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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; I 2 = 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; I 2 = 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; I 2 = 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; I 2 = 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; I 2 = 66%; low-certainty evidence). The risk of leucopenia (7 studies, 869 participants: RR 0.57, 95% CI 0.38 to 0.87; I 2 = 33%; moderate-certainty evidence) and neutropenia (5 studies, 859 participants: RR 0.63, 95% CI 0.44 to 0.90; I 2 = 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., (Copyright © 2025 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Early posttransplant cytomegalovirus (CMV) infections in CMV seronegative solid organ transplant recipients (SOTR) with CMV seronegative donors (D-/R-) are often attributed transfusion-transmitted CMV. The prevalence of false-negative donor CMV serology in D-/R- SOTR with early CMV infections has not been explored., Methods: We determined the frequency and characteristics of CMV DNAemia that occurred within 90 days of transplant among adult SOTR classified as D-/R- who underwent a first SOT at a single center between February 25, 2014 and February 25, 2024. Repeat donor CMV antibody testing was performed on stored donor sera if possible., Results: Thirteen of 737 (1.8%) D-/R- SOTR from 12 donors developed CMV DNAemia within 90 days of transplant (median time to DNAemia: 28 days, interquartile range 23-42 days). Five (38%) recipients experienced CMV disease either before (n = 2) or after (n = 3) CMV DNAemia was identified, and five (38%) developed CMV antiviral resistance mutations during their course. Repeat CMV antibody testing was performed on sera from four donors to five recipients and was positive in three (75%) tested donors., Conclusions: Early CMV infections in D-/R- SOTR are uncommon but associated with high morbidity. CMV transmission from organ donors with false negative CMV serology is an important source of early CMV infections in D-/R- SOTR. Clinicians should suspect and promptly report early CMV infections in D-/R- SOTR as potential donor-derived processes, regardless of donor and/or recipient transfusion histories. Reporting such cases is essential to promote broader investigations that may identify suboptimal donor CMV screening assays., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Cytomegalovirus (CMV) infections continue to be associated with significant morbidity and mortality following solid organ transplantation and haemopoietic stem cell transplantation. Advances in understanding the biology of CMV in the immunosuppressed host will translate into improved management approaches and better clinical outcomes. Updated definitions of resistant and refractory CMV infections will lead to more consistent reporting of CMV outcomes, better inform appropriate antiviral strategies and influence clinical trial design. Improved knowledge of the immunological control of CMV in the immunosuppressed host has led to novel diagnostics, emerging therapeutic cellular therapies and the development of an informed rationale for prophylactic and pre-emptive strategies. As the boundaries of transplantation are extended, new patterns of CMV infection are being recognised. Finally, recent studies support the use of novel antiviral therapies in transplant recipients in the appropriate clinical setting. In this review, we provide an update on important new and emerging concepts in the management of CMV in immunosuppressed transplant recipients., (© 2024 Royal Australasian College of Physicians.)

Cytomegalovirus (CMV) infection in solid organ transplant (SOT) and hematopoietic cell transplant (HCT) recipients may increase the risk of rejection or allograft dysfunction, other infection(s), and morbidity and mortality. Treatment can be challenging due to medication-associated toxicities. Maribavir (MBV) is a promising option for the treatment of resistant or refractory (R/R) CMV infection in lieu of foscarnet (FOS), which has long been the recommended therapy for (val)ganciclovir-resistant infection. This was a single-center retrospective study of clinical outcomes of patients who received MBV compared to a control group who received FOS for an episode of CMV infection. Each cohort consisted of 27 episodes of CMV infection. Twenty patients in the MBV cohort and from the FOS cohort cleared the infection, with five and three patients developing MBV or FOS resistance, respectively. There were no statistically significant differences in failure of therapy as evidenced by persistent DNAemia ( p = 0.56) or development of antiviral resistance ( p = 0.24). In conclusion, MBV was as effective as FOS for the treatment of R/R CMV infection and was better tolerated without increased risk of antiviral resistance.

Background: Cytomegalovirus (CMV) is a significant cause of morbidity and mortality in solid organ transplant recipients (SOTRs). Secondary prophylaxis (SP) is not routinely recommended by guidelines on the management of CMV in SOTR but may be considered in certain higher-risk situations., Methods: A comprehensive search of English language publications up to September 2023 was performed. The primary outcome was CMV relapse, defined as the recurrence of DNAemia or disease. Secondary outcomes included graft loss, mortality, and hematological toxicity. Meta-analysis used the random-effects model. The study protocol is registered in PROSPERO (no. CRD42022357028)., Results: Six retrospective comparative studies were included. A total of 520/727 (72%) of SOTR received SP with valganciclovir. The meta-analysis did not demonstrate a significant difference in CMV relapse (odds ratio [OR] 1.15, 95% confidence interval [CI] 0.79-2.63). Heterogeneity between the studies was low (I 2 = 0%, p = 0.57). SP was significantly associated with a reduction in mortality (OR 0.2, 95% CI 0.07-0.54) but not graft loss (OR 0.67, 0.17-2.63). There was no significant difference in CMV relapse among kidney-specific SOTR (OR 1.38, 95% CI 0.65-2.96)., Conclusion: Evidence from six nonrandomized studies is limited and cannot support a recommendation for or against routine SP in SOTR treated for CMV infection. Awaiting prospective-controlled trials, the decision about SP should depend on individualized risk-profile assessments by experienced clinicians., (© 2024 The Author(s). Transplant Infectious Disease published by Wiley Periodicals LLC.)

