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Purpose: Evaluate cytomegalovirus (CMV) post‐prophylaxis surveillance in high‐risk (D+/R‐) kidney and liver transplant recipients. Methods: Adult D+/R‐ patients were included if transplanted between 6/1/15 and 11/30/22 and divided into a pre‐CMV‐stewardship‐era (6/1/15–5/31/18), CMV‐stewardship‐era (6/1/18–6/30/20), and a surveillance‐era (7/1/2020–11/30/2022) then followed through 12 months. The primary objective was to evaluate CMV‐related outcomes. The secondary objective was to assess graft and patient survival by era. Results: There were 328 patients in the study period; 133 in the pre‐stewardship‐era, 103 in the stewardship‐era, and 92 in the surveillance‐era. Replication rates in the surveillance‐era were significantly higher, as anticipated due to increased sampling (pre 38.4%, stewardship 33.0%, surveillance 52.2%, p = 0.02). Time from transplant to first replication was similar (pre 214.0 ± 79.0 days, stewardship 231.1 ± 65.5, surveillance 234.9 ± 61.4, p = 0.29). CMV viral load (VL) at first detection, maximum‐VL, and incidence of VL > 100 000 IU/mL were numerically lower in the surveillance era, although not statistically significant. CMV end‐organ disease (p < 0.0001) and ganciclovir‐resistance (p = 0.002) were significantly lower in the surveillance era than in both previous eras. Rejection was not different between eras (p = 0.4). Graft (p = 0.0007) and patient survival (p = 0.008) were significantly improved in the surveillance era. Conclusions: Post‐prophylaxis surveillance significantly reduced CMV end‐organ disease and resistance. Despite observing increased replication rates in the surveillance era, rejection was not significantly different and there was no graft loss or patient mortality at 12 months. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose: Valganciclovir (VGC) is the gold‐standard for cytomegalovirus (CMV) prophylaxis (PPX) after solid organ transplant (SOT). Letermovir (LTV) was recently approved in high‐risk kidney transplant and has reduced myelosuppressive toxicity. Conversion from VGC to LTV may be pursued in the setting of leukopenia. It is unknown if this strategy is effective. Methods: Adult patients receiving abdominal SOT were included if converted from VGC to LTV between January 1, 2018 and January 31, 2023. Primary objective was to describe the impact of LTV conversion as measured by WBC recovery, mycophenolate modification, and use of GCSF, and prophylaxis efficacy assessed by course completion and breakthrough DNAemia. Secondary objective was to evaluate rates of post‐prophylaxis CMV. Results: Seventy five SOT recipients met inclusion criteria. Mean change in WBC in response to LTV conversion by day 14 was +2.02 ± 2.52 k/uL. 75%(56/75) of the population did not require mycophenolate adjustment or had their dose increased after conversion. GCSF was required in 38.7%(29/75) prior to conversion; only 21.3%(16/75) of patients required GCSF after conversion. Early termination was uncommon, 14.7%(11/75) stopped due to lack of ongoing insurance approval, only one patient stopped due to adverse effects (1.3%). One patient had clinically significant breakthrough (1.3%) that was successfully managed with VGC. Incidence of post prophylaxis CMV was 40%. Conclusion: Withholding of VGC with LTV conversion may improve leukopenia without need for additional supportive measures. Most importantly, this strategy avoided additional mycophenolate modifications. In our study, LTV was associated with low rates of breakthrough. Post‐prophylaxis CMV was similar to VGC prophylaxis. [ABSTRACT FROM AUTHOR]

Introduction: Invasive fungal infections (IFI), are estimated to occur in 2%–14% of kidney transplant recipients (KTRs) in the current era of immune suppression and are associated with high mortality rates. We hypothesized that hypoalbuminemia in KTRs is a risk factor for IFI and would be associated with poor outcomes. Methods: In this study, using data from a prospective cohort registry, we describe the frequency of IFI due to Blastomycosis, Coccidioidomycosis, Histoplasmosis, Aspergillosis, and Cryptococcus in KTRs with serum albumin levels measured 3–6 months before diagnosis. Controls were selected based on incidence density sampling. KTRs were divided into three groups based on the pre‐IFI serum albumin level: normal (≥4 g/dL), mild (3–4 g/dL), or severe (<3 g/dL) hypoalbuminemia. Outcomes of interest were uncensored graft failure after IFI and overall mortality. Results: A total of 113 KTRs with IFI were compared with 348 controls. The incidence rate of IFI among individuals with normal, mild, and severe hypoalbuminemia was 3.6, 8.7, and 29.3 per 100 person‐years, respectively. After adjustment for multiple variables, the trend for risk of uncensored graft failure following IFI was greater in KTRS with mild (HR = 2.1; 95% CI,.75–6.1) and severe (HR = 4.47; 95% CI, 1.56–12.8) hypoalbuminemia (P‐trend <.001) compared to those with normal serum albumin. Similarly, mortality was higher in severe hypoalbuminemia (HR = 1.9; 95% CI,.67–5.6) compared to normal serum albumin (P‐trend <.001). Conclusion: Hypoalbuminemia precedes the diagnosis of IFI in KTRs, and is associated with poor outcomes following IFI. Hypoalbuminemia may be a useful predictor of IFI in KTRs and could be incorporated into screening algorithms. [ABSTRACT FROM AUTHOR]

