology/Oncology and Transfusion and Hemapheresis Center, Kurashiki Central Hospital, Okayama, Japan
| | - Tatsuo Ichinohe
- Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
| | - Yoshiko Atsuta
- Department of Registry Science for Transplant and Cellular Therapy, Aichi Medical University School of Medicine, Aichi, Japan; Japanese Data Center for Hematopoietic Cell Transplantation, Aichi, Japan
| | - Ken Ishiyama
- Department of Hematology, Center Hospital of the National Cancer for Global Health and Medicine, Japan
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Contreras-Valero JF, Ruíz-Ordóñez I, Pinilla-Monsalve GD, Bautista-Vargas M, Ocampo-Piraquive V, Aguirre-Valencia D. Cytomegalovirus infection and disease in systemic lupus erythematosus patients at a high-complexity hospital in southwestern Colombia. Lupus 2024; 33:797-803. [PMID: 38709545 DOI: 10.1177/09612033241247103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/07/2024]
Abstract
Cytomegalovirus (CMV) infection and disease is a condition usually described in immunocompromised patients, but among them, those with connective tissue diseases are poorly represented. Here we present the clinical, laboratory characteristics, management and outcomes of systemic lupus erythematosus (SLE) patients who presented with a CMV infection/disease to a high complexity hospital in southwestern Colombia between 2011 and 2020. 16 SLE patients were found to have a CMV infection. SLE was predominantly characterized by renal involvement (10 patients; 62.50%), and 14 patients (87.5%) were receiving steroids previous to the CMV infection. The entire sample required hospital admission, mainly related to acute kidney injury, and nine patients were admitted to the intensive care unit (ICU). Gastrointestinal organ damage was the most common CMV disease manifestation. All patients received ganciclovir, five of them (31.25%) suffered from septic shock, and seven (43.75%) died. Age ≥38 years and the presence of septic shock at admission were correlated to the mortality outcome. To our knowledge, this is the first publication evaluating SLE patients with CMV infection/disease in a Colombian population.
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Affiliation(s)
- Juan Fernando Contreras-Valero
- Division of Infectious Diseases, Department of Internal Medicine, Faculty of Medicine, Pontificia Universidad Javeriana, Bogotá, Colombia
| | - Ingrid Ruíz-Ordóñez
- GIRAT: Grupo de Investigación en Reumatología, Inmunología y Medicina Traslacional, School of Medicine, Fundación Valle del Lili, Universidad Icesi, Cali, Colombia
- Facultad de Ciencias de la Salud, Universidad de Caldas, Manizales, Colombia
| | | | - Mario Bautista-Vargas
- Unidad de Reumatología, Facultad de Ciencias de la Salud, Universidad Icesi, Cali, Colombia
| | - Vanessa Ocampo-Piraquive
- GIRAT: Grupo de Investigación en Reumatología, Inmunología y Medicina Traslacional, School of Medicine, Fundación Valle del Lili, Universidad Icesi, Cali, Colombia
- Unidad de Reumatología, Facultad de Ciencias de la Salud, Universidad Icesi, Cali, Colombia
| | - David Aguirre-Valencia
- GIRAT: Grupo de Investigación en Reumatología, Inmunología y Medicina Traslacional, School of Medicine, Fundación Valle del Lili, Universidad Icesi, Cali, Colombia
- Unidad de Reumatología, Facultad de Ciencias de la Salud, Universidad Icesi, Cali, Colombia
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17
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Febres-Aldana A, Khawaja F, Morado-Aramburo O, Shigle TL, Rondon G, Sassine J, Spallone A, Srinivasan K, Ramdial J, Alousi A, Champlin R, Chen G, Daher M, Rezvani K, Ariza-Heredia EJ, Shpall EJ, Chemaly RF. Mortality in recipients of allogeneic haematopoietic cell transplantation in the era of cytomegalovirus primary prophylaxis: a single-centre retrospective experience. Clin Microbiol Infect 2024; 30:803-809. [PMID: 38460821 DOI: 10.1016/j.cmi.2024.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 02/26/2024] [Accepted: 03/03/2024] [Indexed: 03/11/2024]
Abstract
OBJECTIVES Allogeneic haematopoietic cell transplant (allo-HCT) recipients who are cytomegalovirus (CMV)-seronegative have better post-transplant outcomes than CMV-seropositive recipients. Letermovir (LTV) is approved for CMV primary prophylaxis in adults who are CMV-seropositive after allo-HCT, and its use is associated with improved long-term post-transplant outcomes. We analysed whether LTV has affected the relationship between CMV serostatus and post-transplant outcomes. METHODS We conducted a retrospective single-centre cohort study of allo-HCT recipients, stratified according to donor (D) and recipient (R). CMV serostatus and the use of LTV: D-/R-, R+/LTV-, and R+/LTV+. Outcomes measured were all-cause and non-relapse mortality, clinically significant CMV infection, graft-versus-host disease, and relapse up to week 48 after allo-HCT. The D-/R- group served as the reference for comparisons in univariate, competing risk regression, and cumulative incidence functions. RESULTS The analysis included 1071 consecutive allo-HCT recipients: 131 D-/R-, 557 R+/LTV-, and 383 R+/LTV+. All-cause mortality by day 100 was 6.1% for the D-/R- group, compared with 14.0% (p 0.024) and 7.8% (p 0.7) for the R+/LTV- and R+/LTV + groups, respectively. Non-relapse mortality by day 100 was 11.0%, 6.8% and 3.8% for R+/LTV-, R+/LTV+, and D-/R- groups, respectively, without significant difference. When including relapse as a competing event, the hazard ratio for non-relapse mortality was 1.83 (95% CI: 1.12-2.99, p 0.017) for R+/LTV- compared with D-/R- and 1.05 (95% CI 0.62-1.77, p 0.85) for R+/LTV + compared with D-/R-. DISCUSSION CMV primary prophylaxis with LTV abrogated the mortality gap based on CMV serostatus, a protective effect that persisted after discontinuation of primary prophylaxis.
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Affiliation(s)
- Anthony Febres-Aldana
- Department of Infectious Diseases, Infection Control & Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Medicine, Division of Infectious Disease, Moffitt Cancer Center, Tampa, FL, USA
| | - Fareed Khawaja
- Department of Infectious Diseases, Infection Control & Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Oscar Morado-Aramburo
- Department of Infectious Diseases, Infection Control & Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Terri Lynn Shigle
- Division of Pharmacy, The University of Texas MD Anderson Cancer Centre, Houston, TX, USA
| | - Gabriela Rondon
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Joseph Sassine
- Infectious Diseases Section, Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Amy Spallone
- Department of Infectious Diseases, Infection Control & Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Krithika Srinivasan
- Department of Infectious Diseases, Infection Control & Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jeremy Ramdial
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Amin Alousi
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Richard Champlin
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - George Chen
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - May Daher
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Katayoun Rezvani
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ella J Ariza-Heredia
- Department of Infectious Diseases, Infection Control & Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Elizabeth J Shpall
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Roy F Chemaly
- Department of Infectious Diseases, Infection Control & Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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18
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Li H, Fletcher-Etherington A, Hunter LM, Keshri S, Fielding CA, Nightingale K, Ravenhill B, Nobre L, Potts M, Antrobus R, Crump CM, Rubinsztein DC, Stanton RJ, Weekes MP. Human cytomegalovirus degrades DMXL1 to inhibit autophagy, lysosomal acidification, and viral assembly. Cell Host Microbe 2024; 32:466-478.e11. [PMID: 38479395 DOI: 10.1016/j.chom.2024.02.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 01/10/2024] [Accepted: 02/20/2024] [Indexed: 04/13/2024]
Abstract
Human cytomegalovirus (HCMV) is an important human pathogen that regulates host immunity and hijacks host compartments, including lysosomes, to assemble virions. We combined a quantitative proteomic analysis of HCMV infection with a database of proteins involved in vacuolar acidification, revealing Dmx-like protein-1 (DMXL1) as the only protein that acidifies vacuoles yet is degraded by HCMV. Systematic comparison of viral deletion mutants reveals the uncharacterized 7 kDa US33A protein as necessary and sufficient for DMXL1 degradation, which occurs via recruitment of the E3 ubiquitin ligase Kip1 ubiquitination-promoting complex (KPC). US33A-mediated DMXL1 degradation inhibits lysosome acidification and autophagic cargo degradation. Formation of the virion assembly compartment, which requires lysosomes, occurs significantly later with US33A-expressing virus infection, with reduced viral replication. These data thus identify a viral strategy for cellular remodeling, with the potential to employ US33A in therapies for viral infection or rheumatic conditions, in which inhibition of lysosome acidification can attenuate disease.
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Affiliation(s)
- Hanqi Li
- Cambridge Institute for Medical Research, University of Cambridge, Hills Road, Cambridge CB2 0XY, UK; Department of Medicine, University of Cambridge, Hills Road, Cambridge CB2 2QQ, UK
| | - Alice Fletcher-Etherington
- Cambridge Institute for Medical Research, University of Cambridge, Hills Road, Cambridge CB2 0XY, UK; Department of Medicine, University of Cambridge, Hills Road, Cambridge CB2 2QQ, UK
| | - Leah M Hunter
- Cambridge Institute for Medical Research, University of Cambridge, Hills Road, Cambridge CB2 0XY, UK; Department of Medicine, University of Cambridge, Hills Road, Cambridge CB2 2QQ, UK
| | - Swati Keshri
- Cambridge Institute for Medical Research, University of Cambridge, Hills Road, Cambridge CB2 0XY, UK; UK Dementia Institute, University of Cambridge, The Keith Peters Building, Hills Road, Cambridge CB2 0XY, UK
| | - Ceri A Fielding
- Cardiff University School of Medicine, Division of Infection and Immunity, Henry Wellcome Building, Heath Park, Cardiff CF14 4XN, UK
| | - Katie Nightingale
- Cambridge Institute for Medical Research, University of Cambridge, Hills Road, Cambridge CB2 0XY, UK; Department of Medicine, University of Cambridge, Hills Road, Cambridge CB2 2QQ, UK
| | - Benjamin Ravenhill
- Cambridge Institute for Medical Research, University of Cambridge, Hills Road, Cambridge CB2 0XY, UK; Department of Medicine, University of Cambridge, Hills Road, Cambridge CB2 2QQ, UK
| | - Luis Nobre
- Cambridge Institute for Medical Research, University of Cambridge, Hills Road, Cambridge CB2 0XY, UK; Department of Medicine, University of Cambridge, Hills Road, Cambridge CB2 2QQ, UK
| | - Martin Potts
- Cambridge Institute for Medical Research, University of Cambridge, Hills Road, Cambridge CB2 0XY, UK; Department of Medicine, University of Cambridge, Hills Road, Cambridge CB2 2QQ, UK
| | - Robin Antrobus
- Cambridge Institute for Medical Research, University of Cambridge, Hills Road, Cambridge CB2 0XY, UK; Department of Medicine, University of Cambridge, Hills Road, Cambridge CB2 2QQ, UK
| | - Colin M Crump
- Division of Virology, Department of Pathology, University of Cambridge, Cambridge, UK
| | - David C Rubinsztein
- Cambridge Institute for Medical Research, University of Cambridge, Hills Road, Cambridge CB2 0XY, UK; UK Dementia Institute, University of Cambridge, The Keith Peters Building, Hills Road, Cambridge CB2 0XY, UK
| | - Richard J Stanton
- Cardiff University School of Medicine, Division of Infection and Immunity, Henry Wellcome Building, Heath Park, Cardiff CF14 4XN, UK
| | - Michael P Weekes
- Cambridge Institute for Medical Research, University of Cambridge, Hills Road, Cambridge CB2 0XY, UK.
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19
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Moore WJ, Boutin CA, Tanna S. A new direction for cytomegalovirus prophylaxis among transplant recipients: Benefits and nonviral outcomes of letermovir use as primary CMV prophylaxis. Curr Opin Infect Dis 2023; 36:514-521. [PMID: 37773928 DOI: 10.1097/qco.0000000000000983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/01/2023]
Abstract
PURPOSE OF REVIEW Letermovir has changed the game of primary prophylaxis against cytomegalovirus (CMV) for hematopoietic stem cell transplant (HSCT) and more recently, solid organ transplant recipients. This is largely due to letermovir's similar efficacy in protecting against CMV reactivation and disease, along with its superior safety profile, notably reduced myelotoxicity, and lack of renal dose adjustment compared to standard agents like valganciclovir. This review will describe the potential benefits and clinical considerations of letermovir as prophylaxis among transplant recipients, with a focus on recent evidence describing nonviral outcomes of CMV. RECENT FINDINGS Recent evidence has demonstrated improved safety (e.g., less myelosuppression) and tolerability with no difference in rates of CMV infection or disease in kidney transplant recipients given letermovir compared to valganciclovir. Real-world studies and meta-analyses in HSCT populations have explored various nonviral outcomes with letermovir use. Letermovir prophylaxis was associated with reduced mortality, lower rates of graft versus host disease, delayed CMV immune reconstitution, improved tolerability with extended durations, and decreased healthcare utilization. SUMMARY Letermovir is an effective antiviral agent for CMV prevention and has demonstrated enhanced safety, which may allow for extended durations of primary prophylaxis among transplant recipients along with other improved clinical outcomes by mitigating the indirect effects of CMV.
