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Sommerer C, Schröter I, Gruneberg K, Schindler D, Morath C, Renders L, Einecke G, Guthoff M, Heemann U, Schnitzler P, Zeier M, Giese T. Transplant centers' prophylaxis and monitoring strategies: a key determinant of current herpes and polyomavirus incidences - results from the DZIF kidney transplant cohort. BMC Nephrol 2025; 26:218. [PMID: 40307706 PMCID: PMC12045003 DOI: 10.1186/s12882-025-04084-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Accepted: 03/19/2025] [Indexed: 05/02/2025] Open
Abstract
BACKGROUND Herpes- and polyomaviruses are major opportunistic pathogens after renal transplantation. Despite established guidelines, there is limited data on transplant centers' prophylaxis and monitoring strategies and centers' adherence to these guidelines and their impact on infection rates and patient outcomes. METHODS This multicenter cohort study, conducted by the German Center for Infection Research, included 1035 kidney transplant recipients from five centers (01/2014-02/2021), focusing on herpes- and polyomavirus viremia within the first year and adherence to prophylaxis strategies. RESULTS Among 1035 recipients, 26.6% developed herpes- or polyomavirus viremia, predominantly Cytomegalovirus (CMV, 14.3%) and BK-virus (BKV, 13.2%). BKV monitoring frequency was below guideline recommendations. Deviations from guidelines were most common in CMV D-/R- (34.6% with prophylaxis) and D-/R + groups (37.3% without prophylaxis), doubling CMV-incidence in D-/R+ (28.9% vs. 12.5%, p < 0.01). In D+/R - group, six-month-prophylaxis reduced CMV-incidence compared to three months (22.5% vs. 38.4%, p < 0.01). Breakthrough-viremia was most commonly observed in D+/R - recipients who received a six-month-prophylaxis. Overall, viremia was associated with higher incidence of acute rejection (31.9% vs. 17.6%, p < 0.01), with most CMV-viremias occurring after rejection. CMV-viremia was associated with a higher risk of bacterial infection (HR = 1.77, [1.03;3.02]). Other herpesviruses were associated with a quadrupled risk for fungal infection (HR = 4.34, [1.03;18.30]) and the non-administration of CMV-prophylaxis (HR = 0.22, [0.11;0.47]). Graft survival and mortality were unaffected within the first year. CONCLUSION Clinical variability in guideline implementation drives high herpes- and polyomavirus infection rates with suboptimal outcomes. Future guidelines should focus on differentiated risk stratification to address breakthrough, post-prophylaxis, and post-rejection CMV, and include protocols for the early detection of secondary infections.
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Affiliation(s)
- Claudia Sommerer
- Nephrology, University Hospital Heidelberg, Im Neuenheimer Feld 162, D-69120, Heidelberg, Germany.
- German Centre for Infection Research (DZIF), Heidelberg, Germany.
| | - Iris Schröter
- Nephrology, University Hospital Heidelberg, Im Neuenheimer Feld 162, D-69120, Heidelberg, Germany
- German Centre for Infection Research (DZIF), Heidelberg, Germany
| | - Katrin Gruneberg
- Nephrology, University Hospital Heidelberg, Im Neuenheimer Feld 162, D-69120, Heidelberg, Germany
- German Centre for Infection Research (DZIF), Heidelberg, Germany
| | - Daniela Schindler
- Department of Nephrology, Klinikum rechts der Isar of the Technical University Munich, Munich, Germany
- German Centre for Infection Research (DZIF), Heidelberg, Germany
| | - Christian Morath
- Nephrology, University Hospital Heidelberg, Im Neuenheimer Feld 162, D-69120, Heidelberg, Germany
- German Centre for Infection Research (DZIF), Heidelberg, Germany
| | - Lutz Renders
- Department of Nephrology, Klinikum rechts der Isar of the Technical University Munich, Munich, Germany
- German Centre for Infection Research (DZIF), Heidelberg, Germany
| | - Gunilla Einecke
- Department of Nephrology, Hannover Medical School, Hannover, Germany
- Department of Nephrology and Rheumatology, University Medical Centre Göttingen, Göttingen, Germany
| | - Martina Guthoff
- Department of Diabetology, Endocrinology, Nephrology, University Hospital Tuebingen, Tuebingen, Germany
| | - Uwe Heemann
- Department of Nephrology, Klinikum rechts der Isar of the Technical University Munich, Munich, Germany
- German Centre for Infection Research (DZIF), Heidelberg, Germany
| | - Paul Schnitzler
- Department of Infectious Diseases, University Hospital Heidelberg, Heidelberg, Germany
- German Centre for Infection Research (DZIF), Heidelberg, Germany
| | - Martin Zeier
- Nephrology, University Hospital Heidelberg, Im Neuenheimer Feld 162, D-69120, Heidelberg, Germany
- German Centre for Infection Research (DZIF), Heidelberg, Germany
| | - Thomas Giese
- Department of Immunology, University Hospital Heidelberg, Heidelberg, Germany
- German Centre for Infection Research (DZIF), Heidelberg, Germany
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Kotton CN, Kumar D, Manuel O, Chou S, Hayden RT, Danziger-Isakov L, Asberg A, Tedesco-Silva H, Humar A. The Fourth International Consensus Guidelines on the Management of Cytomegalovirus in Solid Organ Transplantation. Transplantation 2025:00007890-990000000-01056. [PMID: 40200403 DOI: 10.1097/tp.0000000000005374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/10/2025]
Affiliation(s)
- Camille N Kotton
- Transplant and Immunocompromised Host Service, Infectious Diseases Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Deepali Kumar
- Division of Infectious Diseases, Department of Medicine, Ajmera Transplant Center and University of Toronto, Toronto, ON, Canada
| | - Oriol Manuel
- Infectious Diseases Service and Transplantation Center, Lausanne University Hospital, Lausanne, Switzerland
| | - Sunwen Chou
- Division of Infectious Diseases, Oregon Health and Science University, Portland, OR
| | - Randall T Hayden
- Department of Pathology, St Jude Children's Research Hospital, Memphis, TN
| | - Lara Danziger-Isakov
- Department of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
| | - Anders Asberg
- Department of Transplantation Medicine, Oslo University Hospital, University of Oslo, Oslo, Norway
| | | | - Atul Humar
- Division of Infectious Diseases, Department of Medicine, Ajmera Transplant Center and University of Toronto, Toronto, ON, Canada
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Bethi SR, Taber DJ, Andrade E, Mesmar ZM, Calimlim I, Harris CE. Disparities in Access to Valganciclovir Cytomegalovirus Prophylaxis in High-Risk African American Kidney Transplant Patients. Transpl Infect Dis 2025; 27:e14416. [PMID: 39692584 DOI: 10.1111/tid.14416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 10/03/2024] [Accepted: 11/20/2024] [Indexed: 12/19/2024]
Abstract
BACKGROUND While access and outcomes disparities for African American (AA) kidney transplant recipients are documented, there are limited studies assessing medication access disparities in transplantation. Cytomegalovirus (CMV) causes severe complications for transplant recipients, and we aimed to understand differences in access to CMV prophylaxis valganciclovir and its impact on CMV infection rates in AA transplant recipients. METHODS This single-center, retrospective longitudinal cohort study examined high-risk (CMV serostatus D+/R-) adult kidney transplant recipients between June 1, 2010, and May 31, 202, through EMR abstraction. Standard univariate comparative statistics were employed alongside binary logistic regression for multivariable modeling. RESULTS During the 10 year period, 418 kidney transplant recipients were included, with 179 (42.8%) identified as AA and 239 as non-AA. There were significant differences in mean age (p = 0.001) and private versus Medicaid insurance status (p < 0.001). AAs experienced higher death-censored graft loss rates (10.6% AA vs. 5.0% non-AA, p = 0.031). CMV infection rate, opportunistic infection rate, leukopenia incidence, and death did not differ significantly between AA and non-AA patients. AA patients were 42% less likely to receive valganciclovir out-of-pocket cost assistance compared to non-AA patients (OR 0.58, [0.379-0.892], p = 0.013). When incorporating age, Medicaid status, and donor marginality in a multivariable model, the impact of AA race on utilizing assistance programs became statistically non-significant (OR 0.70, [0.448-1.094], p = 0.118). CONCLUSIONS AAs were significantly less likely to leverage assistance programs or utilize personal resources to access valganciclovir. This disparity was partially explained by age, insurance status, and donor type. Despite this, CMV infection rates were similar between AA and non-AA cohorts.
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Affiliation(s)
- Shipra R Bethi
- College of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
| | - David J Taber
- Department of Surgery, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Erika Andrade
- College of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Zaid M Mesmar
- Department of General Surgery, Jordan University of Science and Technology, Irbid, Jordan
| | - Isabel Calimlim
- Department of Surgery, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Courtney E Harris
- Division of Infectious Disease, Medical University of South Carolina, Charleston, South Carolina, USA
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Chung MC, Chen CH, Chang SS, Lee CY, Tian YC, Wu MY, Wang HH, Yu CC, Chen TW, Kao CC, Hsu CY, Chiang YJ, Wu MJ, Chen YT, Wu MS. Prevention and management of cytomegalovirus infection and disease in kidney transplant: A consensus statement of the Transplantation Society of Taiwan. J Formos Med Assoc 2025; 124:104-111. [PMID: 38777672 DOI: 10.1016/j.jfma.2024.05.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 03/24/2024] [Accepted: 05/14/2024] [Indexed: 05/25/2024] Open
Abstract
Kidney transplant recipients have an increased risk of cytomegalovirus (CMV) infection and disease. A strategy for mitigating the risk of CMV infection in kidney transplant recipients has not yet been established in Taiwan. The Transplantation Society of Taiwan aimed to develop a consensus by expert opinion on the prevention and management of CMV infection. Based on the results of Consensus Conference, we suggested low-dose valganciclovir prophylaxis (450 mg once daily) for kidney transplant recipients. The prophylaxis duration was ≥6 months for high-risk (D+/R-) patients and 3 months for moderate-risk (R+) patients. Even for low-risk (D-/R-) patients, prophylaxis for at least 3 months is recommended because of the high seroprevalence of CMV in Taiwan. CMV prophylaxis was suggested after anti-thymocyte globulin treatment but not after methylprednisolone pulse therapy. Routine surveillance after prophylaxis, secondary prophylaxis after CMV disease treatment, and mTOR inhibitors for primary CMV prophylaxis were not recommended. Letermovir and marabavir are emerging CMV agents used for prophylaxis and refractory CMV disease. CMV immunoglobulins have been used to treat refractory CMV disease in Taiwan. We hope this consensus will help professionals manage patients with CMV in Taiwan to improve the quality of care.
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Affiliation(s)
- Mu-Chi Chung
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taiwan; Division of Nephrology, Department of Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Cheng-Hsu Chen
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taiwan; Division of Nephrology, Department of Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; Ph.D. Program in Tissue Engineering and Regenerative Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan; Department of Life Science, Tunghai University, Taichung, Taiwan
| | - Shen-Shin Chang
- Division of Transplantation, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chih-Yuan Lee
- Department of Surgery, National Taiwan University Hospital, Taiwan
| | - Ya-Chung Tian
- Kidney Research Center and Department of Nephrology Linkou Chang Aging Memorial Hospital, Taiwan
| | - Mei-Yi Wu
- Division of Nephrology, Department of Internal Medicine, Taipei Medical University-Shuang Ho Hospital, New Taipei City, Taiwan; Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan; TMU Research Center of Urology and Kidney, Taipei Medical University, Taipei, Taiwan
| | - Hsu-Han Wang
- Department of Urology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Chia-Cheng Yu
- Division of Urology, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Teng-Wei Chen
- Division of General Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Chien-Chang Kao
- Division of Urology, Department of Surgery, Tri-service General Hospital, National Defense Medical, Taiwan
| | - Chih-Yang Hsu
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Taiwan
| | - Yang-Jen Chiang
- Department of Urology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Ming-Ju Wu
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taiwan; Division of Nephrology, Department of Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Yen-Ta Chen
- Division of Urology, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Mai-Szu Wu
- Division of Nephrology, Department of Internal Medicine, Taipei Medical University-Shuang Ho Hospital, New Taipei City, Taiwan; TMU Research Center of Urology and Kidney, Taipei Medical University, Taipei, Taiwan; Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
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Cabanilla MG, Dauenhauer A, St John B, Hill D, Larson J. Taming the transplant troll: Exploring racial and ethnic disparities in cytomegalovirus infection among kidney transplant patients. PLoS One 2025; 20:e0317383. [PMID: 39879165 PMCID: PMC11778782 DOI: 10.1371/journal.pone.0317383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Accepted: 12/26/2024] [Indexed: 01/31/2025] Open
Abstract
BACKGROUND Cytomegalovirus (CMV) infection poses a significant risk to kidney transplant recipients. This study investigated CMV disease incidence, outcomes, and management challenges in racial and ethnic minority populations following kidney transplantation. METHODS This single-center, mixed-methods study included a retrospective cohort analysis of kidney transplant recipients (n = 58) and qualitative surveys of healthcare providers. Patients were categorized as minorities (n = 49) or non-Hispanic whites (n = 9). The primary outcome was CMV disease incidence. Secondary outcomes included graft failure, mortality, and identification of management barriers. RESULTS The cumulative incidence of CMV disease was higher in minorities than in non-Hispanic whites (12.3% vs. 0%, p = 0.58), although the difference was not statistically significant. All graft failures (8.6%, n = 5) occurred in the minority group. Although not statistically significant, all-cause mortality was higher in the minority group (24.5% vs. 11.1%, p = 0.54), with 46.2% of the deaths occurring within 90 days of CMV diagnosis. Qualitative analysis revealed challenges in diagnosis, treatment-related side effects, medication costs, and insurance barriers. The providers emphasized the importance of interdisciplinary collaboration and standardized protocols. CONCLUSION While limited by the small sample size, this study highlights potential disparities in the incidence and outcomes of CMV disease among minority kidney transplant recipients, suggesting that barriers in care and access may contribute to these differences. These hypothesis-generating findings underscore the need for larger multicenter studies to validate these patterns and to inform targeted strategies that may reduce inequities in post-transplant outcomes.
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Affiliation(s)
- M. Gabriela Cabanilla
- Division of Infectious Diseases, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, United States of America
- Department of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM, United States of America
| | - Ashlee Dauenhauer
- Department of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM, United States of America
- Division of Transplant Nephrology, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, United States of America
| | - Briana St John
- Department of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM, United States of America
- Division of Transplant Nephrology, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, United States of America
| | - Deirdre Hill
- University of New Mexico School of Medicine, Albuquerque, NM, United States of America
| | - Joshua Larson
- Division of Transplant Nephrology, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, United States of America
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Vernooij RW, Michael M, Colombijn JM, Owers DS, Webster AC, Strippoli GF, Hodson EM. Pre-emptive treatment for cytomegalovirus viraemia to prevent cytomegalovirus disease in solid organ transplant recipients. Cochrane Database Syst Rev 2025; 1:CD005133. [PMID: 39807668 PMCID: PMC11729901 DOI: 10.1002/14651858.cd005133.pub4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/16/2025]
Abstract
BACKGROUND Cytomegalovirus (CMV) is a significant cause of morbidity and death in solid organ transplant recipients. Pre-emptive treatment of patients with CMV viraemia using antiviral agents has been suggested as an alternative to routine prophylaxis to prevent CMV disease. This is an update of a Cochrane review first published in 2006 and updated in 2013. OBJECTIVES To determine the benefits and harms of pre-emptive treatment of CMV viraemia to prevent CMV disease and death (any cause) and the indirect effects of CMV infection (acute rejection, graft loss, opportunistic infections) in solid organ transplant recipients. SEARCH METHODS The Cochrane Kidney and Transplant Register of Studies was searched up to 17 December 2024 using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA We included randomised controlled trials (RCTs) and quasi-RCTs comparing pre-emptive treatment with placebo, no specific treatment, or antiviral prophylaxis in solid organ transplant recipients. DATA COLLECTION AND ANALYSIS Two authors independently assessed the eligibility of the identified studies, assessed the risk of bias, and extracted all data. Results were expressed as risk ratio (RR) and 95% confidence intervals (CI) for dichotomous outcomes. Statistical analyses were performed using a random-effects model. The certainty of evidence was assessed per outcome using the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS In this update, we have included seven new studies, bringing the total number of included studies to 22 (1883 participants). Of these, seven investigated pre-emptive treatment versus placebo or standard care, 12 looked at pre-emptive treatment versus antiviral prophylaxis, one study investigated oral versus intravenous pre-emptive treatment, one investigated pre-emptive valganciclovir versus pre-emptive ganciclovir, and one investigated letermovir 40 mg twice/day versus 80 mg once/day. Studies were conducted in Australia, Brazil, the Czech Republic, Germany, Italy, Japan, Norway, Spain, South Korea, and the USA. Organ transplant recipients included kidney, liver, heart, lung, and kidney-pancreas. Thirteen studies were single-centre studies, six were multicentre, and three were unknown. The number of participants ranged from 12 to 296. Overall, selection bias was unclear (55%); performance, detection and attrition bias were high (91%, 63% and 95%, respectively), and reporting bias was low (55%). Compared with placebo or standard care, pre-emptive treatment probably reduces the risk of CMV disease (7 studies, 315 participants: RR 0.29, 95% CI 0.11 to 0.80; I2 = 54%; moderate-certainty evidence) but may result in little or no difference in death (any cause) (3 studies, 176 participants: RR 1.23, 95% CI 0.35 to 4.30; I2 = 0%; low-certainty evidence). Pre-emptive treatment may result in little or no difference in CMV organ involvement, CMV-associated symptoms, acute rejection, graft loss, other infections or leucopenia. Compared to prophylaxis, pre-emptive treatment may make little or no difference to the risk of developing CMV disease (11 studies, 1322 participants: RR 0.97, 95% CI 0.47 to 2.01; I2 = 54%; low-certainty evidence) and probably makes little or no difference to death (any cause) (9 studies, 1098 participants: RR 0.95, 95% CI 0.60 to 1.52; I2 = 0%; moderate-certainty evidence). Pre-emptive treatment may increase the risk of CMV infection (8 studies, 867 participants: RR 1.97, 95% CI 1.48 to 2.61; I2 = 66%; low-certainty evidence). The risk of leucopenia (7 studies, 869 participants: RR 0.57, 95% CI 0.38 to 0.87; I2 = 33%; moderate-certainty evidence) and neutropenia (5 studies, 859 participants: RR 0.63, 95% CI 0.44 to 0.90; I2 = 0% moderate certainty evidence) probably decreases with pre-emptive therapy. There may be little or no difference in the risks of acute rejection, graft loss, and infections other than CMV. Single studies were identified for comparisons between different pre-emptive treatments: 1) oral ganciclovir versus IV ganciclovir; 2) valganciclovir versus ganciclovir; 3) 40 mg twice/day versus 80 mg once/day. No differences between these treatment modalities in terms of CMV disease, death (any cause), or adverse events were identified. AUTHORS' CONCLUSIONS In this review, we have included seven new studies, yet the available evidence is overall of low certainty and the conclusions remain similar to the previous version of this review. Pre-emptive treatment probably reduces the risk of CMV disease compared with placebo or standard care. There were no clear differences between pre-emptive treatment and prophylaxis to prevent CMV disease or reduce the risk of death (any cause). The risk of CMV infection may be higher for patients receiving pre-emptive therapy, but the risk of adverse events, such as leucopenia, is probably lower.