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., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Julian Torre-Cisneros reports administrative support, article publishing charges, travel, and writing assistance were provided by Spanish Society of Infectious Diseases and Clinical Microbiology. Julian Torre-Cisneros reports a relationship with Merck Sharp & Dohme UK Ltd. that includes: consulting or advisory and speaking and lecture fees. Julian Torre-Cisneros reports a relationship with Takeda Pharmaceutical Company Limited that includes: consulting or advisory. Julian Torre-Cisneros reports a relationship with Biotest AG that includes: consulting or advisory and speaking and lecture fees. Julian Torre-Cisneros reports a relationship with QIAGEN GmbH that includes: consulting or advisory, funding grants, and speaking and lecture fees. Jose Maria Aguado reports a relationship with Mundipharma International Limited that includes: consulting or advisory and speaking and lecture fees. Jose Maria Aguado reports a relationship with Pfizer that includes: consulting or advisory and speaking and lecture fees. Jose Maria Aguado reports a relationship with Merck Sharp & Dohme UK Ltd. that includes: consulting or advisory and speaking and lecture fees. Jose Maria Aguado reports a relationship with Takeda Pharmaceutical Company Limited that includes: consulting or advisory and speaking and lecture fees. Sara Cantisan reports a relationship with QIAGEN GmbH that includes: funding grants and speaking and lecture fees. Juan Jose Caston reports a relationship with Pfizer Inc. that includes: funding grants and speaking and lecture fees. Juan Jose Caston reports a relationship with Merck Sharp & Dohme UK Ltd. that includes: speaking and lecture fees. Juan Jose Caston reports a relationship with A Menarini International Pharmaceutics that includes: speaking and lecture fees. Juan Jose Caston reports a relationship with Novartis Pharmaceuticals Corporation that includes: speaking and lecture fees. Juan Jose Caston reports a relationship with QIAGEN GmbH that includes: funding grants and speaking and lecture fees. Carme Facundo reports a relationship with Merck Sharp & Dohme UK Ltd. that includes: consulting or advisory. Mirian Fernandez-Alonso reports a relationship with Roche Diagnostics Corporation that includes: travel reimbursement. Mirian Fernandez-Alonso reports a relationship with Werfen that includes: travel reimbursement. Mirian Fernandez-Alonso reports a relationship with QIAGEN GmbH that includes: non-financial support. Mario Fernandez-Ruiz reports a relationship with Merck Sharp & Dohme UK Ltd. that includes: consulting or advisory. Mario Fernandez-Ruiz reports a relationship with Biotech that includes: consulting or advisory. Sabina Herrera reports a relationship with Pfizer Inc. that includes: speaking and lecture fees and travel reimbursement. Sabina Herrera reports a relationship with Shionogi Inc. that includes: speaking and lecture fees. Sabina Herrera reports a relationship with Shire that includes: travel reimbursement. Sabina Herrera reports a relationship with A Menarini International Pharmaceutics that includes: travel reimbursement. Oscar Len reports a relationship with Pfizer that includes: funding grants and speaking and lecture fees. Oscar Len reports a relationship with Merck Sharp & Dohme UK Ltd. that includes: funding grants and speaking and lecture fees. Oscar Len reports a relationship with Astellas Pharma Inc. that includes: speaking and lecture fees. Oscar Len reports a relationship with Novartis Pharmaceuticals Corporation that includes: speaking and lecture fees. Ibai Los-Arcos reports a relationship with Pfizer Inc. that includes: speaking and lecture fees and travel reimbursement. Ibai Los-Arcos reports a relationship with Merck Sharp & Dohme UK Ltd. that includes: speaking and lecture fees and travel reimbursement. Ibai Los-Arcos reports a relationship with Gilead Sciences Inc. that includes: travel reimbursement. Ibai Los-Arcos reports a relationship with A Menarini International Pharmaceutics that includes: travel reimbursement. David Navarro reports a relationship with Roche Diagnostics Corporation that includes: consulting or advisory and speaking and lecture fees. David Navarro reports a relationship with Abbott that includes: consulting or advisory and speaking and lecture fees. David Navarro reports a relationship with bioMérieux SA that includes: consulting or advisory and speaking and lecture fees. David Navarro reports a relationship with Beckton Dickinson that includes: consulting or advisory and speaking and lecture fees. David Navarro reports a relationship with Gilead Sciences Inc. that includes: consulting or advisory and speaking and lecture fees. David Navarro reports a relationship with Takeda Pharmaceutical Company Limited that includes: consulting or advisory and speaking and lecture fees. David Navarro reports a relationship with Merck Sharp & Dohme UK Ltd. that includes: consulting or advisory and speaking and lecture fees. David Navarro reports a relationship with Pfizer Inc. that includes: consulting or advisory and speaking and lecture fees. Maricela Valerio reports a relationship with Pfizer Inc. that includes: speaking and lecture fees and travel reimbursement. Maricela Valerio reports a relationship with Merck Sharp & Dohme UK Ltd. that includes: speaking and lecture fees and travel reimbursement. Maricela Valerio reports a relationship with Shionogi and Co Ltd. that includes: speaking and lecture fees and travel reimbursement. Maricela Valerio reports a relationship with GSK that includes: speaking and lecture fees. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Despite advancements in Cytomegalovirus (CMV) management, its impact on graft function, mortality, and cardiovascular (CV) health of organ transplant recipients (OTR) remains a significant concern. We investigated the association between CMV infection and CV events (CVE) in organ (other than heart) transplant recipients., Methods: We conducted a comprehensive literature search in PubMed and EMBASE, including studies that reported on CMV infection or disease and post-transplantation CVE. Studies of heart transplant recipients were excluded., Results: We screened 3875 abstracts and 12 clinical studies were included in the final analysis, mainly in kidney and liver transplant recipients. A significant association was observed between CMV infection and an increased risk of CVE, with a pooled unadjusted hazard ratio (HR) of 1.99 (95% Confidence Intervals [CI] 1.45-2.73) for CMV infection and 1.59 (95% CI 1.21-2.10) for CMV disease. Pooled adjusted HR were 2.17 (95% CI 1.47-3.20) and 1.77 (95% CI 0.83-3.76), respectively. Heterogeneity was low (I 2  = 0%) for CMV infection, suggesting consistent association across studies, and moderate-to-high for CMVdisease (I 2  = 50% for unadjusted, 53% for adjusted HR)., Discussion: We found a significant association between CMV infection and CV risk in abdominal OTR, underscoring the importance of proactive CMV surveillance and early treatment. Future research should aim for more standardized methodologies to fully elucidate the relationship between CMV and CV outcomes, potentially informing novel preventive and therapeutic strategies that could benefit the CV health of OTR., Competing Interests: Declaration of competing interest DF has received research support from Viracor, Astellas, Merck, and Astra-Zeneca, and consultant fee from Viracor. All other authors have nothing to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: The pathogenesis and outcome of cytomegalovirus (CMV) infection after solid organ transplantation (SOT) reflects the interplay between viral replication and CMV-specific immunity. Despite advances in its diagnosis and treatment, CMV continues to cause significant morbidity after SOT. Since CMV is an opportunistic pathogen that occurs as a result of impaired pathogen-specific immunity, laboratory assays that measure CMV-specific immune responses may be useful in assisting clinicians in its management., Methods and Results: The author summarizes the evolving and emerging data on the clinical utility of assays that quantify cell-mediated immune responses to CMV in SOT recipients. The majority of publications are observational studies that demonstrate that a lack or deficiency in CMV-specific cell-mediated immunity is correlated with a heightened risk of primary, reactivation, or recurrent CMV after transplantation. A few prospective interventional studies have utilized CMV-specific cell-mediated immune assays in guiding the duration of antiviral prophylaxis among CMV-seropositive SOT recipients. Likewise, CMV-specific cell-mediated immunity assays have been suggested to inform the need for secondary antiviral prophylaxis and immunologic optimization to prevent CMV relapse after treatment., Conclusions: CMV-specific cell-mediated immune assays are emerging to assist transplant clinicians in predicting a patient's risk of CMV after transplantation, and these assays have been utilized to individualize the approach to CMV prevention and treatment. The author suggests the conduct of more interventional studies to further solidify the role of CMV-specific cell-mediated immune assays in routine clinical practice.

Introduction: Cytomegalovirus (CMV) is a common opportunistic infection after solid organ transplantation, with significant impact on morbidity and long-term survival. Despite advances in diagnostics and therapeutics, the management of CMV remains very challenging., Areas Covered: This article reviews emerging data on the clinical utility of laboratory assays that quantify cell-mediated immune responses to CMV. Observational studies have consistently demonstrated that a deficiency in pathogen-specific cell-mediated immunity is correlated with a heightened risk of primary, reactivation or recurrent CMV after transplantation. A limited number of interventional studies have recently investigated cell-mediated immune assays in guiding the prevention and treatment of CMV infection after solid organ transplantation., Expert Opinion: The pathogenesis and outcome of CMV after solid organ transplantion reflect the interplay between viral replication and CMV-specific immune reconstitution. Research in CMV-specific cell-mediated immunity paved way for the development of several laboratory assays that may assist clinicians in predicting the risk of CMV after transplantation, individualize the approach to CMV disease prevention, guide the need and duration of treatment of CMV infection, and predict the risk of relapse after treatment. More interventional studies are needed to further solidify the role of cell-mediated immune assays in various clinical situations after transplantation.

Background: Preventive strategies for cytomegalovirus (CMV) in the posttransplant period have changed the pattern of CMV infections, now more commonly manifesting as late-onset occurrences known as post-prophylaxis delayed-onset CMV disease (PPDOC). We conducted a survey to investigate provider practices in managing PPDOC., Methods: A web-based provider survey on the management of PPDOC was developed using Research Electronic Data Capture (REDCap). It was distributed to the online forums of the American Society of Transplantation communities of practice (COP) for Infectious Diseases (IDCOP), Kidney and Pancreas (KPCOP), Liver and Intestinal (LICOP), and Thoracic and Critical Care (TCCOP). The survey was posted twice within a span of a month., Results: Fifty-six respondents, comprising 50 (89%) transplant physicians and 6 (11%) transplant pharmacists, from 46 distinct transplant centers, completed the survey. Universal antiviral prophylaxis (UAP) was the predominant preventive approach for both high-risk (85%) and moderate-risk (85%) transplant recipients. Out of 56, 51 respondents completed the questions regarding management of PPDOC. Regular surveillance with nucleic acid amplification tests (NAAT) (88%) was the most commonly used approach in high-risk recipients, while symptom monitoring (73%) was the most common strategy in moderate-risk recipients. Immunologic monitoring was used only by a few respondents who found it moderately useful in high-risk recipients., Conclusion: Management of PPDOC was highly variable among providers and strategies differed based on patient risk profile. These findings could help shape future studies and guidelines to harmonize CMV management., (© 2024 The Author(s). Clinical Transplantation published by John Wiley & Sons Ltd.)

Introduction: Cytomegalovirus (CMV) is a classic opportunistic infection in transplant recipients. Treatment-refractory CMV infections are of concern, with growing identification of strains that have developed genetic mutations which confer resistance to standard antiviral therapy. Resistant and refractory CMV infections are associated with worse patient outcomes, prolonged hospitalization, and increased healthcare costs., Areas Covered: This article provides a comprehensive practical overview of resistant and refractory CMV infections in transplant recipients. We review the updated definitions for these infections, antiviral pharmacology, mechanisms of drug resistance, diagnostic workup, management strategies, and host-related factors including immune optimization., Expert Opinion: Resistant and refractory CMV infections are a significant contributor to post-transplant morbidity and mortality. This is likely the result of a combination of prolonged antiviral exposure and active viral replication in the setting of intensive pharmacologic immunosuppression. Successful control of resistant and refractory infections in transplant recipients requires a combination of immunomodulatory optimization and appropriate antiviral drug choice with sufficient treatment duration.