Introduction: Serum albumin is an indicator of overall health status, but it remains unclear how pre‐transplant hypoalbuminemia is associated with early post‐transplant outcomes. Methods: This study included all adult kidney transplant recipients (KTRs) at our center from 01/01/2001–12/31/2017 with serum albumin measured within 30 days before transplantation. KTRs were grouped based on pretransplant albumin level normal (≥4.0 g/dL), mild (≥3.5 – < 4.0g/dL), moderate (≥3.0 – < 3.5g/dL), or severe hypoalbuminemia (<3.0g/dL). Outcomes of interest included: length of hospital stay (LOS), readmission within 30 days, delayed graft function(DGF), and re‐operation related to post‐transplant surgical complications. We also analyzed rejection, graft failure, and death within 6 months post‐transplant. Results: A total of 2807 KTRs were included 43.6% had normal serum albumin, 35.3% mild, 16.6% moderate, and 4.5% severe hypoalbuminemia. Mild and moderate hypoalbuminemia were associated with a shorter LOS by 1.22 (p < 0.001) and 0.80 days (p = 0.01), respectively, compared to normal albumin. Moderate (HR: 0.58; 95% CI: 0.37‐0.91; p = 0.02) and severe hypoalbuminemia (HR: 0.21; 95% CI: 0.07–0.68; p = 0.01) were associated with significantly lower rates of acute rejection within 6 months post‐transplant. Conclusion: Patients with pre‐transplant hypoalbuminemia have post‐transplant outcomes similar to those with normal serum albumin, but with a lower risk of acute rejection based on the degree of hypoalbuminemia. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Myalgia in liver transplant recipients after receiving tixagevimab/cilgavimab for pre-exposure prophylaxis of COVID-19: A case series At our center, three of 77 liver transplant recipients who have received tixagevimab/cilgavimab (3.9%) have reported myalgia; by contrast, 139 kidney transplant recipients and 101 lung transplant recipients have received tixagevimab/cilgavimab without any reports of myalgia. [Extracted from the article]

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

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. [ABSTRACT FROM AUTHOR]

Biologics have become the forefront of medicine for management of autoimmune conditions, leading to improved quality of life. Many autoimmune conditions occur in solid organ transplant (SOT) recipients and persist following transplant. However, the use of biologics in this patient population is not well studied, and questions arise related to risk of infection and adjustments to induction and maintenance immunosuppression. Guidelines have been published highlighting management strategies of biologics around the time of elective surgical procedures, but this is not always feasible in urgent situations, especially with deceased donor transplantation. The aim of this review is to summarize the current literature regarding the use of these agents in solid organ transplant recipients, and specifically address induction and maintenance immunosuppression, as well as the need for alternative infective prevention strategies to create a practical reference for the frontline clinician, when faced with this complex clinical scenario. [ABSTRACT FROM AUTHOR]

Background: In the general population, use of proton pump inhibitor (PPI) has been linked to higher risk of osteoporotic fractures. PPI is commonly prescribed in kidney transplant recipients (KTRs). However, the effect of PPI on osteoporosis in KTRs is largely unstudied.Methods: A total of 1,774 adult KTRs in the Wisconsin Allograft Recipient Database with at least one eligible bone mineral density (BMD) measurement at least 3 months after transplantation were included in the analyses. Associations between use of PPI and histamine-2 receptor antagonist (H2RA) at 3 months after transplantation and subsequent slope of T-score were assessed.Results: A total of 1,478 (83.3%) participants were using a PPI at 3 months after transplantation. Compared to the use of H2RA, use of PPI was not significantly associated with annualized slope of hip T-score (β = -0.0039, 95% CI -0.00497 to 0.0021) or annualized slope of spine T-score (β = -0.017, 95% CI -0.049 to 0.083) after adjustment for potential confounders. Similarly, no significant association between use of PPI and slope of T-score was observed when defining PPI/H2RA exposure as use within 6 months of the initial BMD measurement, or only including participants with at least 2 BMD measurements, or stratified by different age and sex.Conclusions: Use of PPI was not associated with an increased rate of BMD loss in KTRs. Our results support previous findings that PPI use does not have a significant effect on bone mineral loss. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the association of conversion from valganciclovir to letermovir on cytomegalovirus‐specific cellular immunity. Methods: Adult patients were included if they received a kidney or liver transplant between 8/1/2018‐12/31/20, developed symptomatic, high‐level CMV viremia and were converted to letermovir 480 mg daily as monotherapy after treatment with ganciclovir‐derivatives for a minimum of 4 weeks and had subsequent CMV cell‐mediated immunity (CMI) testing via ICS assay by flow cytometry (Viracor Eurofins T Cell Immunity Panel). Results: Seven patients met inclusion criteria; 87.5% were male and recipients of a kidney transplant. All patients were CMV high risk (D+/R‐). Mean time from transplant to CMV disease was 200 ± 91 days. Peak viral load (VL) during CMV treatment was 540,341 ± 391,211 IU/mL. Patients received a mean of 30 ± 24 weeks (range: 4‐78 weeks) of therapy with ganciclovir‐derivatives at induction doses prior to letermovir introduction. The median absolute lymphocyte count (ALC) at letermovir initiation was 400/μL (IQR 575) and the median VL was 51.6 (range: ND‐490) IU/mL. Most patients (n = 5/7, 71.4%) experienced an increase in VL 1 and/or 2 weeks after conversion to letermovir. All patients had positive CMI per ICS assay after conversion. Patients received a mean of 10.3 ± 6.9 weeks of letermovir prior to having a positive result. Median ALC at positivity was 900/μL. Immunosuppression was not further reduced from initiation of letermovir to demonstration of CMV CMI. No patient had progressive replication or breakthrough disease while maintained on letermovir and three patients (42.9%) underwent antiviral withdrawal without recurrence at the last follow‐up. Conclusion: In this case series of abdominal transplant recipients with severe or persistent CMV infection, patients developed CMV‐specific CMI after conversion to letermovir monotherapy. These data suggest that using letermovir in place of valganciclovir for secondary prophylaxis may address the lack of efficacy previously seen with this approach, as well as the issues that plague antiviral withdrawal with systematic monitoring. Future prospective studies are needed to evaluate this effect in a more controlled research environment with serial CMI testing to elucidate the optimal duration of letermovir when used in this way [ABSTRACT FROM AUTHOR]

