Cytomegalovirus (CMV) infection is a frequent complication following kidney transplantation that affects transplant outcomes. This study aimed to (i) estimate the 12-month cumulative incidence of CMV antigenemia (AG) in adult kidney transplant recipients not receiving antiviral prophylaxis, (ii) identify the risk factors for CMV AG, and (iii) assess the impact of CMV AG on transplant outcomes. This study included 128 living donor kidney recipients (aged ≥20 years) who underwent transplantation between 2012 and 2020. The mean recipient age was 52.8 ± 13.0 years. The overall positive CMV AG rates were 10.9%, 35.9%, 45.3%, 53.1%, and 59.4% (95% confidence interval (CI), 50.9-67.9) at 1, 2, 3, 6, and 12 months posttransplantation, respectively. The 12-month incidence rates in D-/R-, D-/R+, D+/R+, and D+/R - were 0%, 25.0%, 62.2%, and 81.3%, respectively. Multivariable analysis revealed that the risk of CMV AG increased with a stepwise increase in CMV serostatus risk category (hazard ratio (HR), 2.65; 95% CI, 1.66-4.21; p < .001) and recipient age (HR, 1.37 per 10-year increase; 95% CI, 1.14-1.65; p < .001). Positive CMV AG was associated with an increased risk of antibody-mediated rejection (HR, 21.40; 95% CI, 2.59-176.2; p = .005) and lower estimated glomerular filtration rate (p = .026). The risk of CMV AG is highest within the first 3 months posttransplant and persists for approximately 7-8 months in D + recipients. These findings underscore the importance of regular CMV monitoring for at least 6 months posttransplantation, particularly in centers employing preemptive therapy.

The goal of this study was to determine the secular trends in the incidence of CMV sero-mismatch (D+/R -) and if these trends meaningfully impact clinical outcomes.

This was a single-center longitudinal cohort study in adult kidney recipients transplanted between Jan 2012 and June 2021 with follow-up through June 2022. Baseline and follow-up data were collected. Univariate and multivariate statistics were used to analyze the data.

2,392 kidney transplants were performed during the study period; 132 patients did not meet inclusion criteria. The mean age was 52 years, 41% were female, 57% were black, and 19% were CMV D + /R -. The odds of being CMV high-risk increased by 6% each year (OR 1.06, 1.02-1.10 p = 0.003); 48% of the variability associated with CMV serostatus was explained by transplant year (R2 = 0.478, p = 0.002). Sequential modeling demonstrated that CMV D + /R - serostatus was a substantial risk factor for CMV infection (HR 5.7, 4.5-7.3), CMV disease (HR 8.4, 3.9-18.0), CMV resistance (HR 17.9, 3.8-84.2), CMV refractory infection (HR 35, 4-280), late CMV infection (HR 12.0, 8.3-17.1), acute rejection, and hospitalization for opportunistic infections. Secular trend analysis demonstrated that CMV infections, CMV resistance, and late CMV increased in incidence since 2012. The risks of CMV resistance and late infection was significantly influenced by D + /R - serostatus and transplant year, indicating that this risk is worsening over time.

The CMV D + /R - serostatus remains the single most important risk factor for CMV infection, disease, resistance, refractory infection, and late CMV, which appears to be increasing in magnitude.

SUMMARYTransplant recipients require lifelong, multimodal immunosuppression to prevent rejection by dampening alloreactive immunity. These treatments have long been known to lack antigen specificity. Despite empirically selected long-term immunosuppression regimens, most allografts succumb to alloimmune responses that result in chronic inflammation and scarring. Additionally, immunosuppressive medications themselves contribute to unintended intestinal dysbiosis and metabolic disorders. This review focuses on the effect of immunosuppressant treatments on alloimmunity, gut microbiome, and metabolism, with a particular emphasis on the effects on metabolic disorders. We also outline the shared and unique microbial and metabolic signatures produced by each immunosuppressant class, underlining their distinct impacts on immunity and metabolic homeostasis. These observations underscore the need for a holistic understanding of these drugs' on- and off-target effects to refine therapeutic strategies, enhance immunosuppression efficacy, and ultimately enhance graft and patient survival. By characterizing these complex interactions, strategies informed by the gut microbiome and host metabolism may offer a promising adjunctive approach to optimizing immunosuppressive regimens and promoting sustained graft acceptance.