Importance: Cytomegalovirus (CMV) is associated with significant morbidity and mortality in solid organ transplant (SOT) recipients. The risk factors for CMV seropositivity in SOT recipients, including area-level social deprivation in the US, have not been fully characterized., Objective: To (1) evaluate CMV seroprevalence, (2) assess the recipient characteristics associated with CMV seropositivity, and (3) assess the association of area-level social deprivation index (SDI) scores with pretransplant CMV serostatus., Design, Setting, and Participants: This retrospective cross-sectional analysis of the Scientific Registry of Transplant Recipients database included all adult (aged ≥18 years) SOT recipients from January 1, 2008, to May 31, 2022. Data were analyzed from April 10 to October 25, 2023., Exposure: Recipient characteristics and area-level SDI., Main Outcomes and Measures: Multivariable generalized linear models were used to evaluate the association between (1) patient characteristics and CMV and (2) social deprivation (measured by SDI scores, which were assessed in quintiles, from lowest to highest) and CMV seropositivity. In addition, differences based on patient demographics and the transplanted organ(s) were evaluated., Results: Among the 389 288 SOT recipients included in the analysis, mean (SD) age was 53.3 (13.0) years; 63.0% were male, 21.4% were Black, 15.2% were Hispanic White, 56.2% were non-Hispanic White, and 62.7% were CMV seropositive. The mean (SD) age was higher among CMV seropositive (54.0 [12.7] years) compared with CMV seronegative (52.0 [13.5] years) patients. Seropositivity for CMV was higher among women (69.9%) than men (58.5%) and among Black (74.8%) and Hispanic White (80.2%) patients compared with non-Hispanic White patients (50.4%). Seropositivity for CMV was highest among kidney (64.5%), liver (63.6%), and kidney and liver (66.2%) recipients. Greater SDI scores were associated with greater CMV seropositivity, ranging from 51.7% for the least deprived to 75.5% for the most deprived quintiles (P < .001), independent of age, sex, or race., Conclusions and Relevance: In this cross-sectional study, an association between SDI and CMV seropositivity was observed among SOT recipients, independent of age, sex, or race and ethnicity. To optimize posttransplant outcomes in CMV seropositive recipients, efforts targeting prevention of CMV reactivation need to be prioritized in these higher-risk populations.

Cytomegalovirus (CMV) infection and disease are important causes of morbidity and mortality in transplant recipients. For the purpose of developing consistent reporting of CMV outcomes in clinical trials, definitions of CMV infection and disease were developed and most recently published in 2017. Since then, there have been major developments, including registration of new antiviral agents. Therefore, the Transplant Associated Virus Infections Forum, which consists of scientists, clinicians, regulators, and industry representatives, has produced an updated version of these definitions that incorporates recent knowledge with the aim of supporting clinical research and drug development. This also includes an update regarding the definition of resistant and refractory CMV infections previously published in 2019. As the field evolves, the need for updates of these definitions is clear, and collaborative efforts among clinicians, scientists, regulators, and industry representatives can provide a platform for this work., Competing Interests: Potential conflicts of interest. P. L. has received research grants from AlloVir, MSD, Takeda, and Astellas; has received honoraria from MSD, Moderna, and Gilead; participates on Moderna and OctaPharma data and safety monitoring/advisory boards; and participates as a board member of the European Conference on Infections in Leukemia. R. F. C. has received research grants from Merck/MSD, Karius, AiCuris, Ansun Pharmaceuticals, Takeda, Genentech, Oxford Immunotec, and Eurofins-Viracor; reports consulting fees from ADMA Biologics, Janssen, Merck/MSD, Partner Therapeutics, Takeda, Shinogi, AiCuris, Roche/Genentech, Astellas, Adagio Therapeutics, Tether, Oxford Immunotec, Karius, Moderna, and Ansun Pharmaceuticals; participates on ADMA Biologics, Merck/MSD, Takeda, Shinogi, AiCuris, Roche/Genentech, Tether, Karius, Moderna, and Ansun Pharmaceuticals data and safety monitoring/advisory boards; and reports stock options from Xenex. F. K. has received research grants from Eurofins Viracor and has received honoraria from MEDSCAPE. S. A. has received research grants from Takeda, Merck, MSD, BioMerieux, Hologic, and Elitech; has received honoraria from MSD, Biotest, and Takeda; has received support for attending meetings/travel from MSD, Biotest, and Takeda; and participates on Biotest, Takeda, MSD, QCMD, and GSK data and safety monitoring/advisory boards. R. A. has received research grants from AiCuris, Astellas, AstraZeneca, Chimerix, Merck, Oxford Immunotec, Qiagen, Regeneron, and Takeda. C. B. is an employee of Merck & Co. M. B. has received research grants from Merck. M. F. has received support for attending meetings/travel from, is employed by, and is a shareholder of Takeda. A. H. is an employee of the Division of Antiviral Products, Center for Drug Evaluation and Research, US FDA. T. K. is an employee of the Division of Antiviral Products, Center for Drug Evaluation and Research, US FDA. A. P. L. has received research grants from Merck, Moderna, and Takeda; reports consulting fees from Merck, GSK, and Novartis; and participates on the Novartis data and safety monitoring/advisory board. O. M. has received honoraria from Takeda, MSD, Biotest, and AstraZeneca. Y. N. reports consulting fees from Nobel Pharma. D. N. has received research grants from Pfizer, MSD, Abbot Diagnostics, and Roche Diagnostics; reports consulting fees from Roche Diagnostics, Takeda, and AstraZeneca; has received honoraria from Pfizer, MSD, Roche Diagnostics, Abbot Diagnostics, GSK, and BioMerieux; and has received support for attending meetings/travel from Pfizer. A. P. participates on the Antiretroviral Pregnancy Registry and is an employee of the Division of Antiviral Products, Center for Drug Evaluation and Research, US FDA. R. R. R. has received research grants from Regeneron, Roche Diagnostics, and Gilead; reports consulting fees from AlloVir; participates on the Novartis data and safety monitoring/advisory board; and participates in a leadership role for the American Society of Transplantation. G. W. is an employee of the Swedish Medical Products Agency, Uppsala, Sweden. V. M. has received research grants from AiCuris, AlloVir, Evrys Bio, Merck, Takeda, Symbio Pharma, Qiagen, Vera Therapeutics, and Eurofins-Viracor. P. D. G. reports consulting fees from Biotest, Evrys Bio, GSK, Hookipa, Takeda, and Moderna and reports the United Kingdom patent application 2020135.6 “Human CMV Vaccine,” assigned to University College London. C. N. K. reports consulting fees from Biotest, ExeVir, Evrys Bio, Hookipa, Takeda, Merck, Qiagen, Roche Diagnostics, and Abbot Laboratories; has received honoraria from Takeda, Roche Diagnostics, Qiagen, and Biotest; participates on Takeda, Roche Diagnostics, Abbot Laboratories, Biotest, ExeVir, and Evrys Bio data and safety monitoring/advisory boards; and participates in a leadership role for the Transplantation Society. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Cytomegalovirus (CMV) infection is arguably the most important infectious complication that negatively affects the outcome of solid organ transplantation. For decades, CMV management after transplantation has relied on antiviral drugs that inhibit viral DNA polymerase (ganciclovir, foscarnet, and cidofovir). However, their use has been complicated by myelosuppression, nephrotoxicity, and selection of drug-resistant viruses. During the past few years, the therapeutic armamentarium for the management of CMV in solid organ transplant recipients has expanded with the approval of letermovir for CMV prophylaxis in high-risk CMV D+/R- kidney recipients, and maribavir for the treatment of refractory and resistant CMV infection. Both drugs offer significant improvement when compared to standard anti-CMV therapies; letermovir was as efficacious for CMV prevention, whereas maribavir was more effective in treating refractory and resistant CMV infections. Both letermovir and maribavir have favorable safety profiles compared to CMV DNA polymerase inhibitors, without the risk of neutropenia and leukopenia associated with ganciclovir and renal toxicities associated with foscarnet and cidofovir. Moreover, letermovir and maribavir are orally bioavailable, which allows convenient outpatient treatment. However, letermovir and maribavir have a significant drug interaction potential in solid organ transplant recipients, resulting in higher levels of calcineurin inhibitors (cyclosporine and tacrolimus) and mTOR inhibitors (sirolimus and everolimus). Both letermovir and maribavir are CMV-specific and do not have clinical efficacy against other herpes viruses. Thus, there is a need for additional antiviral drugs to prevent herpes simplex and other herpes viruses when clinically indicated. This article provides a comprehensive review of the clinical data supporting the use of letermovir and maribavir in clinical practice. The author provides perspectives on the role of these newly approved drugs in the current management landscape of CMV infection in solid organ transplantation., Competing Interests: Dr Raymund Razonable reports grants from Gilead, grants from Roche, grants from Regeneron, personal fees from Allovir, personal fees from Novartis, outside the submitted work. The author reports no other conflicts of interest in this work., (© 2024 Razonable.)