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Affiliation(s)
- Robin Wm Vernooij
- Department of Nephrology and Hypertension and Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands
| | - Mini Michael
- Division of Pediatric Nephrology, Department of Pediatrics, Texas Children's Hospital/Baylor College of Medicine, Houston, TX, USA
| | - Julia Mt Colombijn
- Department of Nephrology and Hypertension and Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands
| | - Daniel S Owers
- Department of Critical Care, The Canberra Hospital, Garran, Australia
| | - Angela C Webster
- Sydney School of Public Health, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
- Westmead Applied Research Centre, The University of Sydney at Westmead, Westmead, Australia
- Department of Transplant and Renal Medicine, Westmead Hospital, Westmead, Australia
| | - Giovanni Fm Strippoli
- Department of Precision and Regenerative Medicine and Ionian Area (Dimepre-J), University of Bari, Bari, Italy
- Sydney School of Public Health, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
- Cochrane Kidney and Transplant, Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Australia
| | - Elisabeth M Hodson
- Cochrane Kidney and Transplant, Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Australia
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7
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Ruiz-Arabi E, Torre-Cisneros J, Aguilera V, Alonso R, Berenguer M, Bestard O, Bodro M, Cantisán S, Carratalà J, Castón JJ, Cordero E, Facundo C, Fariñas MC, Fernández-Alonso M, Fernández-Ruiz M, Fortún J, García-Cosío MD, Herrera S, Iturbe-Fernández D, Len O, López-Medrano F, López-Oliva MO, Los-Arcos I, Marcos MÁ, Martín-Dávila P, Monforte V, Muñoz P, Navarro D, Páez-Vega A, Pérez AB, Redondo N, Álvarez R R, Rodríguez-Benot A, Rodríguez-Goncer I, San-Juan R, Sánchez-Céspedes J, Valerio M, Vaquero JM, Viasus D, Vidal E, Aguado JM. Management of cytomegalovirus in adult solid organ transplant patients: GESITRA-IC-SEIMC, CIBERINFEC, and SET recommendations update. Transplant Rev (Orlando) 2024; 38:100875. [PMID: 39168020 DOI: 10.1016/j.trre.2024.100875] [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: 07/08/2024] [Revised: 08/02/2024] [Accepted: 08/03/2024] [Indexed: 08/23/2024]
Abstract
Cytomegalovirus (CMV) infection remains a significant challenge in solid organ transplantation (SOT). The last international consensus guidelines on the management of CMV in SOT were published in 2018, highlighting the need for revision to incorporate recent advances, notably in cell-mediated immunity monitoring, which could alter the current standard of care. A working group including members from the Group for the Study of Infection in Transplantation and the Immunocompromised Host (GESITRA-IC) of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) and the Spanish Society of Transplantation (SET), developed consensus-based recommendations for managing CMV infection in SOT recipients. Recommendations were classified based on evidence strength and quality using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. The final recommendations were endorsed through a consensus meeting and approved by the expert panel.
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Affiliation(s)
- Elisa Ruiz-Arabi
- Service of Infectious Diseases, Reina Sofia University Hospital, Maimonides Institute for Biomedical Research (IMIBIC), Cordoba, Spain
| | - Julian Torre-Cisneros
- Service of Infectious Diseases, Reina Sofia University Hospital. Maimonides Institute for Biomedical Research (IMIBIC), University of Cordoba, Córdoba, Spain; Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain.
| | - Victoria Aguilera
- Hepatology and Liver Transplantation Unit, Hospital Universitario La Fe-IIS La Fe Valencia, CiberEHD and University of Valencia, Spain
| | - Rodrigo Alonso
- Lung Transplant Unit, Pneumology Service, Instituto de Investigación Hospital 12 de Octubre (imas12), University Hospital 12 de Octubre, Madrid, Spain
| | - Marina Berenguer
- Hepatology and Liver Transplantation Unit, Hospital Universitario La Fe-IIS La Fe Valencia, CiberEHD and University of Valencia, Spain
| | - Oriol Bestard
- Department of Nephrology and Kidney Transplantation, Vall d'Hebron University Hospital-VHIR, Barcelona, Spain
| | - Marta Bodro
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain; Department of Infectious Diseases, Hospital Clinic-IDIBAPS, University of Barcelona, Spain
| | - Sara Cantisán
- Service of Infectious Diseases, Reina Sofia University Hospital. Maimonides Institute for Biomedical Research (IMIBIC), University of Cordoba, Córdoba, Spain; Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain
| | - Jordi Carratalà
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain; Department of Infectious Diseases, Bellvitge University Hospital-IDIBELL, University of Barcelona, Spain
| | - Juan José Castón
- Service of Infectious Diseases, Reina Sofia University Hospital. Maimonides Institute for Biomedical Research (IMIBIC), University of Cordoba, Córdoba, Spain; Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain
| | - Elisa Cordero
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain; Unit of Infectious Diseases, Microbiology and Parasitology, Instituto de Biomedicina de Sevilla (IBiS), Virgen del Rocío University Hospital, Junta de Andalucía, CSIC, Universidad de Sevilla, Sevilla, Spain; Departament of Medicine, Faculty of Medicine, Universidad de Sevilla, Spain
| | - Carme Facundo
- Department of Nephrology, Fundacio Puigvert, Institut de Recerca Sant Pau (IR Sant Pau), RICORS 2024 (Kidney Disease), Barcelona, Spain
| | - María Carmen Fariñas
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain; Department of Infectious Diseases, Hospital Universitario Marqués de Valdecilla-IDIVAL, Universidad de Cantabria, Santander, Spain
| | - Mirian Fernández-Alonso
- Microbiology Service, Clínica Universidad de Navarra, IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
| | - Mario Fernández-Ruiz
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain; Unit of Infectious Diseases, University Hospital "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (i+12), School of Medicine, Universidad Complutense, Madrid, Spain
| | - Jesús Fortún
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain; Service of Infectious Diseases, Ramón y Cajal University Hospital, IRYCIS, Madrid, Spain
| | - Maria Dolores García-Cosío
- Department of Cardiology, University Hospital "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (i+12), CIBERCV, Madrid, Spain
| | - Sabina Herrera
- Department of Infectious Diseases, Hospital Clinic-IDIBAPS, University of Barcelona, Spain
| | - David Iturbe-Fernández
- Department of Pneumology, University Hospital Marqués de Valdecilla-IDIVAL, Santander, Spain
| | - Oscar Len
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain; Department of Infectious Diseases, Vall d'Hebron for Solid Organ Transplantation Research Group, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Francisco López-Medrano
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain; Unit of Infectious Diseases, University Hospital "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (i+12), School of Medicine, Universidad Complutense, Madrid, Spain
| | | | - Ibai Los-Arcos
- Department of Infectious Diseases, Vall d'Hebron for Solid Organ Transplantation Research Group, Vall d'Hebron University Hospital, Barcelona, Spain
| | - María Ángeles Marcos
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain; Department of Clinical Microbiology, Hospital Clinic, University of Barcelona, ISGlobal Barcelona Institute for Global Health, Barcelona, Spain
| | - Pilar Martín-Dávila
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain; Service of Infectious Diseases, Ramón y Cajal University Hospital, IRYCIS, Madrid, Spain
| | - Víctor Monforte
- Lung Transplant Program, Department of Pulmonology, Hospital Universitari Vall d'Hebron, Barcelona, Spain; CIBER Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain
| | - Patricia Muñoz
- CIBER Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain; Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitario Gregorio Marañon, Departamento de Medicina, Universidad Complutense, Madrid, Spain
| | - David Navarro
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain; Microbiology Service, Clinic University Hospital, INCLIVA Health Research Institute, Valencia, Spain. Department of Microbiology School of Medicine, University of Valencia, Spain
| | - Aurora Páez-Vega
- Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba, Spain
| | - Ana Belén Pérez
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain; Microbiology Unit, Hospital Universitario Reina Sofía-Maimonides Institute for Biomedical Research (IMIBIC), Cordoba, Spain
| | - Natalia Redondo
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain; Unit of Infectious Diseases, University Hospital "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (i+12), School of Medicine, Universidad Complutense, Madrid, Spain
| | | | | | - Isabel Rodríguez-Goncer
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain; Unit of Infectious Diseases, University Hospital "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (i+12), School of Medicine, Universidad Complutense, Madrid, Spain
| | - Rafael San-Juan
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain; Unit of Infectious Diseases, University Hospital "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (i+12), School of Medicine, Universidad Complutense, Madrid, Spain
| | - Javier Sánchez-Céspedes
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain; Unit of Infectious Diseases, Microbiology and Parasitology, Instituto de Biomedicina de Sevilla (IBiS), Virgen del Rocío University Hospital, Junta de Andalucía, CSIC, Universidad de Sevilla, Sevilla, Spain
| | - Maricela Valerio
- CIBER Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain; Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitario Gregorio Marañon, Departamento de Medicina, Universidad Complutense, Madrid, Spain
| | - José Manuel Vaquero
- Unit of Pneumology, Thoracic Surgery, and Lung Transplant, Reina Sofía University Hospital, Cordoba, Spain
| | - Diego Viasus
- Division of Health Sciences, Faculty of Medicine, Universidad del Norte, Hospital Universidad del Norte, Barranquilla, Colombia
| | - Elisa Vidal
- Service of Infectious Diseases, Reina Sofia University Hospital. Maimonides Institute for Biomedical Research (IMIBIC), University of Cordoba, Córdoba, Spain; Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain
| | - José María Aguado
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain; Unit of Infectious Diseases, University Hospital "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (i+12), School of Medicine, Universidad Complutense, Madrid, Spain.
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8
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Villeneuve C, Rerolle JP, Couzi L, Westeel PF, Etienne I, Esposito L, Kamar N, Büchler M, Thierry A, Marquet P, Monchaud C. The Cost-effectiveness of Valganciclovir Prophylaxis Versus Preemptive Therapy in CMV R+ Kidney Transplant Recipients Over the First Year Posttransplantation. Transplant Direct 2024; 10:e1678. [PMID: 39076520 PMCID: PMC11286253 DOI: 10.1097/txd.0000000000001678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 03/27/2024] [Accepted: 03/28/2024] [Indexed: 07/31/2024] Open
Abstract
Background In kidney transplant recipients with positive serology (R+) for the cytomegalovirus (CMV), 2 strategies are used to prevent infection, whose respective advantages over the other are still debated. This study aimed to evaluate the cost-effectiveness and cost utility of antiviral prophylaxis against CMV versus preemptive therapy, considering CMV infection-free survival over the first year posttransplantation as the main clinical outcome. Methods Clinical, laboratory, and economic data were collected from 186 kidney transplant patients CMV (R+) included in the cohort study (85 patients who benefited from CMV prophylaxis and 101 from preemptive therapy). Costs were calculated from the hospital perspective and quality-adjusted life years (QALYs) using the EQ5D form. Using nonparametric bootstrapping, the incremental cost-effectiveness ratio (ICER) and cost utility were estimated (euros) for each case of infection avoided and each QALY gained for 1 y, respectively. Results Prophylaxis significantly decreased the risk of CMV infection over the first year posttransplantation (hazard ratio 0.22, 95% confidence interval = 0.12-0.37, P < 0.01). Compared with preemptive therapy, prophylaxis saved financial resources (€1155 per patient) and was more effective (0.42 infection avoided per patient), resulting in an ICER = €2769 per infection avoided. Prophylaxis resulted in a net gain of 0.046 in QALYs per patient and dominated over preemptive therapy with €1422 cost-saving for 1 QALY gained. Conclusions This study shows that CMV prophylaxis, although considered as a more expensive strategy, is more cost-effective than preemptive therapy for the prevention of CMV infections in renal transplant patients. Prophylaxis had a positive effect on quality of life at reasonable costs and resulted in net savings for the hospital.
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Affiliation(s)
- Claire Villeneuve
- Department of Pharmacology, Toxicology and Centre of Pharmacovigilance, Centre Hospitalier Universitaire (CHU) Limoges, Limoges, France
- INSERM U1248 Pharmacology and Transplantation, Limoges, France
- Fédération Hospitalo-Universitaire, SUrvival oPtimization in ORgan Transplantation, Limoges, France
| | - Jean-Phillipe Rerolle
- INSERM U1248 Pharmacology and Transplantation, Limoges, France
- Fédération Hospitalo-Universitaire, SUrvival oPtimization in ORgan Transplantation, Limoges, France
- Department of Nephrology, Dialysis and Transplantation, Limoges, France
| | - Lionel Couzi
- Department of Nephrology, Transplantation, Dialysis, CHU Pellegrin, Bordeaux, France
- CNRS-UMR 5164 Immuno ConcEpT, Bordeaux University, Bordeaux, France
| | - Pierre-Francois Westeel
- Department of Nephrology and Kidney Transplantation, University Hospital of Amiens, Amiens, France
| | - Isabelle Etienne
- Service de Nephrologie, Rouen University Hospital, Rouen, France
| | - Laure Esposito
- Department of Nephrology and Organ Transplantation, CHU Toulouse, Toulouse, France
| | - Nassim Kamar
- Department of Nephrology and Organ Transplantation, CHU Toulouse, Toulouse, France
- Université Paul Sabatier, Toulouse, France
- INSERM U1043, IFR-BMT, CHU Purpan, Toulouse, France
| | - Mathias Büchler
- Fédération Hospitalo-Universitaire, SUrvival oPtimization in ORgan Transplantation, Limoges, France
- University Hospital of Tours University Hospital of Tours, Tours, France
- François Rabelais University, EA 4245 Tours, France
| | - Antoine Thierry
- Fédération Hospitalo-Universitaire, SUrvival oPtimization in ORgan Transplantation, Limoges, France
- Department of Nephrology, Dialysis and Transplantation, CHU Poitiers, Poitiers, France
| | - Pierre Marquet
- Department of Pharmacology, Toxicology and Centre of Pharmacovigilance, Centre Hospitalier Universitaire (CHU) Limoges, Limoges, France
- INSERM U1248 Pharmacology and Transplantation, Limoges, France
- Fédération Hospitalo-Universitaire, SUrvival oPtimization in ORgan Transplantation, Limoges, France
- Faculty of Medicine, Univ Limoges, Limoges, France
| | - Caroline Monchaud
- Department of Pharmacology, Toxicology and Centre of Pharmacovigilance, Centre Hospitalier Universitaire (CHU) Limoges, Limoges, France
- INSERM U1248 Pharmacology and Transplantation, Limoges, France
- Fédération Hospitalo-Universitaire, SUrvival oPtimization in ORgan Transplantation, Limoges, France
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9
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Khawaja F, Ahmed S, Iyer SP, Sassine J, Handley G, Prakash R, VanWierren T, Jackson J, Zubovskaia A, Ramdial J, Rondon G, Patel KK, Spallone A, Ariza-Heredia EJ, Mulanovich V, Angelidakis G, Jiang Y, Chemaly RF. Cytomegaloviral Infections in Recipients of Chimeric Antigen Receptor T-Cell Therapy: An Observational Study With Focus on Oncologic Outcomes. Open Forum Infect Dis 2024; 11:ofae422. [PMID: 39086466 PMCID: PMC11289494 DOI: 10.1093/ofid/ofae422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Accepted: 07/16/2024] [Indexed: 08/02/2024] Open
Abstract
Background Patients with B-cell lymphoma and acute lymphoblastic leukemia (ALL) who receive chimeric antigen receptor T-cell (CAR-T) therapy may experience clinically significant cytomegalovirus infection (CS-CMVi). However, risk factors for CS-CMVi are not well defined. The aims of our study were to identify risk factors for CS-CMVi and the association between CS-CMVi and nonrelapse mortality (NRM) in lymphoma and ALL patients after CAR-T therapy. Methods We performed a retrospective single-center cohort analysis of CAR-T recipients between January 2018 and February 2021 for treatment of lymphoma and ALL. We collected data on demographics, oncologic history, CAR-T therapy-related complications, and infectious complications within 1 year of therapy. Results Of 230 patients identified, 22 (10%) had CS-CMVi. At 1 year following CAR-T therapy, 75 patients (33%) developed relapsed disease and 95 (41%) died; NRM at 1 year was 37%. On Cox regression analysis, Asian or Middle Eastern race (adjusted hazard ratio [aHR], 13.71 [95% confidence interval {CI}, 5.41-34.74]), treatment of cytokine release syndrome/immune effector cell-associated neurotoxicity syndrome with steroids (aHR, 6.25 [95% CI, 1.82-21.47]), lactate dehydrogenase at time of CAR-T therapy (aHR, 1.09 [95% CI, 1.02-1.16]), and CMV surveillance (aHR, 6.91 [95% CI, 2.77-17.25]) were independently associated with CS-CMVi. CS-CMVi was independently associated with NRM at 1 year after CAR-T therapy (odds ratio, 2.49 [95% CI, 1.29-4.82]). Conclusions Further studies of immunologic correlatives and clinical trials to determine the efficacy of prophylactic strategies are needed to understand the role of CS-CMVi and post-CAR-T mortality.
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Affiliation(s)
- Fareed Khawaja
- Division of Internal Medicine, Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Sairah Ahmed
- Division of Cancer Medicine, Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
- Division of Cancer Medicine, Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Swaminathan P Iyer
- Division of Cancer Medicine, Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Joseph Sassine
- Division of Internal Medicine, Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
- Infectious Diseases Section, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
| | - Guy Handley
- Division of Internal Medicine, Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
- Division of Infectious Disease and International Medicine, Department of Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA
| | - Rishab Prakash
- Division of Cancer Medicine, Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Tracy VanWierren
- Division of Internal Medicine, Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Jennifer Jackson
- Division of Internal Medicine, Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Anna Zubovskaia
- Division of Internal Medicine, Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Jeremy Ramdial
- Division of Cancer Medicine, Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Gabriela Rondon
- Division of Cancer Medicine, Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Krina K Patel
- Division of Cancer Medicine, Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Amy Spallone
- Division of Internal Medicine, Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Ella J Ariza-Heredia
- Division of Internal Medicine, Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Victor Mulanovich
- Division of Internal Medicine, Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Georgios Angelidakis
- Division of Internal Medicine, Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Ying Jiang
- Division of Internal Medicine, Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Roy F Chemaly
- Division of Internal Medicine, Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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10
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García-Campa M, Cisneros MR, Hinojosa MD, Cauich-Carrilo J, Adame-Ávila R, Reyna-Sepulveda F, Zapata-Chavira H, Escobedo-Villareal MM, Hernández-Guedea MA, Rodríguez EP, Flores-Mendoza AP. Gastrointestinal Cytomegalovirus Infection in a Transplantation Recipient With a Negative Serum Viral Load: Case Report. Transplant Proc 2024; 56:1188-1191. [PMID: 38908954 DOI: 10.1016/j.transproceed.2024.05.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Accepted: 05/10/2024] [Indexed: 06/24/2024]
Abstract
BACKGROUND Kidney transplant recipients are vulnerable to infections, especially cytomegalovirus (CMV) disease. It is recommended that clinicians plan their prophylaxis and therapeutic regimens based on viral load testing. OBJECTIVE CMV viral load monitoring testing provides useful information for identifying virologic response and possible antiviral resistance. Due to the paucity of medical literature on guiding viral therapy in cases of CMV tissue disease with nondetectable serum viral load, we intend to provide physicians with evidence on how to guide medical therapy in these cases. CASE REPORT A 49-year-old Hispanic male recipient of a kidney transplant from a cadaver donor presented to the emergency department with anorexia, asthenia, diarrhea, weight loss, and supraclavicular and mediastinal adenomegalies at 2 months post-transplantation. Both patients were serum IgG- and IgM-positive for CMV, which classified them as intermediate risk for developing CMV disease or tissue-invasive disease (donor-positive/recipient-positive [D+/R+]). The patient was induced with basiliximab and methylprednisolone and received maintenance therapy with tacrolimus, mycophenolic acid, and prednisone. Real-time polymerase chain reaction analyses were performed due to suspicion for BK virus, B19 parvovirus, Epstein-Barr virus, and CMV, with an undetectable viral load for all. A biopsy specimen taken from the gastrointestinal tract confirmed CMV infection, which was corroborated through immunocytochemistry. CONCLUSIONS Histopathologic testing is a possible option for patients with CMV tissue disease symptoms but no detectable serum viral load. Clinical observation is fundamental when viral monitoring is difficult.
