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Background: Cytomegalovirus (CMV) is the most prevalent opportunistic infection after lung transplantation. Current strategies do not prevent CMV in most at-risk patients.Objective: To determine whether extending prophylaxis with oral valganciclovir from the standard 3 months to 12 months after lung transplantation is efficacious.Design: Randomized, clinical trial. Patients were randomly assigned by a central automated system to treatment or placebo. Patients and investigators were blinded to treatment status. (ClinicalTrials.gov registration number: NCT00227370)Setting: Multicenter trial involving 11 U.S. lung transplant centers.Patients: 136 lung transplant recipients who completed 3 months of valganciclovir prophylaxis.Intervention: 9 additional months of oral valganciclovir (n = 70) or placebo (n = 66).Measurements: The primary end point was freedom from CMV disease (syndrome or tissue-invasive) on an intention-to-treat basis 300 days after randomization. Secondary end points were CMV disease severity, CMV infection, acute rejection, opportunistic infections, ganciclovir resistance, and safety.Results: CMV disease occurred in 32% of the short-course group versus 4% of the extended-course group (P < 0.001). Significant reductions were observed with CMV infection (64% vs. 10%; P < 0.001) and disease severity (110 000 vs. 3200 copies/mL, P = 0.009) with extended treatment. Rates of acute rejection, opportunistic infections, adverse events, CMV UL97 ganciclovir-resistance mutations, and laboratory abnormalities were similar between groups. During the 6 months after study completion, a low incidence of CMV disease was observed in both groups.Limitation: Longer-term effects of extended prophylaxis were not assessed.Conclusion: In adult lung transplant recipients who have received 3 months of valganciclovir, extending prophylaxis by an additional 9 months significantly reduces CMV infection, disease, and disease severity without increased ganciclovir resistance or toxicity. A beneficial effect with regard to prevention of CMV disease seems to extend at least through 18 months after transplantation. [ABSTRACT FROM AUTHOR]

Immunological parameters that distinguish solid-organ transplant (SOT) recipients at risk for life-threatening cytomegalovirus (CMV) disease are being actively pursued to aid posttransplant management. A candidate marker is programmed death (PD)-1 receptor, whose overexpression has been associated with disease progression during persistent viral infections. To determine whether levels of this negative regulator of T cell activity are altered in SOT recipients with symptoms of CMV disease, a comparative PD-1 expression analysis was done in healthy, CMV-positive individuals and in liver transplant recipients. PD-1 levels were measured among the total population of CD8(+) and CD8(+) T cells binding to CMV-specific major histocompatibility complex class I tetramers. Minimal PD-1 expression was found in the healthy, CMV-positive cohort, and symptomatic SOT recipients had significantly higher PD-1 levels. PD-1 up-regulation was significantly associated with incipient and overt CMV disease and with viremia. Our findings suggest that PD-1 could be developed as a prognostic tool to predict CMV disease and guide therapeutic interventions. Copyright © 2008 Infectious Diseases Society of America [ABSTRACT FROM AUTHOR]

Cytomegalovirus (CMV)-seronegative recipients (R(-)) of a liver transplant from CMV-positive donors (D(+)) are at high risk for developing late CMV disease after discontinuation of antiviral prophylaxis. Levels of viremia and CMV-specific interferon (IFN)- gamma -producing CD4(+) and IFN- gamma -producing CD8(+) T cell responses were prospectively measured from discontinuation of antiviral prophylaxis until 1 year after transplantation in 17 consecutive D(+)/R(-) patients. CMV loads of >1000 copies/mL were strongly associated with CMV disease in the 6 symptomatic patients. Despite immunosuppression, broadly diverse T cells specific for CMV lysate or peptide libraries spanning pp65 and immediate early (IE) 1 immunodominant CMV antigens developed in all patients. A vigorous CD8(+) T cell response to pp65 and IE1 antigens characterized the D(+)/R(-) cohort. Unexpectedly, none of these responses were predictive of CMV disease or viremia. No significant lymphopenia or functional impairment of CMV-specific T cells was detected in the symptomatic patients, whose morbidity was resolved after antiviral treatment while measurable CMV immunity was maintained during the 1-year observation period. [ABSTRACT FROM AUTHOR]

Successful prevention and treatment of cytomegalovirus (CMV) infection remains a central focus of clinical care in solid organ and allogeneic hematopoietic cell transplantation. Over the past 5 years, pivotal clinical trials have created new paradigms in CMV prevention, including diverging approaches in HCT and SOT. We review recent advances in CMV risk assessment and progress in antiviral and immune-based strategies for CMV prevention and treatment. We highlight approaches to optimize CMV-specific immunity through vaccination, monoclonal antibodies, and virus-specific T-cells. Observational studies and interventional trials of commercially-available CMV cell-mediated immunity assays for refining preventive and treatment strategies are summarized. Finally, we discuss the importance of enhancing CMV-specific immunity to mitigate the negative impacts of CMV in different transplant settings. CMV infections in recipients of chimeric antigen receptor-T (CAR-T) cell therapies and other immunocompromised populations are growing areas of importance that are beyond the scope of this review., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The immunocompromised population was disproportionately affected by the severe acute respiratory syndrome coronavirus 2 pandemic. However, these individuals were largely excluded from clinical trials of vaccines, monoclonal antibodies, and small molecule antivirals. Although the community of scientists, clinical researchers, and funding agencies have proven that these therapeutics can be made and tested in record time, extending this progress to vulnerable and medically complex individuals from the start has been a missed opportunity. Here, we advocate that it is paramount to plan for future pandemics by investing in specific clinical trial infrastructure for the immunocompromised population to be prepared when the need arises., Competing Interests: Potential conflicts of interest. M. B.: Moderna (consultant, research support), Merck (research support, consultant), GSK (research support), Vir Biotechnology (consultant), AstraZeneca (research support, consultant). S. P.: Global Life Technologies (research support), F2G (clinical trial activities), Cidara (clinical trial activities), and Symbio (clinical trial activities). S. P. serves as a member of the FDA's Vaccine and Biological Products Advisory Committee. A. P. L.: Merck (site investigator, investigator-initiated research grant, consultant), Novartis (DSMB member), Moderna (consultant, site investigator), Takeda (research support), AiCuris, Vera (research support), GSK (consultant), and Memo (consultant). J. E.: AstraZeneca (research support, consultant), GlaxoSmithKline (research support), Merck (research support), Pfizer (research support, consultant), Abbvie (consultant), Ark Biopharma (consultant), Meissa Vaccines (consultant), Moderna (consultant), Sanofi Pasteur (consultant), and Shinogi (consultant). L. C.: VIR Bio (founder, member of the Scientific Advisory Board); Vaccine Company (cofounder, consultant). J. A. H.: Moderna (consultant), Merck (research support), Gilead (consultant), Allovir (research support, consultant), Takeda (research support, consultant). 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) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Competing Interests: Potential conflicts of interest. S. D. reports grants or contracts from the National Institutes of Health (payments to Fred Hutchinson Cancer Center, which support the author's salary). C. M. K. reports a role as chair of the patient-centered outcomes research institute Clinical Trial Advisory Panel. C. E. F. reports grants or contracts from the National Heart, Lung, and Blood Institute and the National Institute of Allergy and Infectious Diseases and a role as unpaid ad hoc committee member for the Disease Transmission Advisory Committee (United Network for Organ Sharing). A. P. L. is a consulting and/or site investigator for Merck, GlaxoSmithKline, and Takeda Pharmaceuticals. 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.