Background: Human cytomegalovirus (HCMV) is the most common and serious opportunistic infection after solid organ and hematopoietic stem cell transplantation. In this study, we used whole-genome HCMV data to investigate viral factors associated with the clinical outcome., Methods: We sequenced HCMV samples from 16 immunocompromised pediatric patients with persistent viremia. Eight of the 16 patients died of complications due to HCMV infection. We also sequenced samples from 35 infected solid organ adult recipients, of whom 1 died with HCMV infection., Results: We showed that samples from both groups have fixed variants at resistance sites and mixed infections. Next-generation sequencing also revealed nonfixed variants at resistance sites in most of the patients who died (6/9). A machine learning approach identified 10 genes with nonfixed variants in these patients. These genes formed a viral signature that discriminated patients with HCMV infection who died from those who survived with high accuracy (area under the curve = 0.96). Lymphocyte numbers for a subset of patients showed no recovery posttransplant in the patients who died., Conclusions: We hypothesize that the viral signature identified in this study may be a useful biomarker for poor response to antiviral drug treatment and indirectly for poor T-cell function, potentially identifying early those patients requiring nonpharmacological interventions., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Human cytomegalovirus (HCMV) infection remains a major complication for solid organ transplant recipients (SOTRs). The aim of this study was to evaluate the role of HCMV-specific T cell immunity measured at the time of the HCMV-DNA peak in predicting the spontaneous clearance of infection. The performance of cytokine flow cytometry using infected dendritic cells (CFC-iDC), infected cell lysate (CFC-iCL) and pp65 peptide pool (CFC-pp65 pool) as stimuli, as well as ELISPOT assays using infected cell lysate (ELISPOT-iCL) and the pp65 peptide pool (ELISPOT-pp65 pool), was analysed. Among the 40 SOTRs enrolled, 16 patients (40%) required antiviral treatment for an HCMV infection (Non-Controllers), while the others spontaneously cleared the infection (Controllers). At the HCMV-DNA peak, the number of HCMV-specific CD4 + T cells detected by the CFC-iDC, CFC-iCL and CFC-pp65 pool assays in Controllers was higher than that detected in Non-Controllers, while no difference was observed in terms of HCMV-specific CD8 + T cell response. The same trend was observed when the HCMV-specific T cell response was measured by ELISPOT-iCL and ELISPOT-pp65 pool. We observed that the CD4 + CFC-pp65 pool assay was the best predictor of self-resolving HCMV infection at the time of the HCVM-DNA peak. The CFC-pp65 pool assay is able to discriminate between CD4 + and CD8 + T cell responses and could be used in daily clinical practice.

Background: Cytomegalovirus (CMV) mismatched, donor IgG-positive/recipient IgG-negative, solid organ transplant recipients (SOTRs) are at high risk of CMV invasive disease. Post-prophylaxis disease is an issue in this population. Some programs employ surveillance after prophylaxis (SAP) to limit the incidence of post-prophylaxis disease., Methods: This was a single-center retrospective cohort study that included all CMV mismatched SOTRs from 2003 to 2017. Patients underwent SAP with weekly CMV plasma viral load for 12 weeks. The subjects were classified into three post-prophylaxis DNAemia patterns: no DNAemia, one episode of DNAemia, and multiple episodes of DNAemia. We calculated the cumulative incidence of each DNAemia pattern. We also determined 5-year mortality based on DNAemia pattern stratified by organ transplant type., Results: Post-prophylaxis recurrent DNAemia occurred in 63% of lung recipients and 32% of non-lung recipients (p =  .003). Tissue invasive CMV disease was diagnosed in 3% of the population and CMV syndrome was diagnosed in 33%. Recurrent DNAemia was not associated with 5-year mortality., Conclusion: In this cohort, undergoing SAP tissue invasive disease was uncommon and CMV DNAemia recurrence did not have an impact on long-term mortality., (© 2024 The Authors. Transplant Infectious Disease published by Wiley Periodicals LLC.)

Despite the significant progress made, CMV infection is one of the most frequent infectious complications in transplant recipients. CMV infections that become refractory or resistant (R/R) to the available antiviral drugs constitute a clinical challenge and are associated with increased morbidity and mortality. Novel anti-CMV therapies have been recently developed and introduced in clinical practice, which may improve the treatment of these infections. In this review, we summarize the treatment options for R/R CMV infections in adult hematopoietic cell transplant and solid organ transplant recipients, with a special focus on newly available antiviral agents with anti-CMV activity, including maribavir and letermovir.

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., (Copyright © 2024 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Cytomegalovirus (CMV) infection is associated with increased morbidity and mortality in hematopoietic cell transplant (HCT) and solid organ transplant (SOT) recipients, with traditional anti-CMV therapies limited by their associated toxicities and the development of resistance. Clinical providers are often faced with challenging and complicated CMV infections that require multiple courses of antiviral therapies. Increasingly, advanced practice providers (APPs) are playing an important role in the day-to-day management of transplant recipients with CMV infection, including resistant/refractory CMV and other complex CMV syndromes. Here, we provide an overview of current preventative and treatment strategies for CMV infection in HCT and SOT recipients, highlighting the challenging aspects of current management and the potential utility of newer antiviral agents. This article also focuses on how a multidisciplinary team, orchestrated by APPs, can improve CMV-associated patient outcomes. Protocols using antiviral agents for the prevention or treatment of CMV infections require carefully designed and meticulously implemented strategies to ensure the best clinical outcomes for patients. APPs, who have increasingly become the frontline providers of outpatient care for transplant recipients, are ideally positioned to design and carry out these protocols.

Cytomegalovirus (CMV) is one of the most common infections occurring after solid organ transplantation. This high burden of disease, which incurs sizeable morbidity, may be worsening with the proportion of high-risk D+/R- solid organ transplantation recipients increasing in some regions globally. Cohort studies continue to support either universal prophylaxis or preemptive therapy as effective prevention strategies. Letermovir prophylaxis was noninferior to valganciclovir in adult high-risk D+/R- kidney transplant recipients with fewer drug-related adverse events in a recent clinical trial and has now been approved for such use in some regions. Maribavir preemptive therapy failed to demonstrate noninferiority when compared with valganciclovir in hematopoietic stem cell transplant recipients but looked promising for safety. Donor matching could be useful in prevention CMV disease with a survival advantage demonstrated in seronegative recipients waiting up to 30 mo for a seronegative kidney. Immune-guided prophylaxis resulted in fewer CMV infection episodes in lung transplant recipients when compared with fixed-duration prophylaxis in a recent clinical trial. For treatment of refractory or resistant CMV infection, maribavir was more efficacious and better tolerated when compared with investigator-initiated therapy in its registration trial for this condition. Further research regarding best treatment and prophylaxis of resistant or refractory CMV infection is needed to reflect best clinical practice choices. Optimal use of immune globulin or CMV-specific T cells for prevention or treatment of CMV disease remains undefined. Standardized definitions for the design of CMV clinical trials have been developed. In this review, we highlight recent updates in the field from data published since 2018., Competing Interests: C.N.K. has received consulting fees and participated in adjudication committees and advisory boards for Biotest, Merck & Co Inc, Takeda, QIAGEN, and Roche Diagnostics. A.G.S. declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Cytomegalovirus (CMV) infections among hematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT) recipients impose a significant health care resource utilization (HCRU)-related economic burden. Maribavir (MBV), a novel anti-viral therapy (AVT), approved by the United States Food and Drug Administration for post-transplant CMV infections refractory (with/without resistance) to conventional AVTs has demonstrated lower hospital length of stay (LOS) versus investigator-assigned therapy (IAT; valgancilovir, ganciclovir, foscarnet, or cidofovir) in a phase 3 trial (SOLSTICE). This study estimated the HCRU costs of MBV versus IAT., Methods: An economic model was developed to estimate HCRU costs for patients treated with MBV or IAT. Mean per-patient-per-year (PPPY) HCRU costs were calculated using (i) annualized mean hospital LOS in SOLSTICE, and (ii) CMV-related direct costs from published literature. Probabilistic sensitivity analysis with Monte-Carlo simulations assessed model robustness., Results: Of 352 randomized patients receiving MBV (n = 235) or IAT (n = 117) for 8 weeks in SOLSTICE, 40% had HSCT and 60% had SOT. Mean overall PPPY HCRU costs of overall hospital-LOS were $67,205 (95% confidence interval [CI]: $33,767, $231,275) versus $145,501 (95% CI: $62,064, $589,505) for MBV and IAT groups, respectively. Mean PPPY ICU and non-ICU stay costs were: $32,231 (95% CI: $5,248, $184,524) versus $45,307 (95% CI: $3,957, $481,740) for MBV and IAT groups, and $82,237 (95% CI: $40,397, $156,945) MBV versus $228,329 (95% CI: $94,442, $517,476) for MBV and IAT groups, respectively. MBV demonstrated cost savings in over 99.99% of simulations., Conclusions: This analysis suggests that Mean PPPY HCRU costs were 29%-64% lower with MBV versus other-AVTs., (© 2024 Takeda Pharmaceuticals Inc, US and The Authors. Transplant Infectious Disease published by Wiley Periodicals LLC.)