Introduction: BK polyomavirus (BKV) is a common infection among kidney transplant recipients (KTR). Risk factors and outcomes based on donor characteristics remain largely unknown. Methods: In this study, we aimed to analyze the impact of donor factors through a paired kidney analysis. We included 289 pairs of adult deceased donor transplants (578 KTRs total); each pair had received kidneys from the same donor. Recipient pairs were divided into three groups: "no BK group" if neither KTR developed BK viremia (n = 336), "discordant" if the only one did (n = 176), and "concordant" if both did (n = 66). Acute rejection (AR), graft failure, and BK nephropathy (BKN) were outcomes of interest. Results: Donors in the concordant group were younger, had lower kidney donor profile index (KDPI), and were less likely to be donor after circulatory death (DCD). In multivariate analyses, KTRs who had a donor with a higher body mass index (BMI) (hazard ratio (HR): 0.97; 95% confidence interval (CI): 0.95–0.99; p =.009) were less likely to develop BKV. Concordance was not associated with AR (HR: 0.83; 95% CI: 0.51–1.34; p =.45), graft failure (HR: 1.77; 95% CI: 0.42–7.50; p =.43), or BKN (HR: 1.02; 95% CI: 0.51–2.03; p =.96). Discussion: Our study suggests lower donor BMI is associated with BKV infection, and concordance or discordance between paired kidney recipients is not associated with poor outcomes. [ABSTRACT FROM AUTHOR]

Problem: Mathematical modeling suggests aggressive ganciclovir dosing in the first week of cytomegalovirus disease (CMV) treatment may improve response. This has not been evaluated clinically. Methods: Adult kidney and/or pancreas transplant recipients admitted with CMV (4/29/19–7/15/20) received IV ganciclovir(10 mg/kg Q12 h × 7 days) with step‐down to standard‐of‐care (SOC) dosing thereafter (5 mg/kg Q12). A SOC cohort admitted before implementation of the dosing strategy (10/20/16–3/2/19) served as a comparator. Primary objective: rate of viral clearance (delta log CMV) at therapy day 7. Secondary objective: safety/short term efficacy. Results: Fifty‐four patients met inclusion criteria; 22 high‐dose, 32 SOC. Demographics were similar with the exception of more women (45.4% vs. 15.6%,P =.03) and higher presenting viral‐load in the high‐dose group (log 6.0±.7 vs. log 5.2±1.2, P =.02). High‐dose resulted in significantly greater response to therapy at day 7 (log ‐.92±.51 vs. log ‐.56±.79, P =.04). Change in WBC at day 7 was not different (‐.49±1.92 vs. ‐.45±5.1, P =.97). Short‐term clinical outcomes were similar between groups including mean hospital length‐of‐stay (P =.52), readmission rates (30 d: P =.38; 90 d: P =.5) and achievement of CMV viral‐load less‐than‐lower‐limit‐of‐quantification by day 90 (73% vs. 84%, P =.06). Rejection after CMV as well as graft/patient survival were similar between groups (P =.56, P >.99, P >.99). Conclusion: A high‐dose IV ganciclovir strategy results in improved viral clearance kinetics without safety concerns and similar short term clinical outcomes. [ABSTRACT FROM AUTHOR]

Background: Data on epidemiology and outcomes of cytomegalovirus (CMV) nephritis in kidney transplant patients are limited due to the rarity of this condition. Methods: A retrospective review of all kidney transplant recipients (KTR) (n = 6490) and biopsy‐proven CMV nephritis between 1/1997 and 12/2020 was performed. Results: The prevalence of CMV nephritis was low: 13/6490 (0.2%). The diagnosis was made at a median of 7.0 months (range 2.6–15.6 months) after transplant. 6 of 13 (46%) patients were CMV (D+/R−). Median CMV DNA load at biopsy was 376,000, IU/mL (range 87,000–6,460,000 IU/mL). Main biopsy features were CMV glomerulitis (n = 7/13, 54%) followed by CMV tubulointerstitial nephritis (6/13; 46%). Mean eGFR at biopsy (22.7 ± 12 mL/min/1.73 m2) was significantly decreased compared to baseline eGFR (38.7 ± 18.5 mL/min/1.73 m2, p = 0.02). The vast majority, 11 of 13 (85%), experienced graft failure including 5 of 13 (38%) death‐censored. 5 of 13 (38%) patients were diagnosed with acute rejection: three had concurrent acute rejection, and two had rejection within 3 months of index biopsy, respectively. Patients with tubulointerstitial CMV nephritis were significantly more likely to have rejection at the time of biopsy (50% vs. 0%, p < 0.05) compared to those with glomerular CMV nephritis. There were no significant differences between these groups in terms of eGFR at all time points, death, graft failure, immunosuppression changes or rejection after biopsy. Conclusion: CMV nephritis is rare but appears to be associated with poor patient/allograft outcomes. Early identification and timely treatment of CMV infection may prevent end‐organ involvement and improve patient and allograft‐related outcomes. [ABSTRACT FROM AUTHOR]