Chronic lung allograft dysfunction (CLAD) is the most common cause of long-term lung allograft failure. Several factors, including respiratory virus infection (RVI), have been associated with CLAD development, but the underlying mechanisms of these associations are not well understood. We hypothesize that RVI in lung transplant recipients elicits the development of donor-specific antibodies (DSAs), thus providing a mechanistic link between RVI and CLAD development. To test this hypothesis, we retrospectively evaluated for the presence of HLA antibodies in a cohort of lung transplant recipients with symptomatic RVI within the first four months post-transplant using sera at two time points (at/directly after the transplant and following RVI) and time-matched controls without RVI (post-transplant). We found a trend toward the development of de novo DSAs in those with symptomatic RVI versus controls [6/21 (29%) vs. 1/21 (5%), respectively, p = 0.09]. No cases or controls had DSA at baseline. We also found increased rates of CLAD and death among those who developed class II DSA versus those who did not (CLAD: 5/7 (71.4%) vs. 19/34 (54.3%), death: 5/7 (71.4%) vs. 17/35 (48.6%)). Prospective studies evaluating the temporal development of DSA after RVI in lung transplant patients and the subsequent outcomes are warranted.

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.)

CMV-specific T cells, NK cells, and neutralizing antibodies (nAbs) were assessed in a randomized trial of CMV prevention with preemptive antiviral therapy (PET) versus prophylactic antiviral therapy (PRO) in donor-seropositive/recipient-seronegative (D+R-) liver transplant recipients (LTxR) at 100 days (end of intervention) and at 6 and 12 months after transplant. The PET group had significantly increased numbers of circulating polyfunctional T cells, NK cells, and nAbs compared with the PRO group at day 100, and several CMV immune parameters remained significantly higher by 12 months after transplant. Among PET recipients, preceding CMV viremia (vs. no preceding viremia) was associated with significantly higher levels of most CMV immune parameters at day 100. Higher numbers of CMV-specific polyfunctional T cells and NKG2C+ NK cells at day 100 were associated with a decreased incidence of CMV disease in multivariable Cox regression. The strongest associations with protection against CMV disease were with increased numbers of CMV-specific polyfunctional CD4+ T cells, CD3negCD56dimCD57negNKG2Cpos cells, and CD3negCD56dimCD57posNKG2Cpos NK cells. Our results suggest that PET is superior to PRO for CMV disease prevention by allowing low-level CMV replication and associated antigen exposure that is promptly controlled by antiviral therapy and facilitates enhanced CMV protective immunity in D+R- LTxR.

Background: BK polyomavirus-associated nephropathy (BKPyVAN) is an important cause of allograft dysfunction and failure in kidney transplant recipients (KTRs) and there are no proven effective treatments. Case reports and in vitro data support the potential activity of cidofovir against BK polyomavirus (BKPyV)., Methods: We report the results of a phase I/II, double-blind, placebo-controlled randomized dose-escalation trial of cidofovir in KTRs with biopsy-confirmed BKPyVAN and estimated glomerular filtration rate ≥30 mL/min. Intravenous cidofovir (0.25 mg/kg/dose or 0.5 mg/kg/dose) or placebo was administered on days 0, 7, 21, and 35, with final follow-up through day 49., Results: The trial was prematurely discontinued due to slow accrual after 22 KTRs had completed the study. Cidofovir was safe and tolerated at the doses and duration studied. The proportion of subjects with any adverse event (AE) was similar between groups (9/14 [64%] in the combined cidofovir dose groups and 6/8 [75%] in the placebo group); 84% of AEs were mild. BKPyV DNAemia reduction by day 49 was similar between groups (>1 log 10 reduction in (2/9 [22.2%] of 0.25 mg/kg group, 1/5 [20%] of 0.5 mg/kg group, and 2/8 [25%] of placebo group)., Conclusions: These preliminary results indicate that low-dose cidofovir was safe and tolerated but had no significant BKPyV-specific antiviral effect in KTRs with BKPyVAN., (© 2024 The Author(s). Transplant Infectious Disease published by Wiley Periodicals LLC.)