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Affiliation(s)
- Mariano García-Campa
- Transplant Service, School of Medicine and University Hospital "Dr. José Eleuterio González," Autonomous University of Nuevo León, Monterrey, México
| | - Manuel Rubio Cisneros
- Transplant Service, School of Medicine and University Hospital "Dr. José Eleuterio González," Autonomous University of Nuevo León, Monterrey, México
| | - Mariana Dragustinovis Hinojosa
- Transplant Service, School of Medicine and University Hospital "Dr. José Eleuterio González," Autonomous University of Nuevo León, Monterrey, México
| | - Juan Cauich-Carrilo
- Transplant Service, School of Medicine and University Hospital "Dr. José Eleuterio González," Autonomous University of Nuevo León, Monterrey, México
| | - Rubén Adame-Ávila
- Transplant Service, School of Medicine and University Hospital "Dr. José Eleuterio González," Autonomous University of Nuevo León, Monterrey, México
| | - Francisco Reyna-Sepulveda
- Transplant Service, School of Medicine and University Hospital "Dr. José Eleuterio González," Autonomous University of Nuevo León, Monterrey, México
| | - Homero Zapata-Chavira
- Transplant Service, School of Medicine and University Hospital "Dr. José Eleuterio González," Autonomous University of Nuevo León, Monterrey, México
| | - Miguel Mariano Escobedo-Villareal
- Transplant Service, School of Medicine and University Hospital "Dr. José Eleuterio González," Autonomous University of Nuevo León, Monterrey, México
| | - Marco Antonio Hernández-Guedea
- Transplant Service, School of Medicine and University Hospital "Dr. José Eleuterio González," Autonomous University of Nuevo León, Monterrey, México
| | - Edelmiro Pérez Rodríguez
- Transplant Service, School of Medicine and University Hospital "Dr. José Eleuterio González," Autonomous University of Nuevo León, Monterrey, México
| | - Allina P Flores-Mendoza
- Transplant Service, School of Medicine and University Hospital "Dr. José Eleuterio González," Autonomous University of Nuevo León, Monterrey, México.
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11
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Vernooij RW, Michael M, Ladhani M, Webster AC, Strippoli GF, Craig JC, Hodson EM. Antiviral medications for preventing cytomegalovirus disease in solid organ transplant recipients. Cochrane Database Syst Rev 2024; 5:CD003774. [PMID: 38700045 PMCID: PMC11066972 DOI: 10.1002/14651858.cd003774.pub5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/05/2024]
Abstract
BACKGROUND The risk of cytomegalovirus (CMV) infection in solid organ transplant recipients has resulted in the frequent use of prophylaxis to prevent the clinical syndrome associated with CMV infection. This is an update of a review first published in 2005 and updated in 2008 and 2013. OBJECTIVES To determine the benefits and harms of antiviral medications to prevent CMV disease and all-cause death in solid organ transplant recipients. SEARCH METHODS We contacted the information specialist and searched the Cochrane Kidney and Transplant Register of Studies up to 5 February 2024 using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA We included randomised controlled trials (RCTs) and quasi-RCTs comparing antiviral medications with placebo or no treatment, comparing different antiviral medications or different regimens of the same antiviral medications for CMV prophylaxis in recipients of any solid organ transplant. Studies examining pre-emptive therapy for CMV infection are studied in a separate review and were excluded from this review. DATA COLLECTION AND ANALYSIS Two authors independently assessed study eligibility, risk of bias and extracted data. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) and 95% CI for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS This 2024 update found four new studies, bringing the total number of included studies to 41 (5054 participants). The risk of bias was high or unclear across most studies, with a low risk of bias for sequence generation (12), allocation concealment (12), blinding (11) and selective outcome reporting (9) in fewer studies. There is high-certainty evidence that prophylaxis with aciclovir, ganciclovir or valaciclovir compared with placebo or no treatment is more effective in preventing CMV disease (19 studies: RR 0.42, 95% CI 0.34 to 0.52), all-cause death (17 studies: RR 0.63, 95% CI 0.43 to 0.92), and CMV infection (17 studies: RR 0.61, 95% CI 0.48 to 0.77). There is moderate-certainty evidence that prophylaxis probably reduces death from CMV disease (7 studies: RR 0.26, 95% CI 0.08 to 0.78). Prophylaxis reduces the risk of herpes simplex and herpes zoster disease, bacterial and protozoal infections but probably makes little to no difference to fungal infection, acute rejection or graft loss. No apparent differences in adverse events with aciclovir, ganciclovir or valaciclovir compared with placebo or no treatment were found. There is high certainty evidence that ganciclovir, when compared with aciclovir, is more effective in preventing CMV disease (7 studies: RR 0.37, 95% CI 0.23 to 0.60). There may be little to no difference in any outcome between valganciclovir and IV ganciclovir compared with oral ganciclovir (low certainty evidence). The efficacy and adverse effects of valganciclovir or ganciclovir were probably no different to valaciclovir in three studies (moderate certainty evidence). There is moderate certainty evidence that extended duration prophylaxis probably reduces the risk of CMV disease compared with three months of therapy (2 studies: RR 0.20, 95% CI 0.12 to 0.35), with probably little to no difference in rates of adverse events. Low certainty evidence suggests that 450 mg/day valganciclovir compared with 900 mg/day valganciclovir results in little to no difference in all-cause death, CMV infection, acute rejection, and graft loss (no information on adverse events). Maribavir may increase CMV infection compared with ganciclovir (1 study: RR 1.34, 95% CI: 1.10 to 1.65; moderate certainty evidence); however, little to no difference between the two treatments were found for CMV disease, all-cause death, acute rejection, and adverse events at six months (low certainty evidence). AUTHORS' CONCLUSIONS Prophylaxis with antiviral medications reduces CMV disease and CMV-associated death, compared with placebo or no treatment, in solid organ transplant recipients. These data support the continued routine use of antiviral prophylaxis in CMV-positive recipients and CMV-negative recipients of CMV-positive organ transplants.
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Affiliation(s)
- Robin Wm Vernooij
- Department of Nephrology and Hypertension and Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands
| | - Mini Michael
- Division of Pediatric Nephrology, Baylor College of Medicine, Houston, TX, USA
| | - Maleeka Ladhani
- Nephrology, Lyell McEwin Hospital, Elizabeth Vale, Australia
| | - Angela C Webster
- Sydney School of Public Health, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
- NHMRC Clinical Trials Centre, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
- Westmead Applied Research Centre, The University of Sydney at Westmead, Westmead, Australia
- Centre for Transplant and Renal Medicine, Westmead Millennium Institute, The University of Sydney at Westmead, Westmead, Australia
| | - Giovanni Fm Strippoli
- Sydney School of Public Health, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
- Cochrane Kidney and Transplant, Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Australia
| | - Jonathan C Craig
- Cochrane Kidney and Transplant, Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Australia
- College of Medicine and Public Health, Flinders University, Adelaide, Australia
| | - Elisabeth M Hodson
- Sydney School of Public Health, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
- Cochrane Kidney and Transplant, Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Australia
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12
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Dettori M, Riccardi N, Canetti D, Antonello RM, Piana AF, Palmieri A, Castiglia P, Azara AA, Masia MD, Porcu A, Ginesu GC, Cossu ML, Conti M, Pirina P, Fois A, Maida I, Madeddu G, Babudieri S, Saderi L, Sotgiu G. Infections in lung transplanted patients: A review. Pulmonology 2024; 30:287-304. [PMID: 35710714 DOI: 10.1016/j.pulmoe.2022.04.010] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Revised: 03/29/2022] [Accepted: 04/25/2022] [Indexed: 02/07/2023] Open
Abstract
Lung transplantation can improve the survival of patients with severe chronic pulmonary disorders. However, the short- and long-term risk of infections can increase morbidity and mortality rates. A non-systematic review was performed to provide the most updated information on pathogen, host, and environment-related factors associated with the occurrence of bacterial, fungal, and viral infections as well as the most appropriate therapeutic options. Bacterial infections account for about 50% of all infectious diseases in lung transplanted patients, while viruses represent the second cause of infection accounting for one third of all infections. Almost 10% of patients develop invasive fungal infections during the first year after lung transplant. Pre-transplantation comorbidities, disruption of physical barriers during the surgery, and exposure to nosocomial pathogens during the hospital stay are directly associated with the occurrence of life-threatening infections. Empiric antimicrobial treatment after the assessment of individual risk factors, local epidemiology of drug-resistant pathogens and possible drug-drug interactions can improve the clinical outcomes.
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Affiliation(s)
- M Dettori
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy
| | - N Riccardi
- StopTB Italia Onlus, Milan, Italy; Department of Clinical and Experimental Medicine, University of Pisa, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy
| | - D Canetti
- StopTB Italia Onlus, Milan, Italy; Department of Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - R M Antonello
- Clinical Department of Medical, Surgical and Health Sciences, Trieste University, Trieste, Italy
| | - A F Piana
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy
| | - A Palmieri
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy
| | - P Castiglia
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy
| | - A A Azara
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy
| | - M D Masia
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy
| | - A Porcu
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy
| | - G C Ginesu
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy
| | - M L Cossu
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy
| | - M Conti
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy
| | - P Pirina
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy
| | - A Fois
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy
| | - I Maida
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy
| | - G Madeddu
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy
| | - S Babudieri
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy
| | - L Saderi
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy
| | - G Sotgiu
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy; StopTB Italia Onlus, Milan, Italy.
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13
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Huh K, Lee SO, Kim J, Lee SJ, Choe PG, Kang JM, Yang J, Sung H, Kim SH, Moon C, Seok H, Shi HJ, Wi YM, Jeong SJ, Park WB, Kim YJ, Kim J, Ahn HJ, Kim NJ, Peck KR, Kim MS, Kim SI. Prevention of Cytomegalovirus Infection in Solid Organ Transplant Recipients: Guidelines by the Korean Society of Infectious Diseases and the Korean Society for Transplantation. Infect Chemother 2024; 56:101-121. [PMID: 38527780 PMCID: PMC10990892 DOI: 10.3947/ic.2024.0016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Accepted: 03/04/2024] [Indexed: 03/27/2024] Open
Abstract
Cytomegalovirus (CMV) is the most important opportunistic viral pathogen in solid organ transplant (SOT) recipients. The Korean guideline for the prevention of CMV infection in SOT recipients was developed jointly by the Korean Society for Infectious Diseases and the Korean Society of Transplantation. CMV serostatus of both donors and recipients should be screened before transplantation to best assess the risk of CMV infection after SOT. Seronegative recipients receiving organs from seropositive donors face the highest risk, followed by seropositive recipients. Either antiviral prophylaxis or preemptive therapy can be used to prevent CMV infection. While both strategies have been demonstrated to prevent CMV infection post-transplant, each has its own advantages and disadvantages. CMV serostatus, transplant organ, other risk factors, and practical issues should be considered for the selection of preventive measures. There is no universal viral load threshold to guide treatment in preemptive therapy. Each institution should define and validate its own threshold. Valganciclovir is the favored agent for both prophylaxis and preemptive therapy. The evaluation of CMV-specific cell-mediated immunity and the monitoring of viral load kinetics are gaining interest, but there was insufficient evidence to issue recommendations. Specific considerations on pediatric transplant recipients are included.
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Affiliation(s)
- Kyungmin Huh
- Division of Infectious Diseases, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sang-Oh Lee
- Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
| | - Jungok Kim
- Division of Infectious Diseases, Department of Medicine, Chungnam National University School of Medicine, Daejeon, Korea
| | - Su Jin Lee
- Division of Infectious Diseases, Department of Internal Medicine, Pusan National University School of Medicine, Yangsan, Korea
| | - Pyoeng Gyun Choe
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Ji-Man Kang
- Department of Pediatrics, Severance Children's Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Jaeseok Yang
- Department of Internal Medicine, Yonsei University College of Medicine, Severance Hospital, Seoul, Korea
| | - Heungsup Sung
- Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Si-Ho Kim
- Division of Infectious Diseases, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea
| | - Chisook Moon
- Division of Infectious Diseases, Department of Internal Medicine, Inje University Busan Paik Hospital, College of Medicine, Busan, Korea
| | - Hyeri Seok
- Division of Infectious Diseases, Department of Internal Medicine, Korea University Ansan Hospital, Korea University Medicine, Ansan, Korea
| | - Hye Jin Shi
- Division of Infectious Diseases, Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon, Korea
| | - Yu Mi Wi
- Division of Infectious Diseases, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea
| | - Su Jin Jeong
- Division of Infectious Diseases, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Wan Beom Park
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Youn Jeong Kim
- Division of Infectious Diseases, Department of Internal Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Incheon, Korea
| | - Jongman Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hyung Joon Ahn
- Department of Surgery, College of Medicine, Kyung Hee University, Seoul, Korea
| | - Nam Joong Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Kyong Ran Peck
- Division of Infectious Diseases, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Myoung Soo Kim
- Department of Surgery, The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, Korea
| | - Sang Il Kim
- Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
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14
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Kotton CN, Torre-Cisneros J, Yakoub-Agha I. Slaying the "Troll of Transplantation"-new frontiers in cytomegalovirus management: A report from the CMV International Symposium 2023. Transpl Infect Dis 2024; 26:e14183. [PMID: 37942955 DOI: 10.1111/tid.14183] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Accepted: 10/15/2023] [Indexed: 11/10/2023]
Abstract
The 2023 International CMV Symposium took place in Barcelona in May 2023. During the 2-day meeting, delegates and faculty discussed the ongoing challenge of managing the risk of cytomegalovirus infection (the Troll of Transplantation) after solid organ or hematopoietic cell transplantation. Opportunities to improve outcomes of transplant recipients by applying advances in antiviral prophylaxis or pre-emptive therapy, immunotherapy, and monitoring of cell-mediated immunity to routine clinical practice were debated and relevant educational clinical cases presented. This review summarizes the presentations, cases, and discussions from the meeting and describes how further advances are needed before the Troll of Transplantation is slain.
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Affiliation(s)
- Camille N Kotton
- Transplant and Immunocompromised Host Infectious Diseases, Infectious Diseases Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Julian Torre-Cisneros
- Maimónides Institute for Biomedical Research of Cordoba (IMIBIC)/Reina Sofía University Hospital/University of Cordoba (UCO), Cordoba, Spain
- CIBERINFEC, ISCIII - CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain
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15
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Farkas K, Varga M, Dinnyes I, Rem L, Telkes G, Wagner L, Remport A, Piros L, Szijarto A, Huszty G. Low-Dose vs Standard-Dose Valganciclovir for Cytomegalovirus Prophylaxis After Kidney Transplantation: A Single-Center Retrospective Analysis. Transplant Proc 2024; 56:105-110. [PMID: 38199858 DOI: 10.1016/j.transproceed.2023.11.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Accepted: 11/30/2023] [Indexed: 01/12/2024]
Abstract
BACKGROUND Prophylactic administration of valganciclovir (VG) is an accepted method for the prevention of cytomegalovirus (CMV) infection after kidney transplantation (KTx). The standard dosage of oral VG is 900 mg/day, adjusted to renal function. There is growing evidence that low-dose 450 mg/day VG might be safe and effective. We compared low-dose vs standard-dose prophylaxis after KTx in a single-center follow-up study. METHODS Data from 603 renal transplantations at a single center were retrospectively analyzed (2011-2014, 12-month follow-up). Recipients with donor IgG positive-recipient IgG positive (D+/R+), (D+/R-), and (D-/R+) CMV serostatus were routinely treated with 450 mg/day VG for 3 months. Based on the same prophylactic dose, patients could be categorized into two groups according to their postoperative renal function: those receiving standard-dose VG due to a lower estimated glomerular filtration rate (eGFR) (average eGFR<60 mL/min/1.73 m2) and those receiving low-dose VG due to higher eGFR (average eGFR>60 mL/min/1.73 m2). RESULTS Estimated glomerular filtration rate-based VG serum alterations significantly affected the risk of CMV infection with a higher incidence in higher VG levels (standard-dose: 357 patients, CMV: 33 cases (9.2 %); low-dose: 246 patients, CMV: 10 cases (4.1%). The occurrence of known risk factors: serologic risk distribution and rate of induction therapy were not statistically different between the 2 groups. Treatment of an acute rejection episode influenced the infection rate significantly in the standard-dose group. As a side effect of prophylaxis, leucopenia (<3G/L) was 2.46 times higher in standard-dose vs low-dose group. CONCLUSION Low-dose VG administration is safe and non-inferior to the standard dose in the prophylaxis of CMV infection after KTx.
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Affiliation(s)
- Katalin Farkas
- Department of Surgery, Transplantation and Gastroenterology, Semmelweis University, Budapest, Hungary
| | - Marina Varga
- Department of Laboratory Medicine, Semmelweis University, Faculty of Medicine, Budapest, Hungary
| | - Izabella Dinnyes
- Department of Surgery, Transplantation and Gastroenterology, Semmelweis University, Budapest, Hungary
| | - Lili Rem
- Department of Surgery, Transplantation and Gastroenterology, Semmelweis University, Budapest, Hungary
| | - Gabor Telkes
- Department of Surgery, Transplantation and Gastroenterology, Semmelweis University, Budapest, Hungary
| | - Laszlo Wagner
- Department of Surgery, Transplantation and Gastroenterology, Semmelweis University, Budapest, Hungary
| | - Adam Remport
- Department of Surgery, Transplantation and Gastroenterology, Semmelweis University, Budapest, Hungary
| | - Laszlo Piros
- Department of Surgery, Transplantation and Gastroenterology, Semmelweis University, Budapest, Hungary
| | - Attila Szijarto
- Department of Surgery, Transplantation and Gastroenterology, Semmelweis University, Budapest, Hungary
| | - Gergely Huszty
- Department of Surgery, Transplantation and Gastroenterology, Semmelweis University, Budapest, Hungary.
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16
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Romao EA, Yamamoto AY, Gaspar GG, Garcia TMP, Muglia VA, Nardin MEP, Molina CAF, de Figueiredo VCTP, Moyses-Neto M. Significant Increase in Cytomegalovirus (CMV) Infection in Solid Organ Transplants Associated With Increased Use of Thymoglobulin as Induction Therapy? Transplant Proc 2023; 55:2035-2040. [PMID: 37778934 DOI: 10.1016/j.transproceed.2023.08.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 07/06/2023] [Accepted: 08/04/2023] [Indexed: 10/03/2023]
Abstract
BACKGROUND Cytomegalovirus (CMV) infection remains one of the most common viral pathogens affecting solid organ transplants (SOT). In 10 years of following the outcome of transplants, we noticed an increased incidence of CMV infection, along with increased use of rabbit anti-thymocyte globulin (rATG). The study aims to assess the incidence of active CMV infection and disease, response to treatment, and recurrence in a cohort of SOT. Furthermore, we look for correlating the CMV incidence with the type of induction therapy: r-ATG or interleukin 2 receptor-blocking antibody (basiliximab). METHODS This was a single-center, retrospective 10-year study in patients submitted to kidney, kidney-liver, and kidney-pancreas transplants who used a preemptive therapy protocol for CMV. RESULTS Among the 476 enrolled transplant recipients, 306 (64.2 %) had at least one episode of CMV infection (replication), and 71/306 patients (23.2 %) presented CMV-related disease. The most frequent clinical conditions associated with CMV disease were gastrointestinal. Among the 476 transplant patients, 333 received immunosuppressive induction with rATG (69.9 %); 140 (29.4 %) received induction with interleukin 2 receptor-blocking antibody (basiliximab). The initial maintenance immunosuppressive therapy in the patients who presented CMV infection was primarily performed with prednisone, tacrolimus, and sodium mycophenolate (91.7 %). The induction with rATG increased from 35.2%-94.6% in 10 years. The incidence of CMV infection was 20.7 % in the first year of observation and gradually increased to 87.3 % in the last year. CONCLUSIONS The data suggest that the increase in the use of rATG in recent years could be responsible for the very expressive increase in the incidence of CMV infection/disease.