Rising expenditures threaten healthcare sustainability. While transplant programs are typically considered profitable, transplant medications are expensive and frequently targeted for cost savings. This review aims to summarize available literature supporting cost‐containment strategies used in solid organ transplant. Despite widespread use of these tactics, we found the available evidence to be fairly low quality. Strategies mainly focus on induction, particularly rabbit antithymocyte globulin (rATG), given its significant cost and the lack of consensus surrounding dosing. While there is higher‐quality evidence for high single‐dose rATG, and dose‐rounding protocols to reduce waste are likely low risk, more aggressive strategies, such as dosing rATG by CD3+ target‐attainment or on ideal‐body‐weight, have less robust support and did not always attain similar efficacy outcomes. Extrapolation of induction dosing strategies to rejection treatment is not supported by any currently available literature. Cost‐saving strategies for supportive therapies, such as IVIG and rituximab also have minimal literature support. Deferral of high‐cost agents to the outpatient arena is associated with minimal risk and increases reimbursement, although may increase complexity and cost‐burden for patients and infusion centers. The available evidence highlights the need for evaluation of unique patient‐specific clinical scenarios and optimization of therapies, rather than simple blanket application of cost‐saving initiatives in the transplant population. [ABSTRACT FROM AUTHOR]

Problem: Incidence and impact of CMV infection in pancreas‐transplant recipients (PTRs) in the valganciclovir prophylaxis era has not been completely elucidated. Methods: Adult D+/R‐ PTRs were divided into a current era (1/1/2011‐12/31/17; 6‐month PPX) and a historic era (1/1/2003‐12/31/09; 3‐month PPX). Primary objective: effect of prophylaxis extension on the incidence of CMV infection. Secondary objective: impact of extension on valganciclovir‐related toxicity (leukopenia) and transplant outcomes. Results: There were 177 D+/R‐ PTRs in the study period (historic:98, current:79). Prophylaxis extension resulted in significant reduction of CMV infection from 25.4% to 10.9% at 6 months, (57% reduction, p =.021). However, 1‐year rates of CMV infection (historic:31% vs current:36%) and end‐organ disease (historic:7.7% vs current:6.9%) were not different (p =.93). Prophylaxis extension significantly increased leukopenia (white blood cell count<3 K/uL) at 6 months (historic:9.5% vs current:28.6%, p =.018). On multivariable analysis prophylaxis extension was not associated with reduced rates of CMV infection (p =.99) or CMV end‐organ disease (p =.3). Additionally, there was no significant difference in rejection (p =.2), graft survival (p =.08), death‐censored graft survival(p =.07) or patient survival (p =.6). Conclusions: Prophylaxis extension in D+/R‐ PTRs appears to delay time to first CMV but not reduce overall incidence. These findings suggest a hybrid approach, incorporating antiviral withdrawal and protocolized monitoring, may be needed to improve CMV‐related outcomes. [ABSTRACT FROM AUTHOR]

Purpose: Persistent viral replication resulting in ongoing cytomegalovirus (CMV) viremia despite adequate therapy is difficult to manage and associated with negative outcomes. We report a case series of kidney transplant recipients receiving adjunctive letermovir in combination with valganciclovir for refractory CMV. Methods: Adult patients receiving a kidney or kidney‐pancreas transplant were included if they developed CMV viremia and initiated letermovir 480 mg daily as part of a dual therapy regimen with valganciclovir 900 mg twice daily between 1/9/2020 and 31/12/2020. Included patients received ≥90 days of valganciclovir and had a detectable viral load less than 1000 Iu/ml (log10 < 3) at the time of letermovir initiation. The primary objective was to evaluate the impact of adjunctive letermovir on viral clearance to negativity. We also evaluated effect of letermovir on tacrolimus levels. Results: Eight patients were included. Letermovir was added 223 ± 105 days after initiation of CMV treatment with ganciclovir derivatives. Median viral load at initiation was 139.7 (range: 73–355) IU/ml and did not clear or change significantly after 2, 4 and 12 weeks of adjunctive letermovir (132.5 [range: 34.5–513] IU/ml vs. 68.7 [range: 34.5–574] IU/ml vs. 78.3 [range: 34.5–347] IU/ml, p > 0.05). Tacrolimus was reduced by ∼30% in anticipation of a letermovir‐tacrolimus drug interaction. Despite this reduction, mean tacrolimus serum levels two weeks after adjunctive letermovir increased by 43% (5.6 ± 1.6 ng/ml vs 8.0 ± 4.6 ng/ml). Conclusion: In kidney and kidney‐pancreas recipients with refractory CMV, the use of adjunctive letermovir did not result in viral clearance. Additionally, despite a mean tacrolimus dose reduction of 30% at letermovir initiation, serum concentrations increased by over 40%. Further investigation into the optimal approach to refractory CMV is needed. [ABSTRACT FROM AUTHOR]