Background: Herpes simplex viruses (HSVs) frequently reactivate during immunosuppression and may be a risk factor for adverse outcomes after solid organ transplant (SOT). While suppressive antiviral therapy reduces the risk of symptomatic HSV reactivation, the kinetics of asymptomatic viral shedding with chronic immunosuppression after transplant are not well understood. We report the characteristics of oral HSV shedding among 15 HSV-1 seropositive SOT recipients (n = 8 liver, n = 7 kidney, median age 58.5 years, median 20 months post-transplant) who were not taking daily antiviral suppressive therapy., Methods: Participants self-collected oral swabs three times daily for 6 weeks for HSV quantification and recorded the presence of oral symptoms or lesions in a diary., Results: Sample collection adherence was high (median 122 swabs/person, range: 85.7%-101.6% of expected swabs). Most participants (n = 12, 80%) experienced at least one shedding episode, with a median shedding rate of 8.9% (range: 0%-33.6%). There were 32 total shedding episodes, 24 (75%) of which occurred without symptoms or lesions. For episodes of known duration, the median length was 21.8 hrs (interquartile range: 10.8-46.1 hrs)., Conclusion: Most shedding episodes (78.1%) lasted >12 hrs, suggesting that twice-daily sampling may be sufficient to detect most episodes. These data show that self-collection of oral swabs is feasible for patients who have undergone SOTs and can provide insight into the frequency of oral HSV reactivation, which can be used to design future studies in this population., (© 2024 Wiley Periodicals LLC.)

Quantitative monitoring of cytomegalovirus (CMV) DNAemia in venous blood is standard in solid organ transplant recipients (SOTr) but is limited by the need for phlebotomy facilities and personnel. The aim of the study was to evaluate the Tasso+ capillary blood (CB) self-collection device for quantitation of plasma CMV DNAemia. Thirty adult SOTr with suspected CMV DNAemia were enrolled to have a supervised Tasso+ CB sample collection within 24 h of a venous sample. CMV DNA was quantitated in paired samples by using the Abbott M2000 Real-Time qPCR instrument. The participants were provided with a study-specific survey that measured patient acceptability of the Tasso+ device compared with venipuncture. A Tasso + CB sample was successfully collected in 28/30 (93%) patients, and 44 paired samples were analyzed. Concordance for detection of CMV DNAemia above the limit of detection (LOD) was 91% (42/44), and the Tasso + CB sample was estimated to be 95% sensitive at a viral load (VL) of 308 IU/mL. Among samples with a quantifiable DNAemia result with both methods ( N = 31), there was excellent correlation between methods (Spearman R 2 = 0.99). The difference in CMV VL between venous and Tasso+ CB samples was not dependent on time ( P > 0.1). Of 12 who completed the survey, 11 (92%) expressed a preference for Tasso+ CB collection over venipuncture. Collection of CB with the Tasso+ device is feasible, patient-acceptable, and yields generally comparable CMV DNAemia load to standard venous samples, but with lower sensitivity. Future studies to optimize and evaluate this methodology for patient self-collected samples are warranted., Importance: We evaluate an FDA-cleared blood self-collection device (Tasso+) and demonstrate that it is patient-acceptable and yields a liquid blood sample with quantitative CMV DNAemia results comparable to those of standard venipuncture samples. This opens up possibilities for self-blood collection to monitor for CMV and potentially other viruses in transplant and other at-risk populations., Competing Interests: The authors declare no conflict of interest.

The Comparison of Antiviral Preventative Strategies In Liver Transplant (CAPSIL) study showed pre-emptive therapy (PET) to be superior to antiviral prophylaxis for Cytomegalovirus (CMV) disease prevention in high-risk CMV seronegative liver transplant recipients (LTRs) with seropositive donors (D + R - ). Despite the statistical superiority of PET over prophylaxis in research settings, PET is perceived as a logistically more complex strategy that requires careful coordination of weekly CMV PCR testing, prompt initiation of CMV antivirals upon viremia detection, and timely cessation of antivirals following viremia resolution. Transplant centers may be hesitant to use PET for CMV disease prevention in D + R - LTRs out of concern that PET coordination is not feasible in clinical practice. We recently described our experience using PET in CMV D + R - LTRs in a real-world setting, and found it to be as effective for CMV disease prevention as PET performed as part of a clinical trial. Here, we describe a systematic approach for PET implementation in real-world settings and provide practical tools to address anticipated challenges. This framework can support transplant programs in overcoming logistical barriers to PET and incorporating an evidence-based and cost-effective CMV prevention strategy into routine care for high-risk CMV D + R - LTRs., (© 2024 Wiley Periodicals LLC.)

A systematic review of randomized and observational studies from 2013 to 2023 demonstrated that antiviral preemptive therapy started at cytomegalovirus viral load thresholds between 2 and 3 log10 IU/mL was associated with similar cytomegalovirus disease rates. Thus, viral thresholds in this range appear to effectively protect patients not receiving prophylaxis., Competing Interests: Potential conflicts of interest. A. P. L. has received research support from Merck and Takeda; served as a consultant for GSK, Vera, AiCuris, Merck, and Moderna; and served on a data safety and monitoring board for Novartis, Syneos, and Nobelpharma. M. B. received research support from Merck and served as a consultant for Allovir, Symbio Pharmaceuticals, Moderna, and Merck. 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. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