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Affiliation(s)
- Elen Almeida Romao
- Division of Nephrology, School of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil
| | - Aparecida Yulie Yamamoto
- Clinical Virology Laboratory, Hospital das Clinicas, School of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil
| | - Gilberto Gambero Gaspar
- Division Of Infectious Disease, School of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil
| | - Tania Marisa Pisi Garcia
- Division of Nephrology, School of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil
| | - Valmir Aparecido Muglia
- Division of Nephrology, School of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil
| | - Maria Estela Papini Nardin
- Division of Nephrology, School of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil
| | | | | | - Miguel Moyses-Neto
- Division of Nephrology, School of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil.
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17
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Blom KB, Birkeland GK, Midtvedt K, Jenssen TG, Reisæter AV, Rollag H, Hartmann A, Sagedal S, Sjaastad I, Tylden G, Njølstad G, Nilsen E, Christensen A, Åsberg A, Birkeland JA. Cytomegalovirus High-risk Kidney Transplant Recipients Show No Difference in Long-term Outcomes Following Preemptive Versus Prophylactic Management. Transplantation 2023; 107:1846-1853. [PMID: 37211633 PMCID: PMC10358437 DOI: 10.1097/tp.0000000000004615] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 12/23/2022] [Accepted: 01/09/2023] [Indexed: 05/23/2023]
Abstract
BACKGROUND Following kidney transplantation (KT), cytomegalovirus (CMV) infection remains an important challenge. Both prophylactic and preemptive antiviral protocols are used for CMV high-risk kidney recipients (donor seropositive/recipient seronegative; D+/R-). We performed a nationwide comparison of the 2 strategies in de novo D+/R- KT recipients accessing long-term outcomes. METHODS A nationwide retrospective study was conducted from 2007 to 2018, with follow-up until February 1, 2022. All adult D+/R- and R+ KT recipients were included. During the first 4 y, D+/R- recipients were managed preemptively, changing to 6 mo of valganciclovir prophylaxis from 2011. To adjust for the 2 time eras, de novo intermediate-risk (R+) recipients, who received preemptive CMV therapy throughout the study period, served as longitudinal controls for possible confounders. RESULTS A total of 2198 KT recipients (D+/R-, n = 428; R+, n = 1770) were included with a median follow-up of 9.4 (range, 3.1-15.1) y. As expected, a greater proportion experienced a CMV infection in the preemptive era compared with the prophylactic era and with a shorter time from KT to CMV infection ( P < 0.001). However, there were no differences in long-term outcomes such as patient death (47/146 [32%] versus 57/282 [20%]; P = 0.3), graft loss (64/146 [44%] versus 71/282 [25%]; P = 0.5), or death censored graft loss (26/146 [18%] versus 26/282 [9%]; P = 0.9) in the preemptive versus prophylactic era. Long-term outcomes in R+ recipients showed no signs of sequential era-related bias. CONCLUSIONS There were no significant differences in relevant long-term outcomes between preemptive and prophylactic CMV-preventive strategies in D+/R- kidney transplant recipients.
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Affiliation(s)
- Kjersti B. Blom
- Department of Nephrology, Oslo University Hospital, Ullevål, Oslo, Norway
- Institute for Experimental Medical Research, KG Jebsen Center for Cardiac Research, Oslo University Hospital, Ullevål and University of Oslo, Oslo, Norway
- Faculty of Medicine, University of Oslo, Oslo, Norway
| | | | - Karsten Midtvedt
- Department of Transplantation Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Trond G. Jenssen
- Department of Transplantation Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Anna V. Reisæter
- Department of Transplantation Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Halvor Rollag
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Anders Hartmann
- Department of Transplantation Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Solbjørg Sagedal
- Department of Nephrology, Oslo University Hospital, Ullevål, Oslo, Norway
| | - Ivar Sjaastad
- Institute for Experimental Medical Research, KG Jebsen Center for Cardiac Research, Oslo University Hospital, Ullevål and University of Oslo, Oslo, Norway
| | - Garth Tylden
- Department of Microbiology and Infection Control, University Hospital of North Norway, Tromsø, Norway
| | - Gro Njølstad
- Department of Microbiology, Haukeland University Hospital, Bergen, Norway
| | - Einar Nilsen
- Department of Microbiology, Møre and Romsdal Hospital Trust, Molde, Norway
| | - Andreas Christensen
- Department of Medical Microbiology, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
| | - Anders Åsberg
- Department of Transplantation Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- The Norwegian Renal Registry, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Department of Pharmacy, University of Oslo, Oslo, Norway
| | - Jon A. Birkeland
- Department of Nephrology, Oslo University Hospital, Ullevål, Oslo, Norway
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18
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Li QY, van den Anker J, Wu YE, Hao GX, Zhao W. Optimizing ganciclovir and valganciclovir dosing regimens in pediatric patients with cytomegalovirus infection: a spotlight on therapeutic drug monitoring. Expert Rev Clin Pharmacol 2023; 16:727-739. [PMID: 36794592 DOI: 10.1080/17512433.2023.2181161] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Accepted: 02/13/2023] [Indexed: 02/17/2023]
Abstract
INTRODUCTION Infants and immunocompromised children with cytomegalovirus (CMV) infection have significant morbidity and mortality. Ganciclovir (GCV) and its oral prodrug valganciclovir (VGCV) are the major antiviral options of choice for the prophylaxis and treatment of CMV infection. However, with the currently recommended dosing regimens used in pediatric patients, large intra- and inter-individual variability of pharmacokinetic (PK) parameters and exposure are observed. AREAS COVERED This review describes the PK and pharmacodynamic (PD) characteristics of GCV and VGCV in pediatrics. Moreover, the role of therapeutic drug monitoring (TDM) and current clinical practice for GCV and VGCV dosing regimens optimization in pediatrics are discussed. EXPERT OPINION GCV/VGCV TDM has shown the potential value to improve the benefit/risk ratio in pediatrics when using the therapeutic ranges derived from adults. However, well-designed studies are required to evaluate the relationship of TDM with clinical outcomes. Furthermore, studies to explore the children-specific dose-response-effect relationships will be helpful to facilitate the TDM practice. In the clinical setting, optimal sampling methods such as limited sampling strategies for pediatrics can be used in TDM and intracellular ganciclovir triphosphate may be used as an alternative TDM marker.
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Affiliation(s)
- Qiu-Yue Li
- Department of Clinical Pharmacy, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - John van den Anker
- Division of Clinical Pharmacology, Children's National Medical Center, Washington, DC, USA
- Departments of Pediatrics, Pharmacology & Physiology, George Washington University, School of Medicine and Health Sciences, Washington, DC, USA
- Department of Paediatric Pharmacology and Pharmacometrics, University Children's Hospital Basel, Basel, Switzerland
| | - Yue-E Wu
- Department of Clinical Pharmacy, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Guo-Xiang Hao
- Department of Clinical Pharmacy, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Wei Zhao
- Department of Clinical Pharmacy, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
- NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Qilu Hospital of Shandong University, Shandong University, Jinan, China
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19
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Amorim S, Araújo P, Pinto R, Medas R, Pereira P, Lopes J, Santos L, Pinheiro-Torres J, Macedo F, Pinho P. An Unexpected Cause of Acute Abdomen Late After Heart Transplantation-A Case Report. Transplant Proc 2023; 55:1451-1453. [PMID: 37045702 DOI: 10.1016/j.transproceed.2023.03.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Accepted: 03/13/2023] [Indexed: 04/14/2023]
Abstract
Cytomegalovirus (CMV) infection is a frequent complication after a solid organ transplant, and in 86% of the cases, CMV disease occurred during the first 6 months after transplantation. Invasive CMV infections may be present as ulcerative infections of the upper gastrointestinal tract with esophagitis, gastritis, and ulcerations of the duodenum and the small bowel; however, CMV infections of the pancreatobiliary system, especially papillitis, are rarely observed. We present a case report of a man who underwent a heart transplant 6 years before, with a clinical picture of duodenitis and a simultaneous pseudotumor of major duodenal papilla who developed signs of acute abdomen caused by gastrointestinal CMV infection, successfully treated with medical therapy with valganciclovir. There is an urgent need for developments in CMV and solid organ transplantation to stratify the risk of late-onset CMV disease.
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Affiliation(s)
- Sandra Amorim
- Cardiology Department, Centro Hospitalar Universitário São João, Porto, Portugal.
| | - Paulo Araújo
- Cardiology Department, Centro Hospitalar Universitário São João, Porto, Portugal
| | - Roberto Pinto
- Cardiology Department, Centro Hospitalar Universitário São João, Porto, Portugal
| | - Renato Medas
- Gastroenterology Department, Centro Hospitalar Universitário São João, Porto, Portugal
| | - Pedro Pereira
- Gastroenterology Department, Centro Hospitalar Universitário São João, Porto, Portugal
| | - Joanne Lopes
- Pathological Anatomy Department, Centro Hospitalar Universitário São João, Porto, Portugal
| | - Lurdes Santos
- Infectious Diseases Department, Centro Hospitalar Universitário São João, Porto, Portugal
| | - J Pinheiro-Torres
- Cardiothoracic Surgery Department, Centro Hospitalar Universitário São João, Porto, Portugal
| | - Filipe Macedo
- Cardiology Department, Centro Hospitalar Universitário São João, Porto, Portugal
| | - Paulo Pinho
- Cardiothoracic Surgery Department, Centro Hospitalar Universitário São João, Porto, Portugal
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20
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Gardiner BJ, Bailey JP, Percival MA, Morgan BA, Warner VM, Lee SJ, Morrissey CO, Kaye DM, Peleg AY, Taylor AJ. Incidence and severity of cytomegalovirus infection in seropositive heart transplant recipients. Clin Transplant 2023; 37:e14982. [PMID: 36988473 PMCID: PMC10909407 DOI: 10.1111/ctr.14982] [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: 02/15/2023] [Revised: 03/07/2023] [Accepted: 03/16/2023] [Indexed: 03/30/2023]
Abstract
BACKGROUND The frequency and significance of cytomegalovirus (CMV) infection in seropositive (R+) heart transplant recipients (HTR) is unclear, with preventative recommendations mostly extrapolated from other groups. We evaluated the incidence and severity of CMV infection in R+ HTR, to identify risk factors and describe outcomes. METHODS R+ HTR from 2010 to 2019 were included. Antiviral prophylaxis was not routinely used, with clinically guided monitoring the local standard of care. The primary outcome was CMV infection within one-year post-transplant; secondary outcomes included other herpesvirus infections and mortality. RESULTS CMV infection occurred in 27/155 (17%) R+ HTR. Patients with CMV had a longer hospitalization (27 vs. 20 days, unadjusted HR 1.02, 95% CI 1.00-1.02, p = .01), higher rate of intensive care readmission (26% vs. 9%, unadjusted HR 3.46, 1.46-8.20, p = .005), and increased mortality (33% vs. 8%, unadjusted HR 10.60, 4.52-24.88, p < .001). The association between CMV and death persisted after adjusting for multiple confounders (HR 24.19, 95% CI 7.47-78.30, p < .001). Valganciclovir prophylaxis was used in 35/155 (23%) and was protective against CMV (infection rate 4% vs. 27%, adjusted HR .07, .01-.72, p = .025), even though those receiving it were more likely to have received thymoglobulin (adjusted OR 10.5, 95% CI 2.01-55.0, p = .005). CONCLUSIONS CMV infection is common in R+ HTR and is associated with a high burden of disease and increased mortality. Patients who received valganciclovir prophylaxis were less likely to develop CMV infection, despite being at higher risk. These findings support the routine use of antiviral prophylaxis following heart transplantation in all CMV R+ patients.
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Affiliation(s)
- Bradley J. Gardiner
- Department of Infectious DiseasesAlfred Health and Central Clinical SchoolMonash UniversityMelbourneVictoriaAustralia
| | | | | | - Beth A. Morgan
- Department of Infectious DiseasesAlfred Health and Central Clinical SchoolMonash UniversityMelbourneVictoriaAustralia
| | - Victoria M. Warner
- Pharmacy DepartmentAlfred HealthMelbourneVictoriaAustralia
- Department of CardiologyAlfred HealthMelbourneVictoriaAustralia
| | - Sue J. Lee
- Department of Infectious DiseasesAlfred Health and Central Clinical SchoolMonash UniversityMelbourneVictoriaAustralia
| | - C. Orla Morrissey
- Department of Infectious DiseasesAlfred Health and Central Clinical SchoolMonash UniversityMelbourneVictoriaAustralia
| | - David M. Kaye
- Department of CardiologyAlfred HealthMelbourneVictoriaAustralia
- Department of MedicineMonash UniversityMelbourneAustralia
- Baker Heart & Diabetes InstituteMelbourneAustralia
| | - Anton Y. Peleg
- Department of Infectious DiseasesAlfred Health and Central Clinical SchoolMonash UniversityMelbourneVictoriaAustralia
- Department of MicrobiologyBiomedicine Discovery InstituteMonash UniversityClaytonVictoriaAustralia
| | - Andrew J. Taylor
- Department of CardiologyAlfred HealthMelbourneVictoriaAustralia
- Department of MedicineMonash UniversityMelbourneAustralia
- Baker Heart & Diabetes InstituteMelbourneAustralia
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21
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Montero C, Yomayusa N, Torres R, Cortes J, Alvarez C, Gallo J, Aldana G, Acevedo A, Rios M, Echeverri J, Yepes Z, Silva A, Gayon D, Perez J, Ibanez M. Low dose thymoglobulin versus basiliximab in cytomegalovirus positive kidney transplant recipients: Effectiveness of preemptive cytomegalovirus modified strategy. Nefrologia 2022:S2013-2514(22)00143-2. [PMID: 36437203 DOI: 10.1016/j.nefroe.2022.11.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 10/06/2021] [Indexed: 06/16/2023] Open
Abstract
BACKGROUND We performed a retrospective trial to determine asymptomatic CMV reactivation and CMV disease in kidney allograft recipients with positive CMV serostatus. METHODS Preemptive modified strategy under low dose thymoglobulin versus basiliximab induction was evaluated. Patients were monitored by CMV-polymerase chain reaction (PCR); if the viral load was >4000copies/μl, they received valganciclovir adjusted for their renal function. RESULTS 132 recipients were included in the study, 84 and 48 receiving basiliximab and thymoglobulin induction respectively, and followed up for 12 months. Asymptomatic CMV reactivation was significantly higher for thymoglobulin (77.1% vs. 16.7%, p<0.001). Treatment groups had similar rates of CMV disease (3.6% vs. 2.1%, p 0.538). The significant difference in asymptomatic CMV reactivation between two treatment groups did not have any impact on 1 year graft function (71±26ml/min vs. 74±19ml/min; p=0.475) and no histological differences in protocol biopsies were observed among patients with asymptomatic CMV reactivation vs those without CMV reactivation. CONCLUSIONS Due to the high asymptomatic CMV reactivation incidence in patients who received thymoglobulin induction, our results suggest that valganciclovir prophylaxis may be advantageous in CMV seropositive renal transplant recipients after low dose thymoglobulin induction. A preemptive strategy appeared to significantly reduce the likelihood of CMV disease in both groups. Rejection risk and negative impact in renal function associated with asymptomatic CMV reactivation was not found in our series.
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Affiliation(s)
- Camilo Montero
- Renal Transplantation Group, Clinica Reina Sofia, University Clinic, Bogota, Colombia; Translational Investigation Group, Sanitas University, Clinica Colsanitas, Bogota, Colombia.
| | - Nancy Yomayusa
- Renal Transplantation Group, Clinica Reina Sofia, University Clinic, Bogota, Colombia; Translational Investigation Group, Sanitas University, Clinica Colsanitas, Bogota, Colombia; Infectious Diseases Department, Clinica Colsanitas, Bogota, Colombia
| | - Rodolfo Torres
- Renal Transplantation Group, Clinica Reina Sofia, University Clinic, Bogota, Colombia; Translational Investigation Group, Sanitas University, Clinica Colsanitas, Bogota, Colombia
| | - Jorge Cortes
- Facultad de Medicina, Universidad Nacional de Colombia
| | - Carlos Alvarez
- Translational Investigation Group, Sanitas University, Clinica Colsanitas, Bogota, Colombia; Infectious Diseases Department, Clinica Colsanitas, Bogota, Colombia
| | - Juan Gallo
- Renal Transplantation Group, Clinica Reina Sofia, University Clinic, Bogota, Colombia
| | - Guillermo Aldana
- Renal Transplantation Group, Clinica Reina Sofia, University Clinic, Bogota, Colombia
| | - Andres Acevedo
- Renal Transplantation Group, Clinica Reina Sofia, University Clinic, Bogota, Colombia; Translational Investigation Group, Sanitas University, Clinica Colsanitas, Bogota, Colombia
| | - Maria Rios
- Molecular Biology and Immunology Laboratory, Clinica Colsanitas, Bogota, Colombia
| | - Johana Echeverri
- Molecular Biology and Immunology Laboratory, Clinica Colsanitas, Bogota, Colombia
| | - Zuly Yepes
- Molecular Biology and Immunology Laboratory, Clinica Colsanitas, Bogota, Colombia
| | - Adriana Silva
- Renal Transplantation Group, Clinica Reina Sofia, University Clinic, Bogota, Colombia
| | - Diana Gayon
- Renal Transplantation Group, Clinica Reina Sofia, University Clinic, Bogota, Colombia
| | - Jorge Perez
- Renal Transplantation Group, Clinica Reina Sofia, University Clinic, Bogota, Colombia; Translational Investigation Group, Sanitas University, Clinica Colsanitas, Bogota, Colombia; Infectious Diseases Department, Clinica Colsanitas, Bogota, Colombia; Molecular Biology and Immunology Laboratory, Clinica Colsanitas, Bogota, Colombia
| | - Milciades Ibanez
- Renal Transplantation Group, Clinica Reina Sofia, University Clinic, Bogota, Colombia; Translational Investigation Group, Sanitas University, Clinica Colsanitas, Bogota, Colombia
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22
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Albekairy AM, Shawaqfeh MS, Alharbi SH, Almuqbil F, Alghamdi MA, Albekairy NA, Muflih SM, Alkatheri A. Prophylaxis of Cytomegalovirus Infection in Solid Organ Transplantation, Retrospective Evaluation. TRANSPLANT RESEARCH AND RISK MANAGEMENT 2022. [DOI: 10.2147/trrm.s366213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
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23
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Effect of HLA-G5 Immune Checkpoint Molecule on the Expression of ILT-2, CD27, and CD38 in Splenic B cells. J Immunol Res 2022; 2022:4829227. [PMID: 35600048 PMCID: PMC9119744 DOI: 10.1155/2022/4829227] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Accepted: 04/23/2022] [Indexed: 11/18/2022] Open
Abstract
The human leukocyte antigen G (HLA-G) is an immune checkpoint molecule with a complex network of interactions with several inhibitory receptors. Although the effect of HLA-G on T cells and NK cells is well studied, the effect of HLA-G on B cells is still largely elusive. B cells are of particular interest in the context of the HLA-G-ILT-2 interaction because the ILT-2 receptor is constitutively expressed on most B cells, whereas it is only present on some subsets of T and NK cells. To characterize the effect of HLA-G5 molecules on B cells, we studied splenic B cells derived from cytomegalovirus (CMV) sero-positive donors after CMV stimulation with antigens in the presence and absence of soluble HLA-G5. In the presence of HLA-G5, increased expression of the ITIM-bearing Ig-like transcript (ILT-2) was observed on B cells, but its expression was not affected by stimulation with CMV antigens. Moreover, it became evident that HLA-G5 exposure resulted in a decreased expression of CD27 and CD38 and, accordingly, in lower proportions of CD19+CD27+CD38+ and higher proportions of CD19+CD27-CD38- B cells. Taken together, our in vitro findings demonstrate that soluble HLA-G5 suppresses markers of B cell activation, suggesting that HLA-G5 has an impact on splenic B cell differentiation and activation. Based on these results, further investigation regarding the role of HLA-G as a prognostic factor and a potential therapeutic agent with respect to B cell function appears reasonable.
