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1
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George J, Mozessohn L, Lam PW. Cytomegalovirus infection risk with alemtuzumab therapy in hematological malignancies: a retrospective cohort study in the non-transplant setting. Leuk Lymphoma 2024; 65:1716-1723. [PMID: 38949787 DOI: 10.1080/10428194.2024.2371474] [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: 04/22/2024] [Revised: 06/15/2024] [Accepted: 06/18/2024] [Indexed: 07/02/2024]
Abstract
Alemtuzumab is a potent lymphocyte-depleting immunotherapy used in solid organ transplan-tation (SOT), that is increasingly being applied in diverse lymphoproliferative disorders (LPDs). However, a significant toxicity limiting expanded usage is cytomegalovirus (CMV) infection, for which standardized preventive strategies exist in SOT but not in LPDs due to a poor understanding of infection risk in this population, with early LPD studies largely limited to stem cell transplantation. Using one of the most diverse arrays of LPDs studied to date, our retrospective cohort study of non-transplant patients receiving alemtuzumab over a ten-year period at a large regional cancer center examines the incidence and clinical profile of infected patients. Among 24 patients, we identified a composite CMV infection rate of 42% with a symptomatic rate of 21%. We also noted significant variations in preventive strategies, which alongside a high infection rate presents an opportunity to improve outcomes through further work in standardization.
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Affiliation(s)
- Joel George
- Department of Medicine, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Lee Mozessohn
- Department of Medicine, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Division of Hematology/Medical Oncology, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
| | - Philip W Lam
- Department of Medicine, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Division of Infectious Diseases, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
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2
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Kapoor H, Bi C, Kroll MH, Salm AE, Dominguez EA. Burden and frequency of viral testing of kidney and non-kidney transplant recipients. Microbiol Spectr 2024; 12:e0357523. [PMID: 38709030 PMCID: PMC11237713 DOI: 10.1128/spectrum.03575-23] [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: 10/06/2023] [Accepted: 04/15/2024] [Indexed: 05/07/2024] Open
Abstract
Transplant patients are at risk of infections due to long-term immunosuppression contributing to morbidity and mortality in this population. Post-transplant testing guidelines were established to monitor and guide therapeutic interventions in transplant recipients. We hypothesize that there are gaps in adherence to the recommended frequency of laboratory testing in post-transplant patients. We analyzed national reference laboratory data to compare viral post-transplant infection (PTI) testing frequency with their respective published guidelines to understand patient uptake and compliance. We evaluated the ordering patterns, positivity rates, and frequency of molecular infectious disease tests (MIDTs). We included 345 patients with International Classification of Diseases (ICD)-10 codes for transplant (Z940-Z942, Z944, Z9481, Z9483, Z9484) with at least two tests (within 7 days) in January 2019 and at least one test in December 2020 to find patients in the post-transplant period. We analyzed two cohorts: kidney transplant recipients (KTRs; 40%) and non-KTR (60%) then followed them longitudinally for the study period. In KTR cohort, high-to-low proportion of ordered MIDT was blood BK virus (bBKV) followed by cytomegalovirus (CMV); in non-KTR cohort, CMV was followed by Epstein-Barr virus (EBV). KTR cohort positivity was highest for urine BK virus (uBKV; 58%) followed by EBV (46%), bBKV (40%), and CMV (31%). Non-KTR cohort positivity was highest for uBKV (64%), EBV (51%), CMV (30%), bBKV (8%), and adenovirus (7%). All patients were tested at progressively longer intervals from the date of the first post-transplant ICD-10-coded test. More than 40% of the KTR cohort were tested less frequently for EBV and bBKV, and more than 20% of the non-KTR cohort were tested for EBV less frequently than published guidelines 4 months after transplant. Despite regular testing, the results of MIDT testing for KTR and non-KTR patients in the post-transplant period are not aligned with published guidelines.IMPORTANCEGuidance for post-transplant infectious disease testing is established, however, for certain infections it allows for clinician discretion. This leads to transplant center policies developing their own testing/surveillance strategies based on their specific transplant patient population (kidney, stem cell, etc.). The Organ Procurement and Transplant Network (OPTN) has developed a strategic plan to improve and standardize the transplant process in the US to improve outcomes of living donors and recipients. Publishing national reference lab data on the testing frequency and its alignment with the recommended guidelines for post-transplant infectious diseases can inform patient uptake and compliance for these strategic OPTN efforts.
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Affiliation(s)
- Hema Kapoor
- Infectious Diseases/Immunology, Quest Diagnostics, Secaucus, New Jersey, USA
| | - Caixia Bi
- Medical Informatics, Biostatistics and Outcomes Research Group, Quest Diagnostics, Secaucus, New Jersey, USA
| | - Martin H. Kroll
- Analytics and Statistical Applications, Quest Diagnostics, Secaucus, New Jersey, USA
| | - Ann E. Salm
- Infectious Diseases/Immunology, Quest Diagnostics, Secaucus, New Jersey, USA
| | - Edward A. Dominguez
- Organ Transplant Infectious Disease, Methodist Transplant Specialists, Dallas, Texas, USA
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3
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Alsaeed M, Husain S. Infections in Heart and Lung Transplant Recipients. Infect Dis Clin North Am 2024; 38:103-120. [PMID: 38280759 DOI: 10.1016/j.idc.2023.11.003] [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: 01/29/2024]
Abstract
Infections in heart and lung transplant recipients are complex and heterogeneous. This article reviews the epidemiology, risk factors, specific clinical syndromes, and most frequent opportunistic infections in heart and/or lung transplant recipients that will be encountered in the intensive care unit and will provide a practical approach of empirical management.
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Affiliation(s)
- Mohammed Alsaeed
- Division of Infectious Diseases, Multi-Organ Transplant Program, Department of Medicine, University of Toronto, University Health Network, 585 University Avenue, 11 PMB 138, Toronto, Ontario M5G 2N2, Canada; Division of Infectious Diseases, Department of Medicine, Prince Sultan Military Medical City, Makkah Al Mukarramah Road, As Sulimaniyah, Riyadh 12233, Saudi Arabia
| | - Shahid Husain
- Division of Infectious Diseases, Multi-Organ Transplant Program, Department of Medicine, University of Toronto, University Health Network, 585 University Avenue, 11 PMB 138, Toronto, Ontario M5G 2N2, Canada.
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4
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Magda G. Opportunistic Infections Post-Lung Transplantation: Viral, Fungal, and Mycobacterial. Infect Dis Clin North Am 2024; 38:121-147. [PMID: 38280760 DOI: 10.1016/j.idc.2023.12.001] [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] [Indexed: 01/29/2024]
Abstract
Opportunistic infections are a leading cause of lung transplant recipient morbidity and mortality. Risk factors for infection include continuous exposure of the lung allograft to the external environment, high levels of immunosuppression, impaired mucociliary clearance and decreased cough reflex, and impact of the native lung microbiome in single lung transplant recipients. Infection risk is mitigated through careful pretransplant screening of recipients and donors, implementation of antimicrobial prophylaxis strategies, and routine surveillance posttransplant. This review describes common viral, fungal, and mycobacterial infectious after lung transplant and provides recommendations on prevention and treatment.
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Affiliation(s)
- Gabriela Magda
- Columbia University Lung Transplant Program, Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia University Irving Medical Center, Columbia University Vagelos College of Physicians and Surgeons, 622 West 168th Street PH-14, New York, NY 10032, USA.
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5
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Thomas SJ, Ouellette CP. Viral meningoencephalitis in pediatric solid organ or hematopoietic cell transplant recipients: a diagnostic and therapeutic approach. Front Pediatr 2024; 12:1259088. [PMID: 38410764 PMCID: PMC10895047 DOI: 10.3389/fped.2024.1259088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Accepted: 01/26/2024] [Indexed: 02/28/2024] Open
Abstract
Neurologic complications, both infectious and non-infectious, are frequent among hematopoietic cell transplant (HCT) and solid organ transplant (SOT) recipients. Up to 46% of HCT and 50% of SOT recipients experience a neurological complication, including cerebrovascular accidents, drug toxicities, as well as infections. Defects in innate, adaptive, and humoral immune function among transplant recipients predispose to opportunistic infections, including central nervous system (CNS) disease. CNS infections remain uncommon overall amongst HCT and SOT recipients, compromising approximately 1% of total cases among adult patients. Given the relatively lower number of pediatric transplant recipients, the incidence of CNS disease amongst in this population remains unknown. Although infections comprise a small percentage of the neurological complications that occur post-transplant, the associated morbidity and mortality in an immunosuppressed state makes it imperative to promptly evaluate and aggressively treat a pediatric transplant patient with suspicion for viral meningoencephalitis. This manuscript guides the reader through a broad infectious and non-infectious diagnostic differential in a transplant recipient presenting with altered mentation and fever and thereafter, elaborates on diagnostics and management of viral meningoencephalitis. Hypothetical SOT and HCT patient cases have also been constructed to illustrate the diagnostic and management process in select viral etiologies. Given the unique risk for various opportunistic viral infections resulting in CNS disease among transplant recipients, the manuscript will provide a contemporary review of the epidemiology, risk factors, diagnosis, and management of viral meningoencephalitis in these patients.
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Affiliation(s)
- Sanya J. Thomas
- Host Defense Program, Section of Infectious Diseases, Nationwide Children’s Hospital, Columbus, OH, United States
- Division of Infectious Diseases, Department of Pediatrics, Ohio State University College of Medicine, Columbus, OH, United States
| | - Christopher P. Ouellette
- Host Defense Program, Section of Infectious Diseases, Nationwide Children’s Hospital, Columbus, OH, United States
- Division of Infectious Diseases, Department of Pediatrics, Ohio State University College of Medicine, Columbus, OH, United States
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6
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Leuzinger K, Hirsch HH. Amplicon size and non-encapsidated DNA fragments define plasma cytomegalovirus DNA loads by automated nucleic acid testing platforms: A marker of viral cytopathology? J Med Virol 2023; 95:e29139. [PMID: 37804497 DOI: 10.1002/jmv.29139] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 07/31/2023] [Accepted: 09/20/2023] [Indexed: 10/09/2023]
Abstract
Management of cytomegalovirus (CMV) in transplant patients relies on measuring plasma CMV-loads using quantitative nucleic acid testing (QNAT). We prospectively compared the automated Roche-cobas®6800-CMV and Roche-CAP/CTM-CMV with laboratory-developed Basel-CMV-UL54-95bp, and Basel-CMV-UL111a-77bp. Roche-cobas®6800-CMV and Roche-CAP/CTM-CMV were qualitatively concordant in 142/150 cases (95%). In-depth comparison revealed higher CMV-loads of the laboratory-developed assay and correlated with smaller amplicon size. After calibration to the 1.WHO-approved CMV international standard, differences were reduced but remained significant. DNase-I pretreatment significantly reduced CMV-loads for both automated Roche-CAP/CTM-CMV and Roche-cobas®6800-CMV assays, whereby 90% and 95% of samples became undetectable. DNase-I pretreatment also reduced CMV-loads quantified by Basel-CMV-UL54-95bp and Basel-CMV-UL111a-77bp, but remaining detectable in 20% and 35%, respectively. Differences were largest for 110 samples with low-level CMV-DNAemia being detectable but not-quantifiable by Roche-cobas®6800-CMV, whereby the smaller amplicon sizes yielded higher viral loads for concordant positives. We conclude that non-encapsidated fragmented CMV-DNA is the major form of plasma CMV-loads also measured by fully-automated platforms. Amplicons of <150 bp and calibrators are needed for reliable and commutable QNAT-results. We hypothesize that non-encapsidated fragmented CMV-DNA results from lysis of CMV-replicating cells and represent a direct marker of viral cell damage, which contribute to delayed viral load responses despite effective antivirals.
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Affiliation(s)
- Karoline Leuzinger
- Clinical Virology, University Hospital Basel, Basel, Switzerland
- Transplantation & Clinical Virology, Department Biomedicine, University of Basel, Basel, Switzerland
| | - Hans H Hirsch
- Clinical Virology, University Hospital Basel, Basel, Switzerland
- Transplantation & Clinical Virology, Department Biomedicine, University of Basel, Basel, Switzerland
- Infectious Diseases & Hospital Epidemiology, University Hospital Basel, Basel, Switzerland
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7
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Opportunistic Infections Post-Lung Transplantation: Viral, Fungal, and Mycobacterial. Clin Chest Med 2023; 44:159-177. [PMID: 36774162 DOI: 10.1016/j.ccm.2022.10.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/11/2023]
Abstract
Opportunistic infections are a leading cause of lung transplant recipient morbidity and mortality. Risk factors for infection include continuous exposure of the lung allograft to the external environment, high levels of immunosuppression, impaired mucociliary clearance and decreased cough reflex, and impact of the native lung microbiome in single lung transplant recipients. Infection risk is mitigated through careful pretransplant screening of recipients and donors, implementation of antimicrobial prophylaxis strategies, and routine surveillance posttransplant. This review describes common viral, fungal, and mycobacterial infectious after lung transplant and provides recommendations on prevention and treatment.