Purpose of Review: Human cytomegalovirus (CMV) continues to be the most important infectious complication following solid organ transplantation (SOT)., Recent Findings: Universal prophylaxis and preemptive therapy are the most adopted strategies for prevention of CMV disease globally. Prophylaxis with valganciclovir is the most widely used approach to CMV prevention, however leukopenia and late onset CMV disease after discontinuation of prophylaxis requires new strategies to prevent this complication. The use of assays detecting CMV-specific T cell-mediated immunity may individualize the duration of antiviral prophylaxis after transplantation. Letermovir has been recently approved for prophylaxis in kidney transplant recipients. CMV-RNAemia used together with CMV-DNAemia in the viral surveillance of CMV infection provides accurate information on viral load kinetics, mostly in patients receiving letermovir prophylaxis/therapy. The development of refractory and resistant CMV infection remains a major challenge and a new treatment with maribavir is currently available. In the present paper we will review the most recent advances in prevention and treatment of CMV diseases in SOT recipients., Summary: Recent findings, summarized in the present paper, may be useful to optimize prevention and treatment of CMV infection in SOT., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Cytomegalovirus (CMV) remains a serious opportunistic infection in hematopoietic cell transplant (HCT) and solid-organ transplant (SOT) recipients. Traditional anti-CMV drugs are limited by toxicities and the development of resistance. Letermovir and maribavir are newly approved antivirals for the prevention and treatment of CMV., Areas Covered: Prior reviews have discussed use of letermovir for prevention of CMV after HCT and maribavir for resistant or refractory (R/R) CMV post HCT or SOT. Subsequent data have expanded their use including letermovir for primary CMV prophylaxis in high-risk renal transplant recipients and new recommendations for extending prophylaxis through day + 200 in certain HCT patients. Data on the use of maribavir for first asymptomatic CMV infection post-HCT has also been published. This review compares the pharmacology of anti-CMV agents and discusses the updated literature of these new drugs in the prevention and treatment of CMV., Expert Opinion: Letermovir and maribavir are much needed tools that spare toxicities of ganciclovir, foscarnet, and cidofovir. High cost is a challenge preventing their integration into clinical practice in resource-limited countries. Transplant centers need to exercise restraint in overuse to avoid resistance, particularly in the setting of high viral loads.

Cytomegalovirus (CMV) infections are a major source of morbidity and mortality in solid organ transplant recipients. Prophylactic, preemptive, and hybrid prevention strategies have traditionally been the mainstay of CMV prevention but there is growing interest in the use of CMV cell-mediated immune assays to inform novel approaches to risk stratification. Recent evidence suggests that CMV interferon-gamma release assays can offer predictive insights into the risk for CMV-related illnesses, raising the potential for tailored CMV prevention strategies anchored to each individual's unique CMV immune profile. However, the predictive capacity of these assays for CMV-related illnesses can be profoundly influenced by when they are performed relative to transplant, and the induction immunosuppressive regimen the patient has received. In this review, we explore the relevant literature shaping our understanding of the optimal use of these assays. Furthermore, we also highlight the benefits of quantifying the CD4+ and CD8+ T-Cell responses to CMV, which is offered by some interferon-gamma release assays utilizing intracellular cytokine staining, for providing a holistic assessment of the recovery of cell-mediated immunity post-induction immunosuppression., (© 2024 Wiley Periodicals LLC.)

Background: Valganciclovir (VGCV) prophylaxis is associated with an increased risk of hematologic side effects. We analyzed the impact of VGCV prophylaxis on leukopenia and neutropenia rates and explored risk factors for its occurrence., Methods: Retrospective cohort study of adult cytomegalovirus (CMV)-seronegative solid organ transplantation (SOT) recipients of either CMV-seropositive (CMV D+/R-) or CMV-seronegative (CMV D-/R-) donors between July 2005 and March 2019. CMV D+/R- SOT recipients received 3-12 months of VGCV prophylaxis whereas CMV D-/R- SOT recipients received no VGCV prophylaxis. Competing risk regression was used to calculate risk factors for significant neutropenia (neutrophil count < 1000/μL)., Results: A total of 430 CMV-seronegative SOT recipients (median age of 52.1 years, 76.5% males) were included, of which 203 (47.2%) were CMV D+/R- and 227 (52.8%) CMV D-/R-. The unadjusted incidence rate ratio of significant neutropenia attributable to VGCV exposure in the first year post-transplant was 13.50 (95% confidence interval 7.36-27.11). Acute rejection occurred more frequently in neutropenic patients at 32.5% compared to 19.1% in those without neutropenia (p = .033). On multivariate analysis, VGCV prophylaxis for 1-90 days and 91-180 days versus no VGCV were the strongest risk factors for significant neutropenia with a sub-distribution hazard ratio of 39.6 (95% CI, 8.57-182.6) and 13.2 (95% CI, 5.46-32.0), respectively., Conclusions: VGCV prophylaxis is limited by high rates of neutropenia. Future prospective studies are needed to assess alternative CMV prophylactic strategies in SOT recipients., (© 2024 The Authors. Transplant Infectious Disease published by Wiley Periodicals LLC.)

Background: Cytomegalovirus (CMV) infections are common opportunistic infections in solid organ transplants (SOT) with increased health care resource USE and costs. Costs are further increased with ganciclovir-resistance (GR). This study aimed to evaluate the real-world impact of conversion to oral step-down therapy on duration of foscarnet and hospital length of stay (LOS) for treatment of GR-CMV infections in SOT., Methods: This study included adult recipients of kidney or lung transplants who received foscarnet for genotypically documented GR-CMV while admitted at the University of Wisconsin Hospital from October 1, 2015, to January 31, 2022. Patients in the oral step-down group were converted from standard of care (SOC; foscarnet) to maribavir or letermovir; patients in the historical control group were treated with SOC., Results: Twenty-six patients met the inclusion criteria: 5 in the intervention group and 21 in the SOC group. The median viral load at foscarnet initiation was 11,435 IU/mL. Patients who received oral step-down conversion had shorter mean foscarnet duration than those who received SOC (7 ± 4 vs 37 ± 25 days, P = .017). Mean hospital LOS in the oral step-down group (16 ± 3 days) was shorter than the SOC group (33 ± 21 days; P < .001). In the SOC group, 9 patients lost their graft, and 9 patients died; 2 deaths were attributed to CMV. There were 2 deaths in the oral step-down group, neither of which was attributed to CMV., Conclusion and Relevance: In this real-world case series of patients receiving treatment for GR-CMV infection, oral step-down conversion decreased foscarnet therapy duration and hospital LOS. Future studies are needed to evaluate better the effect of oral step-down in treating GR-CMV infection on treatment duration and cost-savings., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The use of assays detecting cytomegalovirus (CMV)-specific T cell-mediated immunity may individualize the duration of antiviral prophylaxis after transplantation., Methods: In this randomized trial, kidney and liver transplant recipients from 6 centers in Switzerland were enrolled if they were CMV-seronegative with seropositive donors or CMV-seropositive receiving antithymocyte globulins. Patients were randomized to a duration of antiviral prophylaxis based on immune monitoring (intervention) or a fixed duration (control). Patients in the control group were planned to receive 180 days (CMV-seronegative) or 90 days (CMV-seropositive) of valganciclovir. Patients were assessed monthly with a CMV ELISpot assay (T-Track CMV); prophylaxis in the intervention group was stopped if the assay was positive. The co-primary outcomes were the proportion of patients with clinically significant CMV infection and reduction in days of prophylaxis. Between-group differences were adjusted for CMV serostatus., Results: Overall, 193 patients were randomized (92 in the immune-monitoring group and 101 in the control group), of whom 185 had evaluation of the primary outcome (87 and 98 patients). CMV infection occurred in 26 of 87 (adjusted percentage, 30.9%) in the immune-monitoring group and in 32 of 98 (adjusted percentage, 31.1%) in the control group (adjusted risk difference, -0.1; 95% confidence interval [CI], -13.0% to 12.7%; P = .064). The duration of prophylaxis was shorter in the immune-monitoring group (adjusted difference, -26.0 days; 95%, CI, -41.1 to -10.8 days; P < .001)., Conclusions: Immune monitoring resulted in a significant reduction of antiviral prophylaxis, but we were unable to establish noninferiority of this approach on the co-primary outcome of CMV infection., Clinical Trials Registration: NCT02538172., Competing Interests: Potential conflicts of interest. O. M. reports research grants from Lophius Biosciences (acquired by Mikrogen), the Novartis Foundation, and the Swiss Transplant Cohort Study; participation on a data and safety monitoring board for Syneos and in advisory boards of MSD, Biotest, and Takeda; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Takeda, paid to their institution. H. H. H. reports grants from Moderna paid to their institution; consulting fees from AiCuris, Allovir, Moderna, VeraTX, and Roche; and honoraria from VeraTX, Takeda, Biotest, and Gilead. P. J. reports serving as an unpaid member of the steering group of a trial funded by Terumo and research grants to their institution from Appili Therapeutics. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

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., (© 2023 The Authors. Transplant Infectious Disease published by Wiley Periodicals LLC.)