In the phase 3 SOLSTICE study (NCT02931539), maribavir was superior to investigator-assigned therapy (IAT) for confirmed cytomegalovirus viremia clearance at study week 8 in hematopoietic cell/solid organ transplant (HCT/SOT) recipients. We report additional efficacy and safety analyses from the SOT subgroup.

Eligible SOT recipients (n=211) received maribavir 400 mg twice daily (n=142) or IAT (n=69) for 8 weeks (12 weeks' follow-up). Cytomegalovirus viremia clearance at week 8 (primary endpoint) and cytomegalovirus viremia clearance plus symptom control at the end of week 8 maintained through week 16 (key secondary endpoint) were assessed. Graft outcomes and treatment-emergent adverse events were analyzed.

A higher proportion of maribavir-treated patients achieved the primary endpoint than with IAT across transplant organ types, including kidney (maribavir: 59.5%, IAT: 34.4%), lung (47.5%, 13.6%), and heart (42.9%, 11.1%). Similar proportions of patients achieved the key secondary endpoint in both arms (13.4% versus 11.6%; adjusted difference: 2.4%; 95% CI: -7.05, 11.83%; p=0.620). Rates of treatment-emergent adverse events were: maribavir (96.5%), IAT (88.4%). Maribavir (3.5%) had fewer treatment discontinuations due to treatment-emergent adverse events than IAT (23.2%). There were no graft losses; patients in both arms experienced acute rejection (maribavir: 9 [6.3%]; IAT: 4 [5.8%]). Treatment-emergent maribavir mutations occurred in 28.2% of patients; 19/33 patients achieved viremia clearance with subsequent alternative treatment.

Consistent with findings in the overall SOLSTICE population, this subgroup analysis of SOT recipients demonstrated greater effectiveness of maribavir for cytomegalovirus viremia clearance and fewer discontinuations due to treatment-emergent adverse events than IAT.

ClinicalTrials.gov; NCT02931539.

Pediatric Infectious Disease (PID) clinicians involved in solid organ transplantation often assess infection risk and mitigation strategies for donor organ offers. While some guidance is available, real-life practice patterns have not been previously described.

We surveyed PID clinicians about organ acceptance and associated posttransplantation interventions using 12 fictitious pediatric case scenarios through 3 PID-specific listservs. Descriptive statistics were employed.

48 (71.6%) of 67 ID respondents were involved in organ offer assessment. Agreement was strong (> 80%) to accept (syphilis, severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2], MRSA, E. coli, TB [liver], rhino/enterovirus) or decline (undifferentiated encephalitis, TB [lung]) organs from these cases, while there was less agreement for cases with risk of coccidioidomycosis, Chagas disease, multi-drug-resistant Acinetobacter baumannii, and influenza. Less agreement was present for posttransplant monitoring and antimicrobial administration. Practice varied in testing and treatment for donors with SARS-CoV-2 positive test, MRSA bacteremia, and Chagas disease.

For many pediatric organ offer scenarios, agreement in donor acceptance was high; however, improved education based on currently available recommendations may enhance organ acceptance decision-making. The variability in management highlights educational and research opportunities to optimize strategies to limit the impact of donor-derived infections in pediatric organ recipients.

Cutaneous cytomegalovirus infection is a rare but serious complication in solid organ transplant recipients. We present a 47-year-old male kidney transplant recipient with a chronic, nonhealing right lower extremity ulcer. Initial biopsies revealed septic vasculopathy, leading to treatment with sodium thiosulfate and antibiotics for suspected calciphylaxis. Despite regular wound care, the ulcer continued to worsen. After completing 6 months of cytomegalovirus prophylaxis, surveillance viral levels remained undetectable, but the ulcer progressed considerably. Worsening severity prompted hospitalization, during which cytomegalovirus viremia was detected, and an ulcer biopsy confirmed cytomegalovirus inclusion bodies. Antiviral therapy was reinitiated, resulting in rapid and sustained wound improvement. Therefore, this case underscores cytomegalovirus' potential for cutaneous invasion in transplant recipients, even without preceding viremia, and highlights the importance of considering cutaneous cytomegalovirus in nonhealing ulcers posttransplant, especially in serodiscordant recipients.

Maribavir and valganciclovir are pharmacotherapeutic options utilized in the management of cytomegalovirus (CMV) infection post-transplantation. Despite their established utility, a comprehensive assessment of their safety profiles in real-world settings remains lacking, particularly with regards to long-term safety outcomes within a sizable cohort.