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8
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Rzymski P, Szuster-Ciesielska A, Dzieciątkowski T, Gwenzi W, Fal A. mRNA vaccines: The future of prevention of viral infections? J Med Virol 2023; 95:e28572. [PMID: 36762592 DOI: 10.1002/jmv.28572] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 02/02/2023] [Accepted: 02/03/2023] [Indexed: 02/11/2023]
Abstract
Messenger RNA (mRNA) vaccines against COVID-19 are the first authorized biological preparations developed using this platform. During the pandemic, their administration has been proven to be a life-saving intervention. Here, we review the main advantages of using mRNA vaccines, identify further technological challenges to be met during the development of the mRNA platform, and provide an update on the clinical progress on leading mRNA vaccine candidates against different viruses that include influenza viruses, human immunodeficiency virus 1, respiratory syncytial virus, Nipah virus, Zika virus, human cytomegalovirus, and Epstein-Barr virus. The prospects and challenges of manufacturing mRNA vaccines in low-income countries are also discussed. The ongoing interest and research in mRNA technology are likely to overcome some existing challenges for this technology (e.g., related to storage conditions and immunogenicity of some components of lipid nanoparticles) and enhance the portfolio of vaccines against diseases for which classical formulations are already authorized. It may also open novel pathways of protection against infections and their consequences for which no safe and efficient immunization methods are currently available.
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Affiliation(s)
- Piotr Rzymski
- Department of Environmental Medicine, Poznan University of Medical Sciences, Poznań, Poland.,Integrated Science Association (ISA), Universal Scientific Education and Research Network (USERN), Poznań, Poland
| | - Agnieszka Szuster-Ciesielska
- Department of Virology and Immunology, Institute of Biological Sciences, Maria Curie-Skłodowska University, Lublin, Poland
| | | | - Willis Gwenzi
- Alexander von Humboldt Fellow & Guest Professor, Grassland Science and Renewable Plant Resources, Faculty of Organic Agricultural Sciences, Universität Kassel, Witzenhausen, Germany.,Alexander von Humboldt Fellow & Guest Professor, Leibniz Institute for Agricultural Engineering and Bioeconomy (ATB), Potsdam, Germany
| | - Andrzej Fal
- Collegium Medicum, Warsaw Faculty of Medicine, Cardinal Stefan Wyszynski University, Warsaw, Poland.,Department of Public Health, Wrocław Medical University, Wrocław, Poland
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9
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The role of RHIM in necroptosis. Biochem Soc Trans 2022; 50:1197-1205. [PMID: 36040212 PMCID: PMC9444067 DOI: 10.1042/bst20220535] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 08/05/2022] [Accepted: 08/09/2022] [Indexed: 11/17/2022]
Abstract
The RIP homotypic interaction motif (RHIM) is a conserved protein domain that is approximately 18–22 amino acids in length. In humans, four proteins carrying RHIM domains have been identified: receptor-interacting serine/threonine protein kinase (RIPK) 1, RIPK3, Z-DNA-binding protein 1 (ZBP1), and TIR domain-containing adapter-inducing IFN-β (TRIF), which are all major players in necroptosis, a distinct form of regulated cell death. Necroptosis is mostly presumed to be a fail-safe form of cell death, occurring in cells in which apoptosis is compromised. Upon activation, RIPK1, ZBP1, and TRIF each hetero-oligomerize with RIPK3 and induce the assembly of an amyloid-like structure of RIPK3 homo-oligomers. These act as docking stations for the recruitment of the pseudokinase mixed-lineage kinase domain like (MLKL), the pore-forming executioner of necroptosis. As RHIM domain interactions are a vital component of the signaling cascade and can also be involved in apoptosis and pyroptosis activation, it is unsurprising that viral and bacterial pathogens have developed means of disrupting RHIM-mediated signaling to ensure survival. Moreover, as these mechanisms play an essential part of regulated cell death signaling, they have received much attention in recent years. Herein, we present the latest insights into the supramolecular structure of interacting RHIM proteins and their distinct signaling cascades in inflammation and infection. Their uncovering will ultimately contribute to the development of new therapeutic strategies in the regulation of lytic cell death.
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10
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Herpesvirus Vaccines. Vaccines (Basel) 2022; 10:vaccines10040628. [PMID: 35455377 PMCID: PMC9029921 DOI: 10.3390/vaccines10040628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 04/08/2022] [Indexed: 12/10/2022] Open
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11
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Alharshawi K, Cox B, Ariza ME. Examination of control asymptomatic cohorts reveals heightened anti-EBV and HHV-6 A/B dUTPase antibodies in the aging populations. J Med Virol 2022; 94:3464-3468. [PMID: 35315111 PMCID: PMC9117428 DOI: 10.1002/jmv.27728] [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: 12/03/2021] [Revised: 03/17/2022] [Accepted: 03/18/2022] [Indexed: 11/18/2022]
Abstract
Members of the human Herpesviridae are found in high prevalence in the human virome. While these viruses are known to cause numerous disease pathologies in symptomatic individuals little is known concerning the role that these viruses may have in modulating the host immune system in asymptomatic “healthy” individuals, especially during the aging process. Examination of three cohorts of “healthy asymptomatic” individuals (n = 255) for the presence of antibodies against the herpesviruses deoxyuridine triphosphate nucleotidohydrolase (dUTPase) as a marker for lytic/abortive‐lytic replication demonstrated that all cohorts exhibited differential anti‐herpesvirus dUTPase antibodies positivity frequencies ranging from 40.4% to 84% with some individuals in these cohorts expressing antibodies to the dUTPases of multiple herpesviruses (17.2%–56%). Furthermore, our results demonstrate that there was a statistically significant difference in anti‐human herpesvirus 6 A and 6B (HHV‐6 A/B) dUTPase antibodies in Cohort 3 (age = 66.2 ± 15.02 years) versus Cohort 1 (age 46.88 ± 8.61 years), suggesting that reactivation of HHV‐6 A/B is not attenuated by aging. It is well established/documented that herpesvirus dUTPases induce immune dysfunction, as such it is of critical importance that additional studies be performed to determine how these viral proteins alter immune responses in asymptomatic individuals.
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Affiliation(s)
- Khaled Alharshawi
- Department of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Brandon Cox
- Department of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Maria E Ariza
- Department of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.,Institute for Behavioral Medicine Research, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
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Rodríguez-Goncer I, Ruiz-Ruigómez M, López-Medrano F, Trujillo H, González E, Polanco N, Gutiérrez E, San Juan R, Corbella L, Ruiz-Merlo T, Parra P, Folgueira MD, Andrés A, Aguado JM, Fernández-Ruiz M. Cytomegalovirus Exposure and the Risk of Overall Infection After Kidney Transplantation: A Cohort Study on the Indirect Effects Attributable to Viral Replication. Transpl Int 2022; 35:10273. [PMID: 35185374 PMCID: PMC8842254 DOI: 10.3389/ti.2021.10273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 12/22/2021] [Indexed: 11/13/2022]
Abstract
Previous reports hypothesized that cytomegalovirus (CMV) may predispose to non-CMV infection after kidney transplantation (KT). We analysed the incidence of non-CMV infection (overall, bacterial and opportunistic) in 291 KT recipients according to the previous development of any level or high-level (≥1,000 IU/ml) CMV viremia. Exposure to CMV replication was assessed throughout fixed intervals covering first the 30, 90, 180 and 360 post-transplant days (cumulative exposure) and non-overlapping preceding periods (recent exposure). Adjusted Cox models were constructed for each landmark analysis. Overall, 67.7 and 50.5% patients experienced non-CMV and CMV infection, respectively. Patients with cumulative CMV exposure had higher incidence of non-CMV infection beyond days 30 (p-value = 0.002) and 90 (p-value = 0.068), although these associations did not remain after multivariable adjustment. No significant associations were observed for the remaining landmark models (including those based on high-level viremia or recent CMV exposure), or when bacterial and opportunistic infection were separately analysed. There were no differences in viral kinetics (peak CMV viremia and area under curve of CMV viral load) either. Our findings do not support the existence of an independent association between previous CMV exposure and the overall risk of post-transplant infection, although results might be affected by power limitations.
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Affiliation(s)
- Isabel Rodríguez-Goncer
- Unit of Infectious Diseases, Hospital Universitario “12 de Octubre”, Instituto de Investigación Sanitaria Hospital “12 de Octubre” (imas12), Madrid, Spain
- Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Infecciosas, Madrid, Spain
- *Correspondence: Isabel Rodríguez-Goncer,
| | - María Ruiz-Ruigómez
- Unit of Infectious Diseases, Hospital Universitario “12 de Octubre”, Instituto de Investigación Sanitaria Hospital “12 de Octubre” (imas12), Madrid, Spain
- Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Infecciosas, Madrid, Spain
| | - Francisco López-Medrano
- Unit of Infectious Diseases, Hospital Universitario “12 de Octubre”, Instituto de Investigación Sanitaria Hospital “12 de Octubre” (imas12), Madrid, Spain
- Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Infecciosas, Madrid, Spain
- School of Medicine, Universidad Complutense, Madrid, Spain
| | - Hernando Trujillo
- Department of Nephrology, Hospital Universitario “12 de Octubre”, Instituto de Investigación Sanitaria Hospital “12 de Octubre” (imas12), Madrid, Spain
| | - Esther González
- Department of Nephrology, Hospital Universitario “12 de Octubre”, Instituto de Investigación Sanitaria Hospital “12 de Octubre” (imas12), Madrid, Spain
| | - Natalia Polanco
- Department of Nephrology, Hospital Universitario “12 de Octubre”, Instituto de Investigación Sanitaria Hospital “12 de Octubre” (imas12), Madrid, Spain
| | - Eduardo Gutiérrez
- Department of Nephrology, Hospital Universitario “12 de Octubre”, Instituto de Investigación Sanitaria Hospital “12 de Octubre” (imas12), Madrid, Spain
| | - Rafael San Juan
- Unit of Infectious Diseases, Hospital Universitario “12 de Octubre”, Instituto de Investigación Sanitaria Hospital “12 de Octubre” (imas12), Madrid, Spain
- Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Infecciosas, Madrid, Spain
- School of Medicine, Universidad Complutense, Madrid, Spain
| | - Laura Corbella
- Unit of Infectious Diseases, Hospital Universitario “12 de Octubre”, Instituto de Investigación Sanitaria Hospital “12 de Octubre” (imas12), Madrid, Spain
- Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Infecciosas, Madrid, Spain
| | - Tamara Ruiz-Merlo
- Unit of Infectious Diseases, Hospital Universitario “12 de Octubre”, Instituto de Investigación Sanitaria Hospital “12 de Octubre” (imas12), Madrid, Spain
- Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Infecciosas, Madrid, Spain
| | - Patricia Parra
- Unit of Infectious Diseases, Hospital Universitario “12 de Octubre”, Instituto de Investigación Sanitaria Hospital “12 de Octubre” (imas12), Madrid, Spain
- Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Infecciosas, Madrid, Spain
| | - María Dolores Folgueira
- School of Medicine, Universidad Complutense, Madrid, Spain
- Department of Microbiology, Hospital Universitario “12 de Octubre”, Instituto de Investigación Sanitaria Hospital “12 de Octubre” (imas12), Madrid, Spain
| | - Amado Andrés
- School of Medicine, Universidad Complutense, Madrid, Spain
- Department of Nephrology, Hospital Universitario “12 de Octubre”, Instituto de Investigación Sanitaria Hospital “12 de Octubre” (imas12), Madrid, Spain
| | - José María Aguado
- Unit of Infectious Diseases, Hospital Universitario “12 de Octubre”, Instituto de Investigación Sanitaria Hospital “12 de Octubre” (imas12), Madrid, Spain
- Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Infecciosas, Madrid, Spain
- School of Medicine, Universidad Complutense, Madrid, Spain
| | - Mario Fernández-Ruiz
- Unit of Infectious Diseases, Hospital Universitario “12 de Octubre”, Instituto de Investigación Sanitaria Hospital “12 de Octubre” (imas12), Madrid, Spain
- Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Infecciosas, Madrid, Spain
- School of Medicine, Universidad Complutense, Madrid, Spain
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13
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Munting A, Manuel O. Viral infections in lung transplantation. J Thorac Dis 2022; 13:6673-6694. [PMID: 34992844 PMCID: PMC8662465 DOI: 10.21037/jtd-2021-24] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 06/21/2021] [Indexed: 12/15/2022]
Abstract
Viral infections account for up to 30% of all infectious complications in lung transplant recipients, remaining a significant cause of morbidity and even mortality. Impact of viral infections is not only due to the direct effects of viral replication, but also to immunologically-mediated lung injury that may lead to acute rejection and chronic lung allograft dysfunction. This has particularly been seen in infections caused by herpesviruses and respiratory viruses. The implementation of universal preventive measures against cytomegalovirus (CMV) and influenza (by means of antiviral prophylaxis and vaccination, respectively) and administration of early antiviral treatment have reduced the burden of these diseases and potentially their role in affecting allograft outcomes. New antivirals against CMV for prophylaxis and for treatment of antiviral-resistant CMV infection are currently being evaluated in transplant recipients, and may continue to improve the management of CMV in lung transplant recipients. However, new therapeutic and preventive strategies are highly needed for other viruses such as respiratory syncytial virus (RSV) or parainfluenza virus (PIV), including new antivirals and vaccines. This is particularly important in the advent of the COVID-19 pandemic, for which several unanswered questions remain, in particular on the best antiviral and immunomodulatory regimen for decreasing mortality specifically in lung transplant recipients. In conclusion, the appropriate management of viral complications after transplantation remain an essential step to continue improving survival and quality of life of lung transplant recipients.