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24
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Kaminski H, Kamar N, Thaunat O, Bouvier N, Caillard S, Garrigue I, Anglicheau D, Rérolle JP, Le Meur Y, Durrbach A, Bachelet T, Savel H, Coueron R, Visentin J, Del Bello A, Pellegrin I, Déchanet-Merville J, Merville P, Thiébaut R, Couzi L. Incidence of cytomegalovirus infection in seropositive kidney transplant recipients treated with everolimus: A randomized, open-label, multicenter phase 4 trial. Am J Transplant 2022; 22:1430-1441. [PMID: 34990047 DOI: 10.1111/ajt.16946] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Revised: 12/02/2021] [Accepted: 12/28/2021] [Indexed: 01/25/2023]
Abstract
Cytomegalovirus (CMV) persists as the most frequent opportunistic infection among solid organ transplant recipients. This multicenter trial aimed to test whether treatment with everolimus (EVR) could decrease the incidence of CMV DNAemia and disease. We randomized 186 CMV seropositive kidney transplant recipients in a 1:1 ratio to receive EVR or mycophenolic acid (MPA) in association with basiliximab, cyclosporin, and steroids and 87 in each group were analyzed. No universal prophylaxis was administered to either group. The composite primary endpoint was the presence of CMV DNAemia, CMV treatment, graft loss, death, and discontinuation of the study at 6 months posttransplant. In the modified intent-to-treat analysis, 42 (48.3%) and 70 (80.5%) patients in the EVR and MPA groups reached the primary endpoint (OR = 0.21, 95% CI: 0.11-0.43, p < .0001). Fewer patients of the EVR group received treatment for CMV (21.8% vs. 47.1%, p = .0007). EVR was discontinued in 31 (35.6%) patients. Among the 56 patients with ongoing EVR treatment, only 7.4% received treatment for CMV. In conclusion, EVR prevents CMV DNAemia requiring treatment in seropositive recipients as long as it is tolerated and maintained.
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Affiliation(s)
- Hannah Kaminski
- Department of Nephrology, Transplantation, Dialysis and Apheresis, CHU Bordeaux, Bordeaux, France.,UMR 5164-ImmunoConcEpT, University of Bordeaux, CNRS, Bordeaux University, Bordeaux, France
| | - Nassim Kamar
- Department of Nephrology and Organ Transplantation, CHU Toulouse, Toulouse, France.,INSERM U1043, IFR-BMT, Toulouse, France
| | - Olivier Thaunat
- Department of Nephrology, Transplantation and Clinical Immunology of Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon-I University UFR Lyon Est, Lyon, France
| | - Nicolas Bouvier
- Department of Nephrology, Transplantation, Dialysis, CHU Caen, Caen, France
| | - Sophie Caillard
- Department of Nephrology and Transplantation, CHU Strasbourg, Strasbourg, France
| | | | - Dany Anglicheau
- Department of Nephrology and Kidney Transplantation, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | | | - Yannick Le Meur
- Department of Nephrology and Transplantation, Brest University Hospital, Brest, France
| | - Antoine Durrbach
- Department of Nephrology and Kidney Transplantation, INSERM 1186, Henri Mondor Hospital, Assistance Publique-Hôpitaux de Paris, Paris Saclay University, Paris, France
| | - Thomas Bachelet
- Department of Nephrology, Transplantation, Dialysis and Apheresis, CHU Bordeaux, Bordeaux, France
| | - Hélène Savel
- CHU Bordeaux, Service d'information médicale, Bordeaux, France
| | - Roxane Coueron
- CHU Bordeaux, Service d'information médicale, Bordeaux, France
| | - Jonathan Visentin
- UMR 5164-ImmunoConcEpT, University of Bordeaux, CNRS, Bordeaux University, Bordeaux, France.,Laboratory of Immunology and Immunogenetics, CHU Bordeaux, Bordeaux, France
| | - Arnaud Del Bello
- Department of Nephrology and Organ Transplantation, CHU Toulouse, Toulouse, France.,INSERM U1043, IFR-BMT, Toulouse, France
| | - Isabelle Pellegrin
- UMR 5164-ImmunoConcEpT, University of Bordeaux, CNRS, Bordeaux University, Bordeaux, France.,Laboratory of Immunology and Immunogenetics, CHU Bordeaux, Bordeaux, France
| | | | - Pierre Merville
- Department of Nephrology, Transplantation, Dialysis and Apheresis, CHU Bordeaux, Bordeaux, France.,UMR 5164-ImmunoConcEpT, University of Bordeaux, CNRS, Bordeaux University, Bordeaux, France
| | - Rodolphe Thiébaut
- CHU Bordeaux, Service d'information médicale, Bordeaux, France.,INSERM U1219 Bordeaux Population Health Research Center, Inria SISTM, Bordeaux University, Bordeaux, France
| | - Lionel Couzi
- Department of Nephrology, Transplantation, Dialysis and Apheresis, CHU Bordeaux, Bordeaux, France.,UMR 5164-ImmunoConcEpT, University of Bordeaux, CNRS, Bordeaux University, Bordeaux, France
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25
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Lee H, Oh EJ. Laboratory diagnostic testing for cytomegalovirus infection in solid organ transplant patients. KOREAN JOURNAL OF TRANSPLANTATION 2022; 36:15-28. [PMID: 35769434 PMCID: PMC9235525 DOI: 10.4285/kjt.22.0001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 02/12/2022] [Accepted: 02/15/2022] [Indexed: 11/12/2022] Open
Abstract
Human cytomegalovirus (CMV) infection, which is one of the most common complications in transplant recipients, increases the risk of graft loss and rejection. Laboratory strategies for diagnosing CMV infection rely on the measurement of viral DNAemia and CMV-specific cell-mediated immunity (CMV-CMI). The CMV quantitative nucleic acid amplification test (QNAT) enabled the spread of preemptive therapy and prompted recommendations for surveillance, diagnosis, and monitoring. Despite the implementation of the World Health Organization international standard for calibration, variability of QNAT persists due to technical issues. CMV immunoglobulin G serology is the standard method for CMV immune screening of transplant candidates and donors. Assays for CMV-CMI play an important role in helping to predict the risk and to develop an individualized CMV management plan. Genotypic testing for resistance is needed when drug-resistant CMV infection is suspected. Here, we review the state of the art of laboratory tests for CMV infection in solid organ transplantation.
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Affiliation(s)
- Hyeyoung Lee
- Department of Laboratory Medicine, International St. Mary’s Hospital, College of Medicine, Catholic Kwandong University, Incheon, Korea
| | - Eun-Jee Oh
- Department of Laboratory Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Research and Development Institute for In Vitro Diagnostic Medical Devices of Catholic University of Korea, College of Medicine, The Catholic University of Korea, Seoul, Korea
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26
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Abstract
Unconventional T cells are a diverse and underappreciated group of relatively rare lymphocytes that are distinct from conventional CD4+ and CD8+ T cells, and that mainly recognize antigens in the absence of classical restriction through the major histocompatibility complex (MHC). These non-MHC-restricted T cells include mucosal-associated invariant T (MAIT) cells, natural killer T (NKT) cells, γδ T cells and other, often poorly defined, subsets. Depending on the physiological context, unconventional T cells may assume either protective or pathogenic roles in a range of inflammatory and autoimmune responses in the kidney. Accordingly, experimental models and clinical studies have revealed that certain unconventional T cells are potential therapeutic targets, as well as prognostic and diagnostic biomarkers. The responsiveness of human Vγ9Vδ2 T cells and MAIT cells to many microbial pathogens, for example, has implications for early diagnosis, risk stratification and targeted treatment of peritoneal dialysis-related peritonitis. The expansion of non-Vγ9Vδ2 γδ T cells during cytomegalovirus infection and their contribution to viral clearance suggest that these cells can be harnessed for immune monitoring and adoptive immunotherapy in kidney transplant recipients. In addition, populations of NKT, MAIT or γδ T cells are involved in the immunopathology of IgA nephropathy and in models of glomerulonephritis, ischaemia-reperfusion injury and kidney transplantation.
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27
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Low dose thymoglobulin versus basiliximab in cytomegalovirus positive kidney transplant recipients: Effectiveness of preemptive cytomegalovirus modified strategy. Nefrologia 2021. [DOI: 10.1016/j.nefro.2021.10.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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28
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Saeed H, Thoendel M, Razonable RR. Individualized management of cytomegalovirus in solid organ transplant recipients. EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 2021. [DOI: 10.1080/23808993.2021.1964951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Affiliation(s)
- Huma Saeed
- Division of Infectious Diseases, Department of Medicine and the William J Von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota, United States
| | - Matthew Thoendel
- Division of Infectious Diseases, Department of Medicine and the William J Von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota, United States
| | - Raymund R Razonable
- Division of Infectious Diseases, Department of Medicine and the William J Von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minnesota, United States
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29
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Märtson AG, Edwina AE, Burgerhof JGM, Berger SP, de Joode A, Damman K, Verschuuren EAM, Blokzijl H, Bakker M, Span LF, van der Werf TS, Touw DJ, Sturkenboom MGG, Knoester M, Alffenaar JWC. Ganciclovir therapeutic drug monitoring in transplant recipients. J Antimicrob Chemother 2021; 76:2356-2363. [PMID: 34160036 PMCID: PMC8361328 DOI: 10.1093/jac/dkab195] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 05/18/2021] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND The use of (val)ganciclovir is complicated by toxicity, slow response to treatment and acquired resistance. OBJECTIVES To evaluate a routine therapeutic drug monitoring (TDM) programme for ganciclovir in a transplant patient population. METHODS An observational study was performed in transplant recipients from June 2018 to February 2020. Dose adjustments were advised by the TDM pharmacist as part of clinical care. For prophylaxis, a trough concentration (Cmin) of 1-2 mg/L and an AUC24h of >50 mg·h/L were aimed for. For treatment, a Cmin of 2-4 mg/L and an AUC24h of 80-120 mg·h/L were aimed for. RESULTS Ninety-five solid organ and stem cell transplant patients were enrolled. Overall, 450 serum concentrations were measured; with a median of 3 (IQR = 2-6) per patient. The median Cmin and AUC24h in the treatment and prophylaxis groups were 2.0 mg/L and 90 mg·h/L and 0.9 mg/L and 67 mg·h/L, respectively. Significant intra- and inter-patient patient variability was observed. The majority of patients with an estimated glomerular filtration rate of more than 120 mL/min/1.73 m2 and patients on continuous veno-venous haemofiltration showed underexposure. The highest Cmin and AUC24h values were associated with the increase in liver function markers and decline in WBC count as compared with baseline. CONCLUSIONS This study revealed that a standard weight and kidney function-based dosing regimen resulted in highly variable ganciclovir Cmin and under- and over-exposure were observed in patients on dialysis and in patients with increased renal function. Clearly there is a need to explore the impact of concentration-guided dose adjustments in a prospective study.
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Affiliation(s)
- Anne-Grete Märtson
- University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands
- Corresponding author. E-mail:
| | - Angela E. Edwina
- University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands
| | - Johannes G. M. Burgerhof
- University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, The Netherlands
| | - Stefan P. Berger
- University of Groningen, University Medical Center Groningen, Department of Internal Medicine, Groningen, The Netherlands
| | - Anoek de Joode
- University of Groningen, University Medical Center Groningen, Department of Internal Medicine, Groningen, The Netherlands
| | - Kevin Damman
- University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen, The Netherlands
| | - Erik A. M. Verschuuren
- University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases and Tuberculosis, Groningen, The Netherlands
| | - Hans Blokzijl
- University of Groningen, University Medical Center Groningen, Department of Gastroenterology and Hepatology, Groningen, The Netherlands
| | - Martijn Bakker
- University of Groningen, University Medical Center Groningen, Department of Hematology, Groningen, The Netherlands
| | - Lambert F. Span
- University of Groningen, University Medical Center Groningen, Department of Hematology, Groningen, The Netherlands
| | - Tjip S. van der Werf
- University of Groningen, University Medical Center Groningen, Department of Internal Medicine, Groningen, The Netherlands
- University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases and Tuberculosis, Groningen, The Netherlands
| | - Daan J. Touw
- University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands
| | - Marieke G. G. Sturkenboom
- University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands
| | - Marjolein Knoester
- University of Groningen, University Medical Center Groningen, Department of Medical Microbiology and Infection Prevention, Groningen, The Netherlands
| | - Jan W. C. Alffenaar
- University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands
- University of Sydney, Faculty of Medicine and Health, School of Pharmacy, New South Wales, Sydney, Australia
- Westmead Hospital, Westmead, New South Wales, Australia
- Marie Bashir Institute of Infectious Diseases and Biosecurity, University of Sydney, Sydney, New South Wales, Australia
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30
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Prakash K, Chandorkar A, Saharia KK. Utility of CMV-Specific Immune Monitoring for the Management of CMV in Solid Organ Transplant Recipients: A Clinical Update. Diagnostics (Basel) 2021; 11:875. [PMID: 34068377 PMCID: PMC8153332 DOI: 10.3390/diagnostics11050875] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 05/07/2021] [Indexed: 02/07/2023] Open
Abstract
Cytomegalovirus (CMV) is one of the most important opportunistic infections in solid organ transplant (SOT) recipients. However, current techniques used to predict risk for CMV infection fall short. CMV-specific cell mediated immunity (CMI) plays an important role in protecting against CMV infection. There is evidence that assays measuring CMV-CMI might better identify SOT recipients at risk of complications from CMV compared to anti-CMV IgG, which is our current standard of care. Here, we review recently published studies that utilize CMV-CMI, at various points before and after transplantation, to help predict risk and guide the management of CMV infection following organ transplantation. The evidence supports the use of these novel assays to help identify SOT recipients at increased risk and highlights the need for larger prospective trials evaluating these modalities in this high-risk population.
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Affiliation(s)
- Katya Prakash
- Division of Infectious Diseases, University of Maryland School of Medicine, Baltimore, MD 21201, USA;
| | - Aditya Chandorkar
- Division of Infectious Diseases and International Medicine, University of Minnesota, Minneapolis, MN 55455, USA;
| | - Kapil K. Saharia
- Division of Infectious Diseases, University of Maryland School of Medicine, Baltimore, MD 21201, USA;
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31
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Jorgenson MR, Wong C, Descourouez JL, Saddler CM, Smith JA, Mandelbrot DA. Conversion from cytomegalovirus universal prophylaxis with valganciclovir to the preemptive monitoring approach to manage leukopenia after kidney or pancreas transplantation. Transpl Infect Dis 2021; 23:e13617. [PMID: 33866643 DOI: 10.1111/tid.13617] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 03/05/2021] [Accepted: 04/05/2021] [Indexed: 01/31/2023]
Abstract
PURPOSE In clinical practice, conversion from universal cytomegalovirus prophylaxis (CMV PPX) with valganciclovir (VGC) to targeted therapy (preemptive monitoring, PEM) is often pursued in the setting of leukopenia. It is unknown if this is an effective strategy. METHODS Adult patients receiving a kidney and/or pancreas transplant were included if converted from PPX to PEM between 9/1/19 and 3/1/20 due to leukopenia. A positive CMV viral load (VL) was defined as CMV PCR greater than the lower limit of quantification (LLOQ) based on local lab testing. A CMV VL of >500 IU/mL was chosen as the preemptive treatment (PET) threshold. Primary objective was to describe the impact of conversion on resolution of leukopenia. Secondary objectives were to assess PEM associated outcomes. RESULTS There were 49 patients converted from PPX to PEM due to leukopenia in the study period; 88% were KTRs and 96% received lymphocyte-depleting induction; 84% were seropositive at transplant (R+) and 16% were high-risk (D+/R-). Mean WBC at time of enrollment was 1.4 ± 0.4. After PEM conversion, WBC recovered to >3 in 87.8% of the population in a mean of 26.8 ± 24.5 days. Immunosuppression was modified in 96% of the population and GCSF was required in 46.9% of patients. CMV viremia occurred in 36.7% of the population; 78% were KTRs and 94% were R+. Time from PEM enrollment to PET was 64 ± 34 days. Median VL at first detection was 587 IU/mL, median peak was 1920 IU/mL. Five patients (27.8%) presented with symptoms consistent with CMV syndrome, none had end organ disease. Six patients (33%) presented with a VL <500 IU/mL at first detection, but all subsequently surpassed the threshold and required PET. Mean duration of PET was 25 ± 11 days. Mean change in WBC in response to PET was -0.4 ± 1.3. Immunosuppression required further adjustment in 61% of patients. There were no deaths or graft loss due to CMV at last follow-up. CONCLUSION In kidney and pancreas transplant recipients who undergo PEM conversion due to leukopenia, withholding of VGC can improve leukopenia, but other concomitant measures are necessary. This population should be considered fairly high risk, with a threshold of treatment of first quantifiable replication. Our findings suggest lack of harm from this approach but highlight the importance of close monitoring to prevent symptomatic replication. Larger studies with longer follow-up are needed to better evaluate the impact of PEM conversion on late-onset CMV and patient and graft outcomes.
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Affiliation(s)
- Margaret R Jorgenson
- Department of Pharmacy, University of Wisconsin Hospital and Clinics, Madison, WI, USA
| | - Cynthia Wong
- Department of Pharmacy, University of Wisconsin Hospital and Clinics, Madison, WI, USA
| | - Jillian L Descourouez
- Department of Pharmacy, University of Wisconsin Hospital and Clinics, Madison, WI, USA
| | - Christopher M Saddler
- Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, University of Wisconsin Hospital and Clinics, Madison, WI, USA
| | - Jeannina A Smith
- Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, University of Wisconsin Hospital and Clinics, Madison, WI, USA
| | - Didier A Mandelbrot
- Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, University of Wisconsin Hospital and Clinics, Madison, WI, USA
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32
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Mazzola P, Schaeffeler E, Witzke O, Nitschke M, Kliem V, Zortel M, Wagner EM, Schwab M, Hauser IA. No association of genetic variants in TLR4, TNF-α, IL10, IFN-γ, and IL37 in cytomegalovirus-positive renal allograft recipients with active CMV infection-Subanalysis of the prospective randomised VIPP study. PLoS One 2021; 16:e0246118. [PMID: 33861738 PMCID: PMC8051780 DOI: 10.1371/journal.pone.0246118] [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: 04/02/2020] [Accepted: 01/04/2021] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND Cytomegalovirus (CMV) infection is amongst the most important factors complicating solid organ transplantation. In a large prospective randomized clinical trial, valganciclovir prophylaxis reduced the occurrence of CMV infection and disease compared with preemptive therapy in CMV-positive renal allograft recipients (VIPP study; NCT00372229). Here, we present a subanalysis of the VIPP study, investigating single nucleotide polymorphisms (SNPs) in immune-response-related genes and their association with active CMV infection, CMV disease, graft loss or death, rejection, infections, and leukopenia. METHODS Based on literature research ten SNPs were analyzed for TLR4, three for IFN-γ, six for IL10, nine for IL37, and two for TNF-α. An asymptotic independence test (Cochran-Armitage trend test) was used to examine associations between SNPs and the occurrence of CMV infection or other negative outcomes. Statistical significance was defined as p<0.05 and Bonferroni correction for multiple testing was performed. RESULTS SNPs were analyzed on 116 blood samples. No associations were found between the analyzed SNPs and the occurrence of CMV infection, rejection and leukopenia in all patients. For IL37 rs2723186, an association with CMV disease (p = 0.0499), for IL10 rs1800872, with graft loss or death (p = 0.0207) and for IL10 rs3024496, with infections (p = 0.0258) was observed in all patients, however did not hold true after correction for multiple testing. CONCLUSION The study did not reveal significant associations between the analyzed SNPs and the occurrence of negative outcomes in CMV-positive renal transplant recipients after correction for multiple testing. The results of this association analysis may be of use in guiding future research efforts.