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Affiliation(s)
- W Justin Moore
- Department of Pharmacy, Northwestern Medicine, Chicago, Illinois, USA
| | - Catherine-Audrey Boutin
- Division of Infectious Disease, Department of Medicine, University of Montreal Hospital Center, Montreal, Quebec, Canada
| | - Sajal Tanna
- Division of Infectious Disease, Department of Medicine, Inova Medical Group, Falls Church, Virginia, USA
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20
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Stern L, McGuire HM, Avdic S, Blyth E, Gottlieb D, Patrick E, Abendroth A, Slobedman B. Circulating cytokine and chemokine patterns associated with cytomegalovirus reactivation after stem cell transplantation. Clin Transl Immunology 2023; 12:e16815. [PMID: 38034080 PMCID: PMC10684332 DOI: 10.1002/cti2.1473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Revised: 08/31/2023] [Accepted: 11/01/2023] [Indexed: 12/02/2023] Open
Abstract
Objectives Human cytomegalovirus (HCMV) reactivation is the leading viral complication after allogeneic haematopoietic stem cell transplantation (allo-HSCT). Understanding of circulating cytokine/chemokine patterns which accompany HCMV reactivation and correlate with HCMV DNAemia magnitude is limited. We aimed to characterise plasma cytokine/chemokine profiles in 36 allo-HSCT patients (21 with HCMV reactivation and 15 without HCMV reactivation) at four time-points in the first 100-day post-transplant. Methods The concentrations of 31 cytokines/chemokines in plasma samples were analysed using a multiplex bead-based immunoassay. Cytokine/chemokine concentrations were compared in patients with high-level HCMV DNAemia, low-level HCMV DNAemia or no HCMV reactivation, and correlated with immune cell frequencies measured using mass cytometry. Results Increased plasma levels of T helper 1-type cytokines/chemokines (TNF, IL-18, IP-10, MIG) were detected in patients with HCMV reactivation at the peak of HCMV DNAemia, relative to non-reactivators. Stem cell factor (SCF) levels were significantly higher before the detection of HCMV reactivation in patients who went on to develop high-level HCMV DNAemia (810-52 740 copies/mL) vs. low-level HCMV DNAemia (< 250 copies/mL). High-level HCMV reactivators, but not low-level reactivators, developed an elevated inflammatory cytokine/chemokine profile (MIP-1α, MIP-1β, TNF, LT-α, IL-13, IL-9, SCF, HGF) at the peak of reactivation. Plasma cytokine concentrations displayed unique correlations with circulating immune cell frequencies in patients with HCMV reactivation. Conclusion This study identifies distinct circulating cytokine/chemokine signatures associated with the magnitude of HCMV DNAemia and the progression of HCMV reactivation after allo-HSCT, providing important insight into immune recovery patterns associated with HCMV reactivation and viral control.
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Affiliation(s)
- Lauren Stern
- Infection, Immunity and Inflammation, School of Medical Sciences, Faculty of Medicine and HealthThe University of SydneySydneyNSWAustralia
- Charles Perkins CentreThe University of SydneySydneyNSWAustralia
| | - Helen M McGuire
- Infection, Immunity and Inflammation, School of Medical Sciences, Faculty of Medicine and HealthThe University of SydneySydneyNSWAustralia
- Charles Perkins CentreThe University of SydneySydneyNSWAustralia
| | - Selmir Avdic
- Westmead Institute for Medical ResearchThe University of SydneySydneyNSWAustralia
| | - Emily Blyth
- Westmead Institute for Medical ResearchThe University of SydneySydneyNSWAustralia
- Blood Transplant and Cell Therapies Program, Department of HaematologyWestmead HospitalSydneyNSWAustralia
- Faculty of Medicine and Health, Sydney Medical SchoolThe University of SydneySydneyNSWAustralia
| | - David Gottlieb
- Westmead Institute for Medical ResearchThe University of SydneySydneyNSWAustralia
- Blood Transplant and Cell Therapies Program, Department of HaematologyWestmead HospitalSydneyNSWAustralia
- Faculty of Medicine and Health, Sydney Medical SchoolThe University of SydneySydneyNSWAustralia
| | - Ellis Patrick
- Westmead Institute for Medical ResearchThe University of SydneySydneyNSWAustralia
- School of Mathematics and StatisticsThe University of SydneySydneyNSWAustralia
| | - Allison Abendroth
- Infection, Immunity and Inflammation, School of Medical Sciences, Faculty of Medicine and HealthThe University of SydneySydneyNSWAustralia
- Charles Perkins CentreThe University of SydneySydneyNSWAustralia
| | - Barry Slobedman
- Infection, Immunity and Inflammation, School of Medical Sciences, Faculty of Medicine and HealthThe University of SydneySydneyNSWAustralia
- Charles Perkins CentreThe University of SydneySydneyNSWAustralia
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21
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Abstract
The respiratory tree maintains sterilizing immunity against human fungal pathogens. Humans inhale ubiquitous filamentous molds and geographically restricted dimorphic fungal pathogens that form small airborne conidia. In addition, pathogenic yeasts, exemplified by encapsulated Cryptococcus species, and Pneumocystis pose significant fungal threats to the lung. Classically, fungal pneumonia occurs in immune compromised individuals, specifically in patients with HIV/AIDS, in patients with hematologic malignancies, in organ transplant recipients, and in patients treated with corticosteroids and targeted biologics that impair fungal immune surveillance in the lung. The emergence of fungal co-infections during severe influenza and COVID-19 underscores the impairment of fungus-specific host defense pathways in the lung by respiratory viruses and by medical therapies to treat viral infections. Beyond life-threatening invasive syndromes, fungal antigen exposure can exacerbate allergenic disease in the lung. In this review, we discuss emerging principles of lung-specific antifungal immunity, integrate the contributions and cooperation of lung epithelial, innate immune, and adaptive immune cells to mucosal barrier immunity, and highlight the pathogenesis of fungal-associated allergenic disease. Improved understanding of fungus-specific immunity in the respiratory tree has paved the way to develop improved diagnostic, pre-emptive, therapeutic, and vaccine approaches for fungal diseases of the lung.
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Affiliation(s)
- Lena J Heung
- Division of Infectious Diseases, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Darin L Wiesner
- Center for Immunity and Inflammation, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, NJ, USA
| | - Keyi Wang
- Center for Immunity and Inflammation, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, NJ, USA
| | - Amariliz Rivera
- Center for Immunity and Inflammation, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, NJ, USA
| | - Tobias M Hohl
- Infectious Disease Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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22
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Sakaguchi M, Atsuta Y, Sekiya N, Najima Y, Fukushima K, Shingai N, Toya T, Kobayashi T, Ohashi K, Doki N. Clinical impact and early prediction of carbapenem-resistant Pseudomonas aeruginosa bacteraemia in allogeneic hematopoietic stem cell transplantation recipients. J Glob Antimicrob Resist 2023; 32:187-194. [PMID: 36806701 DOI: 10.1016/j.jgar.2023.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 01/29/2023] [Accepted: 02/05/2023] [Indexed: 02/19/2023] Open
Abstract
OBJECTIVE Although antipseudomonal agents are administered in high-risk patients, no reports have focused on the risk of carbapenem-resistant (CR) Pseudomonas aeruginosa bacteraemia in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. METHODS We retrospectively studied a cohort of adult allo-HSCT recipients with P. aeruginosa bacteraemia, focusing on a comparison between carbapenem-sensitive (CS) and CR P. aeruginosa after initiating conditioning chemotherapy at our institute between January 2005 and December 2020. The incidence, all-cause 30-d mortality of P. aeruginosa bacteraemia, and risk factors for carbapenem resistance among patients with P. aeruginosa bacteraemia in allo-HSCT recipients were evaluated. RESULTS Forty-eight patients with P. aeruginosa bacteraemia were included, with an incidence of 3.84/100 recipients (CS = 1.92 vs. CR = 1.92). The all-cause 30-d mortality was significantly higher in CR P. aeruginosa bacteraemia (CS = 4.2% vs. CR = 39.1%; P = 0.003). The factor significantly associated with CR P. aeruginosa bacteraemia was carbapenem use for at least 3 d within 30 d before the onset of bacteraemia (odds ratio = 8.92; 95% confidence interval: 1.35-58.90). Inappropriate antimicrobial selection was significantly more frequent in CR P. aeruginosa bacteraemia (CS = 0% vs. CR = 29.2%; P ˂ 0.009). CONCLUSION Empirical combination therapy with reference to antimicrobial susceptibility profiles in each institution should be considered when CR P. aeruginosa bacteraemia is suspected in allo-HSCT recipients based on the risk of carbapenem exposure.
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Affiliation(s)
- Masahiro Sakaguchi
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan; Department of Infection Prevention and Control, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
| | - Yuya Atsuta
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
| | - Noritaka Sekiya
- Department of Infection Prevention and Control, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan; Department of Clinical Laboratory, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.
| | - Yuho Najima
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
| | - Kazuaki Fukushima
- Department of Infection Prevention and Control, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan; Department of Infectious Diseases, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
| | - Naoki Shingai
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
| | - Takashi Toya
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
| | - Takeshi Kobayashi
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
| | - Kazuteru Ohashi
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
| | - Noriko Doki
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
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23
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Zakhour J, Allaw F, Haddad SF, Kanj SS. The Ten Most Common Questions on Cytomegalovirus Infection in Hematopoietic Stem Cell Transplant Patients. Clin Hematol Int 2023; 5:21-28. [PMID: 36577863 PMCID: PMC9797381 DOI: 10.1007/s44228-022-00025-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 11/15/2022] [Indexed: 12/30/2022] Open
Abstract
With the rising number of patients undergoing hematopoietic stem cell transplantation (HSCT), clinicians are more likely to encounter infectious complications in immunocompromised hosts, particularly cytomegalovirus (CMV) infection. Besides the high mortality of CMV end-organ disease, patients with detectable CMV viremia may have worse outcomes and decreased survival even in the absence of end-organ disease. In view of the implications on morbidity and mortality, clinicians should maintain a high index of suspicion and initiate antiviral drugs promptly when CMV infection is confirmed. High-risk patients should be identified in order to provide optimal management. Additionally, novel antiviral agents with a good safety profile and minor adverse events are now available for prophylaxis in high-risk patients and for treatment of resistant or refractory CMV infection. The following review provides concise, yet comprehensive, guidance on the burden and risk factors of CMV in this population, as well as an update on the latest evidence for the management of CMV infection.
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Affiliation(s)
- Johnny Zakhour
- Internal Medicine Department, Infectious Diseases Division, Center of Infectious Disease Research, American University of Beirut Medical Center, Riad El Solh, PO Box 11-0236, Beirut, 1107 2020, Lebanon
| | - Fatima Allaw
- Internal Medicine Department, Infectious Diseases Division, Center of Infectious Disease Research, American University of Beirut Medical Center, Riad El Solh, PO Box 11-0236, Beirut, 1107 2020, Lebanon
| | - Sara F Haddad
- Internal Medicine Department, Infectious Diseases Division, Center of Infectious Disease Research, American University of Beirut Medical Center, Riad El Solh, PO Box 11-0236, Beirut, 1107 2020, Lebanon
| | - Souha S Kanj
- Internal Medicine Department, Infectious Diseases Division, Center of Infectious Disease Research, American University of Beirut Medical Center, Riad El Solh, PO Box 11-0236, Beirut, 1107 2020, Lebanon.
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24
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Ashley CL, McSharry BP, McWilliam HEG, Stanton RJ, Fielding CA, Mathias RA, Fairlie DP, McCluskey J, Villadangos JA, Rossjohn J, Abendroth A, Slobedman B. Suppression of MR1 by human cytomegalovirus inhibits MAIT cell activation. Front Immunol 2023; 14:1107497. [PMID: 36845106 PMCID: PMC9950634 DOI: 10.3389/fimmu.2023.1107497] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Accepted: 01/25/2023] [Indexed: 02/12/2023] Open
Abstract
Introduction The antigen presentation molecule MHC class I related protein-1 (MR1) is best characterized by its ability to present bacterially derived metabolites of vitamin B2 biosynthesis to mucosal-associated invariant T-cells (MAIT cells). Methods Through in vitro human cytomegalovirus (HCMV) infection in the presence of MR1 ligand we investigate the modulation of MR1 expression. Using coimmunoprecipitation, mass spectrometry, expression by recombinant adenovirus and HCMV deletion mutants we investigate HCMV gpUS9 and its family members as potential regulators of MR1 expression. The functional consequences of MR1 modulation by HCMV infection are explored in coculture activation assays with either Jurkat cells engineered to express the MAIT cell TCR or primary MAIT cells. MR1 dependence in these activation assays is established by addition of MR1 neutralizing antibody and CRISPR/Cas-9 mediated MR1 knockout. Results Here we demonstrate that HCMV infection efficiently suppresses MR1 surface expression and reduces total MR1 protein levels. Expression of the viral glycoprotein gpUS9 in isolation could reduce both cell surface and total MR1 levels, with analysis of a specific US9 HCMV deletion mutant suggesting that the virus can target MR1 using multiple mechanisms. Functional assays with primary MAIT cells demonstrated the ability of HCMV infection to inhibit bacterially driven, MR1-dependent activation using both neutralizing antibodies and engineered MR1 knockout cells. Discussion This study identifies a strategy encoded by HCMV to disrupt the MR1:MAIT cell axis. This immune axis is less well characterized in the context of viral infection. HCMV encodes hundreds of proteins, some of which regulate the expression of antigen presentation molecules. However the ability of this virus to regulate the MR1:MAIT TCR axis has not been studied in detail.