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Affiliation(s)
- Aline Munting
- Infectious Diseases Service, Lausanne University Hospital, Lausanne, Switzerland
| | - Oriol Manuel
- Infectious Diseases Service, Lausanne University Hospital, Lausanne, Switzerland.,Transplantation Center, Lausanne University Hospital, Lausanne, Switzerland
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14
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Leuzinger K, Stolz D, Gosert R, Naegele K, Prince SS, Tamm M, Hirsch HH. Comparing cytomegalovirus diagnostics by cell culture and quantitative nucleic acid testing in broncho-alveolar lavage fluids. J Med Virol 2021; 93:3804-3812. [PMID: 33136288 DOI: 10.1002/jmv.26649] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 10/23/2020] [Accepted: 10/30/2020] [Indexed: 12/13/2022]
Abstract
Many clinical laboratories have replaced virus isolation in cell-culture (VIC) for cytomegalovirus (CMV) by quantitative-nucleic-acid testing (QNAT), rendering clinically relevant CMV-replication difficult to distinguish from CMV-shedding or latent infection. We compared direct VIC in 1109 consecutive bronchoalveolar lavage fluids (BALFs) and a well-validated CMV-QNAT (Basel-CMV-UL111a-77bp). In the retrospective Group 1 (N = 694) and Group 2 (N = 303), CMV-QNAT was performed within 48 h from 2-fold and 10-fold concentrated total nucleic acid (TNA) eluates, respectively. In Group 3 (N = 112), 2-fold and 10-fold concentrated TNA eluates were prospectively analyzed in parallel to VIC. CMV was detected by VIC in 79 of 694 (11%) and 26 of 303 (9%) of Groups 1 and 2, but in 114 of 694 (16%) and 57 of 303 (17%) by CMV-QNAT, respectively. Median CMV loads were significantly higher in VIC-positive than in VIC-negative BALF. The likelihood for CMV detection by VIC was 85% for BALF CMV- loads >4 log10 copies/ml. In the prospective Group 3, CMV was detected by VIC in 10 of 112 (9%), and in 14 of 112 (13%) and 20 of 112 (18%) by CMV-QNAT, when using 2-fold and 10-fold concentrated TNA eluates, respectively. Notably, CMV was undetectable by CMV-QNAT in 10 VIC-positive cases of Groups 1 and 2, but in none of Group 3. We conclude that CMV-QNAT can be adopted to BALF diagnostics but requires several careful steps in validation. CMV-QNAT loads >10 000 copies/ml in BALF may indicate significant CMV replication as defined by VIC, if short shipment and processing procedures can be guaranteed. Discordance of detecting CMV in time-matched plasma samples emphasises the role of local pulmonary CMV replication, for which histopathology remains the gold standard of proven CMV pneumonia.
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Affiliation(s)
- Karoline Leuzinger
- Clinical Virology, Laboratory Medicine, University Hospital Basel, Basel, Switzerland
- Transplantation & Clinical Virology, Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Daiana Stolz
- Medical Faculty, University of Basel, Basel, Switzerland
- Clinic of Pneumology and Pulmonary Cell Research, University Hospital Basel, Basel, Switzerland
| | - Rainer Gosert
- Clinical Virology, Laboratory Medicine, University Hospital Basel, Basel, Switzerland
- Transplantation & Clinical Virology, Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Klaudia Naegele
- Clinical Virology, Laboratory Medicine, University Hospital Basel, Basel, Switzerland
- Transplantation & Clinical Virology, Department of Biomedicine, University of Basel, Basel, Switzerland
| | | | - Michael Tamm
- Medical Faculty, University of Basel, Basel, Switzerland
- Clinic of Pneumology and Pulmonary Cell Research, University Hospital Basel, Basel, Switzerland
| | - Hans H Hirsch
- Clinical Virology, Laboratory Medicine, University Hospital Basel, Basel, Switzerland
- Transplantation & Clinical Virology, Department of Biomedicine, University of Basel, Basel, Switzerland
- Medical Faculty, University of Basel, Basel, Switzerland
- Infectious Diseases & Hospital Epidemiology, University Hospital Basel, Basel, Switzerland
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15
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Pyöriä L, Valtonen M, Luoto R, Grönroos W, Waris M, Heinonen OJ, Ruuskanen O, Perdomo MF. Survey of Viral Reactivations in Elite Athletes: A Case-Control Study. Pathogens 2021; 10:666. [PMID: 34071724 PMCID: PMC8229584 DOI: 10.3390/pathogens10060666] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 05/18/2021] [Accepted: 05/26/2021] [Indexed: 12/11/2022] Open
Abstract
Exercise-induced immune perturbations have been proposed to increase susceptibility to viral infections. We investigated the replication of persisting viruses as indicators of immune function in elite cross-country skiers after ten months of sustained high-performance exercise. The viruses evaluated, nine human herpesviruses (HHVs) and torque teno virus (TTV), are typically restrained in health but replicate actively in immunosuppressed individuals. We collected sera from 27 Finnish elite cross-country skiers at the end of the competition's season and 27 matched controls who perform moderate exercise. We quantified all the HHVs and-TTV via highly sensitive qPCRs. To verify equal past exposures between the groups, we assessed the IgG antibody prevalences toward HHV-4 (Epstein-Barr virus, EBV) and HHV-5 (human cytomegalovirus, HCMV). We found equal TTV DNA prevalences in athletes (63%) and controls (63%) and loads with respective geometric means of 1.7 × 103 and 1.2 × 103 copies/mL of serum. Overall, the copy numbers were low and consistent with those of healthy individuals. Neither of the groups presented with herpesvirus viremia despite similar past exposures to HHVs (seroprevalences of EBV 70% vs. 78% and HCMV 52% vs. 44% in athletes and controls, respectively). We found no evidence of increased replication of persistent viruses in elite athletes, arguing against impaired viral immunity due to high-performance exercise.
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Affiliation(s)
- Lari Pyöriä
- Department of Virology, University of Helsinki, 00290 Helsinki, Finland;
| | - Maarit Valtonen
- Research Institute for Olympics Sports, 40700 Jyväskylä, Finland;
| | - Raakel Luoto
- Department of Pediatrics and Adolescent Medicine, Turku University Hospital and University of Turku, 20521 Turku, Finland; (R.L.); (O.R.)
| | - Wilma Grönroos
- Paavo Nurmi Centre and Unit of Health and Physical Activity, University of Turku, 20520 Turku, Finland; (W.G.); (O.J.H.)
| | - Matti Waris
- Institute of Biomedicine, University of Turku and Department of Clinical Microbiology, Turku University Hospital, 20520 Turku, Finland;
| | - Olli J. Heinonen
- Paavo Nurmi Centre and Unit of Health and Physical Activity, University of Turku, 20520 Turku, Finland; (W.G.); (O.J.H.)
| | - Olli Ruuskanen
- Department of Pediatrics and Adolescent Medicine, Turku University Hospital and University of Turku, 20521 Turku, Finland; (R.L.); (O.R.)
| | - Maria F. Perdomo
- Department of Virology, University of Helsinki, 00290 Helsinki, Finland;
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16
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EBV DNA increase in COVID-19 patients with impaired lymphocyte subpopulation count. Int J Infect Dis 2020; 104:315-319. [PMID: 33359064 PMCID: PMC7833117 DOI: 10.1016/j.ijid.2020.12.051] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 12/10/2020] [Accepted: 12/17/2020] [Indexed: 12/29/2022] Open
Abstract
Objectives The immunologic profile and opportunistic viral DNA increase were monitored in Italian patients with COVID-19 in order to identify markers of disease severity. Methods A total of 104 patients infected with SARS-CoV-2 were evaluated in the study. Of them, 42/104 (40.4%) were hospitalized in an intensive care unit (ICU) and 62/104(59.6%) in a sub-intensive care unit (SICU). Human cytomegalovirus (HCMV) and Epstein-Barr virus (EBV), Parvovirus B19 and Human Herpesvirus 6 virus reactivations were determined by real-time PCR, and lymphocyte subpopulation counts were determined by flow cytometry. Results Among opportunistic viruses, only EBV was consistently detected. EBV DNA was observed in 40/42 (95.2%) of the ICU patients and in 51/61 (83.6%) of the SICU patients. Comparing the two groups of patients, the EBV DNA median level among ICU patients was significantly higher than that observed in SICU patients. In parallel, a significant reduction of CD8 T cell and NK count in ICU patients as compared with SICU patients was observed (p < 0.05). In contrast, B cell count was significantly increased in ICU patients (p = 0.0172). Conclusions A correlation between reduced CD8+ T cells and NK counts, EBV DNA levels and COVID-19 severity was observed. Other opportunistic viral infections were not observed. The relationship between EBV load and COVID-19 severity should be further evaluated in longitudinal studies.
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17
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Uehara H, Hirano H, Matsunaga T, Minami K, Komura K, Ibuki N, Inamoto T, Nomi H, Azuma H. Management of alpha-herpesvirus infection following kidney transplantation: Our experience (7 cases). TRANSPLANTATION REPORTS 2020. [DOI: 10.1016/j.tpr.2020.100051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022] Open
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18
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Wei C, Kakazu T, Chuah QY, Tanaka M, Kato G, Sano M. Reactivation of cyprinid herpesvirus 2 (CyHV-2) in asymptomatic surviving goldfish Carassius auratus (L.) under immunosuppression. FISH & SHELLFISH IMMUNOLOGY 2020; 103:302-309. [PMID: 32439507 DOI: 10.1016/j.fsi.2020.05.020] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 05/04/2020] [Accepted: 05/07/2020] [Indexed: 06/11/2023]
Abstract
Cyprinid herpesvirus 2 (CyHV-2) is a highly contagious pathogen of goldfish (Carassius auratus) and Prussian carp (Carassius auratus gibelio) causing herpesviral hematopoietic necrosis. Our previous study revealed that CyHV-2 can persistently infect the kidney and spleen of goldfish that recovered from a primary infection. In this study, we tried to identify the cells persistently infected with the virus in surviving fish and investigated virus reactivation in the survivors injected with immunosuppressants, namely dexamethasone (Dex) and cyclosporine A (CsA). Virus DNA was detected from the monocytes that were isolated from the trunk kidney of the asymptomatic survivors, suggesting that monocytes/macrophages are major cells that may be persistently infected with CyHV-2. A significant increase of virus DNA levels was detected in the group injected with Dex at 10 and 21 days post-injection (dpi). In the fish group injected with CsA, the virus DNA level was the same as that in the control group at 10 dpi but increased in some organs at 21 dpi. Compared with Dex-injected fish at 10 dpi, the group injected with both Dex and CsA showed a greater increase in virus DNA levels. The gene expression of phagocytosis-associated genes, major histocompatibility complex (MHC) class II and p47phox, and anti-virus antibody levels increased in the CsA group due to virus reactivation in the infected cells but not in the Dex and Dex & CsA groups, indicating that Dex effectively suppressed monocyte/macrophage function and antibody production. In addition, recombinant interferon γ (IFNγ) supplementation in the kidney leukocyte culture that was isolated from survivors showed a reduction of virus DNA. CsA may inhibit T-helper 1 (Th1) cells and consequently IFNγ production, causing a synergetic effect with Dex on virus reactivation. The results suggest that the activity of monocytes/macrophages stimulated by IFNγ can relate to virus latency and reactivation in asymptomatic virus carriers.
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Affiliation(s)
- Chang Wei
- Tokyo University of Marine Science and Technology, Tokyo, 108-8477, Japan
| | - Taichi Kakazu
- Tokyo University of Marine Science and Technology, Tokyo, 108-8477, Japan
| | - Qiu Yuan Chuah
- Tokyo University of Marine Science and Technology, Tokyo, 108-8477, Japan
| | - Mikio Tanaka
- Saitama Fisheries Research Institute, Saitama, 347-0011, Japan
| | - Goshi Kato
- Tokyo University of Marine Science and Technology, Tokyo, 108-8477, Japan
| | - Motohiko Sano
- Tokyo University of Marine Science and Technology, Tokyo, 108-8477, Japan.