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Affiliation(s)
- Pascale Mazzola
- Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology (IKP), Stuttgart, Germany
- University of Tuebingen, Tuebingen, Germany
| | - Elke Schaeffeler
- Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology (IKP), Stuttgart, Germany
- University of Tuebingen, Tuebingen, Germany
| | - Oliver Witzke
- Department of Infectious Diseases, West German Centre of Infectious Diseases, Universitätsmedizin Essen, University Duisburg-Essen, Germany
| | - Martin Nitschke
- Transplantation Center, Medical Clinic I, University Hospital Schleswig-Holstein, Luebeck, Germany
| | - Volker Kliem
- Department of Internal Medicine and Nephrology, Nephrology Center of Lower Saxony, Klinikum Hann. Muenden, Hann. Muenden, Germany
| | - Max Zortel
- Roche Pharma AG, Grenzach-Wyhlen, Germany
| | | | - Matthias Schwab
- Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology (IKP), Stuttgart, Germany
- University of Tuebingen, Tuebingen, Germany
- Departments of Clinical Pharmacology, Pharmacy and Biochemistry, University Tuebingen, Tuebingen, Germany
| | - Ingeborg A. Hauser
- Department of Nephrology, University Clinic Frankfurt, Goethe University Frankfurt, Frankfurt, Germany
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Alfieri CM, Molinari P, Gandolfo M, Campise M, Cresseri D, Regalia A, Favi E, Li M, Ikehata M, Delbue S, Messa P. Cytomegalovirus Disease in Renal Transplanted Patients: Prevalence, Determining Factors, and Influence on Graft and Patients Outcomes. Pathogens 2021; 10:473. [PMID: 33919676 PMCID: PMC8069780 DOI: 10.3390/pathogens10040473] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Revised: 04/01/2021] [Accepted: 04/12/2021] [Indexed: 11/16/2022] Open
Abstract
The prevalence and the factors related to cytomegalovirus (CMV) disease (CMVd) during the 1st year of renal transplantation (RTx) and the relationship between CMVd and early and long-term graft and RTx-patient (RTx-p) survival were evaluated. In 505 RTx-p, followed up for 8(5-11) years, data were recorded after 1-(T1) and 12-(T12) months of RTx. CMVd was defined either by CMV replication without clinical signs of disease (CMVr, 43%), or CMV replication with signs of disease (CMVs, 57%). During the 1st year of RTx, 45% of RTx-p had CMVd (CMVd+). CMVd+ patients were older than CMVd- patients. Female gender and Donor CMV-IgG+ (CMV IgG-D+)/recipient IgG- (CMV IgG-R-) status were more prevalent in CMVd+. At T1, CMVd+ had lower albumin, haemoglobin, and higher uric-acid and reactive C-protein than CMVd- and, at T1 and T12, received more steroids. Albumin-T1 was the unique factor in determining CMVd+, maintaining its significance also after the inclusion of IgG-D+/IgG-R- status to the model. CMVs had higher prevalence of CMV IgG-D+/IgG-R- than CMVr. CMVd, CMVr, and CMVs had no impact on graft loss (11% of RTx-p) and RTx-p death (8% of RTx-p). CMVd is highly prevalent during the 1st year of RTx. Albumin-T1 influences CMVd insurgence. CMVd did not impact on RTx and RTx-p loss.
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Affiliation(s)
- Carlo Maria Alfieri
- Department of Nephrology, Dialysis and Renal Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Policlinico Milan, 20122 Milano, Italy; (P.M.); (M.G.); (M.C.); (D.C.); (A.R.); (P.M.)
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milano, Italy;
| | - Paolo Molinari
- Department of Nephrology, Dialysis and Renal Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Policlinico Milan, 20122 Milano, Italy; (P.M.); (M.G.); (M.C.); (D.C.); (A.R.); (P.M.)
| | - Mariateresa Gandolfo
- Department of Nephrology, Dialysis and Renal Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Policlinico Milan, 20122 Milano, Italy; (P.M.); (M.G.); (M.C.); (D.C.); (A.R.); (P.M.)
| | - Mariarosaria Campise
- Department of Nephrology, Dialysis and Renal Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Policlinico Milan, 20122 Milano, Italy; (P.M.); (M.G.); (M.C.); (D.C.); (A.R.); (P.M.)
| | - Donata Cresseri
- Department of Nephrology, Dialysis and Renal Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Policlinico Milan, 20122 Milano, Italy; (P.M.); (M.G.); (M.C.); (D.C.); (A.R.); (P.M.)
| | - Anna Regalia
- Department of Nephrology, Dialysis and Renal Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Policlinico Milan, 20122 Milano, Italy; (P.M.); (M.G.); (M.C.); (D.C.); (A.R.); (P.M.)
| | - Evaldo Favi
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milano, Italy;
- Renal Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Policlinico Milan, 20122 Milano, Italy
| | - Min Li
- Renal Research Laboratory Fondazione IRCCS Ca’ Granda Ospedale Policlinico Milan, 20122 Milano, Italy; (M.L.); (M.I.)
| | - Masami Ikehata
- Renal Research Laboratory Fondazione IRCCS Ca’ Granda Ospedale Policlinico Milan, 20122 Milano, Italy; (M.L.); (M.I.)
| | - Serena Delbue
- Department of Biomedical, Surgical and Dental Sciences, Università degli Studi di Milano, 20122 Milan, Italy;
| | - Piergiorgio Messa
- Department of Nephrology, Dialysis and Renal Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Policlinico Milan, 20122 Milano, Italy; (P.M.); (M.G.); (M.C.); (D.C.); (A.R.); (P.M.)
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milano, Italy;
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Cherneha M, Korth J, Kaulfuß M, Trilling M, Widera M, Rohn H, Dolff S, Babel N, Hoerning A, Kribben A, Witzke O. Reactivations of Latent Viral Infections Are Associated with an Increased Thr389 p70S6k Phosphorylation in Peripheral Lymphocytes of Renal Transplant Recipients. Viruses 2021; 13:v13030424. [PMID: 33800846 PMCID: PMC8000484 DOI: 10.3390/v13030424] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 02/21/2021] [Accepted: 03/03/2021] [Indexed: 01/19/2023] Open
Abstract
Reactivations of BK polyoma virus (BKPyV) and human cytomegalovirus (HCMV) frequently cause life- and graft-threatening complications after renal transplantation. Both viruses are dependent on the mTOR pathway for replication. In this study we investigated the association of viral replication with mTOR activity in peripheral lymphocytes of renal transplant recipients. A flow-cytometry based assay for the measurement of Thr389 p70S6k phosphorylation, a surrogate marker of the mTOR pathway was established. Forty-eight adult renal transplant recipients were recruited to measure p70S6k activity in their peripheral blood mononuclear cells. This data set in conjunction with information concerning previous replication of BKPyV and HCMV was examined for correlations. Episodes of BKPyV replication were significantly associated with increased p70S6k phosphorylation in CD4+ T lymphocytes (p = 0.0002) and CD19+ B lymphocytes (p = 0.0073). HCMV infection of patients with a high-risk HCMV constellation of donor and recipient (D+/R−) was associated with increased p70S6k phosphorylation in CD19+ B lymphocytes (p = 0.0325). These associations were found to be independent of the trough levels of the immunosuppressive drugs. Conclusion: P70S6k phosphorylation in peripheral lymphocytes is associated with BKPyV reactivations and to a lesser extent with HCMV infections in renal transplant recipients.
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Affiliation(s)
- Maxim Cherneha
- West German Centre of Infectious Diseases, Department of Infectious Diseases, Universitätsmedizin Essen, University Duisburg-Essen, 45147 Essen, Germany; (M.K.); (H.R.); (S.D.); (O.W.)
- Correspondence: ; Tel.: +49-(0)-201-723-82552
| | - Johannes Korth
- Department of Nephrology, Universitätsmedizin Essen, University Duisburg-Essen, 45147 Essen, Germany; (J.K.); (A.K.)
| | - Meike Kaulfuß
- West German Centre of Infectious Diseases, Department of Infectious Diseases, Universitätsmedizin Essen, University Duisburg-Essen, 45147 Essen, Germany; (M.K.); (H.R.); (S.D.); (O.W.)
| | - Mirko Trilling
- Institute for Virology, Universitätsmedizin Essen, University Duisburg-Essen, 45147 Essen, Germany; (M.T.); (M.W.)
| | - Marek Widera
- Institute for Virology, Universitätsmedizin Essen, University Duisburg-Essen, 45147 Essen, Germany; (M.T.); (M.W.)
| | - Hana Rohn
- West German Centre of Infectious Diseases, Department of Infectious Diseases, Universitätsmedizin Essen, University Duisburg-Essen, 45147 Essen, Germany; (M.K.); (H.R.); (S.D.); (O.W.)
| | - Sebastian Dolff
- West German Centre of Infectious Diseases, Department of Infectious Diseases, Universitätsmedizin Essen, University Duisburg-Essen, 45147 Essen, Germany; (M.K.); (H.R.); (S.D.); (O.W.)
| | - Nina Babel
- Medical Department I, University Hospital Marien Hospital Herne, Ruhr-University of Bochum, 44625 Bochum, Germany;
| | - André Hoerning
- Department of Paediatrics and Adolescent Medicine, University Hospital Erlangen, 91054 Erlangen, Germany;
| | - Andreas Kribben
- Department of Nephrology, Universitätsmedizin Essen, University Duisburg-Essen, 45147 Essen, Germany; (J.K.); (A.K.)
| | - Oliver Witzke
- West German Centre of Infectious Diseases, Department of Infectious Diseases, Universitätsmedizin Essen, University Duisburg-Essen, 45147 Essen, Germany; (M.K.); (H.R.); (S.D.); (O.W.)
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35
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Boulay H, Oger E, Cantarovich D, Gatault P, Thierry A, Le Meur Y, Duveau A, Vigneau C, Lorcy N. Among CMV-positive renal transplant patients receiving non-T-cell depleting induction, the absence of CMV disease prevention is a safe strategy: A retrospective cohort of 372 patients. Transpl Infect Dis 2021; 23:e13541. [PMID: 33270341 DOI: 10.1111/tid.13541] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 09/23/2020] [Accepted: 10/22/2020] [Indexed: 11/28/2022]
Abstract
Cytomegalovirus (CMV) is the most common opportunistic pathogen affecting renal transplant recipients, especially in the first months. CMV-seropositive renal transplant recipients (CMV R+) are at intermediate risk for CMV disease, but this risk is enhanced among CMV R+ receiving T-cell depleting induction, compared to CMV R+ receiving non-depleting induction. In this second group, data in favor of prophylactic antiviral treatment with valganciclovir to reduce CMV disease is sparse. In this retrospective and multicentric trial, we included 372 CMV R+ transplanted between January 2012 and April 2015 and receiving non-depleting induction. During the first year following transplantation, CMV disease occurred in 5/222 patients (2.25%) in the prophylaxis group and 9/150 (6%) in the no-prophylaxis group (difference +3.7; 95% CI: 0.5-8; P = .002 for non-inferiority). The incidence of allograft rejection and other infectious diseases was similar between the two groups. Graft and patient survival were similar at the end of follow-up. In conclusion, the absence of prophylaxis did not appear to have a deleterious effect for CMV diseases among CMV R+ receiving non-depleting induction.
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Affiliation(s)
- Hugoline Boulay
- Service de Néphrologie, CHU Pontchaillou, Rennes, France.,Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail) UMR_S 1085, Univ Rennes, Rennes, France
| | - Emmanuel Oger
- Service de Pharmacologie clinique et biologique, CHU Pontchaillou, Rennes, France
| | - Diego Cantarovich
- Institut de Transplantation Urologie-Néphrologie, Centre Hospitalier Universitaire de Nantes, Nantes, France
| | - Philippe Gatault
- Service de Néphrologie et Immunologie Clinique, Centre Hospitalier Universitaire de Tours, Tours, France
| | - Antoine Thierry
- Service de Néphrologie, Hémodialyse et Transplantation Rénale, Centre Hospitalier Universitaire de Poitiers, Poitiers, France
| | - Yannick Le Meur
- Service de Néphrologie, Centre Hospitaliser de Brest, Université de Bretagne Occidentale, Brest, France
| | - Agnès Duveau
- Service de Nephrologie-Dialyse-Transplantation, Centre Hospitalier Universitaire d'Angers, Angers, France
| | - Cécile Vigneau
- Service de Néphrologie, CHU Pontchaillou, Rennes, France.,Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail) UMR_S 1085, Univ Rennes, Rennes, France
| | - Nolwenn Lorcy
- Service de Néphrologie, CHU Pontchaillou, Rennes, France
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36
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The NFKB1 Promoter Polymorphism (-94ins/delATTG) Is Associated with Susceptibility to Cytomegalovirus Infection after Kidney Transplantation and Should Have Implications on CMV Prophylaxis Regimens. Cells 2021; 10:cells10020380. [PMID: 33673169 PMCID: PMC7918124 DOI: 10.3390/cells10020380] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 02/09/2021] [Accepted: 02/11/2021] [Indexed: 11/16/2022] Open
Abstract
Infections with cytomegalovirus (CMV) are one of the most frequent opportunistic infections in kidney transplant recipients. Current risk-adapted CMV chemoprophylaxis regimens are based almost solely on the donor and recipient CMV serostatus. Of note, the NFKB1 -94ins/delATTG promoter polymorphism was recently associated with a higher risk of CMV infection. Since single genetic association studies suffer from poor reliability for drawing therapeutic implications, we performed this confirmatory study and included 256 kidney transplant recipients from 2007 to 2014 in this retrospective study. Patients were genotyped for the -94ins/delATTG NFKB1 promoter polymorphism and followed up for 12 months. The incidence of CMV infection within 12 months after kidney transplantation was 37.5% (33/88) for the ins/ins, 21.5% (28/130) for the ins/del, and 23.7% (9/38) for the del/del genotypes (p = 0.023). Moreover, we evaluated the time of CMV infection onset. Ins/ins carriers had primarily late-onset CMV infection (median 194 days; interquartile range (IQR) 117–267 days) compared with heterozygous (ins/del; median 158 days; IQR 82–195 days) and homozygous deletion allele carriers (del/del; median 95 days; 84–123 days). Multivariate-restricted Cox regression model confirmed the ins/ins genotype to be an independent risk factor for the development of late-onset CMV infections. These findings should have an impact on post-kidney transplantation CMV chemoprophylaxis regimens.
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Sommerer C, Schmitt A, Hückelhoven-Krauss A, Giese T, Bruckner T, Wang L, Schnitzler P, Meuer S, Zeier M, Schmitt M. Peptide Vaccination against Cytomegalovirus Induces Specific T Cell Response in Responses in CMV Seronegative End-Stage Renal Disease Patients. Vaccines (Basel) 2021; 9:vaccines9020133. [PMID: 33562163 PMCID: PMC7915922 DOI: 10.3390/vaccines9020133] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 01/23/2021] [Accepted: 02/04/2021] [Indexed: 12/11/2022] Open
Abstract
Introduction: Cytomegalovirus (CMV) reactivation occurs in seronegative patients after solid organ transplantation (SOT) particularly from seropositive donors and can be lethal. Generation of CMV-specific T cells helps to prevent CMV reactivation. Therefore, we initiated a clinical phase I CMVpp65 peptide vaccination trial for seronegative end-stage renal disease patients waiting for kidney transplantation. Methods: The highly immunogenic nonamer peptide NLVPMVATV derived from CMV phosphoprotein 65(CMVpp65) in a water-in-oil emulsion (Montanide™) plus imiquimod (Aldara™) as an adjuvant was administered subcutaneously four times biweekly. Clinical course as well as immunological responses were monitored using IFN-γ ELISpot assays and flow cytometry for CMV-specific CD8+ T cells. Results: Peptide vaccination was well tolerated, and no drug-related serious adverse events were detected except for Grade I–II local skin reactions. Five of the 10 patients (50%) mounted any immune response (responders) and 40% of the patients presented CMV-specific CD8+ T cell responses elicited by these prophylactic vaccinations. No responders experienced CMV reactivation in the 18 months post-transplantation, while all non-responders reactivated. Conclusion: CMVpp65 peptide vaccination was safe, well tolerated, and clinically encouraging in seronegative end-stage renal disease patients waiting for kidney transplantation. Further studies with larger patient cohorts are planned.
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Affiliation(s)
- Claudia Sommerer
- Department of Nephrology, University Hospital Heidelberg, University of Heidelberg, 69117 Heidelberg, Germany;
- German Center for Infection Research DZIF, 69117 Heidelberg, Germany; (T.G.); (S.M.)
- Correspondence: ; Tel.: +49-(0)6221-91120; Fax: +49-(0)6221-9112-990
| | - Anita Schmitt
- Department of Internal Medicine V, University of Heidelberg, 69117 Heidelberg, Germany; (A.S.); (A.H.-K.); (L.W.); (M.S.)
| | - Angela Hückelhoven-Krauss
- Department of Internal Medicine V, University of Heidelberg, 69117 Heidelberg, Germany; (A.S.); (A.H.-K.); (L.W.); (M.S.)
| | - Thomas Giese
- German Center for Infection Research DZIF, 69117 Heidelberg, Germany; (T.G.); (S.M.)
- Institute of Immunology, University of Heidelberg, 69117 Heidelberg, Germany
| | - Thomas Bruckner
- Institute of Medical Biometry and Informatics, University of Heidelberg, 69117 Heidelberg, Germany;
| | - Lei Wang
- Department of Internal Medicine V, University of Heidelberg, 69117 Heidelberg, Germany; (A.S.); (A.H.-K.); (L.W.); (M.S.)
| | - Paul Schnitzler
- Department of Virology, University Hospital Heidelberg, University of Heidelberg, 69117 Heidelberg, Germany;
| | - Stefan Meuer
- German Center for Infection Research DZIF, 69117 Heidelberg, Germany; (T.G.); (S.M.)
- Institute of Immunology, University of Heidelberg, 69117 Heidelberg, Germany
| | - Martin Zeier
- Department of Nephrology, University Hospital Heidelberg, University of Heidelberg, 69117 Heidelberg, Germany;
| | - Michael Schmitt
- Department of Internal Medicine V, University of Heidelberg, 69117 Heidelberg, Germany; (A.S.); (A.H.-K.); (L.W.); (M.S.)