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Affiliation(s)
- Caroline L. Ashley
- Infection, Immunity and Inflammation, School of Medical Sciences, Faculty of Medicine and Health, and the Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia
| | - Brian P. McSharry
- Infection, Immunity and Inflammation, School of Medical Sciences, Faculty of Medicine and Health, and the Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia
- School of Dentistry and Medical Sciences, Faculty of Science and Health, Charles Sturt University, Wagga Wagga, NSW, Australia
| | - Hamish E. G. McWilliam
- Department of Microbiology and Immunology, The Peter Doherty Institute of Infection and Immunity, The University of Melbourne, Melbourne, VIC, Australia
- Department of Biochemistry and Pharmacology, Institute of Molecular Science and Biotechnology (Bio21), The University of Melbourne, Melbourne, VIC, Australia
| | - Richard J. Stanton
- Division of Infection & Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Ceri A. Fielding
- Division of Infection & Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Rommel A. Mathias
- Infection and Immunity Program, Department of Microbiology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia
- Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia
| | - David P. Fairlie
- ARC Centre of Excellence for Innovations in Peptide and Protein Science, Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia
| | - James McCluskey
- Department of Microbiology and Immunology, The Peter Doherty Institute of Infection and Immunity, The University of Melbourne, Melbourne, VIC, Australia
| | - Jose A. Villadangos
- Department of Microbiology and Immunology, The Peter Doherty Institute of Infection and Immunity, The University of Melbourne, Melbourne, VIC, Australia
- Department of Biochemistry and Pharmacology, Institute of Molecular Science and Biotechnology (Bio21), The University of Melbourne, Melbourne, VIC, Australia
| | - Jamie Rossjohn
- Division of Infection & Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom
- Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia
| | - Allison Abendroth
- Infection, Immunity and Inflammation, School of Medical Sciences, Faculty of Medicine and Health, and the Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia
| | - Barry Slobedman
- Infection, Immunity and Inflammation, School of Medical Sciences, Faculty of Medicine and Health, and the Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia
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Douglas G, Yong MK, Tio SY, Chau M, Prabahran A, Sasadeusz J, Slavin M, Ritchie D, Chee L. Effective CMV prophylaxis with high-dose valaciclovir in allogeneic hematopoietic stem-cell recipients at a high risk of CMV infection. Transpl Infect Dis 2023; 25:e13994. [PMID: 36413495 DOI: 10.1111/tid.13994] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 09/29/2022] [Accepted: 10/17/2022] [Indexed: 11/23/2022]
Abstract
BACKGROUND Cytomegalovirus (CMV) infection increases mortality and morbidity following allogeneic hematopoietic stem-cell transplantation (alloHSCT). Universal antiviral prophylaxis with letermovir is effective but unsubsidized in Australia. Valaciclovir demonstrates anti-CMV activity in high doses, but few current real-world studies explore its use as primary prophylaxis in high-risk patients post-alloHSCT. METHODS We performed a retrospective analysis of alloHSCT recipients at high risk of clinically significant CMV infection (cs-CMVi), defined as a plasma CMV DNA viral load of >400 IU/ml requiring preemptive therapy, or CMV disease. High-risk recipients were CMV seropositive and underwent T-cell depleted, haploidentical or umbilical cord stem-cell transplants. Consecutive patients transplanted from July 2018 to January 2020, treated with valaciclovir 2 g TDS from day +7 to +100 (HD-VALA), were compared to a historical cohort (July 2017-June 2018) who only received preemptive CMV therapy, and standard valaciclovir (SD-VALA) for varicella/herpes prophylaxis. We compared incidence of and time to cs-CMVi. RESULTS In the SD-VALA cohort (n = 27, median CMV follow-up duration 259 days), 23/27 (85%) developed cs-CMVi at a median of 39 days. For the HD-VALA cohort (n = 35, median CMV follow-up duration 216 days), 19/35 (54%) developed cs-CMVi, at a median of 68 days. Time to cs-CMVi was significantly longer in HD-VALA cohort (p < .0001). On multivariate analysis, HD VALA reduced the risk of cs-CMVi (HR 0.32, p = .0005). CONCLUSIONS In alloHSCT recipients at high risk for cs-CMVi, HD-VALA resulted in lower cumulative reactivation, and delayed reactivation, reducing requirement for preemptive CMV therapy in the early post-engraftment period.
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Affiliation(s)
- Genevieve Douglas
- Department of Clinical Haematology and Bone Marrow Transplantation, Peter MacCallum Cancer Centre and The Royal Melbourne Hospital, Parkville, Australia
| | - Michelle K Yong
- Department of Infectious Diseases, Royal Melbourne Hospital, Parkville, Australia.,National Centre for Infections in Cancer, Parkville, Australia.,Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia
| | - Shio Yen Tio
- Department of Infectious Diseases, Royal Melbourne Hospital, Parkville, Australia.,National Centre for Infections in Cancer, Parkville, Australia.,Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia
| | - Maggie Chau
- Department of Clinical Haematology and Bone Marrow Transplantation, Peter MacCallum Cancer Centre and The Royal Melbourne Hospital, Parkville, Australia.,Pharmacy Department, Royal Melbourne Hospital, Parkville, Victoria, Australia
| | - Ashvind Prabahran
- Department of Clinical Haematology and Bone Marrow Transplantation, Peter MacCallum Cancer Centre and The Royal Melbourne Hospital, Parkville, Australia
| | - Joe Sasadeusz
- Department of Infectious Diseases, Royal Melbourne Hospital, Parkville, Australia
| | - Monica Slavin
- Department of Infectious Diseases, Royal Melbourne Hospital, Parkville, Australia.,National Centre for Infections in Cancer, Parkville, Australia.,Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia
| | - David Ritchie
- Department of Clinical Haematology and Bone Marrow Transplantation, Peter MacCallum Cancer Centre and The Royal Melbourne Hospital, Parkville, Australia.,Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia.,Department of Medicine, University of Melbourne, Melbourne, Australia
| | - Lynette Chee
- Department of Clinical Haematology and Bone Marrow Transplantation, Peter MacCallum Cancer Centre and The Royal Melbourne Hospital, Parkville, Australia.,Department of Medicine, University of Melbourne, Melbourne, Australia
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Reed DR, Petroni GR, West M, Jones C, Alfaraj A, Williams PG, DeGregory K, Grose K, Monson S, Varadarajan I, Volodin L, Donowitz GR, Kindwall-Keller TL, Ballen KK. Prophylactic Pretransplant Ganciclovir to Reduce Cytomegalovirus Infection After Hematopoietic Stem Cell Transplantation. Hematol Oncol Stem Cell Ther 2023; 16:61-69. [PMID: 36634280 PMCID: PMC11956836 DOI: 10.1016/j.hemonc.2021.05.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 03/22/2021] [Accepted: 05/24/2021] [Indexed: 01/18/2023] Open
Abstract
OBJECTIVE/BACKGROUND Cytomegalovirus (CMV) reactivation remains a serious complication after allogeneic hematopoietic cell transplantation (HCT) occurring in approximately 60-70% of CMV-seropositive HCT recipients. CMV reactivation leads to adverse outcomes including end-organ damage, graft-versus-host disease, and graft failure. METHODS Ganciclovir was administered pretransplant at 5 mg/kg twice daily intravenously from the start of conditioning to Day T-2 to CMV-seropositive patients receiving their first allogeneic HCT. CMV DNA was monitored weekly until at least Day 100 posttransplant. RESULTS A total of 109 consecutive patients were treated, median age 57 (range 20-73) years. Of these, 36 (33%) patients had a CMV reactivation within the first 105 days posttransplant with a median time of reactivation of 52.5 (range 36-104) days posttransplant. The cumulative incidence of CMV reactivation at Day 105 posttransplant was 33.1% (95% confidence interval: 24.4-42.0). One patient developed CMV disease. CONCLUSION The use of pretransplant ganciclovir was associated with low incidence of CMV reactivation and disease. These data suggest that pretransplant ganciclovir with preemptive therapy for viral reactivation may be a useful strategy to reduce CMV reactivation. Future prospective trials are needed to compare strategies for CMV prophylaxis.
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Affiliation(s)
- Daniel R. Reed
- Section of Hematology and Oncology, Comprehensive Cancer Center of Wake Forest Baptist Health, Winston-Salem, NC, USA
| | - Gina R. Petroni
- Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA
| | - Melissa West
- Department of Pharmacy, University of Virginia, Charlottesville, VA, USA
| | - Caroline Jones
- Department of Pharmacy, University of Virginia, Charlottesville, VA, USA
| | - Abeer Alfaraj
- BayHealth Hematology/Oncology Associates, Delaware, PA, USA
| | - Paige G. Williams
- Division of Hematology and Oncology, University of Virginia, Charlottesville, VA, USA
| | - Kathlene DeGregory
- Department of Pharmacy, University of Virginia, Charlottesville, VA, USA
| | - Kyle Grose
- Department of Pharmacy, University of Kansas, Kansas City, KS, USA
| | - Sandra Monson
- Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA
| | - Indumathy Varadarajan
- Division of Hematology and Oncology, University of Virginia, Charlottesville, VA, USA
| | - Leonid Volodin
- Division of Hematology and Oncology, University of Virginia, Charlottesville, VA, USA
| | - Gerald R. Donowitz
- Department of Infectious Disease, University of Virginia, Charlottesville, VA, USA
| | | | - Karen K. Ballen
- Division of Hematology and Oncology, University of Virginia, Charlottesville, VA, USA
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Ranti J, Perkonoja K, Kauko T, Korhonen R. Clinical and healthcare burden of disease associated with cytomegalovirus in allogeneic hematopoietic stem cell transplantation - A retrospective single-center study. Transpl Infect Dis 2022; 24:e13947. [PMID: 36082437 PMCID: PMC10369922 DOI: 10.1111/tid.13947] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 07/21/2022] [Accepted: 08/15/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND CMV infection is a common complication in allogeneic hematopoietic stem cell transplantation (HSCT). We investigated the association of clinically significant CMV (CS-CMV) infection with clinical outcomes and healthcare resource utilization in allogeneic HSCT patients in Finland. METHODS This retrospective study included adult patients who received their first allogeneic HSCT between January 1, 2013, and December 31, 2018, at the Turku University Hospital. Data were collected from the hospital data lake. Clinical and healthcare outcomes were investigated at one year and mortality up to three years. RESULTS The study included 251 patients. CMV seroprevalence was 69.7%. CS-CMV infection occurred in 59.0% of the patients, and of those, 14.2% had ≥2 infections. The median time to CS-CMV infection was 34.5 days (Q1 -Q3 , 27.0-45.0). Recipient and donor seropositivity, and lymphoproliferative diseases were associated with higher, and HLA identical sibling donors with lower CS-CMV infection risk. CS-CMV infection was not associated with mortality in three years of follow-up. One hundred thirty-three (89.8%) and 75 (72.8%) patients with and without CS-CMV infection, respectively, were readmitted to the hospital. Patients with CS-CMV infection had more hospital readmissions (incidence rate ratio [IRR] 1.38, 95% confidence interval [CI] 1.10-1.73, p = .005) and patients with one CS-CMV infection (IRR 1.48, 95% CI 1.12-1.94, p = .005) or ≥2 infections had longer length of hospital stay (IRR 2.71, 95% CI 1.76-4.35, p < .001). CONCLUSION CMV seroprevalence is relatively high among Finnish allogeneic HSCT patients. CS-CMV infection was common and associated with a higher readmission rate and longer length of hospital stay.
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Affiliation(s)
- Juha Ranti
- Department of Hematology, Turku University Hospital, Hospital District of Southwest Finland, Turku, Finland
| | - Katariina Perkonoja
- Auria Clinical Informatics, Hospital District of Southwest Finland, Turku, Finland
| | - Tommi Kauko
- Auria Clinical Informatics, Hospital District of Southwest Finland, Turku, Finland
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Janković M, Knežević A, Todorović M, Đunić I, Mihaljević B, Soldatović I, Protić J, Miković N, Stoiljković V, Jovanović T. Cytomegalovirus infection may be oncoprotective against neoplasms of B-lymphocyte lineage: single-institution experience and survey of global evidence. Virol J 2022; 19:155. [PMID: 36171605 PMCID: PMC9520857 DOI: 10.1186/s12985-022-01884-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 09/16/2022] [Indexed: 11/23/2022] Open
Abstract
Background Although cytomegalovirus (CMV) is not considered tumorigenic, there is evidence for its oncomodulatory effects and association with hematological neoplasms. Conversely, a number of experimental and clinical studies suggest its putative anti-tumour effect. We investigated the potential connection between chronic CMV infection in patients with B-lymphocyte (B-cell) malignancies in a retrospective single-center study and extracted relevant data on CMV prevalences and the incidences of B-cell cancers the world over. Methods In the clinical single-center study, prevalence of chronic CMV infection was compared between patients with B-cell leukemia/lymphoma and the healthy controls. Also, global data on CMV seroprevalences and the corresponding country-specific incidences of B- lineage neoplasms worldwide were investigated for potential correlations. Results Significantly higher CMV seropositivity was observed in control subjects than in patients with B-cell malignancies (p = 0.035). Moreover, an unexpected seroepidemiological evidence of highly significant inverse relationship between country-specific CMV prevalence and the annual incidence of B-cell neoplasms was noted across the populations worldwide (ρ = −0.625, p < 0.001). Conclusions We try to draw attention to an unreported interplay between CMV infection and B-cell lymphomagenesis in adults. A large-scale survey across > 70 countries disclosed a link between CMV and B-cell neoplasms. Our evidence hints at an antagonistic effect of chronic CMV infection against B-lymphoproliferation.