In a post-hoc analysis of the association of CMV DNAemia with long-term mortality in a randomized trial of CMV preemptive therapy vs. antiviral prophylaxis in D+R- liver transplant recipients, post-intervention CMV DNAemia was associated with increased mortality after adjusting for study arm., Competing Interests: Potential conflicts of interest. A. P. L. is a consulting and/or site investigator for and has received institutional payments from Merck & Co, GlaxoSmithKline, Moderna, and Takeda Pharmaceuticals; has received institutional support via consulting fees from AiCures and Vera Therapeutics; reports consulting fees from Merck & Co, Moderna, AlloVir, and GlaxoSmithKline; and was reimbursed for participation on a data and safety monitoring board for Novartis, Syneos, and NobelPharma. C. E. F. is a consulting and/or site investigator holding grants or contracts unrelated to the study for Moderna and Amplyx Pharmaceuticals, Inc; has received support from National Institutes of Health (NIH); reports honoraria from NIH for serving as a VIDD study section ad hoc member; has received travel reimbursement from NIH; and was an unpaid participant of the United Network for Organ Sharing Disease Transmission Advisory Committee. C. M. K. has received institutional funding support unrelated to this article from the NIH, Patient-Centered Outcomes Research Institute (PCORI), and University of New Mexico; was reimbursed for travel expenses for participation on a clinical trials advisory panel for PCORI; and has received honoraria for leadership positions as chair for the PCORI Clinical Trials Advisory Panel and co-chair for the Membership Committee of the Society for Clinical Trials. S. D. has received institutional support from NIH (National Cancer Institute/National Institute of Allergy and Infectious Disease), University of Washington, Gilead Sciences, Inc, and Merck & Co and employee travel support from the Fred Hutchinson Cancer Center. 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. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Cytomegalovirus (CMV) serostatus is a major determinant of CMV infection, disease risk, and transplant outcomes. Current clinical serology assays are limited by relatively slow turnaround time, design for batched testing, need for trained personnel, and/or specialized equipment. Rapid diagnostic assays in development have a role in emerging settings, such as critically ill patients, but have not been systematically evaluated., Methods: We assessed the performance of 3 rapid lateral flow assays (LFAs) for the detection of CMV immunoglobulin (Ig)G antibodies compared with a reference commercially available CMV IgG enzyme-linked immunosorbent assay in residual serum samples from 200 consecutive adults who underwent clinical CMV serology testing. Samples with discrepant results between the LFA and reference assay were tested by a second reference assay. A subset of serum samples was assessed for interoperator variability. Operating characteristics of the QooLabs LFA were separately assessed in plasma samples., Results: The sensitivity and specificity of the individual LFA assays using serum varied significantly: 86%/83%, 99/93%, and 57/97%, for Healgen, QNow automated reader, and nanoComposix, respectively, compared with the reference assay. Results for the QNow assay were comparable between automated and manual reads. Among a subset of 10 serum samples assessed by 5 individual operators, 44 of 50 (88%) results were concordant. Among 50 plasma samples assessed by the QooLabs LFA, the sensitivity and specificity were 72% and 96%., Conclusions: The ease of performance, rapid turnaround time, and good operating characteristics provide the rationale for further evaluation of the Qoolabs QNow LFA in specialized settings where rapid assessment of CMV serostatus would be advantageous., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

The authors summarize recent updates in the prevention and management of cytomegalovirus (CMV) in solid organ transplant (SOT) recipients with a focus on CMV seronegative recipients of organs from seropositive donors (CMV D+/R-) who are at highest risk of CMV infection and disease. They discuss advantages of preemptive therapy for CMV disease prevention in CMV D+/R- liver transplant recipients, letermovir for CMV prophylaxis, and updates in the development of monoclonal antibodies and vaccines as immune-based preventative strategies. They review the roles of maribavir and virus-specific T cells for management of resistant or refractory CMV infection in SOT recipients., Competing Interests: Disclosures The authors have no conflicts of interest to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The optimal strategy for cytomegalovirus (CMV) disease prevention in CMV donor/recipient kidney transplant recipients remains uncertain. Conclusions of prior meta-analyses that CMV disease rates with preemptive therapy (PET) and universal prophylaxis (UP) were comparable may have been affected by inclusion of studies lacking key determinants of efficacy of the respective strategies., Methods: We conducted a systematic review and meta-analysis of PET with weekly CMV polymerase chain reaction monitoring for ≥3 mo and UP with 6 mo of valganciclovir. PubMed and Embase databases were reviewed from January 1, 2010, to April 1, 2022. Risk of bias was assessed with 3 instruments (Cochrane RoB, Cochrane RoBINS-I, and an instrument for assessing risk in observational studies). The primary outcome was CMV disease incidence by 1-y posttransplant. Secondary outcomes by 1-y were graft loss, acute allograft rejection, and mortality. Results were synthesized using generalized linear mixed model meta-analysis. PET studies were stratified into low-threshold (LT) and high-threshold (HT) PET based on the viral load threshold for initiation of antiviral therapy., Results: Twenty-five studies met inclusion criteria (6 PET, 19 UP). CMV disease incidence was significantly higher in HT (0.30 [95% confidence interval (CI), 0.22-0.39]) versus LT PET (0.06 [95% CI, 0.03-0.12]). LT PET was associated with a significantly lower CMV disease incidence (0.06 [95% CI, 0.03-0.12]) versus UP (0.21 [95% CI, 0.17-0.27]). Incidence of graft loss, acute allograft rejection, or mortality was not significantly different between LT PET and UP ( P > 0.05 for all comparisons). Receipt of lymphocyte-depleting antibodies was not associated with a significant difference in CMV disease incidence (odds ratio = 1.34 [95% CI, 0.80-2.25])., Conclusions: LT PET is associated with a significantly lower incidence of CMV disease compared to UP with similar rates of other clinical outcomes. These findings provide rationale and preliminary data for a randomized superiority trial of optimized LT-PET versus UP in donor seropositive recipient seronegative kidney transplant recipients., (Copyright © 2023 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Importance: Valganciclovir for 200 days is standard care for cytomegalovirus (CMV) prophylaxis in high-risk CMV-seronegative kidney transplant recipients who receive an organ from a CMV-seropositive donor, but its use is limited by myelosuppression., Objective: To compare the efficacy and safety of letermovir with valganciclovir for prevention of CMV disease in CMV-seronegative kidney transplant recipients who receive an organ from a CMV-seropositive donor., Design, Setting, and Participants: Randomized, double-masked, double-dummy, noninferiority, phase 3 trial in adult CMV-seronegative kidney transplant recipients who received an organ from a CMV-seropositive donor at 94 participating sites between May 2018 and April 2021 (final follow-up in April 2022)., Interventions: Participants were randomized in a 1:1 ratio (stratified by receipt of lymphocyte-depleting induction immunosuppression) to receive letermovir, 480 mg, orally daily (with acyclovir) or valganciclovir, 900 mg, orally daily (adjusted for kidney function) for up to 200 days after transplant, with matching placebos., Main Outcomes and Measures: The primary outcome was CMV disease, confirmed by an independent masked adjudication committee, through posttransplant week 52 (prespecified noninferiority margin, 10%). CMV disease through week 28 and time to onset of CMV disease through week 52 were secondary outcomes. Exploratory outcomes included quantifiable CMV DNAemia and resistance. The rate of leukopenia or neutropenia through week 28 was a prespecified safety outcome., Results: Among 601 participants randomized, 589 received at least 1 dose of the study drug (mean age, 49.6 years; 422 [71.6%] men). Letermovir (n = 289) was noninferior to valganciclovir (n = 297) for prevention of CMV disease through week 52 (10.4% vs 11.8% of participants with committee-confirmed CMV disease; stratum-adjusted difference -1.4% [95% CI, -6.5% to 3.8%]). No participants who received letermovir vs 5 participants (1.7%) who received valganciclovir developed CMV disease through week 28. Time to onset of CMV disease was comparable between the groups (hazard ratio, 0.90 [95% CI, 0.56-1.47]). Quantifiable CMV DNAemia was detected in 2.1% of participants in the letermovir group vs 8.8% in the valganciclovir group by week 28. Of participants evaluated for suspected CMV disease or CMV DNAemia, none (0/52) who received letermovir and 12.1% (8/66) who received valganciclovir had resistance-associated substitutions. The rate of leukopenia or neutropenia through week 28 was lower with letermovir vs valganciclovir (26% vs 64%; difference, -37.9% [95% CI, -45.1% to -30.3%]; P < .001). Fewer participants in the letermovir group than the valganciclovir group discontinued prophylaxis due to adverse events (4.1% vs 13.5%) or drug-related adverse events (2.7% vs 8.8%)., Conclusion and Relevance: Among adult CMV-seronegative kidney transplant recipients who received an organ from a CMV-seropositive donor, letermovir was noninferior to valganciclovir for prophylaxis of CMV disease over 52 weeks, with lower rates of leukopenia or neutropenia, supporting its use for this indication., Trial Registration: ClinicalTrials.gov Identifier: NCT03443869; EudraCT: 2017-001055-30.

