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Background: Cytomegalovirus (CMV) is associated with detrimental outcomes after lung transplantation (LTX); primary prophylaxis (PPX) with valganciclovir (VGC) is guideline-recommended. VGC is associated with myelosuppression, spurring interest in letermovir (LTV)., Methods: Adults undergoing LTX between January 1, 2021, and July 30, 2022 at our institution who were converted from VGC to LTV for PPX were evaluated. Outcomes included antimetabolite dosing during PPX, the incidence and frequency of myelosuppressive events, and the time to the first myelosuppressive event., Results: Twenty-nine LTX recipients met the inclusion criteria. Most patients received non-lymphocyte-depleting induction (96.6%) and had moderate risk CMV serostatus (D+/R+, 48.3%). Patients transitioned from VGC to LTV 177 days (IQR 102 days) post-transplant. After conversion to LTV, patients tolerated higher daily doses of mycophenolate (721 mg vs. 1000 mg, p = 0.008) or azathioprine (33.3 mg vs. 62.5 mg, p = 0.478). The incidence of myelosuppressive events was reduced (100.0% vs. 62.1%, p < 0.001) including leukopenia (96.6% vs. 58.6%, p = 0.001), severe leukopenia (82.8% vs 31.0%, p < 0.001) and neutropenia requiring GCSF (96.6% vs. 48.3%, p < 0.001) while on VGC compared to LTV. While on LTV, patients had a reduced rate of myelosuppressive events compared to VGC (1 event per 6.2 patient days vs. 1 event per 14.7 patient days, p < 0.001). While on LTV, one patient had breakthrough viremia (3.4%) that was treated with (val)ganciclovir., Conclusions: In this single-center study, patients tolerated higher doses of antimetabolite immunosuppression, and the incidence and frequency of myelosuppressive events were reduced while on LTV compared to VGC. This evidence expands upon the current literature demonstrating improved tolerability of LTV in LTX recipients., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Cytomegalovirus (CMV) is a driver of negative outcomes after lung transplant (LTX) and primary prophylaxis (PPX) with valganciclovir (VGC) is standard-of-care. VGC is associated with myelosuppression, prompting interest in letermovir (LTV)., Methods: Adults receiving LTX between April 1, 2015, and July 30, 2022, at our institution were evaluated. Patients were excluded if low CMV risk (D-/R-), survived <90 days post-LTX, or transferred care before PPX withdrawal. Primary outcomes were leukopenia (white blood cell count [WBC] ≤ 3.0 × 10 9 /L), severe leukopenia (WBC ≤ 2.0 × 10 9 /L), and neutropenia (absolute neutrophil count ≤ 1500 cells/µL) requiring granulocyte-colony stimulating factor (GCSF) on PPX. Secondary outcomes included breakthrough CMV infection and post-PPX CMV infection., Results: 204 patients met inclusion criteria: 175 patients on VGC and 29 patients on LTV (after VGC conversion). Most patients received bilateral LTX (62.7%) with non-lymphocyte-depleting induction (96.6%) and moderate-risk serostatus (D+/R+, 48.5%). Patients transitioned from VGC to LTV after a mean of 178 days (SD 80.8 days) post-transplant. Patients on VGC experienced significantly more leukopenia (82.3% vs. 58.6%, p = 0.008), severe leukopenia (57.1% vs. 31.0%, p = 0.016), and neutropenia requiring GCSF (70.9% vs. 51.7%, p = 0.048). Breakthrough (5.7% vs. 3.4%, p = 0.955) and post-PPX (24.6% vs. 37.9%, p = 0.199) infections were similar. A subgroup analysis of patients with high-risk serostatus showed similar trends, though did not reach statistical significance., Conclusions: In this single-center study, the incidence of leukopenia and neutropenia requiring GCSF were reduced with LTV compared to VGC. Breakthrough and post-PPX infections were not significantly different. This evidence suggests that LTV has comparable efficacy with reduced myelosuppression compared to VGC in LTX recipients, and may be an appropriate alternative for PPX., (© 2024 Wiley Periodicals LLC.)