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Affiliation(s)
- Marko Janković
- Institute of Microbiology and Immunology, Department of Virology, Faculty of Medicine, University of Belgrade, dr Subotića 1, Belgrade, 11000, Republic of Serbia.
| | - Aleksandra Knežević
- Institute of Microbiology and Immunology, Department of Virology, Faculty of Medicine, University of Belgrade, dr Subotića 1, Belgrade, 11000, Republic of Serbia
| | - Milena Todorović
- Clinic for Hematology, Faculty of Medicine, University Clinical Centre of Serbia, University of Belgrade, dr Koste Todorovića 2, Belgrade, 11000, Republic of Serbia
| | - Irena Đunić
- Clinic for Hematology, Faculty of Medicine, University Clinical Centre of Serbia, University of Belgrade, dr Koste Todorovića 2, Belgrade, 11000, Republic of Serbia
| | - Biljana Mihaljević
- Clinic for Hematology, Faculty of Medicine, University Clinical Centre of Serbia, University of Belgrade, dr Koste Todorovića 2, Belgrade, 11000, Republic of Serbia
| | - Ivan Soldatović
- Institute of Medical Statistics and Informatics, Faculty of Medicine, University of Belgrade, dr Subotića 15, Belgrade, 11000, Republic of Serbia
| | - Jelena Protić
- Institute of Virology, Vaccines, and Sera "Torlak",, Vojvode Stepe 458, Belgrade, 11152, Republic of Serbia
| | - Nevenka Miković
- Institute of Virology, Vaccines, and Sera "Torlak",, Vojvode Stepe 458, Belgrade, 11152, Republic of Serbia
| | - Vera Stoiljković
- Institute of Virology, Vaccines, and Sera "Torlak",, Vojvode Stepe 458, Belgrade, 11152, Republic of Serbia
| | - Tanja Jovanović
- Institute of Microbiology and Immunology, Department of Virology, Faculty of Medicine, University of Belgrade, dr Subotića 1, Belgrade, 11000, Republic of Serbia
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29
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Cui J, Zhao K, Sun Y, Wen R, Zhang X, Li X, Long B. Diagnosis and treatment for the early stage of cytomegalovirus infection during hematopoietic stem cell transplantation. Front Immunol 2022; 13:971156. [PMID: 36211358 PMCID: PMC9537469 DOI: 10.3389/fimmu.2022.971156] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 09/05/2022] [Indexed: 11/13/2022] Open
Abstract
Cytomegalovirus (CMV) infection remains a frequent complication after hematopoietic stem cell transplantation (HSCT) and causes significant morbidity and mortality in transplantation recipients. In this review, we highlight the role of major risk factors that are associated with the incidence of CMV infection. Advances in immunosurveillance may predict CMV infection, allowing early interventions to prevent severe infection. Furthermore, numerous therapeutic strategies against CMV infection after HSCT are summarized. A comprehensive understanding of the current situation of CMV treatment may provide a hint for clinical practice and even promote the development of novel strategies for precision medicine.
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Affiliation(s)
| | | | | | | | | | - Xudong Li
- *Correspondence: Bing Long, longb3@ mail.sysu.edu.cn; Xudong Li,
| | - Bing Long
- *Correspondence: Bing Long, longb3@ mail.sysu.edu.cn; Xudong Li,
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30
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Incidence, Clinicomicrobiological Characteristics, Risk Factors, and Treatment Outcomes of Bacterial Infections Following Liver Transplantation in Pediatrics: A Retrospective Cohort Study. ARCHIVES OF PEDIATRIC INFECTIOUS DISEASES 2022. [DOI: 10.5812/pedinfect-118809] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Background: Liver transplantation (LT) is the definitive treatment for patients with advanced liver failure. Bacterial infections are common consequences of organ transplantation resulting from immune suppression and prolonged hospitalization. Methods: This retrospective cohort study examined the records of all liver transplant pediatrics under 18 years of age in Abu-Ali Sina hospital, Shiraz, Fars province, Iran, from April 2019 to February 2020. Demographic, laboratory, and clinical data were extracted along with the administered therapeutic approach for the patient. Results: Of 80 enrolled patients, 52 were male, and 28 were female, with a median age of 60 months. An incidence of 67.9% of bacterial infections was recorded. Gram-negative and Gram-positive pathogens accounted for 64.06% and 35.93% of infections, respectively. Surgical site infections were the most common ones. The length of ICU stay, hospitalization, mechanical ventilation duration, and re-hospitalization were significantly higher in the infected group than in non-infected pediatrics (P-value < 0.05). Multivariate regression analysis showed that the only risk factor for bacterial infections after LT was the length of ICU stay. The mortality rate was 22%, which was significantly higher among the infection group (P = 0.008). Conclusions: A high rate of bacterial infections and an increasing prevalence of nosocomial and antibiotic-resistant pathogens were detected in the early period after LT.
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Rapid DNA visual detection of polymicrobial bloodstream infection using filter paper. Sci Rep 2022; 12:4515. [PMID: 35296724 PMCID: PMC8927095 DOI: 10.1038/s41598-022-08487-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 03/08/2022] [Indexed: 11/16/2022] Open
Abstract
Bloodstream infection (BSI) is a major complication in patients with cancers due to therapy-induced neutropenia and underlying conditions, which increases hospitalization time and mortality rate. Targeted and timely antimicrobial management is crucial to save the patients’ lives and reduce the social and economic burdens. Blood culture is a routine clinical diagnostic method of BSI with a long turnaround time, and generally identifies monomicrobial BSI. Thus, polymicrobial BSI often goes undetected although it occurs more frequently in these patients and results in more severe outcomes compared to monomicrobial BSI. In this work, we apply glutaric anhydride, N-hydroxysuccinimide and N,N′-dicyclohexylcarbodiimide to fabricate a functional surface on cellulose filter paper. Targeting three pathogens (Escherichia coli, Saccharomyces cerevisiae, and human cytomegalovirus) commonly occurring in BSI in neutropenic patients, we demonstrate rapid and accurate triplex pathogen DNA detection using the functionalized paper. All three pathogen DNA was identified in 1–5 min with a detection limit of 0.1–0.5 ng/µL. The developed test tool has the potential to provide rapid polymicrobial BSI diagnosis in support of timely, accurate antimicrobial treatment, and could be integrated into an automatic sample-to-result portable equipment.
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Chaya W, Anurathapan U, Rattanasiri S, Techasaensiri C, Pakakasama S, Apiwattanakul N. Bloodstream bacterial infections in thalassemic pediatric and adolescent patients after hematopoietic stem cell transplantation. Pediatr Transplant 2022; 26:e14168. [PMID: 34668623 DOI: 10.1111/petr.14168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 09/14/2021] [Accepted: 10/06/2021] [Indexed: 11/30/2022]
Abstract
BACKGROUND Thalassemic patients usually require regular blood transfusions; however, HSCT can provide a cure. Incidence of IBI in pediatric patients post-HSCT is still scant. OBJECTIVES This study aimed to explore whether thalassemic patients had a different incidence of post-HSCT IBI compared with patients with other underlying diseases. Factors associated with IBI in the pediatric population undergoing HSCT were also investigated. METHODS In this retrospective cohort study, clinical data of pediatric patients who underwent HSCT during the period from 2011 to 2016 were reviewed and analyzed. The primary outcome was incidence of IBI within 1-year post-HSCT. RESULTS Of 123 patients, 53 were thalassemic. IBI was diagnosed in 23 patients within 1 year after HSCT (incidence: 19.5 episodes/1000 patients/month). The IBI incidence was lower in thalassemic patients than in patients with other underlying diseases (6.9 vs. 31.6 episodes/1000 patients/month). Having thalassemia as an underlying disease was the only factor associated with lower IBI in pediatric post-HSCT patients (hazard ratio: 0.245; 95% confidence interval, 0.080-0.748). In post-HSCT thalassemic patients, IBI mostly occurred within 100 days after HSCT, and most of these cases had catheter-related blood stream infection. The risk of IBI tended higher for haploidentical HSCT, but this difference was not statistically significantly different. CONCLUSION The IBI incidence after HSCT was lower in thalassemic patients than in those with other underlying diseases. Catheter-related blood stream infection was the major IBI in these patients. IBI was not a major complication in thalassemic pediatric patients undergoing HSCT.
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Affiliation(s)
- Weerapong Chaya
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.,Department of Pediatrics, Sawanpracharak Hospital, Nakhon Sawan, Thailand
| | - Usanarat Anurathapan
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Sasivimol Rattanasiri
- Section for Clinical Epidemiology and Biostatistics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Chonnamet Techasaensiri
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Samart Pakakasama
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Nopporn Apiwattanakul
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
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Human cytomegalovirus protein RL1 degrades the antiviral factor SLFN11 via recruitment of the CRL4 E3 ubiquitin ligase complex. Proc Natl Acad Sci U S A 2022; 119:2108173119. [PMID: 35105802 PMCID: PMC8832970 DOI: 10.1073/pnas.2108173119] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/14/2021] [Indexed: 02/08/2023] Open
Abstract
Human cytomegalovirus (HCMV) is an important human pathogen and a paradigm of viral immune evasion, targeting intrinsic, innate, and adaptive immunity. We have employed two orthogonal multiplexed tandem mass tag-based proteomic screens to identify host proteins down-regulated by viral factors expressed during the latest phases of viral infection. This approach revealed that the HIV-1 restriction factor Schlafen-11 (SLFN11) was degraded by the poorly characterized, late-expressed HCMV protein RL1, via recruitment of the Cullin4-RING E3 Ubiquitin Ligase (CRL4) complex. SLFN11 potently restricted HCMV infection, inhibiting the formation and spread of viral plaques. Overall, we show that a restriction factor previously thought only to inhibit RNA viruses additionally restricts HCMV. We define the mechanism of viral antagonism and also describe an important resource for revealing additional molecules of importance in antiviral innate immunity and viral immune evasion.
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Yi ES, Lee JW, Kim YJ, Sung KW, Koo HH, Yoo KH. Risk factors and outcomes of cytomegalovirus infection in children post cord blood transplantation with focus on impact of graft-versus-host disease and immunosuppressants. Ann Hematol 2022; 101:409-419. [PMID: 34725714 DOI: 10.1007/s00277-021-04707-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 10/20/2021] [Indexed: 11/29/2022]
Abstract
Cytomegalovirus (CMV) infection remains an important cause of morbidity and mortality post cord blood transplantation (CBT). It has been suggested that the graft-versus-host disease (GVHD) and immunosuppressants have an impact on CMV infection. This study evaluated the incidence, outcomes, and risk factors of CMV infection, while focusing on GVHD and the use of immunosuppressants, in 103 children who had received CBT. Among the patients, 92.2% were positive for CMV serology, while CMV antigenemia was observed in 68.9% and CMV disease developed in 26.2%. CMV enterocolitis was the most common, followed by retinitis and pneumonia. Patients with positive CMV serology and grade II to IV GVHD were independently associated with CMV antigenemia. Recurrent CMV antigenemia was observed significantly more frequently in patients with extensive chronic GVHD. Patients with CMV disease showed significantly worse overall survival, relapse-free survival, and non-relapse mortality than those without CMV disease. In conclusion, CMV infection is common post-CBT in countries with a high rate of CMV seropositivity in the general population and is related to worse outcomes. GVHD severity is associated with the development and recurrence of CMV infection. Thus, efforts need to be made to prevent CMV infection in children post-CBT.
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Affiliation(s)
- Eun Sang Yi
- Division of Hematology and Oncology, Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
- Department of Pediatrics, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
| | - Ji Won Lee
- Division of Hematology and Oncology, Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yae-Jean Kim
- Division of Pediatric Infectious Diseases and Immunodeficiency, Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Ki Woong Sung
- Division of Hematology and Oncology, Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hong Hoe Koo
- Division of Hematology and Oncology, Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Keon Hee Yoo
- Division of Hematology and Oncology, Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
- Department of Health Science and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea.
- Stem Cell & Regenerative Medicine Institute, Samsung Medical Center, Seoul, Korea.
