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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. [ABSTRACT FROM AUTHOR]

The article discusses the use of pre-emptive therapy (PET) and prophylaxis (PRO) for preventing cytomegalovirus (CMV) disease in liver transplant recipients. The authors compare their real-world experience with PET and PRO to the findings of a previous study. They found that PET did not significantly reduce the incidence of CMV disease compared to PRO, and PET was associated with higher costs. The authors suggest that PET may not have advantages over PRO in certain real-world settings. They also highlight the importance of carefully conducting PET according to rigorous standards for optimal efficacy. [Extracted from the article]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Preliminary evidence suggests that non‐lung organ donation from resolved, asymptomatic or mildly symptomatic SARS‐CoV‐2 infected adults may be safe. However, several biological aspects of SARS‐CoV‐2 infection differ in children and the risk for transmission and outcomes of recipients from pediatric donors with SARS‐CoV‐2 infection are not well described. Methods: We report two unvaccinated asymptomatic pediatric non‐lung organ deceased donors who tested positive for SARS‐CoV‐2 RNA by RT‐PCR. Donor One unexpectedly had SARS‐CoV‐2 RNA detected in nasopharyngeal swab and plasma specimens at autopsy despite several negative tests (upper and lower respiratory tract) in the days prior to organ recovery. Donor Two had SARS‐CoV‐ 2 RNA detected in multiple nasopharyngeal swabs but not lower respiratory tract specimens (endotracheal aspirate and bronchoalveolar lavage) during routine surveillance prior to organ recovery and was managed with remdesivir and monoclonal antibodies prior to organ recovery. Results: Two hearts, two livers and four kidneys were successfully transplanted into seven recipients. No donor to recipient transmission of SARS‐CoV‐2 was observed and graft function of all organs has remained excellent for up to 7 months of followup. Conclusions: Due to the persistent gap between organ availability and the number of children waiting for transplants, deceased pediatric patients with non‐disseminated SARS‐CoV‐2 infection, isolated to upper and/or lower respiratory tract, should be considered as potential non‐lung organ donors. [ABSTRACT FROM AUTHOR]

Key Points: Question: Is prophylaxis with letermovir noninferior to valganiclovir for cytomegalovirus (CMV) disease prevention in high-risk CMV-seronegative kidney transplant recipients who receive an organ from a CMV-seropositive donor? Findings: In this randomized, double-masked trial of CMV-seronegative adults who received an organ from a CMV-seropositive kidney transplant donor (efficacy population; n = 586), letermovir was noninferior to valganciclovir (each given for up to 200 days after transplant) for prevention of CMV disease through 52 weeks after transplant (10.4% vs 11.8%) and had a lower rate of leukopenia or neutropenia (safety population; n = 589). Meaning: Letermovir was noninferior to valganciclovir for prophylaxis of CMV disease in adult CMV-seronegative kidney transplant recipients who received an organ from a CMV-seropositive donor, with lower rates of leukopenia or neutropenia, supporting its use for this indication. 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 This randomized clinical trial compares the efficacy and safety of letermovir vs valganciclovir prophylaxis for cytomegalovirus (CMV) disease in CMV-seronegative kidney transplant recipients receiving an organ from a CMV-seropositive donor. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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). Cancer is a major adverse outcome of solid organ transplantation (SOT), and prior donor and recipient cytomegalovirus (CMV) infections are common; however, associations of CMV with cancer risk among SOT recipients have been incompletely evaluated. In this analysis of 247,318 SOT recipients, an inverse association between risk of CMV infection and diffuse large B‐cell lymphoma was observed; however, CMV status was not associated with risk for most other cancers. [ABSTRACT FROM AUTHOR]