The study aims to analyze the adverse event (AE) profiles of maribavir and valganciclovir using data from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). This endeavor seeks to juxtapose their respective association strengths and furnish clinicians with pertinent clinical reference points.

Employing a methodological framework involving the filtration of the FAERS database by specific drugs (maribavir and valganciclovir), AEs attributed to each agent were meticulously cataloged. We applied various disproportionation analysis techniques, including the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN) and multi-item gamma Poisson shrinker (MGPS) algorithms, to identify and quantify potential signals of AEs associated with maribavir and valganciclovir.

There were 999 and 3,454 reports for maribavir and valganciclovir, respectively. Maribavir was primarily associated with the following AEs: dysgeusia (133, 4.07%), taste disorder (127, 3.89%), death (120, 3.67%), fatigue (105, 3.21%), and diarrhea (69, 2.11%). In contrast, the most notable AEs linked to valganciclovir included death (260, 2.59%) and neutropenia (246, 2.59%), leukopenia (175, 1.74%), diarrhea (117, 1.17%), and thrombocytopenia (113, 1.13%). Remarkably, death emerged as an unexpected AE signature for both agents. Key associations were elucidated, notably taste disorder (ROR: 65.23) for maribavir and CMV colitis (ROR: 152.26) for valganciclovir, accentuating distinct AE propensities. Additionally, median onset times for AE manifestation were delineated, with maribavir exhibiting a median onset time of 40 days, compared to 28 days for valganciclovir-associated AEs.

This comprehensive analysis of FAERS data enhances our understanding of the safety. These findings hold implications for ongoing clinical surveillance efforts and provide a foundational basis for subsequent investigations into the safety profiles of these agents.

To our knowledge, this is the first reported case of a pulmonary mixed infection involving Nocardia cyriacigeorgica, Stenotrophomonas maltophilia, and human cytomegalovirus (HCMV) in a patient with minimal change nephrotic syndrome (MCNS), which is of great clinical significance. We report the case of an 18-year-old male with a two-month history of MCNS who was admitted due to fever, cough, and bright red hemoptysis. Upon admission, he was treated with piperacillin/tazobactam and moxifloxacin for one week; however, the therapeutic response was suboptimal. Metagenomic Next-Generation Sequencing (mNGS) and microbiological culture of bronchoalveolar lavage fluid identified a pulmonary mixed infection involving N. cyriacigeorgica, S. maltophilia, and HCMV. Following the initiation of combination therapy with linezolid, trimethoprim-sulfamethoxazole, and ganciclovir, the patient's condition improved markedly, and he was discharged in a stable condition. One-year follow-up revealed complete recovery with no recurrence. This case highlights the critical role of incorporating advanced molecular diagnostic tools such as mNGS into clinical practice and the need to be vigilance about opportunistic infections involving multiple pathogens, especially in patients receiving immunosuppressive therapy.

Cytomegalovirus (CMV) infection poses significant challenges in pediatric transplant recipients. Ganciclovir and its prodrug valganciclovir are primary treatments because of their potent antiviral effects. Balancing efficacy and toxicity is particularly critical in children. This study aimed to develop a pharmacokinetic/pharmacodynamic (PK/PD) model for (val)ganciclovir and assess the relationship between area under the concentration-time curve (AUC) and CMV viral loads via Monte Carlo simulations.

We conducted a retrospective analysis including 184 viral load samples from 36 transplanted children treated with ganciclovir/valganciclovir. We developed a population pharmacodynamic model using Monolix and performed Monte Carlo simulations to assess viral load decline with varying AUCs. Internal validation was performed using goodness-of-fit plots and bootstraps.

We used a viral turnover model with stimulated degradation to model the pharmacodynamic data. Model validation showed no bias or misspecification. Simulations indicated that maintaining an AUC0-24 ≥ 40 mg·h/L achieved an 85.4% probability of undetectable viral load after 28 days of therapy. An AUC0-24 > 30 mg·h/L provided 80.9% probability of reducing viral loads by - 1 log after 2 weeks. AUC0-24 values > 60 mg·h/L offered minimal incremental benefits.

The pharmacodynamic model accurately predicted observed data. Simulations indicated that maintaining a ganciclovir plasma AUC0-24 around 40-60 mg·h/L maximized antiviral efficacy. An AUC0-24 > 60 mg·h/L might increase the risk of adverse events without providing additional efficacy.