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35
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Kimura SI, Kameda K, Harada K, Saburi M, Okinaka K, Shinohara A, Uchida N, Nishijima A, Ozawa Y, Tanaka M, Kuriyama T, Katayama Y, Sawa M, Ikegame K, Kawakita T, Kanda Y, Nakamae H, Ara T, Kimura T, Sato A, Fukuda T, Atsuta Y, Nakasone H. Risk and predictive factors for candidemia after allogeneic hematopoietic cell transplantation: JSTCT Transplant Complications Working Group. Transplant Cell Ther 2022; 28:209.e1-209.e9. [PMID: 34995815 DOI: 10.1016/j.jtct.2021.12.020] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Revised: 12/27/2021] [Accepted: 12/27/2021] [Indexed: 10/19/2022]
Abstract
BACKGROUND Although antifungal prophylaxis that covers Candida species is a standard of care in allogeneic hematopoietic cell transplantation (HCT), candidemia mainly caused by non-albicans Candida species still occurs and is associated with a high mortality rate. OBJECTIVE This study aimed to evaluate the risk factors for candidemia after allogeneic HCT. Particularly, we evaluated the impact of patient factors such as hematopoietic cell transplantation-specific comorbidity index (HCT-CI) and performance status (PS) in addition to well-recognized risk factors including donor type, delayed engraftment and graft-versus-host disease (GVHD). STUDY DESIGN By using data from a Japanese transplant registry database, we analyzed 26,236 pediatric and adult patients with hematological malignancies who underwent their first allogeneic HCT. The posttransplant period was divided into early (days 0-40), late (days 41-100) and very late (days 101-365) phases RESULTS: The 1-year cumulative incidence of candidemia was 1.8%. When we analyzed pretransplant factors, age ≥ 40 years (hazard ratio [HR] 1.85), male (HR 1.34), HCT-CI (HCT-CI 1-2, HR 1.56; HCT-CI ≥ 3, HR 2.21), PS ≥ 2 (HR 2.01), high-risk disease (HR 1.78) and donor type including HLA-mismatched related donor (MMRD) (HR 1.96), HLA-mismatched unrelated donor (HR 2.05) and cord blood (CB) (HR 2.85) were significantly associated with an increased incidence of candidemia. Focusing on the early phase (days 0-40), HCT-CI, PS, high-risk disease and CB transplantation together with engraftment and severe acute GVHD significantly affected the development of candidemia. In the late phase (days 41-100), higher HCT-CI, male, and donor type including MMRD, and CB were associated with the occurrence of candidemia together with acute GVHD and disease relapse. In the very late phase (days 101-365), HCT-CI ≥ 3 and high-risk disease significantly affected the occurrence of candidemia together with acute and chronic GVHD, and disease relapse. CONCLUSIONS In addition to well-recognized risk factors including donor type, engraftment and GVHD, patient factors such as HCT-CI and PS were associated with the development of candidemia, which suggests that severely ill patients with transplantation-associated complications are more likely to develop candidemia.
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Affiliation(s)
- Shun-Ichi Kimura
- Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan; Transplant Complications Working Group of the Japan Society for Transplantation and Cellular Therapy (JSTCT).
| | - Kazuaki Kameda
- Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan; Transplant Complications Working Group of the Japan Society for Transplantation and Cellular Therapy (JSTCT)
| | - Kaito Harada
- Department of Hematology and Oncology, Tokai University School of Medicine, Kanagawa, Japan; Transplant Complications Working Group of the Japan Society for Transplantation and Cellular Therapy (JSTCT)
| | - Masuho Saburi
- Department of Hematology, Oita Prefectural Hospital, Oita, Japan; Transplant Complications Working Group of the Japan Society for Transplantation and Cellular Therapy (JSTCT)
| | - Keiji Okinaka
- Department of General Medicine and Infectious Diseases, National Cancer Center Hospital East, Chiba, Japan; Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan; Transplant Complications Working Group of the Japan Society for Transplantation and Cellular Therapy (JSTCT)
| | - Akihito Shinohara
- Department of Hematology, Tokyo Women's Medical University, Tokyo, Japan; Transplant Complications Working Group of the Japan Society for Transplantation and Cellular Therapy (JSTCT)
| | - Naoyuki Uchida
- Department of Hematology, Federation of National Public Service Personnel Mutual Aid Associations Toranomon Hospital, Tokyo, Japan
| | - Akihiko Nishijima
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
| | - Yukiyasu Ozawa
- Department of Hematology, Japanese Red Cross Nagoya First Hospital, Aichi, Japan
| | - Masatsugu Tanaka
- Department of Hematology, Kanagawa Cancer Center, Kanagawa, Japan
| | - Takuro Kuriyama
- Department of Hematology, Hamanomachi Hospital, Fukuoka, Japan
| | - Yuta Katayama
- Department of Hematology, Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital, Hiroshima, Japan
| | - Masashi Sawa
- Department of Hematology and Oncology, Anjo Kosei Hospital, Aichi, Japan
| | - Kazuhiro Ikegame
- Department of Hematology, Hyogo College of Medicine Hospital, Hyogo, Japan
| | - Toshiro Kawakita
- Department of Hematology, National Hospital Organization Kumamoto Medical Center, Kumamoto, Japan
| | - Yoshinobu Kanda
- Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan; Division of Hematology, Jichi Medical University, Tochigi, Japan
| | - Hirohisa Nakamae
- Hematology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Takahide Ara
- Department of Hematology, Hokkaido University Hospital, Hokkaido, Japan
| | - Takafumi Kimura
- Preparation Department, Japanese Red Cross Kinki Block Blood Center, Osaka, Japan
| | - Atsushi Sato
- Department of Hematology and Oncology, Miyagi Children's Hospital, Miyagi, Japan
| | - Takahiro Fukuda
- Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan
| | - Yoshiko Atsuta
- Japanese Data Center for Hematopoietic Cell Transplantation, Aichi, Japan; Department of Registry Science for Transplant and Cellular Therapy, Aichi Medical University School of Medicine, Aichi, Japan
| | - Hideki Nakasone
- Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan; Transplant Complications Working Group of the Japan Society for Transplantation and Cellular Therapy (JSTCT)
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36
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A CMV seronegative donor to avoid T-cell inflation? Blood 2021; 138:2751-2752. [PMID: 34967870 DOI: 10.1182/blood.2021012723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 06/10/2021] [Indexed: 11/20/2022] Open
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37
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Yeh AC, Varelias A, Reddy A, Barone SM, Olver SD, Chilson K, Onstad LE, Ensbey KS, Henden AS, Samson L, Jaeger CA, Bi T, Dahlman KB, Kim TK, Zhang P, Degli-Esposti MA, Newell EW, Jagasia MH, Irish JM, Lee SJ, Hill GR. CMV exposure drives long-term CD57+ CD4 memory T-cell inflation following allogeneic stem cell transplant. Blood 2021; 138:2874-2885. [PMID: 34115118 PMCID: PMC8718626 DOI: 10.1182/blood.2020009492] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 05/22/2021] [Indexed: 01/01/2023] Open
Abstract
Donor and recipient cytomegalovirus (CMV) serostatus correlate with transplant-related mortality that is associated with reduced survival following allogeneic stem cell transplant (SCT). Prior epidemiologic studies have suggested that CMV seronegative recipients (R-) receiving a CMV-seropositive graft (D+) experience inferior outcomes compared with other serostatus combinations, an observation that appears independent of viral reactivation. We therefore investigated the hypothesis that prior donor CMV exposure irreversibly modifies immunologic function after SCT. We identified a CD4+/CD57+/CD27- T-cell subset that was differentially expressed between D+ and D- transplants and validated results with 120 patient samples. This T-cell subset represents an average of 2.9% (D-/R-), 18% (D-/R+), 12% (D+/R-), and 19.6% (D+/R+) (P < .0001) of the total CD4+ T-cell compartment and stably persists for at least several years post-SCT. Even in the absence of CMV reactivation post-SCT, D+/R- transplants displayed a significant enrichment of these cells compared with D-/R- transplants (P = .0078). These are effector memory cells (CCR7-/CD45RA+/-) that express T-bet, Eomesodermin, granzyme B, secrete Th1 cytokines, and are enriched in CMV-specific T cells. These cells are associated with decreased T-cell receptor diversity (P < .0001) and reduced proportions of major histocompatibility class (MHC) II expressing classical monocytes (P < .0001), myeloid (P = .024), and plasmacytoid dendritic cells (P = .0014). These data describe a highly expanded CD4+ T-cell population and putative mechanisms by which prior donor or recipient CMV exposure may create a lasting immunologic imprint following SCT, providing a rationale for using D- grafts for R- transplant recipients.
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Affiliation(s)
- Albert C Yeh
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
- Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA
| | - Antiopi Varelias
- QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
- Facuty of Medicine, The University of Queensland, Brisbane, QLD, Australia
| | | | - Sierra M Barone
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN
| | - Stuart D Olver
- QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Kate Chilson
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Lynn E Onstad
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Kathleen S Ensbey
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Andrea S Henden
- QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Luke Samson
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
- QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Carla A Jaeger
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Timothy Bi
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Kimberly B Dahlman
- Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN; and
| | - Tae Kon Kim
- Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN; and
| | - Ping Zhang
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Mariapia A Degli-Esposti
- Infection and Immunity Program, Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
| | - Evan W Newell
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Madan H Jagasia
- Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN; and
| | - Jonathan M Irish
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN
| | - Stephanie J Lee
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
- Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA
| | - Geoffrey R Hill
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
- Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA
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38
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Wiriyachai T, Chaya W, Anurathapan U, Rattanasiri S, Boonsathorn S, Chaisavaneeyakorn S, Techasaensiri C, Apiwattanakul N. Association between adenovirus infection and mortality outcome among pediatric patients after hematopoietic stem cell transplant. Transpl Infect Dis 2021; 23:e13742. [PMID: 34614296 DOI: 10.1111/tid.13742] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 09/18/2021] [Accepted: 09/24/2021] [Indexed: 11/29/2022]
Abstract
BACKGROUND Adenovirus can cause severe diseases in post-hematopoietic stem cell transplant (HSCT) patients. Because these patients also have many other factors contributing to mortality, it remains controversial whether adenovirus infection itself contributes to increased mortality in these patients. OBJECTIVE To determine if adenovirus infection contributes to mortality in pediatric post-HSCT patients. METHODS This retrospective cohort study was performed in post HSCT patients, aged 0-18 years old, admitted at Ramathibodi Hospital from 2016 to 2020. Adenovirus infection was defined as the detection of adenovirus in blood or urine by polymerase chain reaction. Multivariate cox regression was used to identify factors associated with death. RESULTS The incidence of overall adenovirus infection (viremia or viruria) in this cohort was 20.8% (26 out of 125 enrolled patients). From the multivariate cox regression analysis, overall adenovirus infection was not significantly associated with death (hazard ratio [HR]: 2.41; 95% confidence interval [CI]: 0.96-6.06; p = .060). However, presence of viremia (HR: 3.90; 95% CI: 1.40-10.86; p = .009), having maximal serum viral load > 10 000 copies/ml (HR: 3.70; 95% CI: 1.20-11.38; p = .023), presence of end-organ diseases (HR: 3.44; 95% CI: 1.18-10.01; p = .023) were associated with mortality. Underlying diseases requiring long-term immunosuppressive drugs before HSCT, invasive fungal disease, invasive bacterial infection, cytomegalovirus infection, and longer engraftment time were also associated with mortality. CONCLUSION Overall adenovirus infection does not appear to play a significant role in mortality in pediatric post-HSCT patients. However, more invasive forms of adenovirus infection were associated with mortality in these patients.
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Affiliation(s)
- Thakoon Wiriyachai
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Weerapong Chaya
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.,Department of Pediatrics, Sawanpracharak Hospital, Nakhorn Swarn, Thailand
| | - Usanarat Anurathapan
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Sasivimol Rattanasiri
- Department of Clinical Epidemiology and Biostatistics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Sophida Boonsathorn
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Sujittra Chaisavaneeyakorn
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Chonnamet Techasaensiri
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Nopporn Apiwattanakul
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
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39
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Camargo JF, Ebisu Y, Jimenez-Jimenez A, Natori Y, Moroz I, Morris MI, Alencar M, Anderson AD, Lekakis L, Beitinjaneh A, Goodman M, Wang T, Pereira D, Komanduri KV. Lower Incidence of Cytomegalovirus Reactivation Following Post-Transplantation Cyclophosphamide HLA-Mismatched Unrelated Donor Transplantation. Transplant Cell Ther 2021; 27:1017.e1-1017.e7. [PMID: 34543769 DOI: 10.1016/j.jtct.2021.09.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 08/30/2021] [Accepted: 09/08/2021] [Indexed: 12/12/2022]
Abstract
The use of haploidentical or HLA-mismatched unrelated donors (MMUD) allows allogeneic hematopoietic cell transplantation in individuals without suitable matched donors. Post-transplantation cyclophosphamide (PTCy) is used routinely for prevention of graft-versus-host disease in recipients of haploidentical transplants, and its use has been recently explored in MMUD transplantation. We compared the incidence of cytomegalovirus (CMV) reactivation and rate of lymphocyte recovery between PTCy MMUD and alternative transplantation modalities. Single-center retrospective study of 22 consecutive PTCy MMUD recipients transplanted between April 2017 and January 2019. Patients undergoing anti-thymocyte globulin (ATG) MMUD (n = 37) and PTCy haploidentical transplantation (n = 19) between January 2015 and July 2018 served as historical controls. We assessed the incidence of CMV (any viremia) and clinically significant CMV reactivation (cs-CMVi; defined as CMV disease or CMV viremia leading to preemptive treatment) in these 3 groups. Immune reconstitution was assessed by absolute lymphocyte count (ALC) at days 30, 90, 180, and 360 after transplantation. Statistical analyses included Kaplan-Meier plots with a log-rank test, Kruskal-Wallis test, and Fisher's exact test where appropriate, and logistic regression analyses. For PTCy MMUD, PTCy haploidentical and ATG MMUD groups, the 100-day and 200-day incidence of CMV (any viremia) were 41%, 63%, and 77% (P = .02), and 64%, 68%, and 86% (P = .049), respectively. The rate of cs-CMVi was also lower in PTCy MMUD compared to PTCy haploidentical and ATG MMUD (14% versus 53% and 54% at day 100 [P = .01] and 25% versus 53% and 58% at day 200 [P = .03]). There was a trend toward lower 200-day incidence of cs-CMVi in PTCy MMUD compared to ATG MMUD, even after excluding letermovir-treated patients from the analysis (25% versus 58% [P = .06]). The association between PTCy MMUD and lower risk of cs-CMVi remained significant even after adjusting for letermovir prophylaxis (odds ratio = 0.23, 95% confidence interval, 0.07-0.81 [P = .02]). Day 30 ALC was lower in PTCy MMUD compared to PTCy haploidentical and ATG MMUD (0.14, 0.33, 0.44 × 109/L, respectively [P = .005) but similar across groups at other time points. PTCy MMUD transplantation was associated with lower incidence of CMV events, independent of the use of CMV prophylaxis. Larger studies are needed.