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Blazquez-Navarro A, Dang-Heine C, Bauer C, Wittenbrink N, Wolk K, Sabat R, Witzke O, Westhoff TH, Sawitzki B, Reinke P, Thomusch O, Hugo C, Babel N, Or-Guil M. Sex-Associated Differences in Cytomegalovirus Prevention: Prophylactic Strategy is Potentially Associated With a Strong Kidney Function Impairment in Female Renal Transplant Patients. Front Pharmacol 2020; 11:534681. [PMID: 33519427 PMCID: PMC7845412 DOI: 10.3389/fphar.2020.534681] [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: 02/13/2020] [Accepted: 11/03/2020] [Indexed: 12/12/2022] Open
Abstract
Post-transplantation cytomegalovirus (CMV) syndrome can be prevented using the antiviral drug (val)ganciclovir. (Val)ganciclovir is typically administered following a prophylactic or a pre-emptive strategy. The prophylactic strategy entails early universal administration, the pre-emptive strategy, early treatment in case of infection. However, it is not clear which strategy is superior with respect to transplantation outcome; sex-specific effects of these prevention strategies are not known. We have retrospectively analyzed 540 patients from the multi-centre Harmony study along eight pre-defined visits: 308 were treated according to a prophylactic, 232 according to a pre-emptive strategy. As expected, we observed an association of prophylactic strategy with lower incidence of CMV syndrome, delayed onset and lower viral loads compared to the pre-emptive strategy. However, in female patients, the prophylactic strategy was associated with a strong impairment of glomerular filtration rate one year post-transplant (difference: -11.8 ± 4.3 ml min-1·1.73 m-2, p = 0.006). Additionally, we observed a tendency of higher incidence of acute rejection and severe BK virus reactivation in the prophylactic strategy group. While the prophylactic strategy was more effective for preventing CMV syndrome, our results suggest for the first time that the prophylactic strategy might lead to inferior transplantation outcomes in female patients, providing evidence for a strong association with sex. Further randomized controlled studies are necessary to confirm this potential negative effect.
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Affiliation(s)
- Arturo Blazquez-Navarro
- Department of Biology, Systems Immunology Lab, Humboldt-Universität zu Berlin, Berlin, Germany
- Berlin Institute of Health Center for Regenerative Therapies (BCRT), Berlin-Brandenburger Centrum für Regenerative Therapien, Charité–Universitätsmedizin Berlin, Berlin, Germany
- Center for Translational Medicine, Universitätsklinikum der Ruhr-Universität Bochum, Herne, Germany
| | - Chantip Dang-Heine
- Berlin Institute of Health Center for Regenerative Therapies (BCRT), Berlin-Brandenburger Centrum für Regenerative Therapien, Charité–Universitätsmedizin Berlin, Berlin, Germany
- Clinical Study Center (CSC), Berlin Institute of Health, and Charitét - Universitättsmedizin Berlin, Corporate Member of Freie Universitätt Berlin, Humboldt-Universitätt Zu Berlin, Campus Charitét Mitte Berlin, Germany
| | | | - Nicole Wittenbrink
- Department of Biology, Systems Immunology Lab, Humboldt-Universität zu Berlin, Berlin, Germany
- Berlin Institute of Health Center for Regenerative Therapies (BCRT), Berlin-Brandenburger Centrum für Regenerative Therapien, Charité–Universitätsmedizin Berlin, Berlin, Germany
| | - Kerstin Wolk
- Berlin Institute of Health Center for Regenerative Therapies (BCRT), Berlin-Brandenburger Centrum für Regenerative Therapien, Charité–Universitätsmedizin Berlin, Berlin, Germany
- Department of Dermatology and Allergy, Psoriasis Research and Treatment Center, Institute of Medical Immunology, Charité–Universitätsmedizin Berlin, Berlin, Germany
| | - Robert Sabat
- Department of Dermatology and Allergy, Psoriasis Research and Treatment Center, Institute of Medical Immunology, Charité–Universitätsmedizin Berlin, Berlin, Germany
- Department of Dermatology and Allergy, Interdisciplinary Group of Molecular Immunopathology, Institute of Medical Immunology, Charité–Universitätsmedizin Berlin, Berlin, Germany
| | - Oliver Witzke
- Klinik für Infektiologie, Universitätsklinikum Essen, Essen, Germany
| | - Timm H. Westhoff
- Center for Translational Medicine, Universitätsklinikum der Ruhr-Universität Bochum, Herne, Germany
| | - Birgit Sawitzki
- Berlin Institute of Health Center for Regenerative Therapies (BCRT), Berlin-Brandenburger Centrum für Regenerative Therapien, Charité–Universitätsmedizin Berlin, Berlin, Germany
| | - Petra Reinke
- Berlin Institute of Health Center for Regenerative Therapies (BCRT), Berlin-Brandenburger Centrum für Regenerative Therapien, Charité–Universitätsmedizin Berlin, Berlin, Germany
- Berlin Center for Advanced Therapies (BeCAT), Charité–Universitätsmedizin Berlin, Berlin, Germany
| | - Oliver Thomusch
- Klinik für Allgemein- und Viszeralchirurgie, Universitätsklinikum Freiburg, Freiburg, Germany
| | - Christian Hugo
- Medizinische Klinik III - Bereich Nephrologie, Universitätsklinikum Carl Gustav Carus, Dresden, Germany
| | - Nina Babel
- Berlin Institute of Health Center for Regenerative Therapies (BCRT), Berlin-Brandenburger Centrum für Regenerative Therapien, Charité–Universitätsmedizin Berlin, Berlin, Germany
- Center for Translational Medicine, Universitätsklinikum der Ruhr-Universität Bochum, Herne, Germany
| | - Michal Or-Guil
- Department of Biology, Systems Immunology Lab, Humboldt-Universität zu Berlin, Berlin, Germany
- Institute of Medical Immunology, Charité–Universitätsmedizin Berlin, Berlin, Germany
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Von Stein L, Leino AD, Pesavento T, Rajab A, Winters H. Antithymocyte induction dosing and incidence of opportunistic viral infections using steroid-free maintenance immunosuppression. Clin Transplant 2020; 35:e14102. [PMID: 32985025 DOI: 10.1111/ctr.14102] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 09/10/2020] [Indexed: 12/26/2022]
Abstract
BACKGROUND Currently, there is limited literature evaluating rATG induction dosing and incidence of opportunistic viral infections when using steroid-free maintenance immunosuppression. METHODS This single-center, retrospective, study compared high rATG (>4.5 mg/kg) versus low (<4.5 mg/kg) induction dosing and the overall incidence of early opportunistic viral infection at 180 days in the setting of maintenance immunosuppression consisting of tacrolimus, mycophenolate, rapid steroid withdrawal, and a tiered antiviral prevention strategy based on donor-recipient Cytomegalovirus (CMV) serostatus. RESULTS A total of 209 patients were included; 76 patients received low-dose and 133 patients received high-dose rATG. Incidence of overall opportunistic viral infection occurred more frequently in patients who received high compared to low dose (29.8% vs 25% p = .030). Incidence of CMV infection was also significantly increased in the high-dose group (31.6% vs 18.4% p = .039). In a multivariable model, rATG dose, as a continuous variable, remained a significant independent predictor of infection along with CMV risk (OR 1.46, 95% CI 1.02-2.09) controlling for age and CMV risk. There were no differences in graft-related outcomes at 180 days. CONCLUSION Higher cumulative rATG induction dose was associated with increased incidence of opportunistic viral infections, in the setting of a steroid-free maintenance immunosuppression in the early post-transplant period.
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Affiliation(s)
- Lauren Von Stein
- Department of Pharmacy, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Abbie D Leino
- Department of Pharmacy, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Todd Pesavento
- Nephrology, Department of Internal Medicine, Ohio State University, Columbus, OH, USA
| | - Amer Rajab
- Division of Transplantation, Department of General Surgery, Ohio State University College of Medicine, Columbus, OH, USA
| | - Holli Winters
- Department of Pharmacy, The Ohio State University Wexner Medical Center, Columbus, OH, USA
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40
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Limaye AP, Babu TM, Boeckh M. Progress and Challenges in the Prevention, Diagnosis, and Management of Cytomegalovirus Infection in Transplantation. Clin Microbiol Rev 2020; 34:34/1/e00043-19. [PMID: 33115722 PMCID: PMC7920732 DOI: 10.1128/cmr.00043-19] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hosts with compromised or naive immune systems, such as individuals living with HIV/AIDS, transplant recipients, and fetuses, are at the highest risk for complications from cytomegalovirus (CMV) infection. Despite substantial progress in prevention, diagnostics, and treatment, CMV continues to negatively impact both solid-organ transplant (SOT) and hematologic cell transplant (HCT) recipients. In this article, we summarize important developments in the field over the past 10 years and highlight new approaches and remaining challenges to the optimal control of CMV infection and disease in transplant settings.
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Affiliation(s)
- Ajit P Limaye
- Division of Allergy and Infectious Diseases, University of Washington, Seattle, Washington, USA
| | - Tara M Babu
- Division of Infectious Diseases, University of Rochester Medical Center, Rochester, New York, USA
- Department of Infectious Diseases, Overlake Medical Center, Bellevue, Washington, USA
| | - Michael Boeckh
- Division of Allergy and Infectious Diseases, University of Washington, Seattle, Washington, USA
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
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41
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Hellemans R, Abramowicz D. Cytomegalovirus after kidney transplantation in 2020: moving towards personalized prevention. Nephrol Dial Transplant 2020; 37:810-816. [PMID: 33280028 DOI: 10.1093/ndt/gfaa249] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Indexed: 12/24/2022] Open
Abstract
Cytomegalovirus (CMV)-related complications after kidney transplantation remain a substantial challenge. Rather than applying one preventive strategy to all at-risk patients, we can now adapt our strategy at the individual patient level. Antiviral prophylaxis or a strict pre-emptive strategy may be optimal for patients at the highest risk for CMV, while patients at lower risk may benefit particularly from pre-emptive monitoring and the administration of therapy only if needed. CMV-specific T-cell assays may be useful for further refining the pre-transplant determination of CMV risk, and for guiding decisions about antiviral therapy need or duration. An immunosuppressive regimen including a mammalian target of rapamycin inhibitor reduces CMV risk and may thus be an attractive option in some patients. New antiviral agents may further expand our therapeutic arsenal in the near future, and the prospects of CMV vaccination and adoptive T-cell therapy appear to be on the horizon.
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Affiliation(s)
- Rachel Hellemans
- Department of Nephrology, Antwerp University Hospital, Antwerp, Belgium.,Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Belgium
| | - Daniel Abramowicz
- Department of Nephrology, Antwerp University Hospital, Antwerp, Belgium.,Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Belgium
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42
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Raval AD, Kistler K, Tang Y, Murata Y, Snydman DR. Antiviral treatment approaches for cytomegalovirus prevention in kidney transplant recipients: A systematic review of randomized controlled trials. Transplant Rev (Orlando) 2020; 35:100587. [PMID: 33190040 DOI: 10.1016/j.trre.2020.100587] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 10/16/2020] [Accepted: 10/23/2020] [Indexed: 12/17/2022]
Abstract
Various CMV anti-viral (AV) preventive strategies have been utilized in KTRs. We examined efficacy, safety and costs of CMV-AV prevention strategies in KTRs using a systematic literature review (SLR) of randomized controlled trials (RCTs) publications indexed in MEDLINE and Embase (from inception to November 2018). Thirty RCTs met inclusion criteria with 22 unique AV preventive strategies. Prophylaxis was associated with significantly lower rates of CMV infection/disease (CMVi/d) compared to no prophylaxis (pooled odds ratio, pOR with 95% confidence interval (CI): CMVi: 0.33; 0.19, 0.57; CMVd: 0.27; 0.19; 0.39). Preemptive therapy (PET) had lower rates of CMVd (0.29; 0.11, 0.77), and medical costs compared to no PET. Prophylaxis had significantly lower rates of early CMVi/d, and higher rates of late CMVi and hematological adverse events (leukopenia, 2.93; 1.22, 7.04), and similar overall medical costs compared to PET. Studies involving head-to-head comparison of different prophylaxis approaches showed mixed findings with respect to optimum dose, duration and route of administration on CMV outcomes. Although there was heterogeneity across populations and interventions, both prophylaxis and PET strategies reduced CMVi/d compared to no prophylaxis/PET and had differential safety profile in terms of hematological adverse events. For comprehensiveness we did not limit study inclusion based on date; the wide time-period may have contributed to the heterogeneity in prevention approaches which subsequently made pooling studies a challenge. Despite demonstrated efficacy of prophylaxis/PET, our findings highlight the potential need of a novel intervention with a better safety profile and perhaps improved outcomes.
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Kaminski H, Marsères G, Cosentino A, Guerville F, Pitard V, Fournié JJ, Merville P, Déchanet-Merville J, Couzi L. Understanding human γδ T cell biology toward a better management of cytomegalovirus infection. Immunol Rev 2020; 298:264-288. [PMID: 33091199 DOI: 10.1111/imr.12922] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Revised: 09/04/2020] [Accepted: 09/04/2020] [Indexed: 12/28/2022]
Abstract
Cytomegalovirus (CMV) infection is responsible for significant morbidity and mortality in immunocompromised patients, namely solid organ and hematopoietic cell transplant recipients, and can induce congenital infection in neonates. There is currently an unmet need for new management and treatment strategies. Establishment of an anti-CMV immune response is critical in order to control CMV infection. The two main human T cells involved in HCMV-specific response are αβ and non-Vγ9Vδ2 T cells that belong to γδ T cell compartment. CMV-induced non-Vγ9Vδ2 T cells harbor a specific clonal expansion and a phenotypic signature, and display effector functions against CMV. So far, only two main molecular mechanisms underlying CMV sensing have been identified. Non-Vγ9Vδ2 T cells can be activated either by stress-induced surface expression of the γδT cell receptor (TCR) ligand annexin A2, or by a multimolecular stress signature composed of the γδTCR ligand endothelial protein C receptor and co-stimulatory signals such as the ICAM-1-LFA-1 axis. All this basic knowledge can be harnessed to improve the clinical management of CMV infection in at-risk patients. In particular, non-Vγ9Vδ2 T cell monitoring could help better stratify the risk of infection and move forward a personalized medicine. Moreover, recent advances in cell therapy protocols open the way for a non-Vγ9Vδ2 T cell therapy in immunocompromised patients.
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Affiliation(s)
- Hannah Kaminski
- ImmunoConcEpT UMR 5164, CNRS, Bordeaux University, Bordeaux, France.,Department of Nephrology, Transplantation, Dialysis and Apheresis, Bordeaux University Hospital, Bordeaux, France
| | - Gabriel Marsères
- ImmunoConcEpT UMR 5164, CNRS, Bordeaux University, Bordeaux, France
| | - Anaïs Cosentino
- ImmunoConcEpT UMR 5164, CNRS, Bordeaux University, Bordeaux, France.,Department of Nephrology, Transplantation, Dialysis and Apheresis, Bordeaux University Hospital, Bordeaux, France
| | - Florent Guerville
- ImmunoConcEpT UMR 5164, CNRS, Bordeaux University, Bordeaux, France.,CHU Bordeaux, Pôle de gérontologie, Bordeaux, Bordeaux, France
| | - Vincent Pitard
- ImmunoConcEpT UMR 5164, CNRS, Bordeaux University, Bordeaux, France
| | - Jean-Jacques Fournié
- Centre de Recherches en Cancérologie de Toulouse (CRCT), UMR1037 INSERM, Université Toulouse III: Paul-Sabatier, ERL5294 CNRS, Université de Toulouse, Toulouse, France
| | - Pierre Merville
- ImmunoConcEpT UMR 5164, CNRS, Bordeaux University, Bordeaux, France.,Department of Nephrology, Transplantation, Dialysis and Apheresis, Bordeaux University Hospital, Bordeaux, France
| | | | - Lionel Couzi
- ImmunoConcEpT UMR 5164, CNRS, Bordeaux University, Bordeaux, France.,Department of Nephrology, Transplantation, Dialysis and Apheresis, Bordeaux University Hospital, Bordeaux, France
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Hellemans R, Wijtvliet V, Bergs K, Philipse E, Vleut R, Massart A, Couttenye MM, Matheeussen V, Abramowicz D. A split strategy to prevent cytomegalovirus after kidney transplantation using prophylaxis in serological high-risk patients and a pre-emptive strategy in intermediate-risk patients: Combining the best of two options? Transpl Infect Dis 2020; 23:e13467. [PMID: 32935909 DOI: 10.1111/tid.13467] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Revised: 08/27/2020] [Accepted: 09/06/2020] [Indexed: 12/26/2022]
Abstract
BACKGROUND Cytomegalovirus (CMV) remains an important challenge after kidney transplantation. Current Transplantation Society International Consensus Guidelines recommend antiviral prophylaxis or pre-emptive therapy for high-risk CMV-seronegative recipients with a CMV-seropositive donor (D+/R-) and moderate-risk CMV-seropositive recipients (R+). However, a split strategy according to CMV serostatus is not specifically mentioned. METHODS We evaluated a split strategy to prevent CMV infection after kidney transplantation in which D+/R- patients received valganciclovir (VGC) prophylaxis for 200 days, and R + patients were treated pre-emptively according to CMV DNAemia. Patients were followed until 1-year post-transplant. RESULTS Between April 2014 and March 2018, 40 D+/R- and 92 R + patients underwent kidney transplantation. Forty-six percent received antithymocyte globulin (ATG) induction, and 98% was treated with calcineurin inhibitors, mycophenolic acid (MPA), and steroids. No D+/R- patient developed CMV disease during prophylaxis (median 200 days), but 15% developed post-prophylaxis or late-onset disease. Fifty-three percent developed neutropenia during prophylaxis, including 16/40 (40%) grade 3 or 4 neutropenia requiring reduction/discontinuation of MPA (30%) and/or VGC (35%), and an occasional need for granulocyte colony-stimulating factor (5%). In the R + group, 40% received antiviral therapy for a median duration of 21 days; 5% developed early-onset CMV disease. Only 5% developed neutropenia. D+/R + status (hazard ratio (HR) 2.09,P = .004) and ATG use (HR 2.81, P < .0001) were risk factors for CMV reactivation. CONCLUSIONS Prophylaxis leads to acceptable CMV control in high-risk patients but comes with a high risk of neutropenia. Pre-emptive therapy is effective and limits drug exposure in those at lower risk of CMV.