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19
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HERQ-9 Is a New Multiplex PCR for Differentiation and Quantification of All Nine Human Herpesviruses. mSphere 2020; 5:5/3/e00265-20. [PMID: 32581076 PMCID: PMC7316487 DOI: 10.1128/msphere.00265-20] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
By adulthood, almost all humans become infected by at least one herpesvirus (HHV). The maladies inflicted by these microbes extend beyond the initial infection, as they remain inside our cells for life and can reactivate, causing severe diseases. The diagnosis of active infection by these ubiquitous pathogens includes the detection of DNA with sensitive and specific assays. We developed the first quantitative PCR assay (HERQ-9) designed to identify and quantify each of the nine human herpesviruses. The simultaneous detection of HHVs in the same sample is important since they may act together to induce life-threatening conditions. Moreover, the high sensitivity of our method is of extreme value for assessment of the effects of these viruses persisting in our body and their long-term consequences on our health. Infections with the nine human herpesviruses (HHVs) are globally prevalent and characterized by lifelong persistence. Reactivations can potentially manifest as life-threatening conditions for which the demonstration of viral DNA is essential. In the present study, we developed HERQ-9, a pan-HHV quantitative PCR designed in triplex reactions to differentiate and quantify each of the HHV-DNAs: (i) herpes simplex viruses 1 and 2 and varicella-zoster virus; (ii) Epstein-Barr virus, human cytomegalovirus, and Kaposi’s sarcoma-associated herpesvirus; and (iii) HHV-6A, -6B, and -7. The method was validated with prequantified reference standards as well as with mucocutaneous swabs and cerebrospinal fluid, plasma, and tonsillar tissue samples. Our findings highlight the value of multiplexing in the diagnosis of many unsuspected, yet clinically relevant, herpesviruses. In addition, we report here frequent HHV-DNA co-occurrences in clinical samples, including some previously unknown. HERQ-9 exhibited high specificity and sensitivity (LOD95s of ∼10 to ∼17 copies/reaction), with a dynamic range of 101 to 106 copies/μl. Moreover, it performed accurately in the coamplification of both high- and low-abundance targets in the same reaction. In conclusion, we demonstrated that HERQ-9 is suitable for the diagnosis of a plethora of herpesvirus-related diseases. Besides its significance to clinical management, the method is valuable for the assessment of hitherto-unexplored synergistic effects of herpesvirus coinfections. Furthermore, its high sensitivity enables studies on the human virome, often dealing with minute quantities of persisting HHVs. IMPORTANCE By adulthood, almost all humans become infected by at least one herpesvirus (HHV). The maladies inflicted by these microbes extend beyond the initial infection, as they remain inside our cells for life and can reactivate, causing severe diseases. The diagnosis of active infection by these ubiquitous pathogens includes the detection of DNA with sensitive and specific assays. We developed the first quantitative PCR assay (HERQ-9) designed to identify and quantify each of the nine human herpesviruses. The simultaneous detection of HHVs in the same sample is important since they may act together to induce life-threatening conditions. Moreover, the high sensitivity of our method is of extreme value for assessment of the effects of these viruses persisting in our body and their long-term consequences on our health.
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20
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Körber N, Behrends U, Protzer U, Bauer T. Evaluation of T-activated proteins as recall antigens to monitor Epstein-Barr virus and human cytomegalovirus-specific T cells in a clinical trial setting. J Transl Med 2020; 18:242. [PMID: 32552697 PMCID: PMC7298696 DOI: 10.1186/s12967-020-02385-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Accepted: 05/21/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Pools of overlapping synthetic peptides are routinely used for ex vivo monitoring of antigen-specific T-cell responses. However, it is rather unlikely that these peptides match those resulting from naturally processed antigens. T-activated proteins have been described as immunogenic and more natural stimulants, since they have to pass through antigen processing and comprise activation of all clinically relevant effector cell populations. METHODS We performed comparative analysis of numbers and cytokine expression pattern of CD4 and CD8 T cells after stimulation with recombinant, urea-formulated T-activated EBV-BZLF1, -EBNA3A, and HCMV-IE1, and -pp65 proteins or corresponding overlapping peptide pools. Freshly isolated and cryopreserved PBMC of 30 EBV- and 19 HCMV-seropositive and seven EBV- and HCMV-seronegative subjects were stimulated ex vivo and analysed for IFN-γ, TNF and IL-2 production by flow cytometry-based intracellular cytokine staining. RESULTS T-activated proteins showed a high specificity of 100% (EBV-BZLF1, HCMV-IE1, and -pp65) and 86% (EBV-EBNA3A), and a high T-cell stimulatory capacity of 73-95% and 67-95% using freshly isolated and cryopreserved PBMC, respectively. The overall CD4 T-cell response rates in both cohorts were comparable after stimulation with either T-activated protein or peptide pools with the exception of lower numbers of CD8 T cells detected after stimulation with T-activated EBV-EBNA3A- (p = 0.038) and HCMV-pp65- (p = 0.0006). Overall, the number of detectable antigen-specific T cells varied strongly between individuals. Cytokine expression patterns in response to T-activated protein and peptide pool-based stimulation were similar for CD4, but significantly different for CD8 T-cell responses. CONCLUSION EBV and HCMV-derived T-activated proteins represent innovative, highly specific recall antigens suitable for use in immunological endpoint assays to evaluate success or failure in immunotherapy clinical trials (e.g. to assess the risk of EBV and/or HCMV reactivation after allogenic hematopoietic stem cell transplantation). T-activated proteins could be of particular importance, if an impaired antigen processing (e.g. in a post-transplant setting) must be taken into account.
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Affiliation(s)
- Nina Körber
- Institute of Virology, Helmholtz Zentrum München/Technical University of Munich, School of Medicine, Schneckenburgerstr. 8, 81675, Munich, Germany.
| | - Uta Behrends
- Children's Hospital, School of Medicine, Technical University of Munich, Munich, Germany.,Research Unit Gene Vectors, Helmholtz Zentrum München, Munich, Germany.,German Center for Infection Research (DZIF), Partner Site, Munich, Germany
| | - Ulrike Protzer
- Institute of Virology, Helmholtz Zentrum München/Technical University of Munich, School of Medicine, Schneckenburgerstr. 8, 81675, Munich, Germany.,German Center for Infection Research (DZIF), Partner Site, Munich, Germany
| | - Tanja Bauer
- Institute of Virology, Helmholtz Zentrum München/Technical University of Munich, School of Medicine, Schneckenburgerstr. 8, 81675, Munich, Germany.,German Center for Infection Research (DZIF), Partner Site, Munich, Germany
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21
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Silva JT, Fernández-Ruiz M, Aguado JM. Prevention and therapy of viral infections in patients with solid organ transplantation. Enferm Infecc Microbiol Clin 2020; 39:87-97. [PMID: 32143894 DOI: 10.1016/j.eimc.2020.01.021] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 01/13/2020] [Accepted: 01/16/2020] [Indexed: 12/28/2022]
Abstract
Solid organ transplantation (SOT) is the best treatment option for end-stage organ disease. The number of SOT procedures has been steadily increasing worldwide during the past decades. This trend has been accompanied by the continuous incorporation of new antimicrobial drugs and by the refinement of strategies aimed at minimizing the risk of opportunistic infection. Nonetheless, viral infections, which can occur at any stage of the post-transplant period, remain a clinical challenge that negatively impacts both patient and graft outcomes. This review offers an overview of the most relevant viral infections in the SOT population, with a focus on herpesviruses (cytomegalovirus, Epstein-Barr virus, varicella-zoster virus, and herpes simplex virus 1 and 2) and polyomaviruses (human BK polyomavirus). In addition, the currently recommended prophylactic and treatment approaches are summarized, as well as the new antiviral agents in different phases of clinical development.
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Affiliation(s)
- Jose Tiago Silva
- Unit of Infectious Diseases, Hospital Universitario "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (imas12), School of Medicine, Universidad Complutense, Madrid, Spain
| | - Mario Fernández-Ruiz
- Unit of Infectious Diseases, Hospital Universitario "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (imas12), School of Medicine, Universidad Complutense, Madrid, Spain
| | - José María Aguado
- Unit of Infectious Diseases, Hospital Universitario "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (imas12), School of Medicine, Universidad Complutense, Madrid, Spain.
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22
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Pre-transplant assessment of pp65-specific CD4 T cell responses identifies CMV-seropositive patients treated with rATG at risk of late onset infection. Clin Immunol 2020; 211:108329. [DOI: 10.1016/j.clim.2019.108329] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Accepted: 12/27/2019] [Indexed: 11/17/2022]
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23
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Natori Y, Alghamdi A, Husain S, Rotstein C, Selzner N, Tikkanen J, Schiff J, Humar A, Kumar D. Clinical predictors of progression and clearance of low-level CMV DNAemia in solid organ transplant recipients. Transpl Infect Dis 2019; 22:e13207. [PMID: 31677321 DOI: 10.1111/tid.13207] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Revised: 06/10/2019] [Accepted: 10/04/2019] [Indexed: 12/01/2022]
Abstract
BACKGROUND Low-level CMV DNAemia is common and in the absence of treatment may either progress to higher viral loads that require therapy, or may spontaneously resolve. The clinical predictors of progression and spontaneous viral clearance are not well defined. METHODS We performed a retrospective cohort study of organ transplant recipients who had untreated low-level CMV DNAemia (<1000 IU/mL). Outcomes were evaluated for 8 weeks after initial viral detection, and progression to CMV high viral load was defined as CMV viral load ≥1000 IU/mL. CMV DNAemia doubling time was calculated for a subset of patients with sufficient viral load timepoints. RESULTS Of the 297 patients analyzed, 118/297 (39.7%) patients progressed to a high viral load and the remaining cleared DNAemia spontaneously (46.8%) or remained at low level (13.4%). In multivariate analysis, progression was significantly more likely in lung transplant recipients (odds ratio 3.09) and less likely in those with an episode of previously treated CMV infection (odds ratio 0.081). In a subset of 27 patients with progression, the doubling time for CMV DNAemia was a median of 6.1 days (range 2.4-21.8). CONCLUSION We found that previous CMV infection significantly decreased the likelihood of low-level DNAemia progression suggesting that CMV immunity plays a role in progression vs spontaneous clearance.
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Affiliation(s)
- Yoichiro Natori
- Division of Infectious Diseases, Miami Transplant Institute, Jackson Health System, University of Miami, Miami, FL, USA
| | - Ali Alghamdi
- Division of Infectious Diseases, Miami Transplant Institute, Jackson Health System, University of Miami, Miami, FL, USA.,Division of Infectious Diseases, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Shahid Husain
- Multi Organ Transplant Program, University Health Network, Toronto, ON, Canada
| | - Coleman Rotstein
- Multi Organ Transplant Program, University Health Network, Toronto, ON, Canada
| | - Nazia Selzner
- Multi Organ Transplant Program, University Health Network, Toronto, ON, Canada
| | - Jussi Tikkanen
- Multi Organ Transplant Program, University Health Network, Toronto, ON, Canada
| | - Jeffrey Schiff
- Multi Organ Transplant Program, University Health Network, Toronto, ON, Canada
| | - Atul Humar
- Multi Organ Transplant Program, University Health Network, Toronto, ON, Canada
| | - Deepali Kumar
- Multi Organ Transplant Program, University Health Network, Toronto, ON, Canada
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24
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Gong J, Meyerowitz EA, Isidro RA, Kaye KM. Primary cytomegalovirus infection with invasive disease in a patient with inflammatory bowel disease. BMJ Case Rep 2019; 12:12/9/e230056. [PMID: 31570344 PMCID: PMC6768388 DOI: 10.1136/bcr-2019-230056] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
A 37-year-old woman with a history of inflammatory bowel disease on mercaptopurine presented with a week of recurrent fever, headache, myalgias and mildly elevated serum transaminases and leucopenia. Her workup revealed primary cytomegalovirus (CMV) infection with atypical lymphocytosis, elevated viral load, positive IgM and negative IgG. Two weeks after her initial presentation, she developed odynophagia and diarrhoea prompting endoscopic evaluation with biopsies, which demonstrated CMV disease of the gastrointestinal tract. Her fever and systemic symptoms improved rapidly with initiation of intravenous ganciclovir. She was transitioned to and maintained on oral valganciclovir until two and half months after discharge when her symptoms and lab abnormalities had fully subsided.
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Affiliation(s)
- Jingyi Gong
- Internal Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | | | - Raymond A Isidro
- Anatomic Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Kenneth M Kaye
- Infectious Diseases, Brigham and Women's Hospital, Boston, Massachusetts, USA
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25
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Wang D, Lin D, Li P, Liu H, Yang Y, Zhang Z, Kong Q, Zhang Y, Huang X. Joint association of carrying HLA-B*13:01 gene and human herpesvirus-6 with occupational trichloroethylene hypersensitivity syndrome. Int Arch Occup Environ Health 2019; 92:395-401. [PMID: 30758654 DOI: 10.1007/s00420-019-01417-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Accepted: 02/05/2019] [Indexed: 11/30/2022]
Abstract
PURPOSE Occupational trichloroethylene hypersensitivity syndrome (OTHS) clinically manifests as generalized severe rash resembling drug-induced hypersensitivity syndrome (DIHS) and afflicts predominantly HLA-B*13:01 gene carriers after their exposure to trichloroethylene. Meanwhile, OTHS may also be associated with human herpesvirus such as herpesvirus-6 (HHV6) and cytomegalovirus (HCMV) reported to participate in the pathology of DIHS. This study explored the association of carrying HHV6 and HCMV, and the joint association of carrying HLA-B*13:01 and HHV6 and HCMV with OTHS. METHODS We recruited 30 OTHS patients and 40 trichloroethylene-exposed healthy workers as cases and controls, respectively. HLA-B*13:01 was genotyped and HHV6 and HCMV DNA were detected in the DNA extracted from whole-blood sample of each participant with PCR techniques. Positive rates of HLA-B*13:01 gene and HHV6 and HCMV DNA and their association with OTHS were then analyzed. RESULTS The OTHS cases showed significantly higher positive rates of HLA-B*13:01 gene and HHV6 DNA, but not HCMV DNA, than the controls (83.3% vs. 25.0% and 56.7% vs. 10.0%, respectively, both P < 0.001). Positive rate of HHV6 DNA was significantly higher in HLA-B*13:01 carriers than in non-carriers in the cases (68.0% vs. 0, P = 0.005), but not in the controls. Carrying HLA-B*13:01 and HHV6 had an interactive effect on OTHS (OR = 91.80, P < 0.001). CONCLUSIONS Carrying HLA-B*13:01 and HHV6 may be associated with OTHS; furthermore, carrying HLA-B*13:01 and HHV6 may be jointly associated with OTHS.