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Affiliation(s)
- Jose F Camargo
- Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, Florida.
| | - Yosuke Ebisu
- Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, Florida
| | - Antonio Jimenez-Jimenez
- Division of Transplantation and Cellular Therapy, Sylvester Comprehensive Cancer Center, Miami, Florida
| | - Yoichiro Natori
- Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, Florida
| | - Ilona Moroz
- Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, Florida
| | - Michele I Morris
- Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, Florida
| | - Maritza Alencar
- Division of Transplantation and Cellular Therapy, Sylvester Comprehensive Cancer Center, Miami, Florida
| | - Anthony D Anderson
- Department of Pharmacy, Sylvester Comprehensive Cancer Center, Miami, Florida
| | - Lazaros Lekakis
- Division of Transplantation and Cellular Therapy, Sylvester Comprehensive Cancer Center, Miami, Florida
| | - Amer Beitinjaneh
- Division of Transplantation and Cellular Therapy, Sylvester Comprehensive Cancer Center, Miami, Florida
| | - Mark Goodman
- Division of Transplantation and Cellular Therapy, Sylvester Comprehensive Cancer Center, Miami, Florida
| | - Trent Wang
- Division of Transplantation and Cellular Therapy, Sylvester Comprehensive Cancer Center, Miami, Florida
| | - Denise Pereira
- Division of Transplantation and Cellular Therapy, Sylvester Comprehensive Cancer Center, Miami, Florida
| | - Krishna V Komanduri
- Division of Transplantation and Cellular Therapy, Sylvester Comprehensive Cancer Center, Miami, Florida
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40
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Duke ER, Williamson BD, Borate B, Golob JL, Wychera C, Stevens-Ayers T, Huang ML, Cossrow N, Wan H, Mast TC, Marks MA, Flowers ME, Jerome KR, Corey L, Gilbert PB, Schiffer JT, Boeckh M. CMV viral load kinetics as surrogate endpoints after allogeneic transplantation. J Clin Invest 2021; 131:133960. [PMID: 32970635 DOI: 10.1172/jci133960] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Accepted: 09/17/2020] [Indexed: 12/19/2022] Open
Abstract
BACKGROUNDViral load (VL) surrogate endpoints transformed development of HIV and hepatitis C therapeutics. Surrogate endpoints for CMV-related morbidity and mortality could advance development of antiviral treatments. Although observational data support using CMV VL as a trial endpoint, randomized controlled trials (RCTs) demonstrating direct associations between virological markers and clinical endpoints are lacking.METHODSWe performed CMV DNA PCR on frozen serum samples from the only placebo-controlled RCT of ganciclovir for early treatment of CMV after hematopoietic cell transplantation (HCT). We used established criteria to assess VL kinetics as surrogates for CMV disease or death by weeks 8, 24, and 48 after randomization and quantified antiviral effects captured by each marker. We used ensemble-based machine learning to assess the predictive ability of VL kinetics and performed this analysis on a ganciclovir prophylaxis RCT for validation.RESULTSVL suppression with ganciclovir reduced cumulative incidence of CMV disease and death for 20 years after HCT. Mean VL, peak VL, and change in VL during the first 5 weeks of treatment fulfilled the Prentice definition for surrogacy, capturing more than 95% of ganciclovir's effect, and yielded highly sensitive and specific predictions by week 48. In the prophylaxis trial, the viral shedding rate satisfied the Prentice definition for CMV disease by week 24.CONCLUSIONSOur results support using CMV VL kinetics as surrogates for CMV disease, provide a framework for developing CMV preventative and therapeutic agents, and support reductions in VL as the mechanism through which antivirals reduce CMV disease.FUNDINGMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
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Affiliation(s)
- Elizabeth R Duke
- Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.,University of Washington, Seattle, Washington, USA
| | | | - Bhavesh Borate
- Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Jonathan L Golob
- Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.,University of Washington, Seattle, Washington, USA
| | - Chiara Wychera
- Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | | | | | | | - Hong Wan
- Merck & Co., Inc., Kenilworth, New Jersey, USA
| | | | | | - Mary E Flowers
- Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.,University of Washington, Seattle, Washington, USA
| | - Keith R Jerome
- Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.,University of Washington, Seattle, Washington, USA
| | - Lawrence Corey
- Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.,University of Washington, Seattle, Washington, USA
| | - Peter B Gilbert
- Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.,University of Washington, Seattle, Washington, USA
| | - Joshua T Schiffer
- Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.,University of Washington, Seattle, Washington, USA
| | - Michael Boeckh
- Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.,University of Washington, Seattle, Washington, USA
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41
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Zhou X, Moore BB. Experimental Models of Infectious Pulmonary Complications Following Hematopoietic Cell Transplantation. Front Immunol 2021; 12:718603. [PMID: 34484223 PMCID: PMC8415416 DOI: 10.3389/fimmu.2021.718603] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 07/26/2021] [Indexed: 12/23/2022] Open
Abstract
Pulmonary infections remain a major cause of morbidity and mortality in hematopoietic cell transplantation (HCT) recipients. The prevalence and type of infection changes over time and is influenced by the course of immune reconstitution post-transplant. The interaction between pathogens and host immune responses is complex in HCT settings, since the conditioning regimens create periods of neutropenia and immunosuppressive drugs are often needed to prevent graft rejection and limit graft-versus-host disease (GVHD). Experimental murine models of transplantation are valuable tools for dissecting the procedure-related alterations to innate and adaptive immunity. Here we review mouse models of post-HCT infectious pulmonary complications, primarily focused on three groups of pathogens that frequently infect HCT recipients: bacteria (often P. aeruginosa), fungus (primarily Aspergillus fumigatus), and viruses (primarily herpesviruses). These mouse models have advanced our knowledge regarding how the conditioning and HCT process negatively impacts innate immunity and have provided new potential strategies of managing the infections. Studies using mouse models have also validated clinical observations suggesting that prior or occult infections are a potential etiology of noninfectious pulmonary complications post-HCT as well.
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Affiliation(s)
- Xiaofeng Zhou
- Dept. of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, United States.,Division of Pulmonary and Critical Care Medicine, Dept. of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Bethany B Moore
- Dept. of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, United States.,Division of Pulmonary and Critical Care Medicine, Dept. of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, United States
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Hakki M, Aitken SL, Danziger-Isakov L, Michaels MG, Carpenter PA, Chemaly RF, Papanicolaou GA, Boeckh M, Marty FM. American Society for Transplantation and Cellular Therapy Series: #3-Prevention of Cytomegalovirus Infection and Disease After Hematopoietic Cell Transplantation. Transplant Cell Ther 2021; 27:707-719. [PMID: 34452721 DOI: 10.1016/j.jtct.2021.05.001] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 05/02/2021] [Indexed: 11/20/2022]
Abstract
The Practice Guidelines Committee of the American Society for Transplantation and Cellular Therapy partnered with its Transplant Infectious Disease Special Interest Group to update its 2009 compendium-style infectious diseases guidelines for the care of hematopoietic cell transplant (HCT) recipients. A new approach was taken with the goal of better serving clinical providers by publishing each standalone topic in the infectious disease series as a concise format of frequently asked questions (FAQ), tables, and figures. Adult and pediatric infectious disease and HCT content experts developed and answered FAQs. Topics were finalized with harmonized recommendations that were made by assigning an A through E strength of recommendation paired with a level of supporting evidence graded I through III. The third topic in the series focuses on the prevention of cytomegalovirus infection and disease in HCT recipients by reviewing prophylaxis and preemptive therapy approaches; key definitions, relevant risk factors, and diagnostic monitoring considerations are also reviewed.
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Affiliation(s)
- Morgan Hakki
- Division of Infectious Diseases, Department of Medicine, Oregon Health and Science University, Portland, Oregon.
| | - Samuel L Aitken
- Division of Pharmacy, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Lara Danziger-Isakov
- Division of Infectious Disease, Department of Pediatrics, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio
| | - Marian G Michaels
- Division of Pediatric Infectious Diseases, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh and the University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Paul A Carpenter
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Roy F Chemaly
- Department of Infectious Diseases, Infection Control, & Employee Health, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | | | - Michael Boeckh
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Vaccine and Infectious Disease Divisions, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Francisco M Marty
- Division of Infectious Diseases, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, Massachusetts
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Takeshita J, Kimura SI, Nakasone H, Kawamura S, Nakamura Y, Kawamura M, Yoshino N, Misaki Y, Yoshimura K, Matsumi S, Gomyo A, Tamaki M, Akahoshi Y, Kusuda M, Kameda K, Wada H, Sato M, Kako S, Kanda Y. Association between the kinetics of cytomegalovirus reactivation in terms of the area under the curve of cytomegalovirus antigenemia and non-relapse mortality after allogeneic hematopoietic stem cell transplantation. Transpl Infect Dis 2021; 23:e13715. [PMID: 34437758 DOI: 10.1111/tid.13715] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 07/12/2021] [Accepted: 08/09/2021] [Indexed: 11/28/2022]
Abstract
BACKGROUND We assessed the kinetics of cytomegalovirus (CMV) reactivation using the area under the curve (AUC), which simultaneously reflects both the viral load at each time point and the duration of CMV antigenemia (CMV-AG). METHODS We performed a single-institute retrospective analysis in patients who received allogeneic hematopoietic stem cell transplantation (HSCT) between 2007 and 2017 and survived more than 100 days after HSCT. The AUC of CMV-AG (CMV-AUC) was calculated by a trapezoidal method using the number of CMV-AG tested by the C10/C11 method after logarithmic transformation, and plotted weekly up to day 100. RESULTS CMV reactivation was observed in 195 cases and the median CMV-AUC for CMV-reactivated patients was 8.7 (range 0.5-30.7). Older age, corticosteroid administration, CMV-seropositive transplant recipients, HSCT from an unrelated donor, and underlying diseases were independent predictive factors for higher CMV-AUC. Higher CMV-AUC was associated with poor overall survival (OS) with borderline significance in a univariate analysis (p = .07), but was not significant in a multivariate analysis. Older age, high-risk disease status, and female gender were identified as significant factors associated with poor OS in this study. On the other hand, CMV-AUC (hazard ratio: no reactivation reference, low 0.98, high 2.49, p < .01), older age, HCT-CI ≥3, and corticosteroid administration were identified as significant factors associated with increased incidence of non-relapse mortality (NRM). CONCLUSIONS The kinetics of CMV reactivation in terms of CMV-AUC reflect both the severity and duration of CMV reactivation. High CMV-AUC was associated with an increased incidence of NRM in survivors over 100 days.
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Affiliation(s)
- Junko Takeshita
- Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan
| | - Shun-Ichi Kimura
- Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan
| | - Hideki Nakasone
- Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan
| | - Shunto Kawamura
- Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan
| | - Yuhei Nakamura
- Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan
| | - Masakatsu Kawamura
- Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan
| | - Nozomu Yoshino
- Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan
| | - Yukiko Misaki
- Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan
| | - Kazuki Yoshimura
- Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan
| | - Shimpei Matsumi
- Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan
| | - Ayumi Gomyo
- Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan
| | - Masaharu Tamaki
- Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan
| | - Yu Akahoshi
- Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan
| | - Machiko Kusuda
- Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan
| | - Kazuaki Kameda
- Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan
| | - Hidenori Wada
- Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan
| | - Miki Sato
- Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan
| | - Shinichi Kako
- Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan
| | - Yoshinobu Kanda
- Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan
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Jakharia N, Howard D, Riedel DJ. CMV Infection in Hematopoietic Stem Cell Transplantation: Prevention and Treatment Strategies. CURRENT TREATMENT OPTIONS IN INFECTIOUS DISEASES 2021; 13:123-140. [PMID: 34305463 PMCID: PMC8294301 DOI: 10.1007/s40506-021-00253-w] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/12/2021] [Indexed: 12/15/2022]
Abstract
Purpose of Review Cytomegalovirus (CMV) remains a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (Allo-HSCT). New strategies and methods for prevention and management of CMV infection are urgently needed. We aim to review the new developments in diagnostics, prevention, and management strategies of CMV infection in Allo-HSCT recipients. Recent Findings The approval of the novel anti-CMV drug letermovir in 2017 has led to an increase in the use of antiviral prophylaxis as a preferred approach for prevention in many centers. Real-world studies have shown efficacy similar to the clinical trial. CMV-specific T cell-mediated immunity assays identify patients with immune reconstitution and predict disease progression. Phase 2 trials of maribavir have shown its efficacy as preemptive therapy and treatment of resistant and refractory CMV infections. Adoptive T cell therapy is an emerging option for treatment of refractory and resistant CMV. Of the different CMV vaccine trials, PepVax has shown promising results in a phase 1 trial. Summary CMV cell-mediated immunity assays have potential to be used as an adjunctive test to develop individualized management plan by identifying the patients who develop immune reconstitution; however, further prospective interventional studies are needed. Maribavir and adoptive T cell therapy are promising new therapies for treatment of CMV infections. CMV vaccine trials for prevention are also under way.