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Affiliation(s)
- Rachel Hellemans
- Department of Nephrology, Antwerp University Hospital, Edegem, Belgium.,Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Antwerpen, Belgium
| | - Veerle Wijtvliet
- Department of Nephrology, Antwerp University Hospital, Edegem, Belgium.,Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Antwerpen, Belgium
| | - Kristof Bergs
- Department of Microbiology, Antwerp University Hospital, Edegem, Belgium
| | - Ester Philipse
- Department of Nephrology, Antwerp University Hospital, Edegem, Belgium.,Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Antwerpen, Belgium
| | - Rowena Vleut
- Department of Nephrology, Antwerp University Hospital, Edegem, Belgium.,Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Antwerpen, Belgium
| | - Annick Massart
- Department of Nephrology, Antwerp University Hospital, Edegem, Belgium.,Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Antwerpen, Belgium
| | - Marie-Madeleine Couttenye
- Department of Nephrology, Antwerp University Hospital, Edegem, Belgium.,Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Antwerpen, Belgium
| | - Veerle Matheeussen
- Department of Microbiology, Antwerp University Hospital, Edegem, Belgium
| | - Daniel Abramowicz
- Department of Nephrology, Antwerp University Hospital, Edegem, Belgium.,Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Antwerpen, Belgium
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45
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Bischof N, Wehmeier C, Dickenmann M, Hirt-Minkowski P, Amico P, Steiger J, Naegele K, Hirsch HH, Schaub S. Revisiting cytomegalovirus serostatus and replication as risk factors for inferior long-term outcomes in the current era of renal transplantation. Nephrol Dial Transplant 2020; 35:346-356. [PMID: 31943075 DOI: 10.1093/ndt/gfz268] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Accepted: 11/15/2019] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Cytomegalovirus (CMV) serostatus and CMV replication are considered as risk factors for inferior graft and patient survival after renal transplantation, but long-term outcome data are limited. The aim of this retrospective single-centre study was to investigate the impact of CMV serostatus and CMV replication/disease on long-term outcomes in a well-defined cohort managed by a standardized CMV prevention/treatment protocol. METHODS We investigated 599 consecutive kidney transplantations having a CMV prevention protocol consisting of either prophylaxis (D+/R- and R+ with ATG induction) or screening/deferred therapy (R+ without ATG induction). Patients were grouped according to CMV serostatus [high risk (D+/R-): n = 122; intermediate risk (R+): n = 306; low risk (D-/R-): n = 171] and occurrence of CMV replication/disease (no CMV replication: n = 419; asymptomatic CMV replication: n = 110; CMV syndrome: n = 39; tissue-invasive CMV disease: n = 31). The median follow-up time was 6.5 years. RESULTS Graft and patient survival were not different among the three CMV serostatus groups as well as the four CMV replication/disease groups (P ≥ 0.44). Eighty-seven patients died, 17 due to infections (21%), but none was attributable to CMV. The overall hospitalization incidence for CMV-related infection was 3% (17/599 patients). The incidence of clinical and (sub)clinical rejection was similar among the groups (P ≥ 0.17). In a multivariate Cox proportional hazard model, neither CMV serostatus, nor CMV replication, nor CMV disease were independent predictors for patient death or graft failure, respectively. CONCLUSIONS This retrospective single-centre study suggests that the negative impact of CMV infection on long-term patient and allograft survival as well as on allograft rejection can be largely eliminated with current diagnostic/therapeutic management.
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Affiliation(s)
- Nicole Bischof
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - Caroline Wehmeier
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - Michael Dickenmann
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - Patricia Hirt-Minkowski
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - Patrizia Amico
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - Jürg Steiger
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland.,Transplantation Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Klaudia Naegele
- Clinical Virology, Laboratory Medicine, University Hospital Basel, Basel, Switzerland
| | - Hans H Hirsch
- Clinic for Infectious Diseases and Hospital Epidemiology, University Hospital Basel, Basel, Switzerland.,Transplantation and Clinical Virology, Department of Biomedicine (Haus Petersplatz), University of Basel, Basel, Switzerland
| | - Stefan Schaub
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland.,Transplantation Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland.,HLA-Diagnostic and Immunogenetics, Department of Laboratory Medicine, University Hospital Basel, Basel, Switzerland
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Engelmann C, Sterneck M, Weiss KH, Templin S, Zopf S, Denk G, Eurich D, Pratschke J, Weiss J, Braun F, Welker MW, Zimmermann T, Knipper P, Nierhoff D, Lorf T, Jäckel E, Hau HM, Tsui TY, Perrakis A, Schlitt HJ, Herzer K, Tacke F. Prevention and Management of CMV Infections after Liver Transplantation: Current Practice in German Transplant Centers. J Clin Med 2020; 9:2352. [PMID: 32717978 PMCID: PMC7465768 DOI: 10.3390/jcm9082352] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 07/15/2020] [Accepted: 07/20/2020] [Indexed: 12/22/2022] Open
Abstract
Human cytomegalovirus (CMV) remains a major cause of mortality and morbidity in human liver transplant recipients. Anti-CMV therapeutics can be used to prevent or treat CMV in liver transplant recipients, but their toxicity needs to be balanced against the benefits. The choice of prevention strategy (prophylaxis or preemptive treatment) depends on the donor/recipient sero-status but may vary between institutions. We conducted a series of consultations and roundtable discussions with German liver transplant center representatives. Based on 20 out of 22 centers, we herein summarize the current approaches to CMV prevention and treatment in the context of liver transplantation in Germany. In 90% of centers, transient prophylaxis with ganciclovir or valganciclovir was standard of care in high-risk (donor CMV positive, recipient CMV naive) settings, while preemptive therapy (based on CMV viremia detected during (bi) weekly PCR testing for circulating CMV-DNA) was preferred in moderate- and low-risk settings. Duration of prophylaxis or intense surveillance was 3-6 months. In the case of CMV infection, immunosuppression was adapted. In most centers, antiviral treatment was initiated based on PCR results (median threshold value of 1000 copies/mL) with or without symptoms. Therefore, German transplant centers report similar approaches to the prevention and management of CMV infection in liver transplantation.
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Affiliation(s)
- Cornelius Engelmann
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum, Charité University Medicine Berlin, 13353 Berlin, Germany;
- Institute for Liver and Digestive Health, University College London, Royal Free Campus, London NW32PF, UK
- Section Hepatology, Clinic for Gastroenterology and Rheumatology, University Hospital Leipzig, 04103 Leipzig, Germany
| | - Martina Sterneck
- Department of Medicine I, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany;
| | - Karl Heinz Weiss
- Department of Gastroenterology and Hepatology, University of Heidelberg, 69117 Heidelberg, Germany;
| | - Silke Templin
- Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, 72076 Tübingen, Germany;
| | - Steffen Zopf
- Department of Medicine 1, University of Erlangen-Nürnberg, 91054 Erlangen, Germany;
| | - Gerald Denk
- Medical clinic and policlinic II, Campus Grosshadern, Ludwig Maximilians University (LMU), 80333 Munich, Germany;
- Transplantation Center Munich, University Hospital, 81377 LMU Munich, Germany
| | - Dennis Eurich
- Department of Surgery Campus Charité Mitte/Campus Virchow-Klinikum, 13353 Berlin, Germany; (D.E.); (J.P.)
| | - Johann Pratschke
- Department of Surgery Campus Charité Mitte/Campus Virchow-Klinikum, 13353 Berlin, Germany; (D.E.); (J.P.)
| | - Johannes Weiss
- Department of Medicine II, University Hospital Würzburg, 97080 Würzburg, Germany;
| | - Felix Braun
- Department of General, Visceral, Thoracic, Transplant and Pediatric Surgery, University Medical Center Schleswig-Holstein, 24105 Kiel, Germany;
| | - Martin-Walter Welker
- Department of Medicine I, University Hospital Frankfurt, 60590 Frankfurt, Germany;
| | - Tim Zimmermann
- Department of Medicine, Hepatology, University of Mainz, 55101 Mainz, Germany;
| | - Petra Knipper
- Department of Internal Medicine I, University Hospital Bonn, 53127 Bonn, Germany;
| | - Dirk Nierhoff
- Department of Gastroenterology and Hepatology, University Hospital Köln, 50937 Köln, Germany;
| | - Thomas Lorf
- Clinic for General, Visceral and Pediatric Surgery, University Medical Center Goettingen, 37075 Goettingen, Germany;
| | - Elmar Jäckel
- Department of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, 30625 Hannover, Germany;
| | - Hans-Michael Hau
- Department of Visceral, Transplantation, Thoracic, and Vascular Surgery, University Hospital Leipzig, 04103 Leipzig, Germany;
| | - Tung Yu Tsui
- Section of Oncological Surgery and Transplantation, Rostock University Medical Center, 18057 Rostock, Germany;
| | - Aristoteles Perrakis
- Department of General, Visceral, Vascular and Transplant Surgery, University Hospital Magdeburg, 39120 Magdeburg, Germany;
| | | | - Kerstin Herzer
- Knappschafts-Hospital Bad Neuenahr, Deutsche Rentenversicherung, Knappschaft-Bahn-See, 53474 Bad Neuenahr-Ahrweiler, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum, Charité University Medicine Berlin, 13353 Berlin, Germany;
- Department of Medicine III, University Hospital Aachen, 52074 Aachen, Germany
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47
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Keskinoglu A, Bulut İK, Taner S, Turkes AZ, Kabasakal C. Cytomegalovirus Experience in Pediatric Kidney Transplantation in 26 Years' Time. Transplant Proc 2020; 52:3186-3191. [PMID: 32646585 DOI: 10.1016/j.transproceed.2020.03.023] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Revised: 02/22/2020] [Accepted: 03/12/2020] [Indexed: 11/30/2022]
Abstract
INTRODUCTION In this study,we investigated the presence of cytomegalovirus (CMV) infection in kidney transplanted children and its effect on kidney dysfunction. MATERIAL AND METHODS One hundred thirty-five pediatric renal transplant patients were included in this study. The presence of CMV infection, CMV risk status, and other clinical features of the patients were evaluated retrospectively. RESULTS Fifty-three percent of all patients and 68.8% of patients with CMV were male. The mean age was 12 years in all patients and CMV groups. According to the CMV risk classification, 40.9% of the patients with CMV infection/disease were in the high-risk group (CMV D+R-). In CMV risk groups, the presence of CMV infection/disease was similar. Cold ischemia time, male sex (patients and donors), deceased donor, higher HLA-mismatches, and cumulative antithymocyte globulin dose were found as risk factors for CMV infection/disease. Acute rejection/graft failure was observed in 27% of all patients. CMV infection has no effect on rejection/graft failure and survival. DISCUSSION The frequency and risk factors of CMV in renal transplant children in our study were consistent with the literature. CONCLUSIONS CMV infection was found in one-fifth of our patients and the majority (71.9%) of them developed infection in the first 6 months. In one-third of our patients acute rejection/graft failure was observed. There was no effect of CMV infection on rejection/graft failure and survival in pediatric patients with proper and effective treatment.
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Affiliation(s)
- Ahmet Keskinoglu
- Department of Pediatric Nephrology, Ege University Faculty of Medicine Children's Hospital, Bornova-İzmir, Turkey.
| | - İpek Kaplan Bulut
- Department of Pediatric Nephrology, Ege University Faculty of Medicine Children's Hospital, Bornova-İzmir, Turkey
| | - Sevgin Taner
- Department of Pediatric Nephrology, Ege University Faculty of Medicine Children's Hospital, Bornova-İzmir, Turkey
| | - Ayşın Zeytinoglu Turkes
- Department of Medical Microbiology, Ege University Faculty of Medicine, Bornova-İzmir, Turkey
| | - Caner Kabasakal
- Department of Pediatric Nephrology, Ege University Faculty of Medicine Children's Hospital, Bornova-İzmir, Turkey
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Kaminski H, Belanger J, Mary J, Garrigue I, Acquier M, Déchanet-Merville J, Merville P, Couzi L. Effect of mTOR inhibitors during CMV disease in kidney transplant recipients: Results of a pilot retrospective study. Microbiol Immunol 2020; 64:520-531. [PMID: 32249964 DOI: 10.1111/1348-0421.12794] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 03/28/2020] [Accepted: 03/31/2020] [Indexed: 12/12/2022]
Abstract
mTOR inhibitors exert a preventive effect on cytomegalovirus (CMV) disease in CMV seropositive (R+) kidney transplant recipients, but their impact during the curative treatment of CMV disease in high-risk kidney transplant recipients has not been investigated. We aimed to evaluate the efficacy and tolerance of mTOR inhibitors compared with mycophenolic acid in 63 consecutive kidney transplant recipients (80% of D+R-) suffering from CMV disease with a persistent or a recurrent CMV DNAemia. In this monocentric retrospective study, 16 had their treatment converted to mTOR inhibitors and 47 did not. The Kaplan-Meier curves did not show any significant differences in CMV DNAemia eradication (77% vs. 88% respectively; hazard ratio (HR), 1.648 [95% confidence interval (CI), 0.913-2.973]; log-rank test, P = .132), DNAemia recurrence (36% vs. 47%; HR, 1.517 [95% CI, 0.574-4.007]; log-rank test, P = .448) and CMV clinical recurrence (17% vs. 27%; HR, 1.375 [95% CI, 0.340-5.552]; log-rank test, P = .677) between patients who received mTOR inhibitors and those who did not. These results were confirmed in uni- and multivariate time-dependent Cox regressions. In summary, conversion from mycophenolic acid to mTOR inhibitors seems inadequate for improving CMV clearance or in better preventing CMV recurrences during severe or persistent CMV disease.
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Affiliation(s)
- Hannah Kaminski
- Department of Nephrology, Transplantation, Dialysis and Apheresis, Pellegrin University Hospital, Bordeaux, France.,CNRS-UMR 5164 ImmunoConcEpT, Bordeaux University, Bordeaux, France
| | - Juliette Belanger
- Department of Nephrology, Transplantation, Dialysis and Apheresis, Pellegrin University Hospital, Bordeaux, France
| | - Julien Mary
- Department of Nephrology, Transplantation, Dialysis and Apheresis, Pellegrin University Hospital, Bordeaux, France
| | - Isabelle Garrigue
- Laboratory of Virology, Pellegrin University Hospital, Bordeaux, France
| | - Mathieu Acquier
- Department of Nephrology, Transplantation, Dialysis and Apheresis, Pellegrin University Hospital, Bordeaux, France
| | | | - Pierre Merville
- Department of Nephrology, Transplantation, Dialysis and Apheresis, Pellegrin University Hospital, Bordeaux, France.,CNRS-UMR 5164 ImmunoConcEpT, Bordeaux University, Bordeaux, France
| | - Lionel Couzi
- Department of Nephrology, Transplantation, Dialysis and Apheresis, Pellegrin University Hospital, Bordeaux, France.,CNRS-UMR 5164 ImmunoConcEpT, Bordeaux University, Bordeaux, France
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Song T, Yin S, Li X, Jiang Y, Lin T. Thymoglobulin vs. ATG-Fresenius as Induction Therapy in Kidney Transplantation: A Bayesian Network Meta-Analysis of Randomized Controlled Trials. Front Immunol 2020; 11:457. [PMID: 32318057 PMCID: PMC7146975 DOI: 10.3389/fimmu.2020.00457] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2019] [Accepted: 02/27/2020] [Indexed: 02/05/2023] Open
Abstract
Background: Thymoglobulin (THG) and antithymocyte globulin-Fresenius (ATG-F) have not been compared directly as induction therapies in kidney transplantation. Materials and Methods: We performed a Bayesian network meta-analysis to compare THG with ATG-F by pooling direct and indirect evidence. Surface under the cumulative ranking curve (SUCRA) values were used to compare the superiority of one method over the other. Results: A total of 27 randomized controlled trials (RCT) were eligible for the network meta-analysis. Efficacy endpoints, as well as safety indicators, were statistically comparable. For efficacy endpoints, THG seemed inferior to ATG-F in preventing delayed graft function [odds ratio (OR): 1.27; SUCRA: 78% vs. 58%], patient deaths (OR: 2.78; SUCRA: 83% vs. 34%), and graft loss (OR: 1.40; SUCRA: 83% vs. 59%), but superior to ATG-F in biopsy-proven acute rejection (BPAR; OR: 0.59; SUCRA: 78% vs. 39%) and steroid-resistant BPAR prevention (OR: 0.61; SUCRA: 76% vs. 49%) within the first year. For safety endpoints, THG was associated with higher risk of infection (OR: 1.49, SUCRA: 79% vs. 54%), cytomegalovirus infection (OR: 1.04; SUCRA: 40% vs. 37%), de novo diabetes (OR: 1.10; SUCRA: 90% vs. 30%), and malignancy (OR: 8.40; SUCRA: 89% vs. 6%) compared to ATG-F. A subgroup analysis of patients at high risk for immunologic complications revealed similar results, but THG performed better for graft loss (OR: 0.82; SUCRA: 68% vs. 54%). Conclusion: ATG-F seemed to be more effective than THG in improving the short-term kidney transplantation outcomes. Prospective head-to-head comparison of THG and ATG-F with larger sample sizes and longer follow-up is still required.
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Affiliation(s)
- Turun Song
- Department of Urology, Organ Transplantation Center, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China.,West China Medical School, Sichuan University, Chengdu, China
| | - Saifu Yin
- Department of Urology, Organ Transplantation Center, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China.,West China Medical School, Sichuan University, Chengdu, China
| | - Xingxing Li
- West China Medical School, Sichuan University, Chengdu, China
| | - Yamei Jiang
- Department of Urology, Organ Transplantation Center, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Tao Lin
- Department of Urology, Organ Transplantation Center, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China.,West China Medical School, Sichuan University, Chengdu, China
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50
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Singh N, Winston DJ, Razonable RR, Lyon GM, Silveira FP, Wagener MM, Stevens-Ayers T, Edmison B, Boeckh M, Limaye AP. Effect of Preemptive Therapy vs Antiviral Prophylaxis on Cytomegalovirus Disease in Seronegative Liver Transplant Recipients With Seropositive Donors: A Randomized Clinical Trial. JAMA 2020; 323:1378-1387. [PMID: 32286644 PMCID: PMC7157180 DOI: 10.1001/jama.2020.3138] [Citation(s) in RCA: 114] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
IMPORTANCE Despite the use of a cytomegalovirus (CMV) prevention strategy of antiviral prophylaxis for high-risk CMV-seronegative liver transplant recipients with seropositive donors, high rates of delayed-onset postprophylaxis CMV disease occur. An alternate approach, preemptive therapy (initiation of antiviral therapy for early asymptomatic CMV viremia detected by surveillance testing), has not previously been directly compared with antiviral prophylaxis in these patients. OBJECTIVE To compare preemptive therapy with antiviral prophylaxis in CMV-seronegative liver transplant recipients with seropositive donors for the prevention of CMV disease. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial of preemptive therapy vs antiviral prophylaxis in 205 CMV-seronegative liver transplant recipients with seropositive donors aged older than 18 years. The trial was conducted at 6 academic transplant centers in the United States between October 2012 and June 2017, with last follow-up in June 2018. INTERVENTIONS Patients were randomized 1:1 to receive either preemptive therapy (valganciclovir, 900 mg, twice daily until 2 consecutive negative tests a week apart) for viremia detected by weekly plasma CMV polymerase chain reaction for 100 days (n = 100) or valganciclovir, 900 mg, daily for 100 days as antiviral prophylaxis (n = 105). MAIN OUTCOMES AND MEASURES The primary outcome was incidence of CMV disease by 12 months, defined as CMV syndrome (CMV viremia and clinical or laboratory findings) or end-organ disease. Secondary outcomes included acute allograft rejection, opportunistic infections, graft and patient survival, and neutropenia. RESULTS Among 205 patients who were randomized (mean age, 55 years; 62 women [30%]), all 205 (100%) completed the trial. The incidence of CMV disease was significantly lower with preemptive therapy than antiviral prophylaxis (9% [9/100] vs 19% [20/105]; difference, 10% [95% CI, 0.5% to 19.6%]; P = .04]). The incidence of allograft rejection (28% vs 25%; difference, 3% [95% CI, -9% to 15%]), opportunistic infections (25% vs 27%; difference, 2% [95% CI, -14% to 10%]), graft loss (2% vs 2%; difference, <1% [95% CI, -4% to 4%]), and neutropenia (13% vs 10%; difference, 3% [95% CI, -5% to 12%]) did not differ significantly for the preemptive therapy vs antiviral prophylaxis group, respectively. All-cause mortality at last follow-up was 15% in the preemptive therapy vs 19% in the antiviral prophylaxis group (difference, 4% [95% CI, -14% to 6%]; P = .46). CONCLUSIONS AND RELEVANCE Among CMV-seronegative liver transplant recipients with seropositive donors, the use of preemptive therapy, compared with antiviral prophylaxis, resulted in a lower incidence of CMV disease over 12 months. Further research is needed to replicate these findings and assess long-term outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01552369.
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Affiliation(s)
- Nina Singh
- University of Pittsburgh, Pittsburgh, Pennsylvania
- VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania
| | - Drew J. Winston
- University of California Los Angeles Medical Center, Los Angeles
| | | | | | | | | | | | | | - Michael Boeckh
- Fred Hutchinson Cancer Research Center, Seattle, Washington
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