Purpose: In clinical practice, conversion from universal cytomegalovirus prophylaxis (CMV PPX) with valganciclovir (VGC) to targeted therapy (preemptive monitoring, PEM) is often pursued in the setting of leukopenia. It is unknown if this is an effective strategy. Methods: Adult patients receiving a kidney and/or pancreas transplant were included if converted from PPX to PEM between 9/1/19 and 3/1/20 due to leukopenia. A positive CMV viral load (VL) was defined as CMV PCR greater than the lower limit of quantification (LLOQ) based on local lab testing. A CMV VL of >500 IU/mL was chosen as the preemptive treatment (PET) threshold. Primary objective was to describe the impact of conversion on resolution of leukopenia. Secondary objectives were to assess PEM associated outcomes. Results: There were 49 patients converted from PPX to PEM due to leukopenia in the study period; 88% were KTRs and 96% received lymphocyte‐depleting induction; 84% were seropositive at transplant (R+) and 16% were high‐risk (D+/R−). Mean WBC at time of enrollment was 1.4 ± 0.4. After PEM conversion, WBC recovered to >3 in 87.8% of the population in a mean of 26.8 ± 24.5 days. Immunosuppression was modified in 96% of the population and GCSF was required in 46.9% of patients. CMV viremia occurred in 36.7% of the population; 78% were KTRs and 94% were R+. Time from PEM enrollment to PET was 64 ± 34 days. Median VL at first detection was 587 IU/mL, median peak was 1920 IU/mL. Five patients (27.8%) presented with symptoms consistent with CMV syndrome, none had end organ disease. Six patients (33%) presented with a VL <500 IU/mL at first detection, but all subsequently surpassed the threshold and required PET. Mean duration of PET was 25 ± 11 days. Mean change in WBC in response to PET was −0.4 ± 1.3. Immunosuppression required further adjustment in 61% of patients. There were no deaths or graft loss due to CMV at last follow‐up. Conclusion: In kidney and pancreas transplant recipients who undergo PEM conversion due to leukopenia, withholding of VGC can improve leukopenia, but other concomitant measures are necessary. This population should be considered fairly high risk, with a threshold of treatment of first quantifiable replication. Our findings suggest lack of harm from this approach but highlight the importance of close monitoring to prevent symptomatic replication. Larger studies with longer follow‐up are needed to better evaluate the impact of PEM conversion on late‐onset CMV and patient and graft outcomes. [ABSTRACT FROM AUTHOR]

Cytomegalovirus (CMV) infection is one of the most common and significant complications after solid organ transplant (SOT). Severe acute respiratory coronavirus 2 (SARS‐CoV‐2), which causes the novel betacoronavirus 2019 disease (COVID‐19), has become the first global pandemic in 100 years. The world's attention has turned to address this unanticipated development; however, the viral infection that has long plagued outcomes after solid organ transplantation still requires vigilance. With physical distancing as the key intervention to reduce the healthcare burden, and the unease related to healthcare contact within the transplant population given the associated morbidity and mortality of COVID‐19 in transplant recipients, providers have struggled to evaluate and streamline essential in‐person healthcare contact, including laboratory visits. Owing to this, the COVID‐19 pandemic has placed a significant strain on the delivery of CMV prophylaxis and treatment after solid organ transplantation. In this piece, we will describe issues our CMV antiviral stewardship service has encountered in the care of the transplant recipient with CMV during the this unprecedented time and share our expert opinion to approaches to providing optimal, evidenced based care during a pandemic associated with a seemingly unrelated viral infection. [ABSTRACT FROM AUTHOR]

Background: Primary cytomegalovirus (CMV) disease in high‐risk (D+/R‐) abdominal solid organ transplant recipients (aSOTRs) is well described, however, little is known of primary CMV disease in low‐risk (D‐/R‐) patients. Methods: Observational study of adult aSOTRs between 1/1/2009 and 9/1/2019 screened based on serostatus at transplant; D‐/R‐ and D+/R‐ patients were included. Primary objective: Describe epidemiology of primary CMV in D‐/R‐ aSOTRs. Secondary objective: Compare infectious and transplant‐related outcomes of primary CMV disease in the first 90 days (early CMV) between D‐/R‐ and D+/R‐. Results: Of 782 D‐/R‐ aSOTRs in the study period, 13 developed CMV at any time after transplant to last follow‐up. Of 671 D+/R‐ patients, 186 developed CMV. Early CMV disease was significantly more common in the D‐/R‐ group (54% vs 15.6%, P =.0005) despite populations being similar demographically, including allograft subtype. D‐/R‐ patients with early CMV disease had median viral load >100 000 IU/mL and 42.9% had end‐organ manifestations; 71.4% required hospital admission. Immunosuppressive therapy was adjusted in 100% of patients, there was an approximately 14.3% rate of antiviral resistance and 28.6% had concomitant opportunistic infection. These findings were similar to D+/R‐ patients. There was no difference in risk of rejection or all‐cause mortality associated with early CMV disease, however, graft loss was significantly higher in D‐/R‐. Conclusion: D‐/R‐ aSOTRs infrequently develop CMV, however, when it occurs, they present with disease manifestations similar to and graft outcomes inferior to D+/R‐ with CMV. Additionally, the majority of CMV disease in D‐/R‐ occurs in the first 90 days after transplant, suggesting possible donor subclinical infection or transfusion source. The complicated course in D‐/R‐ is likely caused by low clinical suspicion. Awareness of disease severity and aggressive upfront management may promote positive outcomes. [ABSTRACT FROM AUTHOR]