Introduction: Solid organ transplantation (SOT) and hematopoietic stem cell transplantation (HSCT) recipients are susceptible to cytomegalovirus (CMV) infection. The incidence of refractoriness to antivirals, with or without resistance, is unclear. The purpose of this review was to describe the epidemiology of refractory CMV infection in Spain to understand the current unmet needs., Methods: PubMed, EMBASE, Cochrane and MEDES were searched systematically for relevant articles. We included randomized controlled trials and observational studies published during the period from January 1990 to June 2021., Results: From 212 screened records, we selected 19 papers including 1973 transplant recipients. Refractory infection ranged from 3 to 10% in studies with SOT recipients. The incidence of CMV resistance ranged from 1% to 36% in these patients. The incidence of CMV refractory infection in HSCT recipients ranged from 11 to 50%, while values for resistant infection ranged from 0% to 21%., Conclusion: The wide range of definitions and values observed does not allow us to establish the true incidence of refractory CMV infection with or without resistances in SOT and HSCT patients in Spain. This review highlights the gap between clinical practice and clinical trials' definitions which needed to be updated to be easier followed in current clinical practice., Competing Interests: Declaration of Competing Interest This work has been supported by Takeda Pharmaceutical Company Limited, Spain. D.N. received consultancy fees from Takeda. J.M.A. received funding for acting as speaker in symposia and serving on advisory boards for Takeda, Merck Sharp & Dohme (MSD), Roche, GSK, Biotest, Pfizer, Shionogi, Angelini and United Medical. I.D.C.O and C.M. are employees of Takeda. MY is employed by Pharmacoeconomics & Outcomes Research Iberia (PORIB) a consulting company specialized in the economic evaluation of health interventions which received funding from Takeda to carry out this work., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Importance: This observation provides comprehensive data on the clinical correlates of both cytomegalovirus (CMV) genotypic follow-up and clinical monitoring and outcomes for two different solid organ transplantation recipients that received letermovir as secondary prophylaxis. Our study emphasizes that monitoring of CMV disease in the patient and early genotypic detection of resistance mutations are essential when using new antiviral drugs for off-label indication in patients experiencing CMV relapses or not responding to standard antiviral therapy. These cases and the bibliography reviewed can be helpful for other researchers and clinicians working in the field to optimize the use of new treatments for transplant recipients since drug-resistant CMV infection is an important emerging problem even with new developments in antiviral treatment., Competing Interests: The authors declare no conflict of interest.

Optimal dosing of valganciclovir (VGCV) for cytomegalovirus (CMV) prevention in pediatric solid organ transplantation recipients (SOTR) is controversial. Dosing calculated based on body surface area (BSA) and creatinine clearance is recommended but simplified body weight (BW) dosing is often prescribed. We conducted a retrospective 6-center study to compare safety and efficacy of these strategies in the first-year posttransplant There were 100 (24.2%) pediatric SOTR treated with BSA and 312 (75.7%) with BW dosing. CMV DNAemia was documented in 31.0% vs 23.4% (P = .1) at any time during the first year and breakthrough DNAemia in 16% vs 12.2% (P = .3) of pediatric SOTR receiving BSA vs BW dosing, respectively. However, neutropenia (50% vs 29.3%, P <.001), lymphopenia (51% vs 15.0%, P <.001), and acute kidney injury causing treatment modification (8.0% vs 1.8%, P <.001) were documented more frequently during prophylaxis in pediatric SOTR receiving BSA vs BW dosing. The adjusted odds ratio of VGCV-attributed toxicities comparing BSA and BW dosing was 2.3 (95% confidence interval [CI], 1.4-3.7] for neutropenia, 7.0 (95% CI, 3.9-12.4) for lymphopenia, and 4.6 (95% CI, 2.2-9.3) for premature discontinuation or dose reduction of VGCV, respectively. Results demonstrate that BW dosing is associated with significantly less toxicity without any increase in CMV DNAemia., Competing Interests: Disclosure The authors of this manuscript have no conflicts of interest to disclose, as described by the American Journal of Transplantation., (Copyright © 2023 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: This review describes current knowledge of ganciclovir (GCV) and valganciclovir (ValGCV) pharmacokinetic/pharmacodynamic characteristics, highlighting the likely contribution from host genetic factors to interpatient variability. The evidence and challenges surrounding optimization of drug dosing through therapeutic drug monitoring (TDM) are examined, with recommendations made., Recent Findings: Pharmacokinetic studies of current dosing guidelines have shown high interindividual and intraindividual variability of GCV concentrations. This is sometimes associated with a slow decline in cytomegalovirus (CMV) viral load in some transplant recipients. A high incidence of GCV-associated myelosuppression has limited the use of this drug in the transplant setting. Patient groups identified to benefit from GCV TDM include pediatric patients, cystic fibrosis with lung transplantation, obese with kidney transplantation, and patients with fluctuating renal function or on hemodialysis. The emergence of refractory resistant CMV, particularly in immune compromised patients, highlights the importance of appropriate dosing of these antivirals. Host genetic factors need to be considered where recently, two host genes were shown to account for interpatient variation during ganciclovir therapy. Therapeutic Drug Monitoring has been shown to improve target antiviral-level attainment. The use of TDM may guide concentration-based dose adjustment, potentially improving virological and clinical outcomes. However, evidence supporting the use of TDM in clinical practice remains limited and further study is needed in the transplant cohort., Summary: Further studies examining novel biomarkers are needed to guide target concentrations in prophylaxis and treatment. The use of TDM in transplant recipients is likely to improve the clinical efficacy of current antivirals and optimize outcomes in transplant recipients., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: Cytomegalovirus (CMV) is a driver of negative patient and allograft outcomes after solid organ transplantation (SOT) and new tools are needed to circumvent these outcomes. We will review key elements of CMV antiviral stewardship in SOT, discuss the available evidence for CMV antiviral stewardship programs and feature areas for expansion in the current landscape of CMV management., Recent Findings: CMV remains a common complication after SOT. While consensus guidelines provide recommendations for the prevention and treatment of CMV, a one-size-fits-all approach is not necessarily appropriate for all unique patients and posttransplant courses, types of SOT recipients and transplant centers. Additionally, consensus guidelines have not been updated since the approval of two new antiviral therapies for the treatment of CMV after SOT or emerging evidence for the incorporation of immune functional assays into clinical practice.From the models provided in recent literature, CMV antiviral stewardship programs have demonstrated efficacy by increasing successful treatment of viremia, optimizing and reducing unnecessary use of (val)ganciclovir for both prophylaxis and treatment, and preventing development of ganciclovir-resistant CMV infections. These models highlight the multidisciplinary approach required of CMV antiviral stewardship programs to provide standardization of management, including incorporation of new therapies and diagnostic tools., Summary: CMV antiviral stewardship programs represent a promising avenue to considerably improve the management of CMV after SOT. Future studies are needed to evaluate a potential positive impact on graft outcomes and patient survival., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest No potential competing interest was reported by the authors. Supported by Fundação de Apoio ao Ensino, Pesquisa e Assistência do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo (FAEPA)., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: The aim of this study is to explore the relationship between ganciclovir exposure and clinical efficacy and/or safety in non-renal solid organ transplant (SOT) recipients receiving preemptive therapy with ganciclovir/valganciclovir and undergoing therapeutic drug monitoring (TDM)-guided dosing optimization., Methods: Non-renal SOT recipients admitted to IRCCS Azienda Ospedaliero-Universitaria of Bologna receiving preemptive therapy with ganciclovir or valganciclovir for active cytomegalovirus (CMV) infection and who underwent at least one TDM were included. Desired ganciclovir C min range was set at 1-3 mg/L, and average ganciclovir trough concentrations (C min ) were calculated for each patient. Reduced CMV viral load below the lower limit of quantification (LLQ) at 30 days and occurrence of myelotoxicity were selected as the primary outcome. Univariate analysis was performed by comparing patients with average C min below or above 1 or 3 mg/L. Receiver operating characteristic (ROC) curve analysis was performed to identify the average ganciclovir C min cut-off predictive for clinical efficacy or toxicity., Results: Twenty-nine out of 89 retrieved patients met the inclusion criteria, with a median (interquartile [IQR]) baseline CMV viral load of 27,163 copies/mL (IQR 13 159.75-151 340.25 copies/mL). Reduced CMV viral load below the LLQ at 30 days was found in 17 patients (58.6%). No difference was found in the primary outcome between patients showing average C min below or above 1 mg/L (100.0% vs. 53.8%; p = .25) and/or 3 mg/L (65.2% vs. 33.3%; p = .20). ROC analysis did not allow to identify an average C min cut-off predictive of clinical efficacy or toxicity., Conclusions: No clear relationship between ganciclovir C min and neither CMV eradication nor safety issues was identified., (© 2023 The Authors. Transplant Infectious Disease published by Wiley Periodicals LLC.)