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Affiliation(s)
- Niyati Jakharia
- Department of Internal Medicine, Section of Infectious Diseases, Stanford University Hospital, 300 Pasteur Dr., Lane L 134, Stanford, CA 94305 USA
| | - Dianna Howard
- Department of Internal Medicine, Section of Hematology-Oncology, Wake Forest Baptist Medical Center, Winston-Salem, NC USA
| | - David J Riedel
- Department of Internal Medicine, Division of Infectious Diseases, University of Maryland School of Medicine, Baltimore, MD USA
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Mendoza-Palomar N, Soques E, Benitez-Carabante MI, Gonzalez-Amores M, Fernandez-Polo A, Renedo B, Martin MT, Soler-Palacin P, Diaz-de-Heredia C. Low-dose liposomal amphotericin B for antifungal prophylaxis in paediatric allogeneic haematopoietic stem cell transplantation. J Antimicrob Chemother 2021; 75:2264-2271. [PMID: 32335674 DOI: 10.1093/jac/dkaa149] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 03/14/2020] [Accepted: 03/25/2020] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Primary antifungal prophylaxis in paediatric allogeneic HSCT recipients is mainly based on azoles, which can have related toxicity and drug interactions. Low-dose liposomal amphotericin B (L-AmB) is an attractive intravenous alternative because of its low toxicity and lower risk of interactions. OBJECTIVES To evaluate the effectiveness and safety of L-AmB (1 mg/kg/day) for primary antifungal prophylaxis in pre-engraftment paediatric HSCT patients. PATIENTS AND METHODS Retrospective, observational study including all consecutive patients aged ≤18 years who underwent HSCT and received antifungal prophylaxis with intravenous L-AmB (1 mg/kg/day, from day -1 to 48 h before discharge) between January 2012 and December 2016. RESULTS In total, 125 HSCT procedures in 118 patients were included, median age 7.2 years (IQR 4.2-11.5). Haematological malignancies were the main underlying condition (63.6%), and 109 (87.2%) were considered at high risk for invasive fungal infection (IFI). Ten patients (7.7%), all high risk, developed breakthrough IFI (three Candida spp., seven invasive mould infections) and tended to have higher overall mortality. The only statistically significant risk factor for IFI was cytomegalovirus co-infection. Adverse events, all grade I, occurred in 25 (20%), requiring L-AmB withdrawal in one case. Overall survival at 30 days was 99.2%. At study completion, one patient had died of IFI. CONCLUSIONS The incidence of breakthrough IFI was comparable to that of previous reports, with a very low rate of significant toxicity. Thus, prophylactic L-AmB may be a safe, effective option for antifungal prophylaxis in the pre-engraftment phase for children undergoing HSCT, even those at high risk.
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Affiliation(s)
- Natalia Mendoza-Palomar
- Paediatric Infectious Diseases and Immunodeficiencies Unit, University Hospital Vall d'Hebron, Barcelona, Spain.,Vall d'Hebron Research Institute, Autonomous University of Barcelona, Barcelona, Spain
| | - Elena Soques
- Paediatric Oncology and Haematology Department, University Hospital Vall d'Hebron, Barcelona, Spain
| | | | - Miriam Gonzalez-Amores
- Paediatric Infectious Diseases and Immunodeficiencies Unit, University Hospital Vall d'Hebron, Barcelona, Spain.,Vall d'Hebron Research Institute, Autonomous University of Barcelona, Barcelona, Spain
| | - Aurora Fernandez-Polo
- Vall d'Hebron Research Institute, Autonomous University of Barcelona, Barcelona, Spain.,Pharmacy Department, University Hospital Vall d'Hebron, Barcelona, Spain
| | - Berta Renedo
- Pharmacy Department, University Hospital Vall d'Hebron, Barcelona, Spain
| | - Maria Teresa Martin
- Vall d'Hebron Research Institute, Autonomous University of Barcelona, Barcelona, Spain.,Microbiology Department, University Hospital Vall d'Hebron, Barcelona, Spain.,Autonomous University of Barcelona, Barcelona, Spain
| | - Pere Soler-Palacin
- Paediatric Infectious Diseases and Immunodeficiencies Unit, University Hospital Vall d'Hebron, Barcelona, Spain.,Vall d'Hebron Research Institute, Autonomous University of Barcelona, Barcelona, Spain.,Autonomous University of Barcelona, Barcelona, Spain
| | - Cristina Diaz-de-Heredia
- Vall d'Hebron Research Institute, Autonomous University of Barcelona, Barcelona, Spain.,Paediatric Oncology and Haematology Department, University Hospital Vall d'Hebron, Barcelona, Spain.,Autonomous University of Barcelona, Barcelona, Spain
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46
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Immune control of cytomegalovirus reactivation in stem cell transplantation. Blood 2021; 139:1277-1288. [PMID: 34166512 DOI: 10.1182/blood.2020010028] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 06/22/2021] [Indexed: 11/20/2022] Open
Abstract
The reactivation of viruses from latency after allogeneic stem cell transplantation (SCT) continues to represent a major clinical challenge requiring sophisticated monitoring strategies in the context of prophylactic and/or pre-emptive antiviral drugs that are associated with significant expense, toxicity, and rates of failure. Accumulating evidence has demonstrated the association of polyfunctional virus-specific T-cells with protection from viral reactivation, affirmed by the ability of adoptively transferred virus-specific T-cells to prevent and treat reactivation and disease. The roles of innate cells (NK cells) in early viral surveillance, and dendritic cells in priming of T-cells have also been delineated. Most recently, a role for strain-specific humoral responses in preventing early cytomegalovirus (CMV) reactivation has been demonstrated in preclinical models. Despite these advances, many unknowns remain: what are the critical innate and adaptive responses over time, is the origin (e.g. recipient versus donor) and localization (e.g. in parenchymal tissue versus lymphoid organs) of these responses important, how does GVHD and the prevention/treatment thereof (e.g. high dose steroids) impact the functionality and relevance of a particular immune axis, do the immune parameters that control latency, reactivation and dissemination differ, and what is the impact of new antiviral drugs on the development of enduring antiviral immunity. Thus, whilst antiviral drugs have provided major improvements over the last two decades, understanding the immunological paradigms underpinning protective antiviral immunity after SCT offers the potential to generate non-toxic immune-based therapeutic approaches for lasting protection from viral reactivation.
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Paulson JN, Williams BL, Hehnly C, Mishra N, Sinnar SA, Zhang L, Ssentongo P, Mbabazi-Kabachelor E, Wijetunge DSS, von Bredow B, Mulondo R, Kiwanuka J, Bajunirwe F, Bazira J, Bebell LM, Burgoine K, Couto-Rodriguez M, Ericson JE, Erickson T, Ferrari M, Gladstone M, Guo C, Haran M, Hornig M, Isaacs AM, Kaaya BN, Kangere SM, Kulkarni AV, Kumbakumba E, Li X, Limbrick DD, Magombe J, Morton SU, Mugamba J, Ng J, Olupot-Olupot P, Onen J, Peterson MR, Roy F, Sheldon K, Townsend R, Weeks AD, Whalen AJ, Quackenbush J, Ssenyonga P, Galperin MY, Almeida M, Atkins H, Warf BC, Lipkin WI, Broach JR, Schiff SJ. Paenibacillus infection with frequent viral coinfection contributes to postinfectious hydrocephalus in Ugandan infants. Sci Transl Med 2021; 12:12/563/eaba0565. [PMID: 32998967 DOI: 10.1126/scitranslmed.aba0565] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Accepted: 05/06/2020] [Indexed: 12/14/2022]
Abstract
Postinfectious hydrocephalus (PIH), which often follows neonatal sepsis, is the most common cause of pediatric hydrocephalus worldwide, yet the microbial pathogens underlying this disease remain to be elucidated. Characterization of the microbial agents causing PIH would enable a shift from surgical palliation of cerebrospinal fluid (CSF) accumulation to prevention of the disease. Here, we examined blood and CSF samples collected from 100 consecutive infant cases of PIH and control cases comprising infants with non-postinfectious hydrocephalus in Uganda. Genomic sequencing of samples was undertaken to test for bacterial, fungal, and parasitic DNA; DNA and RNA sequencing was used to identify viruses; and bacterial culture recovery was used to identify potential causative organisms. We found that infection with the bacterium Paenibacillus, together with frequent cytomegalovirus (CMV) coinfection, was associated with PIH in our infant cohort. Assembly of the genome of a facultative anaerobic bacterial isolate recovered from cultures of CSF samples from PIH cases identified a strain of Paenibacillus thiaminolyticus This strain, designated Mbale, was lethal when injected into mice in contrast to the benign reference Paenibacillus strain. These findings show that an unbiased pan-microbial approach enabled characterization of Paenibacillus in CSF samples from PIH cases, and point toward a pathway of more optimal treatment and prevention for PIH and other proximate neonatal infections.
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Affiliation(s)
- Joseph N Paulson
- Department of Biostatistics, Product Development, Genentech Inc., South San Francisco, CA 94080, USA
| | - Brent L Williams
- Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, NY 10032, USA.,Department of Epidemiology, Columbia University Mailman School of Public Health, New York, NY 10032, USA
| | - Christine Hehnly
- Institute for Personalized Medicine, Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
| | - Nischay Mishra
- Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, NY 10032, USA.,Department of Epidemiology, Columbia University Mailman School of Public Health, New York, NY 10032, USA
| | - Shamim A Sinnar
- Center for Neural Engineering, Pennsylvania State University, University Park, PA 16802, USA.,Department of Medicine, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
| | - Lijun Zhang
- Institute for Personalized Medicine, Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
| | - Paddy Ssentongo
- Center for Neural Engineering, Pennsylvania State University, University Park, PA 16802, USA.,Department of Engineering Science and Mechanics, Pennsylvania State University, University Park, PA 16802, USA.,Department of Public Health Sciences, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
| | | | - Dona S S Wijetunge
- Department of Pathology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
| | - Benjamin von Bredow
- Department of Pathology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
| | - Ronnie Mulondo
- CURE Children's Hospital of Uganda, Plot 97-105, Bugwere Road, P.O. Box 903 Mbale, Uganda
| | - Julius Kiwanuka
- Department of Pediatrics, Mbarara University of Science and Technology, P.O. Box 1410 Mbarara, Uganda
| | - Francis Bajunirwe
- Department of Epidemiology, Mbarara University of Science and Technology, P.O. Box 1410, Mbarara, Uganda
| | - Joel Bazira
- Department of Microbiology, Mbarara University of Science and Technology, P.O. Box 1410 Mbarara, Uganda
| | - Lisa M Bebell
- Division of Infectious Disease, Massachusetts Genereal Hospital, Harvard Medical School, 55 Fruit St, GRJ-504, Boston, MA 02114, USA
| | - Kathy Burgoine
- Neonatal Unit, Department of Paediatrics and Child Health, Mbale Regional Referral Hospital, Plot 29-33 Pallisa Road, P.O. Box 1966, Mbale, Uganda.,Mbale Clinical Research Institute, Mbale Regional Referral Hospital, Plot 29-33 Pallisa Road, P.O. Box 1966 Mbale, Uganda.,University of Liverpool, Liverpool, L69 3BX, UK
| | - Mara Couto-Rodriguez
- Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, NY 10032, USA.,Biotia, 100 6th avenue, New York, NY 10013, USA
| | - Jessica E Ericson
- Division of Pediatric Infectious Disease, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
| | - Tim Erickson
- CURE Children's Hospital of Uganda, Plot 97-105, Bugwere Road, P.O. Box 903 Mbale, Uganda
| | - Matthew Ferrari
- Center for Infectious Disease Dynamics, Pennsylvania State University, University Park, PA 16802, USA.,Department of Biology, Pennsylvania State University, University Park, PA 16802, USA.,Department of Statistics, Pennsylvania State University, University Park, PA 16802, USA
| | - Melissa Gladstone
- Institute for Translational Medicine, University of Liverpool, Liverpool, L12 2AP, UK
| | - Cheng Guo
- Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, NY 10032, USA
| | - Murali Haran
- Department of Statistics, Pennsylvania State University, University Park, PA 16802, USA
| | - Mady Hornig
- Department of Epidemiology, Columbia University Mailman School of Public Health, New York, NY 10032, USA
| | - Albert M Isaacs
- Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63130, USA
| | - Brian Nsubuga Kaaya
- CURE Children's Hospital of Uganda, Plot 97-105, Bugwere Road, P.O. Box 903 Mbale, Uganda
| | - Sheila M Kangere
- CURE Children's Hospital of Uganda, Plot 97-105, Bugwere Road, P.O. Box 903 Mbale, Uganda
| | - Abhaya V Kulkarni
- Division of Neurosurgery, Hospital for Sick Children, University of Toronto, Toronto, Ontario, M5G 1X8, Canada
| | - Elias Kumbakumba
- Department of Pediatrics, Mbarara University of Science and Technology, P.O. Box 1410 Mbarara, Uganda
| | - Xiaoxiao Li
- Institute for Translational Medicine, University of Liverpool, Liverpool, L12 2AP, UK
| | - David D Limbrick
- Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63130, USA
| | - Joshua Magombe
- CURE Children's Hospital of Uganda, Plot 97-105, Bugwere Road, P.O. Box 903 Mbale, Uganda
| | - Sarah U Morton
- Division of Newborn Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston MA 02115, USA
| | - John Mugamba
- CURE Children's Hospital of Uganda, Plot 97-105, Bugwere Road, P.O. Box 903 Mbale, Uganda
| | - James Ng
- Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, NY 10032, USA