Backgrounds: Effective management of BK viremia (BKPyV‐DNAemia) in kidney transplant recipients (KTRs) involves regular monitoring and adjustment of immunosuppression. With this strategy, the majority of patients will clear BK or have ongoing, but non‐significant, low‐level BKPyV‐DNAemia. However, despite adjustments, some will develop more severe sequelae of BK including BKPyV‐DNAemia >5 log10 copies/mL and BK nephropathy, and others may develop de novo DSA (dnDSA) or acute rejection (AR). Methods: This was a single‐center study of KTRs transplanted at the University of Wisconsin‐Madison between 01/01/2015 and 12/31/2017. In this study, we sought to elucidate characteristics associated with the progression of BKPyV‐DNAemia to unfavorable outcomes after decreasing immunosuppressive medications for the management of BK viremia as described in consensus guidelines. Results: A total of 224 KTRs fulfilled our selection criteria; 118 (53%) resolved or had persistent low DNAemia, 64 (28%) had severe BK/nephropathy, and 42 (19%) developed dnDSA or AR. In multivariable analysis, female gender (HR: 2.05; 95% CI: 1.08‐3.90; P =.02); previous rejection (HR: 2.90; 95% CI: 1.04‐8.12; P =.04), and early infection (HR: 0.81; 95% CI: 0.72‐0.90; P <.001) were associated with the development of severe BK/nephropathy. Conversely, non‐depleting induction at transplant (HR: 2.06; 95% CI: 1.03‐4.11; P =.03), HLA mismatches >3 (HR: 2.27; HR: 1.01‐5.06; P =.04), and delayed graft function (HR: 4.14; 95% CI: 1.12‐15.28; P =.03) were associated with development of dnDSA and/or rejection. Conclusion: Our study suggests that almost half of KTRs with BKPyV‐DNAemia managed by our immunosuppressant adjustment protocol progress unfavorably. Identification of these risk factors could assist the frontline clinician in creating an individualized immunosuppressive modification plan potentially mitigating negative outcomes. [ABSTRACT FROM AUTHOR]

Aim: The impact of pre‐transplant (pre‐TXP) bariatric surgery (BS) on outcomes after liver transplant (LTX) has not been completely elucidated. Roux‐en Y gastric bypass (RYGB) is one of the most common BS procedures. The primary objective of this study was to identify the risk of infection in LTX recipients with pre‐TXP RYGB. Methods: Adult patients with LTX between 1/1/2001 and 9/30/2018 at our center were screened for pre‐TXP RYGB; patients with gastrectomy via sleeve or banding were excluded. Patients with no history of BS pre‐ or post‐transplant were placed in a comparator group, matched 2:1 via incidence density sampling on age epoch. Results: There were 16 LTX recipients with pre‐TXP RYGB matched to 32 controls. Median time from RYGB to transplant was 11.7 years. Mean weight loss was 66 ± 19 kg. There were significantly more women with pre‐TXP RYGB than in the matched control (RYGB:68.8% vs control:25%, P =.009). Demographics were otherwise similar between groups. Pre‐TXP RYGB did not significantly increase hospital or ICU length of stay (P =.5, P =.3) but was associated with a significantly increased rate of fungal infection at 1 year (RYGB:33.4% vs control:9.7%, P =.01), and a numerical trend to increased bacterial infection (RYGB:56.2% vs control:32.2%, P =.09). Conclusion: Despite the substantial weight loss attributed to BS, patients with pre‐TXP RYGB demonstrated increased rates of fungal infection after transplant and trended toward increased bacterial infection. While the anatomical complexity associated with LTX surgery after RYGB did not appear to significantly affect ICU or hospital length of stay, it may have contributed to overall infectious risk, and possibly to impaired survival. Additionally, bypass of the host natural barrier defenses of the stomach could also have contributed to infectious risk. Our findings highlight the complexity of this patient population. Future prospective studies are needed to investigate risk of infection after LTX in the setting of pre‐Txp BS. Potential modification in fungal prophylaxis protocols to include pre‐TXP RYGB may be warranted. [ABSTRACT FROM AUTHOR]

A recently published report titled "Increased incidence and unusual presentations of CMV disease in kidney transplant recipients after conversion to belatacept" by Chavarot et al. observed that patients converted to belatacept have a sevenfold higher incidence of cytomegalovirus (CMV) disease and atypical, aggressive disease phenotype.1 These results coincided with earlier published studies that similarly observed that belatacept-based maintenance immunosuppression regimens in kidney transplant recipients are associated with increased rates of opportunistic infections, particularly primary CMV infections with prolonged viral replication in high-risk (seronegative recipient receiving a graft from seropositive donor, D+/R-) patients.2,3 We concur with these findings and propose the etiology may be attributed to a prolonged inhibitory effect of belatacept on CMV-specific cell-mediated immunity (CMI), which persists beyond discontinuation, based on our experience with the following case (Figure 1). Increased incidence and unusual presentations of CMV disease in kidney transplant recipients after conversion to belatacept. CMV high-risk status and posttransplant outcomes in kidney transplant recipients treated with belatacept. [Extracted from the article]