Management of cytomegalovirus (CMV) viremia/disease in transplant recipients may be complicated by toxicities and resistance to conventional antivirals, adding to the overall healthcare burden. Despite advances in analyzing real-world data in current years, little is known about refractory and resistant CMV. This study therefore aimed to characterize treatment patterns and patient numbers with special focus on refractory and resistant CMV.

Two classical three-round Delphi consensus panels with German clinical experts in CMV following solid organ transplantations (SOT) and hematopoietic stem cell transplantations (HSCT) were held between October and December 2021 using online questionnaires. Consensus was defined as agreement of 75% of participants.

Following SOT, experts agreed that on average 65% of SOT patients are not affected by CMV at all, while 35% of patients experience CMV viremia or disease. Of SOT patients treated with antiviral therapies, experts agreed that 90% respond to their first-line treatment and 10% do not. For HSCT, experts agreed that 62% of patients experience no CMV, while 38% of patients are diagnosed with either CMV viremia or CMV disease. It was further estimated that 23% HSCT patients receiving antiviral treatment do not respond to their first-line CMV treatment. Experts reached consensus on the reasons for non-response, suggesting that among non-responders, 55% were intolerant, while 45% of non-responders were refractory/resistant to first-line treatment.

Based on the current incidence of transplantations in Germany, experts estimated that 103 SOT and 225 HSCT patients need second-line CMV treatment annually.

Immune control of human cytomegalovirus (HCMV) replication is critical in bone marrow and solid organ transplant recipients, where uncontrolled replication can lead to high mortality. Current commercial immune monitoring tools have several limitations, such as a lack of appropriate test cutoff values and the inability to characterise antigen-specific T cells. The main aim of our study was to develop a new interferon-γ (IFN-γ) release assay (IGRA), easy to use, to quantify and characterise the HCMV-specific T-cell response (pp65-IGRA). Secondary analyses included an evaluation of the performance of pp65-IGRA to assess whether its specificity and sensitivity were equal to or greater than those of the intracellular cytokine staining (ICS) and enzyme-linked immunospot (ELISpot) assays. In the study, 76 immunocompetent donors and nine solid organ transplant recipients were enrolled. Blood samples or peripheral blood mononuclear cells were stimulated with HCMV pp65-recombinant protein or with a complete pool of overlapping pp65 peptides. IFN-γ production was analysed by enzyme-linked immunoassay, ELISpot assays, and flow cytometry. For each assay, appropriate cutoff values were calculated. Our data demonstrate the suitability of pp65-IGRA for the quantification of HCMV-specific CD4+ T-cell responses and may support its use in routine clinical practice to improve the management of immunocompromised patients.

Human cytomegalovirus (HCMV) is the leading infectious cause of birth defects. Despite the global disease burden, there is no Food and Drug Administration (FDA)-approved HCMV vaccine. The most efficacious HCMV vaccine candidates to date have used glycoprotein B (gB), a class III viral fusion protein, in its postfusion form. While some viral fusion proteins have been shown to elicit stronger neutralizing responses in their prefusion conformation, HCMV prefusion-like and postfusion gB were recently shown to elicit antibodies with similar fibroblast neutralization titers in mice. We aimed to define and compare the specificity and functionality of plasma IgG elicited by distinct prefusion-like and postfusion gB constructs. Prefusion-like and postfusion gB elicited comparable IgG responses that predominantly mapped to the AD-5 antigenic domain known to elicit neutralizing antibodies. Interestingly, postfusion gB elicited significantly higher plasma IgG binding to cell-associated gB and antibody-dependent cellular phagocytosis than that of prefusion-like gB. The vaccines elicited comparable neutralization titers of heterologous HCMV strain AD169r in fibroblasts; however, neither elicited neutralizing titers against the vaccine-matched strain Towne in fibroblasts. Our data indicate that gB in this prefusion-like conformation elicits similar specificity and functional humoral immunity to that of postfusion gB, unlike certain class I viral fusion proteins that have been used as vaccine antigens. These findings deepen our understanding of the immune response elicited by class III fusion proteins and may inform further design and testing of conformationally dependent herpesvirus glycoprotein vaccine candidates.IMPORTANCEVaccines against human cytomegalovirus (HCMV) still remain elusive in spite of the high disease burden of the virus, especially in pre-term infants and immunocompromised individuals. While vaccine efforts have focused on vaccine-induced antibodies to neutralize the virus, studies have increasingly shown the importance of other antibody functions in protection against cytomegalovirus (CMV) transmission. In this study, we comprehensively evaluated immune responses elicited by the prefusion state of an important HCMV protein called glycoprotein B (gB) in mice. Our results indicate that prefusion gB elicits immune responses similar to that of postfusion gB in mice and reveals areas for further redesign and testing for prefusion vaccine antigens against CMV and other herpesviruses, which could help in furthering vaccine development against HCMV.