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Affiliation(s)
- Dianpeng Wang
- Clinical Laboratory, Shenzhen Prevention and Treatment Center for Occupational Diseases, 2019 Buxin Rd., Luohu District, Shenzhen, 518020, China.,Poisoning Detection Center, Shenzhen Prevention and Treatment Center for Occupational Diseases, Shenzhen, China
| | - Dafeng Lin
- Clinical Laboratory, Shenzhen Prevention and Treatment Center for Occupational Diseases, 2019 Buxin Rd., Luohu District, Shenzhen, 518020, China. .,Poisoning Detection Center, Shenzhen Prevention and Treatment Center for Occupational Diseases, Shenzhen, China.
| | - Peimao Li
- Clinical Laboratory, Shenzhen Prevention and Treatment Center for Occupational Diseases, 2019 Buxin Rd., Luohu District, Shenzhen, 518020, China.,Poisoning Detection Center, Shenzhen Prevention and Treatment Center for Occupational Diseases, Shenzhen, China
| | | | | | - Zhimin Zhang
- Clinical Laboratory, Shenzhen Prevention and Treatment Center for Occupational Diseases, 2019 Buxin Rd., Luohu District, Shenzhen, 518020, China.,Poisoning Detection Center, Shenzhen Prevention and Treatment Center for Occupational Diseases, Shenzhen, China
| | | | - Yanfang Zhang
- Clinical Laboratory, Shenzhen Prevention and Treatment Center for Occupational Diseases, 2019 Buxin Rd., Luohu District, Shenzhen, 518020, China.,Poisoning Detection Center, Shenzhen Prevention and Treatment Center for Occupational Diseases, Shenzhen, China
| | - Xianqing Huang
- Poisoning Detection Center, Shenzhen Prevention and Treatment Center for Occupational Diseases, Shenzhen, China
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26
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Abstract
Infections in heart and lung transplant recipients are complex and heterogeneous. This article reviews the epidemiology, risk factors, specific clinical syndromes, and most frequent opportunistic infections in heart and/or lung transplant recipients that will be encountered in the intensive care unit and will provide a practical approach of empirical management.
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Affiliation(s)
- Mohammed Alsaeed
- Division of Infectious Diseases, Multi-Organ Transplant Program, Department of Medicine, University of Toronto, University Health Network, 585 University Avenue, 11 PMB 138, Toronto, Ontario M5G 2N2, Canada; Division of Infectious Diseases, Department of Medicine, Prince Sultan Military Medical City, Makkah Al Mukarramah Road, As Sulimaniyah, Riyadh 12233, Saudi Arabia
| | - Shahid Husain
- Division of Infectious Diseases, Multi-Organ Transplant Program, Department of Medicine, University of Toronto, University Health Network, 585 University Avenue, 11 PMB 138, Toronto, Ontario M5G 2N2, Canada.
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27
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Hakimi Z, Ferchichi S, Aballea S, Odeyemi I, Toumi M, English M, Yakoub-Agha I. Burden of cytomegalovirus disease in allogeneic hematopoietic cell transplant recipients: a national, matched cohort study in an inpatient setting. Curr Res Transl Med 2018; 66:95-101. [PMID: 30274738 DOI: 10.1016/j.retram.2018.08.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Revised: 08/07/2018] [Accepted: 08/21/2018] [Indexed: 11/17/2022]
Abstract
PURPOSE OF THE STUDY No studies have compared the risk of mortality or graft-versus-host disease, in an inpatient setting in France, in allogeneic hematopoietic cell transplant recipients who develop cytomegalovirus disease with those who do not. This study assessed the impact of cytomegalovirus disease on clinical outcomes and healthcare resource utilization in allogeneic hematopoietic cell transplant recipients using the French Programme de Médicalisation des Systèmes d'Information database. PATIENTS AND METHODS Recipients who had undergone allogeneic hematopoietic cell transplant in French hospitals between 2008 and 2011 were included in this retrospective, matched cohort study. Those with cytomegalovirus disease were each matched with two allogeneic hematopoietic cell transplant recipients without cytomegalovirus disease according to demographic and clinical characteristics. Probabilities of in-hospital mortality, graft rejection and/or graft-versus-host disease, and healthcare resource utilization were compared up to 12 months after cytomegalovirus disease diagnosis. RESULTS Overall, 4884 transplant recipients were enrolled, of which 194 had cytomegalovirus disease. Of these, 165 recipients with cytomegalovirus disease were matched to 330 without cytomegalovirus disease (1:2 ratio). The development of cytomegalovirus disease was associated with a significantly higher risk of in-hospital mortality (relative risk = 1.7, p = 0.0005) and higher cumulative number of inpatient days (p < 0.0001), but was not associated with a significantly higher risk of graft rejection and/or graft-versus-host disease or healthcare costs. CONCLUSIONS Due to the increased risk of in-hospital mortality and higher cumulative number of inpatient days in allogeneic hematopoietic cell transplant recipients with cytomegalovirus disease versus those without, new strategies to prevent and manage cytomegalovirus disease are warranted.
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Affiliation(s)
- Z Hakimi
- Astellas Pharma Europe B.V., Sylviusweg 62, PO Box 344, Leiden, 2300 AH, The Netherlands
| | - S Ferchichi
- Health Economics & Outcomes Research, Creativ-Ceutical, 215 rue du Faubourg Saint-Honoré, Paris, 750086, France
| | - S Aballea
- Health Economics & Outcomes Research, Creativ-Ceutical, 215 rue du Faubourg Saint-Honoré, Paris, 750086, France
| | - I Odeyemi
- Astellas Pharma Europe Ltd., 2000 Hillswood Drive, Chertsey, KT16 0RS, UK
| | - M Toumi
- University Claude Bernard Lyon 1, 43 Boulevard du 11 Novembre 1918, Lyon, 69622, France
| | - M English
- Astellas Pharma Global Development, Inc., Northbrook, 60062, IL, USA.
| | - I Yakoub-Agha
- CHU de Lille, LIRIC, INSERM U995, Université de Lille, 59000, France
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28
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Cutaneous Complications in Recipients of Lung Transplants: A Pictorial Review. Chest 2018; 155:178-193. [PMID: 30201407 DOI: 10.1016/j.chest.2018.08.1060] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Accepted: 08/16/2018] [Indexed: 12/26/2022] Open
Abstract
Lung transplant is now an established modality for a broad spectrum of end-stage pulmonary diseases. According to the International Society for Heart and Lung Transplantation Registry, more than 50,000 lung transplants have been performed worldwide, with nearly 11,000 recipients of lung transplants alive in the United States. With the increasing use of lung transplant, pulmonologists must be cognizant of the common as well as the unique posttransplant dermatologic complications. Immunosuppression, infections, and a variety of medications and environmental exposures can contribute to these complications. This review aims to provide representative pictures and describe the pathogenesis, epidemiologic characteristics, and clinical manifestations of dermatologic complications encountered among recipients of lung transplants.
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29
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Bagdonaite I, Vakhrushev SY, Joshi HJ, Wandall HH. Viral glycoproteomes: technologies for characterization and outlook for vaccine design. FEBS Lett 2018; 592:3898-3920. [PMID: 29961944 DOI: 10.1002/1873-3468.13177] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2018] [Revised: 06/13/2018] [Accepted: 06/26/2018] [Indexed: 12/27/2022]
Abstract
It has long been known that surface proteins of most enveloped viruses are covered with glycans. It has furthermore been demonstrated that glycosylation is essential for propagation and immune evasion for many viruses. The recent development of high-resolution mass spectrometry techniques has enabled identification not only of the precise structures but also the positions of such post-translational modifications on viruses, revealing substantial differences in extent of glycosylation and glycan maturation for different classes of viruses. In-depth characterization of glycosylation and other post-translational modifications of viral envelope glycoproteins is essential for rational design of vaccines and antivirals. In this Review, we provide an overview of techniques used to address viral glycosylation and summarize information on glycosylation of enveloped viruses representing ongoing public health challenges. Furthermore, we discuss how knowledge on glycosylation can be translated to means to prevent and combat viral infections.
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Affiliation(s)
- Ieva Bagdonaite
- Department of Cellular and Molecular Medicine, Copenhagen Center for Glycomics, University of Copenhagen, Denmark
| | - Sergey Y Vakhrushev
- Department of Cellular and Molecular Medicine, Copenhagen Center for Glycomics, University of Copenhagen, Denmark
| | - Hiren J Joshi
- Department of Cellular and Molecular Medicine, Copenhagen Center for Glycomics, University of Copenhagen, Denmark
| | - Hans H Wandall
- Department of Cellular and Molecular Medicine, Copenhagen Center for Glycomics, University of Copenhagen, Denmark
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30
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Temporal dynamics of the lung and plasma viromes in lung transplant recipients. PLoS One 2018; 13:e0200428. [PMID: 29979780 PMCID: PMC6034876 DOI: 10.1371/journal.pone.0200428] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Accepted: 06/26/2018] [Indexed: 12/31/2022] Open
Abstract
The human virome plays an important role for the clinical outcome of lung transplant recipients (LTRs). While pathogenic viruses may cause severe infections, non-pathogenic viruses may serve as potential markers for the level of immunosuppression. However, neither the complexity of the virome in different compartments nor the dynamics of the virus populations posttransplantation are yet understood. Therefore, in this study the virome was analyzed by metagenomic sequencing in simultaneously withdrawn bronchoalveolar lavage (BAL) and plasma samples of 15 LTRs. In seven patients, also follow-up samples were investigated for abundance and dynamics of virus populations posttransplantation. Five eukaryotic and two prokaryotic virus families were identified in BAL, and nine eukaryotic and two prokaryotic families in plasma. Anelloviruses were the most abundant in both compartments, followed by Herpes- and Coronaviruses. Virus abundance was significantly higher in LTRs than in healthy controls (Kruskal-Wallis test, p<0.001). Up to 48 different anellovirus strains were identified within a single LTR. Analyses in the follow-up patients revealed for the first time a highly complex and unique dynamics of individual anellovirus strains in the posttransplantation period. The abundance of anelloviruses in plasma was inversely correlated with that of other eukaryotic viruses (Pearson correlation coefficient r = -0.605; p<0.05). A broad spectrum of virus strains co-exists in BAL and plasma of LTRs. Especially for the anelloviruses, a high degree of co-infections and a highly individual and complex dynamics after transplantation was observed. The biological impact of these findings and their relation to clinical variables remain to be elucidated by future analyses.
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31
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Bagdonaite I, Wandall HH. Global aspects of viral glycosylation. Glycobiology 2018; 28:443-467. [PMID: 29579213 PMCID: PMC7108637 DOI: 10.1093/glycob/cwy021] [Citation(s) in RCA: 181] [Impact Index Per Article: 25.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Revised: 02/10/2018] [Accepted: 03/21/2018] [Indexed: 12/15/2022] Open
Abstract
Enveloped viruses encompass some of the most common human pathogens causing infections of different severity, ranging from no or very few symptoms to lethal disease as seen with the viral hemorrhagic fevers. All enveloped viruses possess an envelope membrane derived from the host cell, modified with often heavily glycosylated virally encoded glycoproteins important for infectivity, viral particle formation and immune evasion. While N-linked glycosylation of viral envelope proteins is well characterized with respect to location, structure and site occupancy, information on mucin-type O-glycosylation of these proteins is less comprehensive. Studies on viral glycosylation are often limited to analysis of recombinant proteins that in most cases are produced in cell lines with a glycosylation capacity different from the capacity of the host cells. The glycosylation pattern of the produced recombinant glycoproteins might therefore be different from the pattern on native viral proteins. In this review, we provide a historical perspective on analysis of viral glycosylation, and summarize known roles of glycans in the biology of enveloped human viruses. In addition, we describe how to overcome the analytical limitations by using a global approach based on mass spectrometry to identify viral O-glycosylation in virus-infected cell lysates using the complex enveloped virus herpes simplex virus type 1 as a model. We underscore that glycans often pay important contributions to overall protein structure, function and immune recognition, and that glycans represent a crucial determinant for vaccine design. High throughput analysis of glycosylation on relevant glycoprotein formulations, as well as data compilation and sharing is therefore important to identify consensus glycosylation patterns for translational applications.