Purpose: Describe use and predictive potential of an intracellular cytokine staining (ICS) cytomegalovirus cell‐mediated immunity (CMV CMI) assay and a risk factor screening tool on CMV reactivation in a real‐world clinical setting and compare this to serologically demonstrated immunity by CMV IGG. Methods: Adult transplant patients at our center with the ICS assay resulted between 10/1/2018 and 9/1/2019 were included. Assays were considered positive per manufacturer specifications. Results: Twenty‐five patients underwent ICS CMV CMI testing at our institution during the study period. The majority were kidney transplant recipients, 76% were D+/R−, and 76% were receiving CMV treatment. The positive predictive value (PPV) of the assay to predict lack of CMV was 87%; 93% when patients with antiviral resistance were excluded and 91% in only those receiving treatment. The presence of ≤2 clinical risk factors on the screening tool had a PPV of 92% in predicting lack of recurrence. In comparison, serologically demonstrated immunity by CMV IGG had a PPV of 62%. Conclusions: In our study representing real‐world clinical use, the ICS CMV CMI assay and the risk factor screening tool had predictive potential that was superior to serologically demonstrated immunity. The reliability of the assay seemed to decrease with higher degrees of clinical risk suggesting a multimodal screening approach is warranted. [ABSTRACT FROM AUTHOR]

Given the current climate of drug shortages in the United States, this review summarizes available comparative literature on the use of alternative immunosuppressive agents in adult solid organ transplant recipients including kidney, pancreas, liver, lung, and heart, when immediate‐release tacrolimus (IR‐TAC) is not available. Alternative options explored include extended‐release tacrolimus (ER‐TAC) formulations, cyclosporine, belatacept, mammalian target of rapamycin inhibitors, and novel uses of induction therapy for maintenance immunosuppression. Of available alternatives, only ER‐TAC formulations are of non‐inferior efficacy compared to IR‐TAC when used de novo or after conversion in stable kidney transplant recipients (KTRs). All other alternatives were associated with higher rates of biopsy‐proven rejection, but improved tolerance from classic adverse effects of IR‐TAC including nephrotoxicity and development of diabetes. While most alternative therapies are approved in KTRs, access via third‐party payors is an obstacle in non‐KTRs. In the setting of IR‐TAC shortage, alternate therapeutic options may be plausible depending on the organ population and individual patient situation to ensure appropriate, effective immunosuppression for each patient. [ABSTRACT FROM AUTHOR]

Background: Published literature on predictors of polyomavirus (BKV) and cytomegalovirus (CMV) infections in simultaneous pancreas and kidney (SPK) transplant and their impact on allograft outcomes remain sparse. We hypothesize that BKV and CMV viremia infections decrease allograft survival in SPK. Identifying modifiable predictors of BKV and CMV may help tailor immunosuppression and improve allograft survival. Methods: All SPK recipients at our institution between January 2000 and April 2016 were included (n = 757). Thirty‐nine recipients had BKV only and 25 had CMV only, and infection occurred at median follow‐up times of 217 and 163 days, respectively. Event density sampling was used to match recipients with BKV or CMV to up to 10 recipients without infection by age, sex, and HLA mismatch status, and these were followed for a median of 4.3 years after infection. Results: Older age (HR 1.49 for each decade; 95% CI: 0.95, 2.35; P =.083) and tacrolimus use (HR 20.6; 95% CI: 2.37, 179.53; P =.006) were associated with increased incidence of BKV, but not CMV, infection. Both BKV and CMV infections were associated with increased risk of allograft failure for both pancreas (BKV [HR 2.17; 95% CI 1.47, 3.208; P =.000], CMV [HR 1.7; 95% CI 1.077, 2.687; P =.023]) and kidney (BKV [HR 2.65; 95% CI 1.765, 3.984; P =.000], CMV [HR 2.07; 95% CI 1.295, 3.308; P =.002]). Conclusion: Older age at time of transplant and tacrolimus may help predict BKV infection in SPK recipients. [ABSTRACT FROM AUTHOR]

The risk of subsequent cytomegalovirus infection (CMV) in kidney transplant recipients (KTR) after diagnosis of BK polyomavirus viremia (BKV) is unclear, and current evidence is conflicting. We reviewed all KTR transplanted at our institution between 1/1/2005 and 12/31/2015. Follow‐up began 3 months after transplantation to avoid confounding effects of prophylaxis. Clinically significant BKV, defined as detectable BK viremia >1000 copies/mL via molecular diagnostic testing (PCR), was treated as a time‐varying exposure with 1‐year follow‐up. This viral load cutoff was chosen to ensure a more homogenous population that would be considered to have clinically significant BK viremia that necessitated management via immunosuppressive modification. Patients were then screened for subsequent CMV infection. 2435 RTX recipients met inclusion criteria; of these, 314 developed BKV during follow‐up (BK+). Lymphocyte depletion, tacrolimus maintenance, and biopsy‐proven rejection were significantly higher in the BK+ group. BK+ was associated with lower risk of subsequent CMV infection (BK+ HR 0.45, 95% CI 0.22‐0.94, P =.03, relative risk reduction 55%). When adjusted for significant confounding factors, CMV incidence remained reduced in the BK+ population (HR 0.47, 95% CI 0.22‐0.98, P =.04). This large series of KTR demonstrates that BKV is associated with lower risk of subsequent CMV infection. [ABSTRACT FROM AUTHOR]

A recent study in liver transplant recipients with pre-transplant RYGB demonstrated an increased risk of fungal infections and a trend toward an increase in bacterial infections [10]. Pre-transplant bariatric surgery is not associated with an increased risk of infection after kidney transplant Patients in the pre-transplant BS cohort did not exhibit a statistically increased risk of graft loss (HR 1.5 95% CI 0.98-2.28, I P i = 0.06), although there was a trend toward increased graft loss. [Extracted from the article]