Lung transplantation (LTx) is essential for treating end-stage lung diseases in Japan, achieving favorable long-term survival despite donor shortages. However, factors associated with long-term survival after transplantation remain unclear. This study aims to identify key predictors influencing post-transplant outcomes.

A retrospective analysis was conducted on LTx recipients at Tohoku University Hospital from 2000 to 2019, with a follow-up period of five years to 2024. Recipients were categorized into short survivors (<5 years) and long survivors (≥5 years). The analysis focused on recipient demographics, donor characteristics, surgical factors, and post-transplant outcomes.

Of 124 recipients, 36 were short survivors, and 88 were long survivors. Long-term survivors were younger, with a lower prevalence of patients aged 55 years and older. Additionally, fewer long-term survivors received lungs from critically marginal donors compared to short-term survivors. CMV serology was a significant factor, with a higher incidence of CMV disease observed in short-term survivors.

The study identified younger age, selective donor use, and CMV status as key predictors associated with long-term survival after LTx in Japan. The findings underscore the importance of targeted CMV management strategies and suggest that future multicenter studies with larger, more diverse populations are needed to confirm these results and further enhance long-term survival outcomes.

Cytomegalovirus (CMV) disease in the upper gastrointestinal (UGI) tract frequently occurs in immunocompromised patients. However, data regarding UGI CMV disease in non-transplant patients compared with those in transplant recipients are limited. Therefore, we compared the clinical characteristics, endoscopic findings, and outcomes of UGI CMV disease in non-transplant patients with those in transplant recipients.

We reviewed the medical records of patients diagnosed with UGI CMV disease between May 1999 and January 2022. UGI CMV disease was defined as symptoms or signs of gastrointestinal disease with typical findings of CMV inclusion body and positive immunochemistry stain or CMV polymerase chain reaction from the endoscopic biopsy specimen.

Among the 219 eligible patients, 132 (60.3%) were transplant patients. Age, male sex, and Charlson Comorbidity Index were significantly higher in the non-transplant group than in the transplant group. The most common symptoms were pain and odynophagia (43.8%). Transplant recipients more frequently experienced UGI CMV disease in the stomach than non-transplant patients, typically presenting as erosions or mucosal hyperemia. However, non-transplant patients more commonly experienced UGI CMV disease in the esophagus than transplant recipients, typically presenting as ulcers. The transplant group had a significantly higher clinical response than the non-transplant group.

UGI CMV disease in transplant patients can be present in the stomach in various forms, including ulcers or erosions. In transplant patients suspected of UGI CMV disease, conducting an esophagogastroduodenoscopy with tissue biopsy in any area where even the slightest mucosal abnormality is observed is essential to facilitate a prompt diagnosis.

Cytomegalovirus (CMV) drives negative outcomes after liver transplant (LT), with patients having high-risk serostatuses (D+/R-) being especially vulnerable. While valganciclovir (VGC) remains the standard-of-care, letermovir (LTV) represents a promising potential in LT, given the reduced myelosuppression.

Adult patients receiving an LT with high-risk CMV serostatus (D+/R-) June 1, 2021-June 6, 2024 were evaluated. Patients were included in the standard-of-care (SOC) or LTV cohort based on de novo antiviral prophylaxis regimen. The primary objective was the safety and tolerability of VGC compared to LTV.

Sixty-one patients met inclusion criteria: 35 in SOC and 26 in LTV cohorts. A significantly higher proportion of patients in the LTV cohort completed antiviral prophylaxis (28.6% vs. 80.8%, p < 0.001), with most patients in the SOC cohort experiencing VGC intolerance (71.4%). No patients terminated LTV due to intolerance or breakthrough. Patients in the SOC cohort had lower white blood cell (1.6 vs. 2.75 × 103 cells/mm3; p < 0.001) and absolute neutrophil (850 vs. 2260 cells/µL p = 0.003) nadir at 6 months. Significantly more patients in the SOC cohort required granulocyte-colony stimulating factor (57.1% vs. 15.4%, p < 0.001). Patients in the LTV cohort tolerated significantly higher doses of mycophenolate through 12 months post-transplant.