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Affiliation(s)
- Ieva Bagdonaite
- Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3B, Copenhagen N, Denmark
| | - Hans H Wandall
- Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3B, Copenhagen N, Denmark
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32
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Cytomegalovirus sequence variability, amplicon length, and DNase-sensitive non-encapsidated genomes are obstacles to standardization and commutability of plasma viral load results. J Clin Virol 2018; 104:39-47. [DOI: 10.1016/j.jcv.2018.04.013] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Revised: 04/16/2018] [Accepted: 04/18/2018] [Indexed: 11/22/2022]
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33
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Cristelli MP, Esmeraldo RM, Pinto CM, Sandes-Freitas TV, Felipe C, Lobo CF, Viana L, Mansur J, Stopa S, Santos DWC, Grenzi PC, Aguiar WF, Tedesco-Silva H, Pestana JOM. The influence of mTOR inhibitors on the incidence of CMV infection in high-risk donor positive-recipient negative (D+/R−) kidney transplant recipients. Transpl Infect Dis 2018; 20:e12907. [DOI: 10.1111/tid.12907] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Revised: 03/20/2018] [Accepted: 03/24/2018] [Indexed: 12/16/2022]
Affiliation(s)
- Marina Pontello Cristelli
- Kidney Transplant Division; Hospital do Rim; São Paulo Brazil
- Universidade Federal de São Paulo; São Paulo Brazil
| | | | - Cahue Motta Pinto
- Kidney Transplant Division; Hospital do Rim; São Paulo Brazil
- Universidade Federal de São Paulo; São Paulo Brazil
| | - Taina Veras Sandes-Freitas
- Nephrology Division; Hospital Geral de Fortaleza; Fortaleza Brazil
- Clinical Medicine Division; Universidade Federal do Ceara; Fortaleza Brazil
| | - Claudia Felipe
- Kidney Transplant Division; Hospital do Rim; São Paulo Brazil
- Universidade Federal de São Paulo; São Paulo Brazil
| | | | - Laila Viana
- Kidney Transplant Division; Hospital do Rim; São Paulo Brazil
- Universidade Federal de São Paulo; São Paulo Brazil
| | - Juliana Mansur
- Kidney Transplant Division; Hospital do Rim; São Paulo Brazil
- Universidade Federal de São Paulo; São Paulo Brazil
| | - Suelen Stopa
- Kidney Transplant Division; Hospital do Rim; São Paulo Brazil
- Universidade Federal de São Paulo; São Paulo Brazil
| | - Daniel Wagner Castro Santos
- Kidney Transplant Division; Hospital do Rim; São Paulo Brazil
- Universidade Federal de São Paulo; São Paulo Brazil
| | - Patricia Cristina Grenzi
- Kidney Transplant Division; Hospital do Rim; São Paulo Brazil
- Universidade Federal de São Paulo; São Paulo Brazil
| | - Wilson Ferreira Aguiar
- Kidney Transplant Division; Hospital do Rim; São Paulo Brazil
- Universidade Federal de São Paulo; São Paulo Brazil
| | - Helio Tedesco-Silva
- Kidney Transplant Division; Hospital do Rim; São Paulo Brazil
- Universidade Federal de São Paulo; São Paulo Brazil
| | - Jose Osmar Medina Pestana
- Kidney Transplant Division; Hospital do Rim; São Paulo Brazil
- Universidade Federal de São Paulo; São Paulo Brazil
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34
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Kim W, Kim S, Oh J, Jeong YJ, Rhu J, Kim KS, Lee J, Choi GS, Kim JM, Joh JW. Incidence and risk factors for herpes zoster after adult liver transplantation. Ann Surg Treat Res 2018; 96:95-99. [PMID: 30746357 PMCID: PMC6358591 DOI: 10.4174/astr.2019.96.2.95] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Revised: 09/18/2018] [Accepted: 10/05/2018] [Indexed: 12/16/2022] Open
Abstract
Purpose Herpes zoster (HZ) is caused by reactivation of the varicella zoster virus, which occurs frequently in liver transplant recipients with impaired cellular immunity. The purpose of this study was to evaluate the incidence and risk factors for HZ after adult liver transplantation (LT). Methods In our institution, 993 patients underwent adult LT from January 1997 to December 2013. We retrospectively analyzed the incidence rate of HZ and risk factors for HZ after LT. Results Of 993 LT recipients, 101 (10.2%) were diagnosed with HZ. The incidence of HZ at 1, 3, 5, and 10 years was 6.6%, 9.1%, 10.0%, and 11.9%, respectively. Therefore, we observed that the incidence of HZ after LT was 16.3 per 1,000 person-years. Older age (≥50 years) at LT and mycophenolate mofetil (MMF) exposure were independent risk factors of HZ infection after adult LT. Conclusion Patients older than 50 years or with MMF exposure are considered to be at high risk for HZ. Therefore, adult liver recipients with such factors should not be given strong immunosuppression treatments.
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Affiliation(s)
- Wontae Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sangjin Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jongwook Oh
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Young Jae Jeong
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jinsoo Rhu
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kyung Sik Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jisoo Lee
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Gyu-Sung Choi
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jong Man Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jae-Won Joh
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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35
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Abstract
The α herpes viruses HSV-1, HSV-2, and VZV often reactivate in the setting of immune suppression after solid organ transplantation. Oral or genital mucocutaneous disease is the most common clinical manifestation of HSV disease while VZV manifests as varicella (or chickenpox) or reactivation herpes zoster, characterized by a diffuse rash, or a painful unilateral vesicular eruption in a dermatomal distribution, respectively. The diagnosis of HSV and VZV is primarily based on history and clinical presentation, although diagnostic tests may be necessary for atypical presentations of disease. Treatment usually involves oral or intravenous antiviral therapy, depending on severity of illness.
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Affiliation(s)
- Cybele Lara Abad
- Division of Infectious Diseases, Department of Medicine, Mayo Clinic, Rochester, MN
| | - Raymund R Razonable
- Division of Infectious Diseases, Department of Medicine, Mayo Clinic, Rochester, MN; The William J. Von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN.
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36
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Markolović M, Ćupić M. The prevalence of herpesvirus infections in children and young adults transplant recipients - kidney and hematopoetic stem cells. MEDICINSKI PODMLADAK 2018. [DOI: 10.5937/mp69-16747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022] Open
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37
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Selvey LA, Lim WH, Boan P, Swaminathan R, Slimings C, Harrison AE, Chakera A. Cytomegalovirus viraemia and mortality in renal transplant recipients in the era of antiviral prophylaxis. Lessons from the western Australian experience. BMC Infect Dis 2017; 17:501. [PMID: 28716027 PMCID: PMC5514475 DOI: 10.1186/s12879-017-2599-y] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Accepted: 07/11/2017] [Indexed: 12/12/2022] Open
Abstract
Background Cytomegalovirus (CMV) establishes a lifelong infection that is efficiently controlled by the immune system; this infection can be reactivated in case of immunosuppression such as following solid organ transplantation. CMV viraemia has been associated with CMV disease, as well as increased mortality and allograft failure. Prophylactic antiviral medication is routinely given to renal transplant recipients, but reactivation during and following cessation of antiviral prophylaxis is known to occur. The aims of this study were to assess the incidence, timing and impact of CMV viraemia in renal transplant recipients and to determine the level of viraemia associated with adverse clinical outcomes. Methods Data from all adult (18 years and over) Western Australian renal transplant recipients transplanted between 1 January 2007 and 31 December 2012 were obtained from the Australia and New Zealand Dialysis and Transplant registry and were supplemented with data obtained from clinical records. Potential risk factors for detectable CMV viraemia (≥600 copies/ml) and all-cause mortality were assessed using univariable analysis and Cox Proportional Hazards Regression. Results There were 438 transplants performed on 435 recipients. The following factors increased the risk of CMV viraemia with viral loads ≥600 copies/ml: Donor positive/Recipient negative status; receiving a graft from a deceased donor; and receiving a graft from a donor aged 60 years and over. CMV viraemia with viral loads ≥656 copies/ml was a risk factor for death following renal transplantation, as was being aged 65 years and above at transplant, being Aboriginal and having vascular disease. Importantly 37% of the episodes of CMV viraemia with viral loads ≥656 copies/ml occurred while the patients were expected to be on CMV prophylaxis. Conclusions CMV viraemia (≥656 copies/ml) was associated with all-cause mortality in multivariable analysis, and CMV viraemia at ≥656 copies/ml commonly occurred during the period when renal transplant recipients were expected to be on antiviral prophylaxis. A greater vigilance in monitoring CMV levels if antiviral prophylaxis is stopped prematurely or poor patient compliance is suspected could protect some renal transplant recipients from adverse outcomes such as premature mortality.
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Affiliation(s)
- Linda A Selvey
- School of Public Health, Curtin University, Bentley, WA, Australia.
| | - Wai H Lim
- ANZDATA Registry, Adelaide, Australia.,Department of Renal Medicine, Sir Charles Gairdner Hospital, Perth, WA, Australia
| | - Peter Boan
- Department of Infectious Diseases, Fiona Stanley Hospital, Murdoch, WA, Australia.,Department of Microbiology, PathWest Laboratory Medicine, Perth, WA, Australia
| | - Ramyasuda Swaminathan
- Department of Nephrology and Renal Transplantation, Fiona Stanley Hospital, Murdoch, WA, Australia
| | | | - Amy E Harrison
- School of Public Health, Curtin University, Bentley, WA, Australia
| | - Aron Chakera
- Department of Renal Medicine, Sir Charles Gairdner Hospital, Perth, WA, Australia.,Translational Renal Research Group, Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, WA, Australia
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38
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Martin-Gandul C, Stampf S, Héquet D, Mueller NJ, Cusini A, van Delden C, Khanna N, Boggian K, Hirzel C, Soccal P, Hirsch HH, Pascual M, Meylan P, Manuel O. Preventive Strategies Against Cytomegalovirus and Incidence of α-Herpesvirus Infections in Solid Organ Transplant Recipients: A Nationwide Cohort Study. Am J Transplant 2017; 17:1813-1822. [PMID: 28039960 DOI: 10.1111/ajt.14192] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2016] [Revised: 12/15/2016] [Accepted: 12/29/2016] [Indexed: 01/25/2023]
Abstract
We assessed the impact of antiviral preventive strategies on the incidence of herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections in a nationwide cohort of transplant recipients. Risk factors for the development of HSV or VZV infection were assessed by Cox proportional hazards regression. We included 2781 patients (56% kidney, 20% liver, 10% lung, 7.3% heart, 6.7% others). Overall, 1264 (45%) patients received antiviral prophylaxis (ganciclovir or valganciclovir, n = 1145; acyclovir or valacyclovir, n = 138). Incidence of HSV and VZV infections was 28.9 and 12.1 cases, respectively, per 1000 person-years. Incidence of HSV and VZV infections at 1 year after transplant was 4.6% (95% confidence interval [CI] 3.5-5.8) in patients receiving antiviral prophylaxis versus 12.3% (95% CI 10.7-14) in patients without prophylaxis; this was observed particularly for HSV infections (3% [95% CI 2.2-4] versus 9.8% [95% CI 8.4-11.4], respectively). A lower rate of HSV and VZV infections was also seen in donor or recipient cytomegalovirus-positive patients receiving ganciclovir or valganciclovir prophylaxis compared with a preemptive approach. Female sex (hazard ratio [HR] 1.663, p = 0.001), HSV seropositivity (HR 5.198, p < 0.001), previous episodes of rejection (HR 1.95, p = 0.004), and use of a preemptive approach (HR 2.841, p = 0.017) were significantly associated with a higher risk of HSV infection. Although HSV and VZV infections were common after transplantation, antiviral prophylaxis significantly reduced symptomatic HSV infections.
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Affiliation(s)
- C Martin-Gandul
- Transplantation Center, University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland.,Infectious Diseases Service, University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland
| | - S Stampf
- Institute for Clinical Epidemiology and Biostatistics, University Hospital of Basel, Basel, Switzerland
| | - D Héquet
- Transplantation Center, University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland.,Infectious Diseases Service, University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland
| | - N J Mueller
- Division of Infectious Diseases and Hospital Epidemiology, University Hospital, University of Zurich, Zürich, Switzerland
| | - A Cusini
- Department of Infectious Diseases, Bern University Hospital, University of Bern, Bern, Switzerland
| | - C van Delden
- Transplant Infectious Diseases Unit, University Hospital Geneva, Geneva, Switzerland
| | - N Khanna
- Division of Infectious Diseases and Hospital Epidemiology, University Hospital of Basel, Basel, Switzerland
| | - K Boggian
- Division of Infectious Diseases and Hospital Hygiene, Kantonsspital St. Gallen, St. Gallen, Switzerland
| | - C Hirzel
- Department of Infectious Diseases, Bern University Hospital, University of Bern, Bern, Switzerland
| | - P Soccal
- Division of Pneumology, Department of Medicine, University Hospital Geneva, Geneva, Switzerland
| | - H H Hirsch
- Transplantation & Clinical Virology, Department Biomedicine (Haus Petersplatz), University of Basel, Basel, Switzerland
| | - M Pascual
- Transplantation Center, University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland
| | - P Meylan
- Infectious Diseases Service, University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland.,Institute of Microbiology, University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland
| | - O Manuel
- Transplantation Center, University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland.,Infectious Diseases Service, University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland
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39
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Lollinga WT, Rurenga-Gard L, van Doesum W, van Bergen R, Diepstra A, Vonk JM, Riezebos-Brilman A, Niesters HGM, van Son WJ, van den Born J, Sanders JS. High human cytomegalovirus DNAemia early post-transplantation associates with irreversible and progressive loss of renal function - a retrospective study. Transpl Int 2017; 30:817-826. [DOI: 10.1111/tri.12972] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Revised: 10/02/2016] [Accepted: 04/18/2017] [Indexed: 01/06/2023]
Affiliation(s)
- Wouter T. Lollinga
- Division of Nephrology; Department of Internal Medicine; University Medical Center Groningen; University of Groningen; Groningen The Netherlands
| | - Lilli Rurenga-Gard
- Department of Medical Microbiology; University Medical Center Groningen; University of Groningen; Groningen The Netherlands
| | - Willem van Doesum
- Division of Nephrology; Department of Internal Medicine; University Medical Center Groningen; University of Groningen; Groningen The Netherlands
| | - Rik van Bergen
- Division of Nephrology; Department of Internal Medicine; University Medical Center Groningen; University of Groningen; Groningen The Netherlands
| | - Arjan Diepstra
- Division of Pathology; Department of Pathology and Medical Biology; University Medical Center Groningen; University of Groningen; Groningen The Netherlands
| | - Judith M. Vonk
- Department of Epidemiology; University Medical Center Groningen; University of Groningen; Groningen The Netherlands
| | - Annelies Riezebos-Brilman
- Department of Medical Microbiology; University Medical Center Groningen; University of Groningen; Groningen The Netherlands
| | - H. G. M. Niesters
- Department of Medical Microbiology; University Medical Center Groningen; University of Groningen; Groningen The Netherlands
| | - Willem J. van Son
- Division of Nephrology; Department of Internal Medicine; University Medical Center Groningen; University of Groningen; Groningen The Netherlands
| | - Jacob van den Born
- Division of Nephrology; Department of Internal Medicine; University Medical Center Groningen; University of Groningen; Groningen The Netherlands
| | - Jan-Stephan Sanders
- Division of Nephrology; Department of Internal Medicine; University Medical Center Groningen; University of Groningen; Groningen The Netherlands
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40
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Aiba N, Shiraki A, Yajima M, Oyama Y, Yoshida Y, Ohno A, Yamada H, Takemoto M, Daikoku T, Shiraki K. Interaction of Immunoglobulin with Cytomegalovirus-Infected Cells. Viral Immunol 2017; 30:500-507. [PMID: 28598267 DOI: 10.1089/vim.2016.0151] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Intravenous immunoglobulin (IVIG) is used to treat or prevent severe viral infection, especially cytomegalovirus (CMV) infections. IVIG was characterized to understand its interaction with CMV-infected cells. IVIG retarded CMV spread and reduced virus yields depending on the neutralizing (NT) antibody titer. Immediate early protein synthesis was reduced by IVIG in 3 to 15 h, and IVIG specifically reduced the ratio of 66/68k protein synthesis among immediate early proteins in an NT antibody-dependent manner between 4 and 8 h after infection, indicating that antigenic modulation of CMV-infected cells by IVIG reduced viral protein synthesis and virus production. The half-life of antibody bound to CMV-infected cells was 3.8 h. NT antibody titers to varicella-zoster virus (VZV) and CMV in IVIG were dose dependently absorbed by cells infected with VZV and CMV, respectively, but the antibody titers to CMV and VZV, respectively, were not affected. NT antibody in 0.3 mL of IVIG (15 mg) was specifically absorbed by 108 CMV-infected cells and 107 VZV-infected cells, suggesting that the NT antibody in IVIG might be inactivated by one-tenth of a similar volume of CMV-infected or VZV-infected cells. Various antiviral activities of IVIG may contribute to control and alleviation of CMV infection.