Objective: To review the efficacy and safety of eculizumab for prevention and treatment of antibody-mediated rejection (AMR) in lung transplant recipients (LTRs)., Data Sources: A literature search of PubMed and the Cochrane Controlled Trials Register (2007 to mid-October 2023) was performed using the following search terms: eculizumab, complement inhibitor, solid organ transplant, lung transplant , and AMR ., Study Selection and Data Extraction: All relevant English-language studies were reviewed and considered., Data Synthesis: Eculizumab, a monoclonal antibody that binds complement protein C5 to inhibit its cleavage and subsequent generation of the membrane attack complex, is currently approved to treat paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, generalized myasthenia and neuromyelitis optica spectrum disorder. Given the role of antibodies directed against donor antigens that are produced by allospecific B-cells and plasma cells in AMR, eculizumab is being investigated for use within this indication. Three case reports have described the successful use of eculizumab for the prevention and treatment of AMR in LTRs. Given this lack of robust data, evidence for the use of eculizumab in other solid organ transplant recipients is of increased value. Early experiences from a single center's use of eculizumab in LTRs are also described., Relevance to Patient Care and Clinical Practice: Lung transplant is a recognized treatment for end-stage lung disease, though complications posttransplant can be associated with significant morbidity and mortality. While prevention and management of AMR remains a substantial challenge without comprehensive guidance from societal guidelines, recently published literature may be helpful to guide clinical practice using alternative treatment options. However, this remains an area of great clinical importance, given the impact of AMR on long-term allograft function., Conclusions: Optimizing use of current therapies, as well as identifying and advancing novel therapeutic modalities such as eculizumab, are vital for the improvement of AMR prevention and treatment in LTRs to extend long-term allograft function and survival., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: While presumably less common with modern molecular diagnostic and imaging techniques, fever of unknown origin (FUO) remains a challenge in kidney transplant recipients (KTRs). Additionally, the impact of FUO on patient and graft survival is poorly described., Methods: A cohort of adult KTRs between January 1, 1995 and December 31, 2018 was followed at the University of Wisconsin Hospital. Patients transplanted from January 1, 1995 to December 31, 2005 were included in the "early era"; patients transplanted from January 1, 2006 to December 31, 2018 were included in the "modern era". The primary objective was to describe the epidemiology and etiology of FUO diagnoses over time. Secondary outcomes included rejection, graft and patient survival., Results: There were 5590 kidney transplants at our center during the study window. FUO was identified in 323 patients with an overall incidence rate of .8/100 person-years. Considering only the first 3 years after transplant, the incidence of FUO was significantly lower in the modern era than in the early era, with an Incidence Rate Ratio (IRR) per 100 person-years of .48; 95% CI: .35-.63; p < .001. A total of 102 (31.9%) of 323 patients had an etiology determined within 90 days after FUO diagnosis: 100 were infectious, and two were malignancies. In the modern era, FUO remained significantly associated with rejection (HR = 44.1; 95% CI: 16.6-102; p < .001) but not graft failure (HR = 1.21; 95% CI: .68-2.18; p = .52) total graft loss (HR = 1.17; 95% CI: .85-1.62; p = .34), or death (HR = 1.17; 95% CI: .79-1.76; p = .43., Conclusions: FUO is less common in KTRs during the modern era. Our study suggests infection remains the most common etiology. FUO remains associated with significant increases in risk of rejection, warranting further inquiry into the management of immunosuppressive medications in SOT recipients in the setting of FUO., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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.)

Objective: To review the efficacy and safety of maribavir for management of cytomegalovirus (CMV) in solid organ transplant recipients., Data Sources: A literature search of PubMed and the Cochrane Controlled Trials Register (1960 to early July 2022) was performed using the following search terms: maribavir, 1263W94 , and cytomegalovirus ., Study Selection and Data Extraction: All relevant English-language studies were reviewed and considered, with a focus on phase 3 trials., Data Synthesis: Maribavir, an orally available benzimidazole riboside with minimal adverse effects, was originally studied for universal prophylaxis in phase 3 trials but failed to demonstrate noninferiority over placebo and oral ganciclovir. It was effective for preemptive treatment in a dose-finding Phase 2 study. Maribavir is FDA approved for treatment of refractory/resistant CMV infection based on improved response rate at 8 weeks compared with investigator-assigned therapy (IAT) when initiated at median viral loads less than approximately 10 000 IU/mL (55.7% vs 23.9%, P < 0.001). Recurrence after 8-week treatment for refractory/resistant CMV was high (maribavir 50% vs IAT 39%). Significant drug interactions exist and must be managed by a pharmacotherapy expert to prevent harm., Relevance to Patient Care and Clinical Practice: The addition of maribavir to the antiviral armamentarium should improve the management of refractory/resistant CMV, allowing early transition from toxic, high-cost, intravenous agents such as foscarnet and outpatient management. Optimal timing of initiation, duration, and potential alternative uses are unclear., Conclusion: Future studies are needed to fully elucidate the role of maribavir in the management of CMV after transplant.