De novo LTV for primary prophylaxis after LT appears to be safe and effective. LTV is more likely to be successfully completed than the current SOC and is associated with less myelosuppressive toxicity, which allows maintenance of higher mycophenolate doses. Future studies are needed to evaluate the impact of LTV on rejection rates and transplant outcomes.

Herpes- and polyomaviruses are major opportunistic pathogens after renal transplantation. Despite established guidelines, there is limited data on transplant centers' prophylaxis and monitoring strategies and centers' adherence to these guidelines and their impact on infection rates and patient outcomes.

This multicenter cohort study, conducted by the German Center for Infection Research, included 1035 kidney transplant recipients from five centers (01/2014-02/2021), focusing on herpes- and polyomavirus viremia within the first year and adherence to prophylaxis strategies.

Among 1035 recipients, 26.6% developed herpes- or polyomavirus viremia, predominantly Cytomegalovirus (CMV, 14.3%) and BK-virus (BKV, 13.2%). BKV monitoring frequency was below guideline recommendations. Deviations from guidelines were most common in CMV D-/R- (34.6% with prophylaxis) and D-/R + groups (37.3% without prophylaxis), doubling CMV-incidence in D-/R+ (28.9% vs. 12.5%, p < 0.01). In D+/R - group, six-month-prophylaxis reduced CMV-incidence compared to three months (22.5% vs. 38.4%, p < 0.01). Breakthrough-viremia was most commonly observed in D+/R - recipients who received a six-month-prophylaxis. Overall, viremia was associated with higher incidence of acute rejection (31.9% vs. 17.6%, p < 0.01), with most CMV-viremias occurring after rejection. CMV-viremia was associated with a higher risk of bacterial infection (HR = 1.77, [1.03;3.02]). Other herpesviruses were associated with a quadrupled risk for fungal infection (HR = 4.34, [1.03;18.30]) and the non-administration of CMV-prophylaxis (HR = 0.22, [0.11;0.47]). Graft survival and mortality were unaffected within the first year.

Clinical variability in guideline implementation drives high herpes- and polyomavirus infection rates with suboptimal outcomes. Future guidelines should focus on differentiated risk stratification to address breakthrough, post-prophylaxis, and post-rejection CMV, and include protocols for the early detection of secondary infections.

Cytomegalovirus (CMV) infection poses a significant risk to kidney transplant recipients. CMV immunoglobulin shows promising prophylactic effect, particularly in the context of ABO-incompatible transplants. However, its efficacy in preventing CMV viremia remains underexplored.

In this retrospective study, we enrolled patients who underwent ABO-incompatible living donor kidney transplantation between May 2021 and September 2023. Prophylactic CMV immunoglobulin was administered at 100 mg/kg weekly for one month in the combined prophylaxis group, while no prophylactic medication was applied in the preemptive therapy group. The primary outcome was measured as the incidence of clinically relevant CMV viremia (CMV DNA >10,000 copies/mL) within one year after transplantation. Both groups received standard preemptive therapy with ganciclovir or valganciclovir after diagnosed with clinically relevant CMV viremia.

Prophylactic CMV immunoglobulin significantly reduced clinically relevant viremia incidence compared to preemptive therapy group (16.0% vs. 34.0%, P = 0.04). At the end of the follow-up, the combined prophylaxis group showed higher eGFR (56.40 ± 14.19 vs. 47.30 ± 13.01 mL/min/1.73m², P = 0.0014) and lower serum creatinine (146.5 ± 57.07 vs. 171.2 ± 51.48 µmol/L, P = 0.0274). However, no significant differences in renal function were observed between the groups at1,3, or 6 months post-transplantation.

CMV immunoglobulin represents a promising prophylactic option for reducing clinically relevant CMV viremia incidence and delaying infection onset in ABO-incompatible kidney transplant recipients.