Background: Despite superiority of preemptive therapy (PET) compared to universal prophylaxis for prevention of cytomegalovirus (CMV) disease in the CAPSIL randomized trial among CMV D+R- liver transplant recipients (LTxRs), real-world effectiveness may be lower because of logistical concerns about feasibility of PET., Methods: We retrospectively assessed PET as standard clinical care at a single transplant center among 50 consecutive adult CMV D+R- LTxRs undergoing a first liver transplant between 4/4/2019 and 5/18/2021 and compared outcomes and adherence to those randomized to PET in the CAPSIL study (N = 100). The primary outcome was CMV disease and secondary outcomes were biopsy-confirmed acute allograft rejection, retransplant, invasive fungal infections, and death, all assessed by 1-year post-transplant. Exploratory outcomes included virologic parameters and measures of adherence to protocol-specified CMV qPCR monitoring., Results: Baseline characteristics were similar between groups. The cumulative incidence of CMV disease at 1-year post-transplant was 4/50 (8%) versus 9/100 (9%) in the real-world and CAPSIL cohorts, respectively, p = 1.0. The rate of breakthrough CMV disease during the 100-day PET period was low (2/50 [4%]) and similar to the PET cohort from the CAPSIL study (3/100 [3%]).  All secondary and exploratory outcomes were not significantly different between the real-world and CAPSIL PET cohorts., Conclusions: In this first reported study of real-world PET, the feasibility and effectiveness for CMV disease prevention and for other clinical outcomes in CMV D+R- LTxRs were similar to those reported with PET in a clinical trial. Additional studies to confirm feasibility and generalizability in other settings are warranted., (© 2023 Wiley Periodicals LLC.)

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.)

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. H.I. declares no conflicts of interest.

Background: Epstein-Barr virus (EBV) seronegative solid organ transplant recipients (SOTRs) are at increased risk for post-transplant lymphoproliferative disorder (PTLD). Assays for EBV serostatus assess antibody to both EBV viral capsid antigen (VCA) and Epstein-Barr nuclear antigen-1 (EBNA-1), but PTLD risk among SOT recipients with discordant VCA and EBNA-1 results is unknown., Methods: We performed a retrospective, single-center cohort study to determine the risk of PTLD among adult (≥ 18 years) SOTRs with discordant pre-transplant VCA and EBNA-1 IgG compared to that of SOTRs with concordantly negative or concordantly positive serology using univariable and multivariable Cox-proportional hazards models., Results: Of 4106 SOTRs, the number (%) who were concordantly positive, concordantly negative, and discordant was 3787 (92.2%), 149 (3.6%), and 170 (4.2%), respectively. The adjusted hazard of PTLD was significantly higher among discordant SOTRs compared to concordantly positive SOTRs (aHR 2.6, 95% CI 1.04-6.6, p =.04) and lower compared to concordantly negative SOTRs (aHR 0.27, 95% CI 0.10-0.76, p <.001). The adjusted hazard of EBV+ PTLD among those with discordant serology was also significantly higher compared to the concordantly positive cohort (aHR 3.53, 95% CI 1.04-12.0, p =.04) and significantly lower compared to the concordantly negative cohort (aHR 0.23, 95% CI 0.06-0.82, p =.02)., Conclusions: Risk of PTLD among SOTRs with discordant VCA and EBNA-1 may be intermediate between those with concordantly positive and negative serology. If confirmed in future studies, revision of national EBV serology reporting to include both VCA and EBNA results may be needed to optimize PTLD risk stratification., (© 2022 Wiley Periodicals LLC.)