| | - Peter Olupot-Olupot
- Mbale Clinical Research Institute, Mbale Regional Referral Hospital, Plot 29-33 Pallisa Road, P.O. Box 1966 Mbale, Uganda.,Busitema University, Mbale Campus, Plot 29-33 Pallisa Road, P.O. Box 1966, Mbale, Uganda
| | - Justin Onen
- CURE Children's Hospital of Uganda, Plot 97-105, Bugwere Road, P.O. Box 903 Mbale, Uganda
| | - Mallory R Peterson
- Center for Neural Engineering, Pennsylvania State University, University Park, PA 16802, USA.,Department of Engineering Science and Mechanics, Pennsylvania State University, University Park, PA 16802, USA
| | - Farrah Roy
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
| | - Kathryn Sheldon
- Institute for Personalized Medicine, Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
| | - Reid Townsend
- Department of Medicine, Washington University School of Medicine , St. Louis, MO 63130, USA
| | - Andrew D Weeks
- Sanyu Research Unit, Liverpool Women's Hospital, University of Liverpool, Liverpool L8 7SS, UK
| | - Andrew J Whalen
- Department of Mechanical Engineering, Pennsylvania State University, University Park, PA 16802, USA
| | - John Quackenbush
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
| | - Peter Ssenyonga
- CURE Children's Hospital of Uganda, Plot 97-105, Bugwere Road, P.O. Box 903 Mbale, Uganda
| | - Michael Y Galperin
- National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA
| | - Mathieu Almeida
- Université Paris-Saclay, INRAE, MGP, Jouy-en-Josas, 78350, France
| | - Hannah Atkins
- Department of Comparative Medicine, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
| | - Benjamin C Warf
- Department of Neurosurgery, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - W Ian Lipkin
- Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, NY 10032, USA.,Department of Epidemiology, Columbia University Mailman School of Public Health, New York, NY 10032, USA
| | - James R Broach
- Institute for Personalized Medicine, Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
| | - Steven J Schiff
- Center for Neural Engineering, Pennsylvania State University, University Park, PA 16802, USA. .,Department of Engineering Science and Mechanics, Pennsylvania State University, University Park, PA 16802, USA.,Center for Infectious Disease Dynamics, Pennsylvania State University, University Park, PA 16802, USA.,Department of Neurosurgery, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.,Department of Physics, Pennsylvania State University, University Park, PA 16802, USA
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Alsumali A, Chemaly RF, Graham J, Jiang Y, Merchant S, Miles L, Schelfhout J, Yang J, Tang Y. Cost-effectiveness analysis of cytomegalovirus prophylaxis in allogeneic hematopoietic cell transplant recipients from a US payer perspective. J Med Virol 2021; 93:3786-3794. [PMID: 32844453 DOI: 10.1002/jmv.26462] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 08/19/2020] [Accepted: 08/22/2020] [Indexed: 12/16/2022]
Abstract
To evaluate the cost-effectiveness of letermovir versus no prophylaxis for the prevention of cytomegalovirus infection and disease in adult cytomegalovirus-seropositive allogeneic hematopoietic cell transplantation (allo-HCT) recipients. A decision model for 100 patients was developed to estimate the probabilities of cytomegalovirus infection, cytomegalovirus disease, various other complications, and death in patients receiving letermovir versus no prophylaxis. The probabilities of clinical outcomes were based on the pivotal phase 3 trial of letermovir use for cytomegalovirus prophylaxis versus placebo in adult cytomegalovirus-seropositive recipients of an allo-HCT. Costs of prophylaxis with letermovir and of each clinical outcome were derived from published sources or the trial clinical study reports. Incremental cost-effectiveness ratios (ICERs) in terms of cost per quality-adjusted life year (QALY) gained were used in the model. One-way and probabilistic sensitivity analyses were conducted to explore uncertainty around the base-case analysis. In this model, the use of letermovir prophylaxis would lead to an increase of QALYs (619) and direct medical cost ($1 733 794) compared with no prophylaxis (578 QALYs; $710 300) in cytomegalovirus-seropositive recipients of an allo-HCT. Letermovir use for cytomegalovirus prophylaxis was a cost-effective option versus no prophylaxis with base-case analysis ICER $25 046/QALY gained. One-way sensitivity analysis showed the most influential parameter was mortality rate. The probabilistic sensitivity analysis showed a 92% probability of letermovir producing an ICER below the commonly accepted willingness-to-pay threshold of $100 000/QALY gained. Based on this model, letermovir use for cytomegalovirus prophylaxis was a cost-effective option in adult cytomegalovirus-seropositive recipients of an allo-HCT.
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Affiliation(s)
- Adnan Alsumali
- Center for Observational and Real-world Evidence, Merck & Co, Inc, Kenilworth, New Jersey
| | - Roy F Chemaly
- Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jonathan Graham
- Health Economics, RTI Health Solutions, Research Triangle Park, North Carolina
| | - Yiling Jiang
- Center for Observational and Real-world Evidence, MSD Ltd, Hoddesdon, Hertfordshire, UK
| | - Sanjay Merchant
- Center for Observational and Real-world Evidence, Merck & Co, Inc, Kenilworth, New Jersey
| | - LaStella Miles
- Health Economics, RTI Health Solutions, Research Triangle Park, North Carolina
| | - Jonathan Schelfhout
- Center for Observational and Real-world Evidence, Merck & Co, Inc, Kenilworth, New Jersey
| | - Joe Yang
- Center for Observational and Real-world Evidence, Merck & Co, Inc, Kenilworth, New Jersey
| | - Yuexin Tang
- Center for Observational and Real-world Evidence, Merck & Co, Inc, Kenilworth, New Jersey
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Heterogeneous impact of cytomegalovirus reactivation on nonrelapse mortality in hematopoietic stem cell transplantation. Blood Adv 2021; 4:1051-1061. [PMID: 32191806 DOI: 10.1182/bloodadvances.2019000814] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Accepted: 02/22/2020] [Indexed: 11/20/2022] Open
Abstract
Cytomegalovirus (CMV) infection is a major complication in allogeneic stem cell transplantation. The utility of CMV prophylaxis with letermovir has been reported; however, the specific applications remain unclear. In this study, we retrospectively analyzed large-scale registry data (N = 10 480) to clarify the risk factors for nonrelapse mortality (NRM) in connection with CMV reactivation. First, we identified risk factors for CMV reactivation using multivariate analysis and developed a scoring model. Although the model effectively stratified reactivation risk into 3 groups (43.7% vs 60.9% vs 71.5%; P < .001), the 3-year NRM was significantly higher in patients with CMV reactivation, even in the low (20.9% vs 13.0%, P < .001), intermediate (21.4% vs 15.6%; P < .001), and high (29.3% vs 18.0%; P < .001) reactivation risk groups. Next, survival analysis considering competing risks, time-dependent covariates, and interaction terms for exploring the heterogeneous impact of CMV reactivation on NRM in the training cohort revealed that chronic myeloid leukemia (CML) (hazard ratio [HR], 1.76; 95% confidence interval [CI], 1.05-2.96; P = .033), good performance status (PS) (HR, 1.42; 95% CI, 1.04-1.94; P = .028), HLA-matched donor (HR, 1.34; 95% CI, 1.06-1.70; P = .013), and standard-risk disease (HR, 1.28; 95% CI, 1.04-1.58; P = .022) were associated with increased NRM. In the test cohort, CMV reactivation was significantly associated with increased 3-year NRM among patients with 2 to 4 factors (22.1% vs 13.1%; P < .001) but was comparable among patients with 0 or 1 factor (23.2% vs 20.4%; P = .62). We propose that CMV prophylaxis should be determined based on reactivation risk, as well as these other factors.
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Nikoloudis A, Wagner H, Machherndl-Spandl S, Buxhofer-Ausch V, Strassl I, Stiefel O, Wipplinger D, Milanov R, Kaynak E, Hasengruber P, Binder M, Weltermann A, Petzer A, Wolf D, Nachbaur D, Clausen J. Relapse Protection Following Early Cytomegalovirus Reactivation after Hematopoietic Stem Cell Transplantation Is Limited to HLA-C Killer Cell Immunoglobulin-Like Receptor Ligand Homozygous Recipients. Transplant Cell Ther 2021; 27:686.e1-686.e9. [PMID: 33991724 DOI: 10.1016/j.jtct.2021.04.028] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 04/23/2021] [Accepted: 04/29/2021] [Indexed: 11/29/2022]
Abstract
Although the risk for nonrelapse mortality (NRM) associated with early cytomegalovirus (CMV) reactivation (CMVR) after allogeneic hematopoietic stem cell transplantation (HSCT) is well established, debate is ongoing on whether CMVR may reduce the risk of primary disease relapse. The aim of this study was to evaluate relapse protection following early CMV reactivation after HSCT in the context of the recipient HLA-C killer cell immunoglobulin-like receptor ligands (KIRLs). In this retrospective bicentric study, 406 matched related or unrelated donor transplantations for acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) were stratified by HLA-C KIRL group (homozygous versus heterozygous) and analyzed separately for the impact of early CMVR on the cumulative incidences of relapse, NRM, and acute and chronic graft-versus-host-disease (GVHD) using landmark and multistate analyses. By landmark analysis of patients alive and relapse-free at 45 days post-HSCT, HLA-C KIRL homozygous recipients (C1/1 or C2/2) had a lower risk of subsequent relapse if CMVR occurred before this landmark (subhazard ratio [sHR], 0.36; P = .002). In contrast, in HLA-C KIRL heterozygous (C1/2) recipients, early CMVR had no impact on subsequent relapse (sHR, 0.88; P = .63). NRM (sHR, 3.31; P < .001) and grade III-IV acute GVHD (sHR, 2.60; P = .04) were significantly increased after early CMVR in the homozygous cohort, but not in the heterozygous cohort (NRM: sHR, 1.23; P = .53; grade III-IV acute GVHD: sHR, 1.40; P = .50). Multivariable landmark analyses and a multistate model confirmed the limitation of the relapse-protective effect of early CMVR to the homozygous cohort. Chronic GVHD and overall survival were not influenced in neither cohort. An antileukemic effect of early CMVR after HSCT for AML/MDS was significant but strictly limited to recipients homozygous for HLA-C KIRL. However, particularly in this cohort, CMVR had an adverse impact on aGVHD and NRM.
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Affiliation(s)
- Alexander Nikoloudis
- Department of Internal Medicine I: Hematology with Stem Cell Transplantation, Hemostaseology and Medical Oncology, Ordensklinikum Linz Elisabethinen, Linz, Austria; Medical Faculty, Johannes Kepler University, Linz, Austria.
| | - Helga Wagner
- Department of Applied Statistics: Medical Statistics and Biometry and Competence Center for Clinical Studies, Johannes Kepler University, Linz, Austria
| | - Sigrid Machherndl-Spandl
- Department of Internal Medicine I: Hematology with Stem Cell Transplantation, Hemostaseology and Medical Oncology, Ordensklinikum Linz Elisabethinen, Linz, Austria; Medical Faculty, Johannes Kepler University, Linz, Austria
| | - Veronika Buxhofer-Ausch
- Department of Internal Medicine I: Hematology with Stem Cell Transplantation, Hemostaseology and Medical Oncology, Ordensklinikum Linz Elisabethinen, Linz, Austria; Medical Faculty, Johannes Kepler University, Linz, Austria
| | - Irene Strassl
- Department of Internal Medicine I: Hematology with Stem Cell Transplantation, Hemostaseology and Medical Oncology, Ordensklinikum Linz Elisabethinen, Linz, Austria
| | - Olga Stiefel
- Department of Internal Medicine I: Hematology with Stem Cell Transplantation, Hemostaseology and Medical Oncology, Ordensklinikum Linz Elisabethinen, Linz, Austria
| | - Dagmar Wipplinger
- Department of Internal Medicine I: Hematology with Stem Cell Transplantation, Hemostaseology and Medical Oncology, Ordensklinikum Linz Elisabethinen, Linz, Austria
| | - Robert Milanov
- Department of Internal Medicine I: Hematology with Stem Cell Transplantation, Hemostaseology and Medical Oncology, Ordensklinikum Linz Elisabethinen, Linz, Austria
| | - Emine Kaynak
- Department of Internal Medicine I: Hematology with Stem Cell Transplantation, Hemostaseology and Medical Oncology, Ordensklinikum Linz Elisabethinen, Linz, Austria
| | - Petra Hasengruber
- Department of Internal Medicine I: Hematology with Stem Cell Transplantation, Hemostaseology and Medical Oncology, Ordensklinikum Linz Elisabethinen, Linz, Austria
| | - Michaela Binder
- Department of Internal Medicine I: Hematology with Stem Cell Transplantation, Hemostaseology and Medical Oncology, Ordensklinikum Linz Elisabethinen, Linz, Austria
| | - Ansgar Weltermann
- Department of Internal Medicine I: Hematology with Stem Cell Transplantation, Hemostaseology and Medical Oncology, Ordensklinikum Linz Elisabethinen, Linz, Austria; Medical Faculty, Johannes Kepler University, Linz, Austria
| | - Andreas Petzer
- Department of Internal Medicine I: Hematology with Stem Cell Transplantation, Hemostaseology and Medical Oncology, Ordensklinikum Linz Elisabethinen, Linz, Austria
| | - Dominik Wolf
- University Hospital of Internal Medicine V, Hematology & Oncology, Medical University of Innsbruck, Innsbruck, Austria
| | - David Nachbaur
- University Hospital of Internal Medicine V, Hematology & Oncology, Medical University of Innsbruck, Innsbruck, Austria
| | - Johannes Clausen
- Department of Internal Medicine I: Hematology with Stem Cell Transplantation, Hemostaseology and Medical Oncology, Ordensklinikum Linz Elisabethinen, Linz, Austria; Medical Faculty, Johannes Kepler University, Linz, Austria
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