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Affiliation(s)
- Nobuyasu Aiba
- 1 Health Care Center, Takaoka Fushiki Hospital , Takaoka City, Japan
| | - Atsuko Shiraki
- 2 Department of Virology, University of Toyama , Toyama City, Japan
| | - Misako Yajima
- 2 Department of Virology, University of Toyama , Toyama City, Japan
| | - Yukari Oyama
- 2 Department of Virology, University of Toyama , Toyama City, Japan
| | | | - Ayumu Ohno
- 2 Department of Virology, University of Toyama , Toyama City, Japan
| | - Hiroshi Yamada
- 2 Department of Virology, University of Toyama , Toyama City, Japan
| | - Masaya Takemoto
- 3 Faculty of Pharmaceutical Sciences, Hokuriku University , Kanazawa City, Japan
| | - Tohru Daikoku
- 3 Faculty of Pharmaceutical Sciences, Hokuriku University , Kanazawa City, Japan
| | - Kimiyasu Shiraki
- 2 Department of Virology, University of Toyama , Toyama City, Japan
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Abstract
Human embryonic stem cells (hESCs) can undergo unlimited self-renewal and differentiate into all cell types in human body, and therefore hold great potential for cell therapy of currently incurable diseases including neural degenerative diseases, heart failure, and macular degeneration. This potential is further underscored by the promising safety and efficacy data from the ongoing clinical trials of hESC-based therapy of macular degeneration. However, one main challenge for the clinical application of hESC-based therapy is the allogeneic immune rejection of hESC-derived cells by the recipient. The breakthrough of the technology to generate autologous-induced pluripotent stem cells (iPSCs) by nuclear reprogramming of patient’s somatic cells raised the possibility that autologous iPSC-derived cells can be transplanted into the patients without the concern of immune rejection. However, accumulating data indicate that certain iPSC-derived cells can be immunogenic. In addition, the genomic instability associated with iPSCs raises additional safety concern to use iPSC-derived cells in human cell therapy. In this review, we will discuss the mechanism underlying the immunogenicity of the pluripotent stem cells and recent progress in developing immune tolerance strategies of human pluripotent stem cell (hPSC)-derived allografts. The successful development of safe and effective immune tolerance strategy will greatly facilitate the clinical development of hPSC-based cell therapy.
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Affiliation(s)
- Xin Liu
- Center for Regenerative and Translational Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.,Division of Biological Sciences, University of California, San Diego, La Jolla, CA, United States
| | - Wenjuan Li
- Center for Regenerative and Translational Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xuemei Fu
- The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Yang Xu
- Center for Regenerative and Translational Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.,Division of Biological Sciences, University of California, San Diego, La Jolla, CA, United States
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Peghin M, Hirsch HH, Len Ó, Codina G, Berastegui C, Sáez B, Solé J, Cabral E, Solé A, Zurbano F, López‐Medrano F, Román A, Gavaldá J. Epidemiology and Immediate Indirect Effects of Respiratory Viruses in Lung Transplant Recipients: A 5-Year Prospective Study. Am J Transplant 2017; 17:1304-1312. [PMID: 27615811 PMCID: PMC7159570 DOI: 10.1111/ajt.14042] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2016] [Revised: 08/23/2016] [Accepted: 09/01/2016] [Indexed: 01/25/2023]
Abstract
The epidemiology of respiratory viruses (RVs) in lung transplant recipients (LTRs) and the relationship of RVs to lung function, acute rejection (AR) and opportunistic infections in these patients are not well known. We performed a prospective cohort study (2009-2014) by collecting nasopharyngeal swabs (NPSs) from asymptomatic LTRs during seasonal changes and from LTRs with upper respiratory tract infectious disease (URTID), lower respiratory tract infectious disease (LRTID) and AR. NPSs were analyzed by multiplex polymerase chain reaction. Overall, 1094 NPSs were collected from 98 patients with a 23.6% positivity rate and mean follow-up of 3.4 years (interquartile range 2.5-4.0 years). Approximately half of URTIDs (47 of 97, 48.5%) and tracheobronchitis cases (22 of 56, 39.3%) were caused by picornavirus, whereas pneumonia was caused mainly by paramyxovirus (four of nine, 44.4%) and influenza (two of nine, 22.2%). In LTRs with LRTID, lung function changed significantly at 1 mo (p = 0.03) and 3 mo (p = 0.04). In a nested case-control analysis, AR was associated with RVs (hazard ratio [HR] 6.54), Pseudomonas aeruginosa was associated with LRTID (HR 8.54), and cytomegalovirus (CMV) replication or disease was associated with URTID (HR 2.53) in the previous 3 mo. There was no association between RVs and Aspergillus spp. colonization or infection (HR 0.71). In conclusion, we documented a high incidence of RV infections in LTRs. LRTID produced significant lung function abnormalities. Associations were observed between AR and RVs, between P. aeruginosa colonization or infection and LRTID, and between CMV replication or disease and URTID.
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Affiliation(s)
- M. Peghin
- Department of Infectious DiseasesHospital Universitari de la Vall d'HebronBarcelonaSpain,Spanish Network for Research in Infectious Diseases (REIPI)SevilleSpain
| | - H. H. Hirsch
- Transplantation & Clinical VirologyDepartment Biomedicine (Haus Petersplatz)University of BaselBaselSwitzerland,Division Infection DiagnosticsDepartment Biomedicine (Haus Petersplatz)University of BaselBaselSwitzerland,Infectious Diseases & Hospital EpidemiologyUniversity Hospital BaselBaselSwitzerland
| | - Ó. Len
- Department of Infectious DiseasesHospital Universitari de la Vall d'HebronBarcelonaSpain,Spanish Network for Research in Infectious Diseases (REIPI)SevilleSpain
| | - G. Codina
- Spanish Network for Research in Infectious Diseases (REIPI)SevilleSpain,Department of MicrobiologyHospital Universitari de la Vall d'HebronBarcelonaSpain
| | - C. Berastegui
- Department of Pulmonology and Lung Transplant UnitHospital Universitari de la Vall d'HebronBarcelonaSpain,CIBER de Enfermedades Respiratorias (CIBERES)Instituto de Salud Carlos IIIMadridSpain
| | - B. Sáez
- Department of Pulmonology and Lung Transplant UnitHospital Universitari de la Vall d'HebronBarcelonaSpain,CIBER de Enfermedades Respiratorias (CIBERES)Instituto de Salud Carlos IIIMadridSpain
| | - J. Solé
- Department of Thoracic SurgeryHospital Universitari de la Vall d'HebronBarcelonaSpain
| | - E. Cabral
- Department of Infectious DiseasesHospital Universitari de la Vall d'HebronBarcelonaSpain
| | - A. Solé
- Spanish Network for Research in Infectious Diseases (REIPI)SevilleSpain,Lung Transplant UnitHospital Universitario y Politécnico La FeValenciaSpain
| | - F. Zurbano
- Spanish Network for Research in Infectious Diseases (REIPI)SevilleSpain,Division of PneumologyHospital Universitario Marqués de ValdecillaIDIVALUniversity of CantabriaSantanderSpain
| | - F. López‐Medrano
- Spanish Network for Research in Infectious Diseases (REIPI)SevilleSpain,Department of Infectious DiseasesHospital Universitario 12 de OctubreMadridSpain
| | - A. Román
- Infectious Diseases & Hospital EpidemiologyUniversity Hospital BaselBaselSwitzerland,CIBER de Enfermedades Respiratorias (CIBERES)Instituto de Salud Carlos IIIMadridSpain
| | - J. Gavaldá
- Department of Infectious DiseasesHospital Universitari de la Vall d'HebronBarcelonaSpain,Spanish Network for Research in Infectious Diseases (REIPI)SevilleSpain
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Mirarab A, Mohebbi A, Moradi A, Javid N, Vakili MA, Tabarraei A. Frequent pUL27 Variations in HIV-Infected Patients. Intervirology 2017; 59:262-266. [PMID: 28402975 DOI: 10.1159/000471484] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2016] [Accepted: 03/15/2017] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVE Drug-resistant isolates of human cytomegalovirus (HCMV) have led to the development of new anti-HCMV drugs. Maribavir (MBV) is a novel inhibitor of the HCMV viral kinase. Resistance to MBV is mapped to gene UL27, a viral nuclear protein. In this study, we investigated UL27 polymorphisms in MBV-naive HIV-positive and HCMV congenitally infected clinical samples. METHODS DNA was extracted from 20 CMV-positive HIV (9/20) and congenitally infected (11/20) patients and used for UL27 polymerase chain reaction amplification. Sanger sequencing and multiple sequence alignment of products was performed. RESULTS K90 was the most prevalent polymorphism in both HIV-positive and congenitally infected patients. Polymorphisms Q54, D123, and R107 (10%) were seen in more than one sample. There were significantly more polymorphisms in the HIV-positive samples (p = 0.038). CONCLUSION HCMV pUL27 is highly variable in adult immunocompromised HIV-positive patients.
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Affiliation(s)
- Azam Mirarab
- Student Research Committee, Golestan University of Medical Sciences, Gorgan, Iran
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Fishman JA. Infection in Organ Transplantation. Am J Transplant 2017; 17:856-879. [PMID: 28117944 DOI: 10.1111/ajt.14208] [Citation(s) in RCA: 504] [Impact Index Per Article: 63.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Accepted: 01/09/2017] [Indexed: 01/25/2023]
Abstract
The prevention, diagnosis, and management of infectious disease in transplantation are major contributors to improved outcomes in organ transplantation. The risk of serious infections in organ recipients is determined by interactions between the patient's epidemiological exposures and net state of immune suppression. In organ recipients, there is a significant incidence of drug toxicity and a propensity for drug interactions with immunosuppressive agents used to maintain graft function. Thus, every effort must be made to establish specific microbiologic diagnoses to optimize therapy. A timeline can be created to develop a differential diagnosis of infection in transplantation based on common patterns of infectious exposures, immunosuppressive management, and antimicrobial prophylaxis. Application of quantitative molecular microbial assays and advanced antimicrobial therapies have advanced care. Pathogen-specific immunity, genetic polymorphisms in immune responses, and dynamic interactions between the microbiome and the risk of infection are beginning to be explored. The role of infection in the stimulation of alloimmune responses awaits further definition. Major hurdles include the shifting worldwide epidemiology of infections, increasing antimicrobial resistance, suboptimal assays for the microbiologic screening of organ donors, and virus-associated malignancies. Transplant infectious disease remains a key to the clinical and scientific investigation of organ transplantation.