Background: Cytomegalovirus (CMV) is among the most common viral infections after solid organ transplantation (SOT). Associations of CMV with cancer risk among SOT recipients have been incompletely evaluated., Methods: The authors used linked data from the US SOT registry and 32 cancer registries. Poisson regression was used to compare cancer incidence across CMV risk groups based on donor (D) and recipient (R) immunoglobulin G (IgG) serostatus: high risk (R-negative/D-positive), moderate risk (R-positive), and low risk (R-negative/D-negative)., Results: In total, 247,318 SOT recipients were evaluated during 2000-2017 (R-negative/D-positive, 20.3%; R-positive, 62.9%; R-negative/D-negative, 16.8%). CMV-seropositive recipients were older, more racially/ethnically diverse, and had lower socioeconomic status than CMV-seronegative recipients. Compared with R-negative/D-negative recipients, recipients in the R-negative/D-positive and R-positive groups had a lower incidence of diffuse large B-cell lymphoma (DLBCL; R-negative/D-positive: adjusted incidence rate ratio [aIRR], 0.74; 95% confidence interval [CI], 0.59-0.91; R-positive: aIRR, 0.83; 95% CI, 0.69-1.00). CMV serostatus modified the association between Epstein-Barr virus (EBV) status and DLBCL (p = .0006): DLBCL incidence was increased for EBV R-negative/D-positive recipients (aIRR, 3.46; 95% CI, 1.50-7.95) among CMV R-negative/D-negative recipients but not among the other CMV risk groups. Compared with recipients who were CMV R-negative/D-negative, those who were R-negative/D-positive had a lower incidence of small intestine cancer (aIRR, 0.23; 95% CI, 0.09-0.63), and R-positive recipients had a higher incidence of lung cancer (aIRR, 1.24; 95% CI, 1.05-1.46). CMV status was not associated with risk for other cancers., Conclusions: CMV status was not associated with risk for most cancers among SOT recipients. The inverse association with DLBCL may reflect the protective effects of CMV prophylaxis or treatment with off-target efficacy against EBV infection (the major cause of lymphoma in SOT recipients)., (© 2022 American Cancer Society.)