Abstract: Purpose: To evaluate the effect of mycophenolate (mycophenolic acid, MPA) dose on pancreas allograft survival following simultaneous pancreas kidney (SPK) transplant. Methods: This was an observational study of adult SPK recipients transplanted between 1/1/2002 and 6/30/2015. Recipients were divided into cohorts based on MPA dose at discharge: high dose (HD), 1000 mg three times daily mycophenolate mofetil (MMF) and standard dose (SD), 1000 mg twice daily MMF. Primary outcome was pancreas allograft survival. Secondary endpoints included kidney allograft survival, pancreas allograft rejection, infection, time to initial dose decrease, and patient survival (PS). Results: In all, 453 patients met inclusion criteria: 324 in HD‐MPA group and 129 in SD‐MPA group. HD‐MPA patients had higher rates of pancreas graft survival (P = .003). There were no differences in rates of pancreas allograft rejection (P = .8), kidney graft survival (P = .15), overall infection (P = .4), overall malignancy (P = .93), time to first dose reduction (P = .35), or patient survival (P = .3). In a multivariable analysis adjusted for differences between groups and known confounders, dosing group continued to significantly affect incidence of pancreas allograft failure (P = .02). Conclusions: HD‐MPA significantly impacted pancreas allograft survival in SPK recipients independent of graft rejection. Further studies are warranted to investigate the etiology of this finding and determine the optimal duration of HD‐MPA associated with positive graft outcomes. [ABSTRACT FROM AUTHOR]

This article summarizes available literature regarding the utilization of probiotic and synbiotics in liver transplant (LTX) recipients, reviewing efficacy in both decreasing infectious complications and immunomodulation, as well as exploring safety concerns. Data suggest that the use of probiotics containing Lactobacillus spp, either alone or in combination with prebiotics (referred to as synbiotics), may be effective in reducing infectious complications after LTX, a major contributor to graft loss, hospital length of stay, and mortality. Literature evaluating the use of probiotics to induce tolerance, reduce rejection, and prevent damage associated with ischemia–reperfusion injury is limited to animal models but compelling, as it suggests the use of probiotics may augment deleterious immune‐mediated processes in this population. While the benefits of probiotics should be weighed against potential risks, these concerns are largely theoretical in the LTX recipient, with the majority of evidence extrapolated from case reports in other immunosuppressed populations. Based on available literature, it may be prudent to avoid products containing Saccharomyces sp, as these were not used in the efficacy studies, and the majority of the adverse event reporting stems from the use of products containing this organism. Further evaluation of the safety and efficacy of probiotic therapy is warranted. Studies specifically designed to elucidate the optimal product and initiation scenario and delineate safety in this population are needed to allow expanded use of this inexpensive, relatively nontoxic, and potentially beneficial therapeutic option after LTX. [ABSTRACT FROM AUTHOR]

Study Objective: To evaluate the clinical course and long‐term impact of high‐dose acyclovir (HD‐A, 800 mg 4 times/day) cytomegalovirus (CMV) prophylaxis failure in a CMV‐seropositive abdominal solid organ transplant population. Design: Retrospective cohort study. Setting: Tertiary academic medical center. Patients: A total of 691 adults who received solid organ transplants between January 1, 2008, and June 30, 2013, without lymphocyte‐depleting induction and were prescribed 3 months of HD‐A prophylaxis at the time of hospital discharge. Of those patients, 54 experienced prophylaxis failure, defined as CMV detected via molecular diagnostics or on biopsy while receiving HD‐A (prophylaxis failure group), and 637 did not (comparator group). Measurements and Main Results: Mean ± SD time to failure was 64 ± 23 days; 98% (53/54 patients) was attributable to viremia diagnosed via positive polymerase chain reaction (PCR). Of these 53 patients, 34% (18 patients) were below the quantifiable range when detected. Median initial and peak CMV PCR for quantifiable readings were 1531 IU/ml (interquartile range [IQR] less than 250–2947) and 4442 IU/ml (IQR less than 250–32,500); 19 (36%) had a single detectable CMV PCR. Treatment was required in 56% (30/54 patients), with a median duration of 63 days; 40% (12 patients) were treated with valganciclovir alone, and the remainder received intravenous ganciclovir. CMV disease resulted in hospitalization in 28% (15 patients). Immunosuppression was modified in 52% (28 patients). The rate of CMV recurrence after 100 days was significantly higher in the prophylaxis failure group (59% vs 13%, p<0.0001). Higher rates of rejection; higher rates of 1‐, 3‐, and 5‐year graft failure; and higher rates of 1‐, 3‐, and 5‐year mortality were noted in the prophylaxis failure group on univariate analysis (43% vs 30%, p=0.045; 8%, 17%, and 34% vs 4%, 12%, and 17%, p=0.006; and 6%, 17%, and 26% vs 1%, 6%, and 10%, p=0.003, respectively). Multivariate analysis demonstrated an increased risk of graft failure in the prophylaxis failure group (hazard ratio [HR] 1.76, 95% confidence interval [CI] 1–3.1, p=0.0499) and a trend to increased mortality (HR 1.6, 95% CI 0.83–3.1, p=0.16). Conclusion: Prophylaxis failure with HD‐A was mostly limited to mild viremia; however, it was associated with significantly reduced long‐term graft survival, likely reflecting the negative impact of CMV viremia. [ABSTRACT FROM AUTHOR]