Background: Cytomegalovirus (CMV) is a frequent infectious complication following solid organ transplantation (SOT). Considering significant differences in healthcare systems, a systematic review was conducted to describe the epidemiology, management, and burden of CMV post-SOT in selected countries outside of Europe and North America., Methods: MEDLINE, Embase, and Cochrane databases were searched for observational studies in SOT recipients across 15 countries in the regions of Asia, Pacific, and Latin America (search period: January 1, 2011 to September 17, 2021). Outcomes included incidence of CMV infection/disease, recurrence, risk factors, CMV-related mortality, treatment patterns and guidelines, refractory and/or resistant CMV, patient-reported outcomes, and economic burden., Results: Of 2708 studies identified, 49 were eligible (n = 43/49; 87.8% in adults; n = 34/49, 69.4% in kidney recipients). Across studies, selection of CMV preventive strategy was based on CMV serostatus. Overall, rates of CMV infection (within 1 year) and CMV disease post-SOT were respectively, 10.3%-63.2% (9 studies) and 0%-19.0% (17 studies). Recurrence occurred in 35.4%-41.0% cases (3 studies) and up to 5.3% recipients died of CMV-associated causes (11 studies). Conventional treatments for CMV infection/disease included ganciclovir (GCV) or valganciclovir. Up to 4.4% patients were resistant to treatment (3 studies); no studies reported on refractory CMV. Treatment-related adverse events with GCV included neutropenia (2%-29%), anemia (13%-48%), leukopenia (11%-37%), and thrombocytopenia (13%-24%). Data on economic burden were scarce., Conclusion: Outside of North America and Europe, rates of CMV infection/disease post-SOT are highly variable and CMV recurrence is frequent. CMV resistance and treatment-associated adverse events, including myelosuppression, highlight unmet needs with conventional therapy., (© 2023 The Authors. Transplant Infectious Disease published by Wiley Periodicals LLC.)

Introduction: Herpes virus infections are a major concern after solid organ transplantation and linked to the immune function of the recipient. We aimed to determine the incidence of positive herpes virus (cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus type 1/2 (HSV-1/2), and varicella zoster virus (VZV)) PCR tests during the first year post-transplantation and assess whether a model including immune function pre-transplantation and three months post-transplantation could predict a subsequent positive herpes virus PCR., Methods: All participants were preemptively screened for CMV, and EBV IgG-negative participants were screened for EBV during the first year post-transplantation. Herpes virus PCR tests for all included herpes viruses (CMV, EBV, HSV-1/2, and VZV) were retrieved from the Danish Microbiology database containing nationwide PCR results from both hospitals and outpatient clinics. Immune function was assessed by whole blood stimulation with A) LPS, B) R848, C) Poly I:C, and D) a blank control. Cytokine concentrations (TNF-α, IL-1β, IL-6, IL-8, IL-10, IL-12p40, IL-17A, IFN-α, and IFN-γ) were measured using Luminex., Results: We included 123 liver (54%), kidney (26%), and lung (20%) transplant recipients. The cumulative incidence of positive herpes virus PCR tests was 36.6% (95% CI: 28.1-45.1) during the first year post-transplantation. The final prediction model included recipient age, type of transplantation, CMV serostatus, and change in Poly I:C-induced IL-12p40 from pre-transplantation to three months post-transplantation. The prediction model had an AUC of 77% (95% CI: 61-92). Risk scores were extracted from the prediction model, and the participants were divided into three risk groups. Participants with a risk score <5 (28% of the cohort), 5-10 (45% of the cohort), and >10 (27% of the cohort) had a cumulative incidence of having a positive herpes virus PCR test at 5.8%, 25%, and 73%, respectively (p < 0.001)., Conclusion: In conclusion, the incidence of positive herpes virus PCR tests was high, and a risk model including immune function allowed the prediction of positive herpes virus PCR and may be used to identify recipients at higher risk., Competing Interests: OR received a grant from the Research Foundation of Rigshospitalet related to this work, and a grant from AP Møller Fonden not related to this work. MP has participated in advisory boards for Takeda, and PulmonX, served as a research consultant for AMBU, received an unlimited institutional research grant from Roche and travel grants from Boeringer-Ingelheim, received lecturing honorary from AstraZeneca, GSK, Therakos and PulmonX but declares no conflict of interest directly related to the study; FG reports consulting fees from Pfizer, Alnylam, Ionis, and Abbott and lecture fees from Novartis, not related to this work; SN received unrestricted research grants from Novo Nordisk Foundation and Independent Research Fund FSS. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Møller, Sørensen, Rezahosseini, Rasmussen, Arentoft, Loft, Perch, Gustafsson, Lundgren, Scheike, Knudsen, Ostrowski, Rasmussen and Nielsen.)

Genotypically resistant cytomegalovirus (CMV) infection is associated with increased morbi-mortality. We herein aimed at understanding the factors that predict CMV genotypic resistance in refractory infections and disease in the SOTR (Solid Organ Transplant Recipients) population, and the factors associated with outcomes. We included all SOTRs who were tested for CMV genotypic resistance for CMV refractory infection/disease over ten years in two centers. Eighty-one refractory patients were included, 26 with genotypically resistant infections (32%). Twenty-four of these genotypic profiles conferred resistance to ganciclovir (GCV) and 2 to GCV and cidofovir. Twenty-three patients presented a high level of GCV resistance. We found no resistance mutation to letermovir. Age (OR = 0.94 per year, IC95 [0.089-0.99]), a history of valganciclovir (VGCV) underdosing or of low plasma concentration (OR= 5.6, IC95 [1.69-20.7]), being on VGCV at infection onset (OR = 3.11, IC95 [1.18-5.32]) and the recipients' CMV negative serostatus (OR = 3.40, IC95 [0.97-12.8]) were independently associated with CMV genotypic resistance. One year mortality was higher in the resistant CMV group (19.2 % versu s 3.6 %, p = 0.02). Antiviral drugs severe adverse effects were also independently associated with CMV genotypic resistance. CMV genotypic resistance to antivirals was independently associated with a younger age, exposure to low levels of GCV, the recipients' negative serostatus, and presenting the infection on VGCV prophylaxis. This data is of importance, given that we also found a poorer outcome in the patients of the resistant group., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Tamzali, Pourcher, Azoyan, Ouali, Barrou, Conti, Coutance, Gay, Tourret and Boutolleau.)