Background: Because of the continued demand in kidney transplantation, organs from donors with risk criteria for blood-borne viruses, high Kidney Donor Profile Index (KDPI) kidneys, and hepatitis C virus (HCV)-positive kidneys are being considered. There continues to be reluctance on the part of the providers and the candidates to accept HCV-positive kidneys., Methods: We conducted a retrospective analysis of the Organ Procurement and Transplantation Network database of all adult (≥18 y old) recipients undergoing kidney transplant from May 10, 2013, to June 30, 2021. We compared patient and graft survival in candidates who received HCV-positive kidneys versus non-hepatitis C (Hep C) high KDPI kidneys by estimated posttransplant survival (EPTS) groups., Results: HCV-viremic kidneys were transplanted in 5.6% of patients in the EPTS >61% group compared with 5.1% of patients in the 21%-60% EPTS group and 1.9% of 0%-20% EPTS group ( P < 0.001). Of all transplants performed in the EPTS 61%-100% group, 11.9% were KDPI >85% compared with 5.2% in the EPTS 21%-60%, and 0.5% in the EPTS 0%-20%. Patient survival was significantly longer at 1, 3, and 5 y in the EPTS >61% group who received Hep C-viremic or -nonviremic allografts compared with non-Hep C kidneys with KDPI >85%. When it comes to listing, only 25% of candidates in the EPTS >61% group were listed for Hep C nucleic acid testing-positive kidneys in 2021., Conclusions: Our findings could be used for counseling candidates on the types of kidneys they should consider for transplantation. Also, listing practices for viremic Hep C kidneys need continued re-evaluation., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: BK polyomavirus (BKPyV) infection and BK polyomavirus nephropathy (BKPyVAN) are important causes of allograft dysfunction and premature allograft loss in renal transplant recipients., Results and Discussion: Controlled clinical trials to evaluate new agents for prevention and treatment are needed but are hampered by the lack of outcome measures that accurately assess the effect of the intervention, are clinically relevant, and are acceptable from a regulatory perspective., Methods: To facilitate consistent end points in clinical trials and to support clinical research and drug development, definitions of BKPyV infection and disease have been developed by the BK Disease Definitions Working Group of the Transplantation Associated Virus Infection Forum with the Forum for Collaborative Research, which consists of scientists, clinicians, regulators, and industry representatives., Conclusions: These definitions refine established principles of "proven" BKPyV disease and introduce a "probable" disease category that could be used in clinical trials to prevent or treat BKPyVAN in renal transplant recipients., Competing Interests: Potential conflicts of interest. P. B. has received salary, stock options, and support for attending meetings or travel from Roche Diagnostics. D. C. B. has received grants/research support from CareDx (to John Hopkins for research on donor-derived cell-free DNA and relation to BK infection), Natera, Amplyx Pharmaceuticals (to John Hopkins for research on BK), and AlloVir (to John Hopkins for research on BK); consulting fees from CareDx, Medeor, Natera, and Sanofi (use of donor-derived cell-free DNA); honoraria from CareDx (use of donor-derived cell-free DNA), Sanofi (Infections in Transplantation), and Veloxis; and has served on the editorial boards of Transplantation and UpToDate. M. R. H. has received salary and consulting fees from Amplyx Pharmaceuticals and consulting fees from Pfizer, Hybridize Therapeutics, and AlloVir. P. L. has participated in a contract for a clinical trial with AlloVir (planned clinical trial at institution). V. M. receives support as part of the TAVI Forum from Amplyx Pharmaceuticals, Everys Bio, Mikrogen GmbH, Merck, Quest Diagnostics, Roche, SymBio Pharmaceuticals, and Viracor. V. N. has received grants or contracts with AlloVir and is on the advisory board for Hybridize Therapeutics. P. S. R. has a leadership role (president) of the Renal Pathology Society. A. P. L. has received consulting fees and contracts with Amplyx Pharmaceuticals (grant for being site investigator for BKPyV therapy and consulting fees for providing guidance on study design for BKPyV therapies) and has received consulting fees from AlloVir (for providing guidance on study design for immune therapies for viral infectious including BKPyV). All remaining authors: No reported conflicts of interest. 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) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Purpose of Review: To review and summarize the evolution of the Public Health Service (PHS) guidelines and Organ Procurement and Transplantation Network (OPTN) regulations for the prevention of blood borne virus transmission in solid organ transplant through the lens of popular culture, scientific evolution, patient and practitioner bias and outcomes research., Recent Findings: The most recent set of guidelines and regulations were released in 2020 and represent a culmination of decades of opinion, research and debate within the scientific and lay communities., Summary: The guidelines were created to address public concern, and the risk of undiagnosed disease transmission in the context of the novel public health crisis of AIDS. We reviewed milestone publications from the scientific and lay press from the first description of AIDS in 1981 to the present to help illustrate the context in which the guidelines were created, the way they changed with subsequent editions, and offer critical consideration of issues with the current set of guidelines and a potential way forward. Further consideration should be given to the way in which the current guidelines identify donors with risk criteria for infectious disease transmission and mandate explanation of donor-specific risk factors to potential recipients, in our era of universal donor screening and recipient surveillance., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Most studies of solid organ transplant (SOT) recipients with COVID-19 focus on outcomes within one month of illness onset. Delayed mortality in SOT recipients hospitalized for COVID-19 has not been fully examined., Methods: We used data from a multicenter registry to calculate mortality by 90 days following initial SARS-CoV-2 detection in SOT recipients hospitalized for COVID-19 and developed multivariable Cox proportional-hazards models to compare risk factors for death by days 28 and 90., Results: Vital status at day 90 was available for 936 of 1117 (84%) SOT recipients hospitalized for COVID-19: 190 of 936 (20%) died by 28 days and an additional 56 of 246 deaths (23%) occurred between days 29 and 90. Factors associated with mortality by day 90 included: age > 65 years [aHR 1.8 (1.3-2.4), p =<0.001], lung transplant (vs. non-lung transplant) [aHR 1.5 (1.0-2.3), p=0.05], heart failure [aHR 1.9 (1.2-2.9), p=0.006], chronic lung disease [aHR 2.3 (1.5-3.6), p<0.001] and body mass index ≥ 30 kg/m 2 [aHR 1.5 (1.1-2.0), p=0.02]. These associations were similar for mortality by day 28. Compared to diagnosis during early 2020 (March 1-June 19, 2020), diagnosis during late 2020 (June 20-December 31, 2020) was associated with lower mortality by day 28 [aHR 0.7 (0.5-1.0, p=0.04] but not by day 90 [aHR 0.9 (0.7-1.3), p=0.61]., Conclusions: In SOT recipients hospitalized for COVID-19, >20% of deaths occurred between 28 and 90 days following SARS-CoV-2 diagnosis. Future investigations should consider extending follow-up duration to 90 days for more complete mortality assessment., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Detailed cytomegalovirus (CMV) kinetics in donor CMV-seropositive, recipient CMV-seronegative (D+/R-) transplant recipients receiving preemptive therapy (PET) have not been fully defined., Methods: The study population consisted of the PET arm of a randomized CMV prevention trial in D+/R- liver transplant recipients. CMV DNA polymerase chain reaction (PCR) assays were performed weekly for 100 days using a sensitive assay. Viral load and clinical parameters were compared for patients with or without high-level increase (defined as higher than the group median log10 increase in viral load from baseline after PET initiation)., Results: Among 79 patients, 93.6% (74/79) developed an increase from baseline viral loads of median 120 IU/mL to 3350 IU/mL; 25.7% (19/74) of the patients had peak levels >10 000 IU/mL. None of the patients with rise in viral load underwent testing for CMV resistance, and viremia resolved with PET with valganciclovir. Patients with high-level increase in viral load had a