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Affiliation(s)
- J A Fishman
- Transplant Infectious Disease and Immunocompromised Host Program and MGH Transplant Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA
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45
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Neuberger JM, Bechstein WO, Kuypers DRJ, Burra P, Citterio F, De Geest S, Duvoux C, Jardine AG, Kamar N, Krämer BK, Metselaar HJ, Nevens F, Pirenne J, Rodríguez-Perálvarez ML, Samuel D, Schneeberger S, Serón D, Trunečka P, Tisone G, van Gelder T. Practical Recommendations for Long-term Management of Modifiable Risks in Kidney and Liver Transplant Recipients: A Guidance Report and Clinical Checklist by the Consensus on Managing Modifiable Risk in Transplantation (COMMIT) Group. Transplantation 2017; 101:S1-S56. [PMID: 28328734 DOI: 10.1097/tp.0000000000001651] [Citation(s) in RCA: 216] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Short-term patient and graft outcomes continue to improve after kidney and liver transplantation, with 1-year survival rates over 80%; however, improving longer-term outcomes remains a challenge. Improving the function of grafts and health of recipients would not only enhance quality and length of life, but would also reduce the need for retransplantation, and thus increase the number of organs available for transplant. The clinical transplant community needs to identify and manage those patient modifiable factors, to decrease the risk of graft failure, and improve longer-term outcomes.COMMIT was formed in 2015 and is composed of 20 leading kidney and liver transplant specialists from 9 countries across Europe. The group's remit is to provide expert guidance for the long-term management of kidney and liver transplant patients, with the aim of improving outcomes by minimizing modifiable risks associated with poor graft and patient survival posttransplant.The objective of this supplement is to provide specific, practical recommendations, through the discussion of current evidence and best practice, for the management of modifiable risks in those kidney and liver transplant patients who have survived the first postoperative year. In addition, the provision of a checklist increases the clinical utility and accessibility of these recommendations, by offering a systematic and efficient way to implement screening and monitoring of modifiable risks in the clinical setting.
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Affiliation(s)
- James M Neuberger
- 1 Liver Unit, Queen Elizabeth Hospital Birmingham, United Kingdom. 2 Department of General and Visceral Surgery, Frankfurt University Hospital and Clinics, Germany. 3 Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Campus Gasthuisberg, Belgium. 4 Department of Surgery, Oncology, and Gastroenterology, Padova University Hospital, Padova, Italy. 5 Renal Transplantation Unit, Department of Surgical Science, Università Cattolica Sacro Cuore, Rome, Italy. 6 Department of Public Health, Faculty of Medicine, Institute of Nursing Science, University of Basel, Switzerland. 7 Department of Public Health, Faculty of Medicine, Centre for Health Services and Nursing Research, KU Leuven, Belgium. 8 Department of Hepatology and Liver Transplant Unit, Henri Mondor Hospital (AP-HP), Paris-Est University (UPEC), France. 9 Department of Nephrology, University of Glasgow, United Kingdom. 10 Department of Nephrology and Organ Transplantation, CHU Rangueil, Université Paul Sabatier, Toulouse, France. 11 Vth Department of Medicine & Renal Transplant Program, University Hospital Mannheim, University of Heidelberg, Mannheim, Germany. 12 Department of Gastroenterology and Hepatology, Erasmus MC, University Hospital Rotterdam, the Netherlands. 13 Department of Gastroenterology and Hepatology, University Hospitals KU Leuven, Belgium. 14 Abdominal Transplant Surgery, Microbiology and Immunology Department, University Hospitals KU Leuven, Belgium. 15 Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, IMIBIC, CIBERehd, Spain. 16 Hepatobiliary Centre, Hospital Paul-Brousse (AP-HP), Paris-Sud University, Université Paris-Saclay, Villejuif, France. 17 Department of Visceral, Transplant and Thoracic Surgery, Innsbruck Medical University, Austria. 18 Nephrology Department, Hospital Vall d'Hebrón, Autonomous University of Barcelona, Spain. 19 Transplant Center, Institute for Clinical and Experimental Medicine (IKEM), Prague, Czech Republic. 20 Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Italy. 21 Department of Hospital Pharmacy and Internal Medicine, Erasmus MC, the Netherlands
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Rahbar M, Poormand G, Mahmoodi MK, Jazayeri A, Jazayeri SM. Asymptomatic Epstein-Barr Virus Shedding in the Urine of Kidney Transplant Recipients: Case Reports and Review of the Literature. Infect Dis Rep 2016; 8:6817. [PMID: 28191298 PMCID: PMC5226041 DOI: 10.4081/idr.2016.6817] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Revised: 08/30/2016] [Accepted: 10/10/2016] [Indexed: 12/13/2022] Open
Abstract
Epstein-Barr virus (EBV) is associated with a wide range of malignancies and complications like post-transplant lymphoproliferative disorder (PTLD). To suppress active EBV infection in transplant recipients, who are at a heightened risk of developing PTLD, EBV DNAemia monitoring has been recommended. Quantitative multiplex real time polymerase chain reaction (QMRTPCR) offered the advantage of detection of more than one target in the same sample. We present four cases of kidney transplant recipient who were admitted for rising serum creatinine between 9 and 20 months post-transplant with a suspicion of BKV-associated nephropathy. All but one patient had unusual sonography findings in their genitourinary tracts and were positive for urinary culture for bacteria. Using a commercial QMRTPCR that could detect and quantitate BKV, EBV and cytomegalovirus simultaneously, all patients were positive for EBV in their urine for the levels between 2500 and 8×108 U/mL. None of the patients had any symptoms regarding this finding. On following up survey 3 month post discharge from hospital, all patients were negative for plasma and urine EBV. Absent of EBV DNAemia together with alternating phases of detectable EBV in urine might reflect the presence of functionally efficient central/effector memory T cells against EBV. The significance of this finding in immunocompromized patients necessitates prospective longitudinal studies.
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Affiliation(s)
| | | | - Masoud Karkhaneh Mahmoodi
- Hepatitis B Molecular Laboratory, Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Seyed Mohammad Jazayeri
- Hepatitis B Molecular Laboratory, Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
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Affiliation(s)
- Amy Tran
- In Cincinnati, Ohio, Amy Tran is an RN in the renal/transplant unit at the University of Cincinnati Medical Center and Jody Miniard is a visiting instructor at the University of Cincinnati College of Nursing
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Partners in Crime: The Role of CMV in Immune Dysregulation and Clinical Outcome During HIV Infection. Curr HIV/AIDS Rep 2016; 13:10-9. [PMID: 26810437 DOI: 10.1007/s11904-016-0297-9] [Citation(s) in RCA: 88] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
In the current era of combination antiretroviral therapy (ART), human immunodeficiency virus (HIV)-infected individuals are living longer and healthier lives. Nevertheless, HIV-infected persons are at greater risk for age-related disorders, which have been linked to residual immune dysfunction and inflammation. HIV-infected individuals are almost universally co-infected with cytomegalovirus (CMV) and both viruses are associated with inflammation-related morbidities. Therefore, a detailed investigation of the relationship between CMV and aging-related morbidities emerging during chronic HIV infection is warranted. Here, we review the literature on how CMV co-infection affects HIV infection and host immunity and we discuss the gaps in our knowledge that need elucidation.
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49
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Przybylski M, Majewska A, Dzieciatkowski T, Rusicka P, Basak GW, Nasilowska-Adamska B, Bilinski J, Jedrzejczak WW, Wroblewska M, Halaburda K, Mlynarczyk G, Tomaszewska A. Infections due to alphaherpesviruses in early post-transplant period after allogeneic haematopoietic stem cell transplantation: Results of a 5-year survey. J Clin Virol 2016; 87:67-72. [PMID: 28033514 DOI: 10.1016/j.jcv.2016.12.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2016] [Revised: 09/30/2016] [Accepted: 12/13/2016] [Indexed: 12/23/2022]
Abstract
BACKGROUND Infections caused by human α-herpesviruses usually have a benign course with recurrencies. However, they may become dangerous in immunocompromised hosts. In this case, molecular methods constitute a reliable diagnostic tool enabling rapid assessment of the efficacy of antiviral treatment strategies. OBJECTIVES We estimated the frequency of alphaherpesviral DNAemia and the viral load during early post-transplantation period after alloHSCT; we also analyzed association of the DNAemia and chosen parameters of the patients. STUDY DESIGN A cohort of 190 alloHSCT recipients from two hospitals in Warsaw, Poland, was examined weekly during 100-day early post-transplantation period using quantitative real time PCR assays. A total of 2475 sera samples were evaluated for the presence of α-herpesviral DNA in patients, of whom 117 (62%) received unrelated grafts, while the remaining 73 (38%) received grafts from sibling donors. All patients received standard antiviral prophylaxis with acyclovir. In the examined group, anti-HSV-1, anti-HSV-2 and anti-VZV IgGs were examined prior to transplantation, RESULTS: Within the study period, DNA of α-herpesviruses was detected in 44 patients (23.2%). Most patients tested positive for HSV-1 DNA (43 patients, 22.6%), single patient for HSV-2, and no patient positive for VZV. Clinical symptoms such as pneumonia, skin changes, elevated levels of aminotransferases were observed in five patients, four of these patients presented symptoms of GvHD at the same time. (2,6%). Statistics shows that GvHD (P<0.001) and matched unrelated donor as a source of HSCT (P=0.048) are associated with the development of HSV-1 DNAemia. CONCLUSIONS Although our data demonstrate frequent reactivation of HSV-1 in the early post-transplant period, the rate of symptomatic infections was low. We did not find association between HSV-1 viremia and mortality, but significant association with GvHD and donor source was observed.
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Affiliation(s)
- Maciej Przybylski
- Department of Microbiology, Independent Public Central Clinical Hospital in Warsaw, 1A Banacha Str., 02-097 Warsaw, Poland; Chair and Department of Medical Microbiology, Medical University of Warsaw, 5 Chalubinskiego Str., 02-004 Warsaw, Poland
| | - Anna Majewska
- Chair and Department of Medical Microbiology, Medical University of Warsaw, 5 Chalubinskiego Str., 02-004 Warsaw, Poland.
| | - Tomasz Dzieciatkowski
- Department of Microbiology, Independent Public Central Clinical Hospital in Warsaw, 1A Banacha Str., 02-097 Warsaw, Poland; Chair and Department of Medical Microbiology, Medical University of Warsaw, 5 Chalubinskiego Str., 02-004 Warsaw, Poland
| | - Patrycja Rusicka
- Department of Haematology, Oncology and Internal Medicine, Medical University of Warsaw, 1A Banacha Str., 02-097 Warsaw, Poland
| | - Grzegorz W Basak
- Department of Haematology, Oncology and Internal Medicine, Medical University of Warsaw, 1A Banacha Str., 02-097 Warsaw, Poland
| | - Barbara Nasilowska-Adamska
- Department of Haematopoietic Stem Cell Transplantation, Institute of Haematology and Transfusion Medicine, 14 Gandhi Str., 02-776 Warsaw, Poland
| | - Jaroslaw Bilinski
- Department of Haematology, Oncology and Internal Medicine, Medical University of Warsaw, 1A Banacha Str., 02-097 Warsaw, Poland
| | - Wieslaw W Jedrzejczak
- Department of Haematology, Oncology and Internal Medicine, Medical University of Warsaw, 1A Banacha Str., 02-097 Warsaw, Poland
| | - Marta Wroblewska
- Department of Microbiology, Independent Public Central Clinical Hospital in Warsaw, 1A Banacha Str., 02-097 Warsaw, Poland; Department of Dental Microbiology, Medical University of Warsaw, 1A Banacha Str., 02-097 Warsaw, Poland; Infection Control Unit, Institute of Haematology and Transfusion Medicine, 14 Gandhi Str., 02-776 Warsaw, Poland
| | - Kazimierz Halaburda
- Department of Haematopoietic Stem Cell Transplantation, Institute of Haematology and Transfusion Medicine, 14 Gandhi Str., 02-776 Warsaw, Poland
| | - Grazyna Mlynarczyk
- Chair and Department of Medical Microbiology, Medical University of Warsaw, 5 Chalubinskiego Str., 02-004 Warsaw, Poland
| | - Agnieszka Tomaszewska
- Department of Haematopoietic Stem Cell Transplantation, Institute of Haematology and Transfusion Medicine, 14 Gandhi Str., 02-776 Warsaw, Poland
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Abad CL, Razonable RR. Treatment of alpha and beta herpesvirus infections in solid organ transplant recipients. Expert Rev Anti Infect Ther 2016; 15:93-110. [PMID: 27911112 DOI: 10.1080/14787210.2017.1266253] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Human herpesviruses frequently cause infections in solid organ transplant (SOT) recipients. Areas covered: We provide an overview of the clinical impact of alpha and beta herpesviruses and highlight the mechanisms of action, pharmacokinetics, clinical indications, and adverse effects of antiviral drugs for the management of herpes simplex virus, varicella zoster virus and cytomegalovirus. We comprehensively evaluated key clinical trials that led to drug approval, and served as the foundation for management guidelines. We further provide an update on investigational antiviral agents for alpha and beta herpesvirus infections after SOT. Expert commentary: The therapeutic armamentarium for herpes infections is limited by the emergence of drug resistance. There have been major efforts for discovery of new drugs against these viruses, but the results of early-phase clinical trials have been less than encouraging. We believe, however, that more antiviral drug options are needed given the adverse side effects associated with current antiviral agents, and the emergence of drug-resistant virus populations in SOT recipients. Likewise, optimized use and strategies are needed for existing and novel antiviral drugs against alpha and beta-herpesviruses in SOT recipients.
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Affiliation(s)
- C L Abad
- a Division of Infectious Diseases, Department of Medicine , Mayo Clinic , Rochester , MN , USA.,b Department of Medicine, Section of Infectious Diseases , University of the Philippines - Philippine General Hospital , Manila , Philippines
| | - R R Razonable
- a Division of Infectious Diseases, Department of Medicine , Mayo Clinic , Rochester , MN , USA.,c The William J. Von Liebig Center for Transplantation and Clinical Regeneration , Mayo Clinic , Rochester , MN , USA
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