Cytomegalovirus (CMV), a beta-herpesvirus capable of maintaining lifelong latency, presents a substantial risk to transplant recipients, resulting in significant morbidity and mortality among both hematopoietic stem cell and solid organ transplantation recipients. Recent advances have shifted management from reactive approaches, such as preemptive therapy, to preventive strategies to reduce active infections and disease burden. Letermovir, a selective CMV terminase inhibitor, has emerged as a critical prophylactic agent in high-risk transplant populations, significantly lowering infection rates and improving survival with fewer adverse effects than older antivirals. Maribavir, a UL97 kinase inhibitor, is another recently approved promising option for treating CMV, especially in patients with ganciclovir-resistant or refractory CMV infections. Despite these achievements, the risk of late-onset CMV infection after prophylaxis discontinuation remains a significant clinical challenge. Current research seeks to refine prophylactic regimens and develop advanced diagnostic tools, notably interferon-gamma release assays that measure CMV-specific T cell responses. These immunologic assays may help clinicians identify individuals capable of controlling CMV replication, thus guiding the safer discontinuation of prophylaxis and reducing unnecessary drug exposure. Conversely, patients lacking robust immune reconstitution could be targeted for extended prophylaxis or closer follow-up. Looking into the future, ongoing innovations in immune monitoring and antiviral development will likely lead to a more personalized approach to CMV prevention and treatment, optimizing care based on patient-specific risk profiles and immune competence. As this field continues to evolve, integrating novel therapies, improved diagnostics, and immunity-driven protocols holds promise for further reducing CMV-related complications and improving overall outcomes for transplant recipients.

Relative to healthy individuals, in severely immunocompromised transplant recipients, the presentation of cytomegalovirus (CMV) is characterized by delayed clearance, more recurrent episodes, and faster changes in their condition over time. This study investigates CMV occurrence in solid organ transplantation (SOT) recipients, addressing a gap in epidemiological research.

Using National Health Insurance Research Database data, a cross-sectional study observed SOT recipients (2003-2019) with propensity score matching. The case group was 11,028 SOT recipients and 44,112 patients with chronic kidney disease (CKD) as the comparison. Logistic regression, adjusting for sex, age, insured salary, urbanization, and comorbidities, estimated CMV risk in a 3-year follow-up. Sensitivity analysis was performed to compare the risk of CMV at different follow-up periods (6-month, 1-year, and 2-year follow-up).

At 3-year follow-up, SOT recipients exhibited a higher CMV risk (aOR: 57.14, 95 % CI: 39.51-82.63) than CKD patients. Risks persisted at 6 months (aOR: 89.53, 95 % CI: 47.24-169.68), 1 year (aOR: 54.11, 95 % CI: 48.94-144.54), and 2 years (aOR: 62.82, 95 % CI: 41.71-94.61). In subgroup analysis, lung transplant recipients had the highest risk (aOR: 177.98, 95 % CI: 79.41-399.75), followed by kidney (aOR: 75.97, 95 % CI: 52.33-110.27) and liver transplant recipients (aOR: 31.44, 95 % CI: 20.78-47.50).

CMV risk persists post-SOT, peaking at 6 months. Lung transplant recipients face the highest risk, trailed by kidney and liver recipients.

Human cytomegalovirus (HCMV) is a critical pathogen in immunocompromised populations, such as organ transplant recipients as well as congenitally infected neonates with immature immune systems. Despite decades of research and the growing financial burden associated with the management of HCMV, there is no licensed vaccine to date. In this review, we aim to outline the complexity of HCMV and the antigens it presents and the journey and challenges of developing an effective HCMV vaccine, as well as further highlight the recent analyses of the most successful vaccine candidate so far-gB/MF59.

Cytomegalovirus (CMV) is a major opportunistic pathogen in recipients of solid organ transplantation. Maribavir, a pUL97 protein kinase inhibitor, was approved for the treatment of refractory post-transplant CMV infection in the US in 2021. However, it is rarely used in pediatric patients worldwide. Here, we report the case of a Chinese boy with Schimke's immune-osseous dysplasia (SIOD) who developed refractory CMV infection after a renal transplantation. An 11-year-old boy was hospitalized with recurrent abdominal and testicular pain 50 days after renal transplantation. Diagnoses included urinary tract infection, epididymitis, CMV viremia, stage 2 chronic kidney disease, and SIOD. After five days of treatment, his pain improved, but he developed persistent fever and shortness of breath. Blood CMV levels rose to 1.64 × 105 copies/ml after one month of ganciclovir treatment. Significant bone marrow suppression was observed after combined treatment with foscarnet. Anti-rejection treatment was discontinued due to compromised immune function. On day 40, maribavir was initiated with parental consent, resulting in undetectable CMV copies within four days. The patient's clinical status and bone marrow suppression had improved. Continuing maribavir for two weeks led to the disappearance of CMV viremia, no bone marrow suppression, and normal liver and kidney functions. This case demonstrates the successful short-term use of maribavir in the treatment of refractory CMV infection in an immune-deficient child after renal transplantation. Further studies are required to explore the efficacy and safety of maribavir in pediatric patients.