significantly lower rate of recurrent viremia than those without such increase (16/40 [40%] vs 28/39 [71.8%], respectively; P = .004)., Conclusions: A majority of D+/R- recipients had a marked increase in viral load after initiation of PET before resolution of viremia. This phenomenon is associated with lower rates of subsequent recurrent viremia and does not necessarily imply antiviral resistance., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Mortality among patients hospitalized for COVID-19 has declined over the course of the pandemic. Mortality trends specifically in solid organ transplant recipients (SOTR) are unknown. Using data from a multicenter registry of SOTR hospitalized for COVID-19, we compared 28-day mortality between early 2020 (March 1, 2020-June 19, 2020) and late 2020 (June 20, 2020-December 31, 2020). Multivariable logistic regression was used to assess comorbidity-adjusted mortality. Time period of diagnosis was available for 1435/1616 (88.8%) SOTR and 971/1435 (67.7%) were hospitalized: 571/753 (75.8%) in early 2020 and 402/682 (58.9%) in late 2020 (p < .001). Crude 28-day mortality decreased between the early and late periods (112/571 [19.6%] vs. 55/402 [13.7%]) and remained lower in the late period even after adjusting for baseline comorbidities (aOR 0.67, 95% CI 0.46-0.98, p = .016). Between the early and late periods, the use of corticosteroids (≥6 mg dexamethasone/day) and remdesivir increased (62/571 [10.9%] vs. 243/402 [61.5%], p < .001 and 50/571 [8.8%] vs. 213/402 [52.2%], p < .001, respectively), and the use of hydroxychloroquine and IL-6/IL-6 receptor inhibitor decreased (329/571 [60.0%] vs. 4/492 [1.0%], p < .001 and 73/571 [12.8%] vs. 5/402 [1.2%], p < .001, respectively). Mortality among SOTR hospitalized for COVID-19 declined between early and late 2020, consistent with trends reported in the general population. The mechanism(s) underlying improved survival require further study., (© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: The coronavirus disease 2019 (COVID-19) pandemic has led to significant reductions in transplantation, motivated in part by concerns of disproportionately more severe disease among solid organ transplant (SOT) recipients. However, clinical features, outcomes, and predictors of mortality in SOT recipients are not well described., Methods: We performed a multicenter cohort study of SOT recipients with laboratory-confirmed COVID-19. Data were collected using standardized intake and 28-day follow-up electronic case report forms. Multivariable logistic regression was used to identify risk factors for the primary endpoint, 28-day mortality, among hospitalized patients., Results: Four hundred eighty-two SOT recipients from >50 transplant centers were included: 318 (66%) kidney or kidney/pancreas, 73 (15.1%) liver, 57 (11.8%) heart, and 30 (6.2%) lung. Median age was 58 (interquartile range [IQR] 46-57), median time post-transplant was 5 years (IQR 2-10), 61% were male, and 92% had ≥1 underlying comorbidity. Among those hospitalized (376 [78%]), 117 (31%) required mechanical ventilation, and 77 (20.5%) died by 28 days after diagnosis. Specific underlying comorbidities (age >65 [adjusted odds ratio [aOR] 3.0, 95% confidence interval [CI] 1.7-5.5, P < .001], congestive heart failure [aOR 3.2, 95% CI 1.4-7.0, P = .004], chronic lung disease [aOR 2.5, 95% CI 1.2-5.2, P = .018], obesity [aOR 1.9, 95% CI 1.0-3.4, P = .039]) and presenting findings (lymphopenia [aOR 1.9, 95% CI 1.1-3.5, P = .033], abnormal chest imaging [aOR 2.9, 95% CI 1.1-7.5, P = .027]) were independently associated with mortality. Multiple measures of immunosuppression intensity were not associated with mortality., Conclusions: Mortality among SOT recipients hospitalized for COVID-19 was 20.5%. Age and underlying comorbidities rather than immunosuppression intensity-related measures were major drivers of mortality., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Chronic lung transplant rejection occurs in over 50% of lung transplant recipients and mechanism of chronic rejection is unknown. Evaluation of potential mechanism of exosomes from lung transplant recipients diagnosed with respiratory viral infection (RVI) in inducing chronic lung allograft dysfunction (CLAD)., Method: Exosomes were isolated from lung transplant recipients followed by DNA and RNA isolation from exosomes. Cell signaling mechanisms were studied by co-culturing exosomes with human epithelial cells. Mice were immunized with exosomes and lung homogenates were studied for immune signaling proteins., Results: Exosomes from lung transplant recipients with RVI carry nucleic acids which are capable of inducing innate immune signaling, endoplasmic reticulum stress, and epithelial mesenchymal transition., Conclusion: Therefore, we propose that RVI can lead to induction of exosomes that initiate the process leading to CLAD in mice models. These novel findings identified the molecular mechanisms by which RVI increases the risk of CLAD., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: The relative costs of preemptive therapy (PET) or prophylaxis for the prevention of cytomegalovirus (CMV) disease in high-risk donor CMV-seropositive/recipient-seronegative (D+/R-) liver transplant recipients have not been assessed in the context of a randomized trial., Methods: A decision tree model was constructed based on the probability of outcomes in a randomized controlled trial that compared valganciclovir as PET or prophylaxis for 100 days in 205 D+/R- liver transplant recipients. Itemized costs for each site were obtained from a federal cost transparency database. Total costs included costs of implementation of the strategy and CMV disease treatment-related costs. Net cost per patient was estimated from the decision tree for each strategy., Results: PET was associated with a 10% lower absolute rate of CMV disease (9% vs 19%). The cost of treating a case of CMV disease in our patients was $88 190. Considering cost of implementation of strategy and treatment-related cost for CMV disease, the net cost-savings per patient associated with PET was $8707 compared to prophylaxis. PET remained cost-effective across a range of assumptions (varying costs of monitoring and treatment, and rates of disease)., Conclusions: PET is the dominant CMV prevention strategy in that it was associated with lower rates of CMV disease and lower overall costs compared to prophylaxis in D+/R- liver transplant recipients. Costs were driven primarily by more hospitalizations and higher CMV disease-associated costs due to delayed onset postprophylaxis disease in the prophylaxis group., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Risk factors, virological parameters, and outcomes associated with HHV-6 viremia in high-risk donor CMV-seropositive and recipient CMV-seronegative (D+R-) liver transplant recipients in the current era are incompletely defined., Methods: The study population consisted of patients in the preemptive therapy (PET) arm of a randomized, controlled trial of PET versus valganciclovir prophylaxis for CMV prevention in D+R- liver transplant recipients. Weekly blood samples through 100 d in the PET group were tested for HHV-6 viremia using a real-time quantitative polymerase chain reaction. Assessments included virological characteristics and relationship with CMV, risk factors, and impact of HHV-6 viremia with outcomes through 12 mo posttransplant., Results: HHV-6 viremia at any level developed in 42% (40 of 96). Older patient age (P = 0.03), longer hospitalization (P = 0.015), and ICU stay at transplantation (P = 0.029) were significantly associated with high-grade viremia. Concurrent HHV-6 and CMV viremia was associated with earlier onset of HHV-6 viremia (P = 0.004), higher HHV-6 area under the curve (P = 0.043), and higher peak HHV-6 viral load (P = 0.006) versus HHV-6 viremia alone. High-grade viremia was independently associated with biopsy-proven rejection within 12 mo (P = 0.045) posttransplant., Conclusions: Among D+R- liver transplant recipients receiving valganciclovir as PET, high-grade HHV-6 viremia was associated with increased age and critical illness in ICU at time of transplant and was independently associated with allograft rejection., Competing Interests: D.J.W. has received research support form Merck, Chimerix, Shire, Gilead, and Oxford Immnotech. G.M.L. has received research support from Takeda pharmaceutical company. F.P.S. has received research support from Shire, Ansun, and Novartis. A.P.L. has received research support from Merck and Astellas, and consulting support from Helocyte, Inc, Amplyx, Novartis, and AlloVir. The other authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)