Cytomegalovirus (CMV) infection remains a significant infectious complication after transplantation. In this article, we summarize the recent advances in the management of CMV infection in solid-organ and hematopoietic stem-cell transplant recipients. Firstly, recent trials have better delineated the indications for the preventive strategies available, namely antiviral prophylaxis and the preemptive approach. Secondly, the antiviral armamentarium has been expanded with the advent of less toxic oral drugs that are available for antiviral prophylaxis and for therapy of refractory/resistant CMV infection. Finally, increasing evidence suggests that cell-mediated immune assays can be used in routine care for individualizing the prevention strategies against CMV., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Background: Cytomegalovirus (CMV) donor-positive/recipient-negative (D+R-) serostatus is independently associated with worse allograft and patient survival across solid organ transplant (SOT) types. We characterized trends in CMV D+R- serostatus among adult SOT recipients performed in the United States., Methods: Donor (D) and recipient (R) CMV serostatus and demographic factors were obtained from the Scientific Registry of Transplant Recipients for persons ≥18 y undergoing a first SOT between January 1, 2000, and December 31, 2020. The proportions of D+R- SOTs over time were assessed using Chi square for trend and modeled through 2040. Factors associated with D/R seropositivity were assessed using logistic models., Results: Among 472 549 SOTs, the average proportion of D+R- SOTs increased significantly among kidney, liver, heart, and lung between 2000 to 2009 and 2010 to 2020: 18.0% to 18.3% ( P  = 0.034), 19.4% to 21.8% ( P  < 0.001), 22.2% to 25.5% ( P  < 0.001), and 23.6% to 27.0% ( P  < 0.001), respectively. The increased proportion over time resulted from a disproportionate increase in R- (34.9% to 37.0% for all organ types, P  < 0.001) and a smaller corresponding change in D+ (60.8% to 60.3%, P  < 0.001)., Conclusions: The proportion of high-risk CMV D+R- SOTs increased significantly across all organs and is projected to continue to increase. These findings inform population-level strategies to mitigate the negative impact of CMV D+R- in SOT., Competing Interests: A.P.L. has received consulting fees, research support, contracted research, or consulting fees from: Amplyx Pharmaceuticals, Novartis, Merck, J&J, NovoNordisc, GSK, NobelPharma, Hologic, and Allovir. The other authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: Despite the availability of potent antivirals, consensus guidelines and decades of research, cytomegalovirus (CMV) continues to be associated with negative outcomes after solid organ transplant. This has been attributed to postprophylaxis CMV infection and a lack of development of CMV-specific cell mediated immunity (CMI). A shift from a focus on antiviral prevention to a focus on CMI target attainment is needed to improve CMV outcomes after transplantation., Recent Findings: There are many obstacles to CMI target attainment. Antiviral stewardship programs (AVS) have been employed to improve patient outcomes through appropriate antiviral use, reduction of unnecessary exposure and resistance mitigation. By focusing on the patient's unique substrate of conglomerate risk factors and addressing these factors specifically with evidenced based methodology, the AVS can address these obstacles, increasing rates of CMI and subsequently reducing risk of future CMV infection and negative outcomes., Summary: With its multidisciplinary composition utilizing decades of experience from antimicrobial stewardship principles and practices, the AVS is uniquely poised to facilitate the shift from a focus on prevention to CMI target attainment and be the supporting pillar for the frontline transplant clinician caring for transplant patients with CMV., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Limited data exist to describe sex-based differences in the severity of cytomegalovirus (CMV) infection after solid organ transplant (SOT). We sought to identify if a difference exists in likelihood of tissue-invasive disease between male and female SOT recipients and to understand how age affects this relationship., Methods: A retrospective cohort of 180 heart, liver, and kidney recipients treated for CMV was examined. A logistic regression model was developed to assess the relationship between female sex and CMV type (noninvasive vs. invasive). A secondary regression analysis looked at the relationship of invasive CMV with a variable combining sex with age above or below 50., Results: There were 37 cases of proven or probable invasive CMV, occurring in 30% of females versus 16% of males. After adjustment for potential confounders, females with CMV infection were significantly more likely to have invasive disease (odds ratio (OR) 2.69, 95% confidence interval (CI) 1.25-5.90, p = .01). Females 50 years or older were at particular risk compared with males under 50 years (adjusted OR 4.54, 95% CI 1.33-18.83, p = .02)., Conclusion: Female SOT recipients with CMV in our cohort were more likely than males to have tissue-invasive disease, with the highest risk among older females. Further prospective studies are warranted to explore underlying immunologic mechanisms., (© 2022 Wiley Periodicals LLC.)

Purpose: This study aimed to describe the cytomegalovirus (CMV) infection rate, rehospitalizations, and comorbidities following allogeneic hematopoietic stem cell transplantation (allo-HSCT) and solid organ transplantation (SOT)., Methods: Patients who received allo-HSCT or SOT in 01/07/2015-30/06/2018 were identified using anonymized German claims data. The transplantation-related hospital admission date was defined as the index date, and patients were followed for up to 12 months (or death, first event relevant). The frequency of CMV infections (confirmed outpatient/inpatient diagnoses, ICD-10-GM codes: B25.-/B27.1) and the rate, number, and duration of all-cause rehospitalizations in the follow-up period were evaluated., Results: A total of 226 allo-HSCT and 250 SOT patients were identified (mean age 52.8 years, 38.9% female). During the 12 months after transplantation, 29.2% of allo-HSCT patients and 16.8% of SOT patients received a CMV diagnosis. The majority of these diagnoses were given during the initial hospitalization or within the following 3 months. Across transplantation types, CMV patients had more hospital readmission days per patient-year (allo-HSCT 93.3 vs. 49.4, p = 0.001; SOT 42.0 vs. 20.7, p = 0.005), with a longer mean duration of readmissions (allo-HSCT 22.4 vs. 15.4 days, p < 0.001; SOT 11.6 vs. 7.5 days, p = 0.003). Comorbidity burden in transplantation patients was substantial, with several diagnoses being significantly more common among patients with CMV vs. non-CMV. One-year mortality did not differ significantly between patients with/without CMV., Conclusion: Burden of transplant recipients with CMV in terms of rehospitalizations and comorbidities is substantial, highlighting the need for improved CMV prevention and treatment., (© 2022. The Author(s).)

The CMV Symposium in September 2021 was an international conference dedicated to cytomegalovirus (CMV) infection after solid organ or hematopoietic stem cell transplantation. This review provides an overview of the presentations given by the expert faculty, supplemented with educational clinical cases. Topics discussed include CMV epidemiology and diagnosis, the burden of CMV infection and disease, CMV-specific immunity and management of CMV in transplant settings. Major advances in the prevention and treatment of CMV in the past decade and increased understanding of CMV immunity have led to improved patient outcomes. In the future, management algorithms may be individualized based on the transplant recipient's immune profile, which will mark the start of a new era for patients with CMV., (© 2022 The Authors. Transplant Infectious Disease published by Wiley Periodicals LLC.)

Background: Cytomegalovirus (CMV) infection is a leading cause of morbidity and mortality after transplantation. This study aimed to investigate CMV seroprevalence, infection, and disease in Chinese thoracic organ transplant recipients., Methods: The clinical data of the patients who underwent lung and/or heart transplantation between January 2015 and October 2020 were retrospectively collected from four transplantation centers in China., Results: A total of 308 patients were analyzed. The CMV serostatus was donor positive (D + ) recipient negative (R - ) in 19 (6.17%) patients, D + /R + in 233 (75.65%), D - /R + in 36 (11.69%), and D - /R - in 20 (6.50%). CMV DNAemia was detected in 52.3% of the patients and tissue-invasive CMV disease was diagnosed in 16.2% of the patients. Only 31.8% of the patients adhered to the postdischarge valganciclovir therapy. The D + /R - serostatus (odds ratio [OR]: 18.32; 95% confidence interval [CI]:1.80-188.68), no valganciclovir prophylaxis (OR: 2.64; 95% CI: 1.05-6.64), and higher doses of rabbit anti-human thymocyte globulin (> 2 mg/kg) (OR: 4.25; 95% CI: 1.92-9.42) were risk factors of CMV disease., Conclusion: CMV seroprevalence was high in Chinese thoracic organ transplant donors and recipients. The low adherence rate to the postdischarge CMV prophylaxis therapy in Chinese patients is still an unresolved issue., (© 2022. The Author(s).)

Purpose: Antimicrobial stewardship programs (ASPs) are essential entities that promote the appropriate use of antimicrobials, leading to improved patient outcomes and reduced resistance. Application to the immunocompromised host is a natural progression for expansion. Cytomegalovirus (CMV) infection is a common complication following solid organ transplant with significant implications on graft survival, making it an attractive ASP target. The aim of this piece is to review our center-specific experience with the development, implementation, and maintenance of a CMV stewardship initiative at a large transplant center., Methods: Our CMV stewardship initiative began in 2018. Herein, we review 3 years' experience and quality-related improvement that occurred from initiation to present state and share our stewardship algorithms. Special attention is paid to the impact of the program as well as our increased understanding of the complex interplay between prevention, treatment, and host development of CMV-specific cell-mediated immunity (CMI)., Results: We found our stewardship initiative not only reduced the incidence of ganciclovir resistance but also streamlined care via a centralized and structured approach. This objective, protocolized program has resulted in a significant shift away from a reactive to a proactive state and in turn, reduced CMV treatment rates (26% at initiation to 12% in the current state, p = .012)., Conclusion: A dedicated multidisciplinary team focused on CMV stewardship is imperative in providing a patient-centered approach focused on development of CMV-specific CMI, and as a result prevention of CMV disease. We believe these programs will be the new gold standard for CMV management., (© 2022 Wiley Periodicals LLC.)