Purpose: Studies conducted in the northern United States found cytomegalovirus (CMV) disease after liver transplantation follows a seasonal pattern, with increased incidence in fall and winter. This has not been evaluated in kidney transplant recipients. Improved understanding of CMV seasonality may help guide use of preventative therapies., Methods: We evaluated adult patients receiving a kidney transplant at our center in Wisconsin from January 1, 1995 to December 31, 2018. CMV event was defined as quantifiable viral replication with clinical signs or symptoms suspicious for CMV per current consensus recommendations. Seasons were divided as follows: winter (December-February), spring (March-May), summer (June-August), and fall (September-November). The primary objective was to evaluate the annual distribution of CMV disease and determine whether this differed by season., Results: There were 6151 kidney transplants in the study period. A total of 913 patients had 1492 episodes of CMV. Median time from transplant to first detection was 5.51 months (interquartile range [IQR] 2.87-11.7). The observed overall incidence exceeded the expected incidence in winter (+.7%), spring (+5.5%), and fall (+3.4%) and was less than expected in summer (-9.5%) (p = .18). The incidence of CMV during summer, however, was 21% less than expected (p = .001) in recipients who were CMV positive (R+) at the time of transplantation. No such difference was observed in CMV negative recipients (R-; p = .58)., Conclusion: CMV after kidney transplant appears to be less common during the summer season in patients who were R+ at transplant but does not follow seasonal variation in R-. Reasons for this are unclear but are likely related to CMV-specific cell-mediated immunity. These findings may have clinical implications, particularly the use of non-pharmacologic strategies to improve response to antiviral therapy., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: To evaluate epidemiology, risk-factors, and outcomes of high-level (HL) cytomegalovirus (CMV) viremia in liver transplant recipients., Methods: Adult patients receiving a liver transplant between 1/1/2017 and 9/30/2020 were evaluated. Viral loads at University of Wisconsin Health Clinical Laboratories were required to allow for numerical comparison. Primary objective was incidence and outcomes of HL CMV viremia (viral-load > 100 000 IU/ml). Secondary objective was to elucidate risk factors to allow targeted interventions., Results: Two hundred nine patients met inclusion criteria; 175 kept their graft for at least 240 days. Of these nine patients developed HL CMV, 28 developed low-level (LL CMV, viral-load 250-100 000 IU/ml), and 138 did not develop CMV viremia. When comparing these three groups via classic statistical methods time from transplant to viremia was similar (HL 158 ± 77 days, LL 150 ± 76 days). Clinical factors were also similar with the exception of donor seropositivity (HL 87.5%, LL 70.4%, No CMV 49.6%, p = 0.025). HL CMV was significantly associated with graft loss (p < 0.0001) on Kaplan-Meier analysis; graft loss in the LL CMV group did not differ from the no CMV group (p = 0.96). To allow valid assessment of risk factors in the total study population (n = 209), models of time-varying covariates were used, and Cox proportional hazards ratios were calculated. In this analysis, HL CMV was associated with a significantly increased risk of graft loss (HR 5.6, p = 0.0016). When investigating risk factors associated with HL CMV, donor seropositivity significantly increased risk (HR 8.85, 95% CI 1.13-71.43, p = 0.038). Pretransplant total bilirubin (HR 1.04, 95% CI 0.998-1.07, p = 0.06) trended toward significance. Recipient seronegativity, liver disease, clinical and allocation model for end-stage liver disease (MELD), transplant surgery duration, age, sex, induction immunosuppression, and maintenance immunosuppression were not significantly associated with development of HL CMV., Conclusion: HL CMV after liver transplant is uncommon but is associated with a significantly increased risk of graft loss that is not present in those patients who develop LL CMV or do not develop CMV viremia. Given these negative graft effects, CMV stewardship interventions targeting recipients of CMV seropositive allografts are warranted. Future larger scale studies evaluating the potential role of other factors in risk stratification are needed., (© 2022 Wiley Periodicals LLC.)