Cytomegalovirus (CMV) is a common opportunistic infection in solid organ transplant patients. Intravenous CMV immunoglobulin (CMV-IVIG) is a pharmacotherapy option with limited data within heart transplantation. At UCHealth, CMV-IVIG was removed from the heart transplant CMV prophylaxis protocol in July 2022. This study evaluated the efficacy and cost outcomes of CMV-IVIG removal from the protocol.

This was a single-center, retrospective cohort study of heart transplant recipients transplanted at UCHealth between October 2020 and March 2023. Patients were included if seronegative for CMV, and excluded if they died or were lost to follow-up within 12 months of transplantation. Patients included were compared after being separated into pre- and post-protocol cohorts if transplanted prior to July 1, 2022 when CMV-IVIG was removed from the protocol and afterward, respectively. Standard universal prophylaxis with valganciclovir was used in both cohorts. The primary outcome was CMV DNAemia within 12 months of heart transplant, and secondary outcomes included cost avoidance and CMV DNAemia within 18 months.

Forty-two patients were included in this study. There was no significant difference in CMV DNAemia between pre- and post-protocol groups at 12 months (9.5% vs. 4.8%, p = 0.55) or 18 months (28.6% vs. 19%, p = 0.53). Median cost avoidance for removing CMV-IVIG from the protocol per patient was $30 652.13-$40 331.75.

Removing CMV-IVIG from a heart transplant protocol was associated with cost avoidance without worsened outcomes in CMV DNAemia. CMV-IVIG likely does not have significant benefits for preventing CMV DNAemia with concomitant universal antiviral prophylaxis in heart transplant recipients.

Diagnosis of cytomegalovirus (CMV) ileocolitis traditionally requires colonoscopy with tissue biopsy. Due to potential complications in high-risk patients, there is growing interest in serum and stool tests for diagnosing this condition. We aimed to evaluate the diagnostic accuracy of these noninvasive tests compared to traditional gold standards.

Two independent reviewers performed a comprehensive search on MEDLINE and Embase from inception up to October 1, 2023. Prospective and retrospective studies evaluating the performance of serum CMV polymerase chain reaction (PCR), serum CMV antigen (Ag), and stool CMV PCR in diagnosing CMV ileocolitis were included. Tissue histopathology or tissue CMV PCR served as reference standards. Diagnostic performances of each serum and stool test were calculated based on a meta-analysis using random-effects model.

A total of 30 studies, comprising 23 studies of serum CMV PCR, 9 of serum CMV Ag, and 7 of stool CMV PCR, were included. The pooled sensitivity, specificity, and area under summary receiver operating characteristic curves were 62% (95% confidence interval [CI], 51%-72%), 90% (95% CI, 79%-96%), and 0.81 for serum CMV PCR, 38% (95% CI, 26%-51%), 94% (95% CI, 70%-99%), and 0.56 for serum CMV Ag, and 53% (95% CI, 35%-70%), 91% (95% CI, 84%-95%), and 0.84 for stool CMV PCR.

Serum and stool tests cannot replace colonoscopy for diagnosing CMV ileocolitis due to their low sensitivities but may be useful when colonoscopy is not feasible. Positive results can aid diagnosis, given their high specificities. Serum and/or stool CMV PCR are preferred over CMV Ag.

Cytomegalovirus (CMV) is one of the most common opportunistic infections affecting solid organ transplant recipients (SOTRs). In this article, we presented the case of a 39-year-old patient with end-stage renal disease after kidney transplantation with refractory CMV infection, who was successfully treated with maribavir for the first time in Poland. The use of maribavir resulted in a significant reduction of CMV viremia in ganciclovir/valganciclovir-resistant CMV infection and resolution of CMV disease symptoms in the absence of drug-related adverse events.

Cytomegalovirus prophylaxis with valganciclovir and ganciclovir is associated with increased neutropenia risk in kidney transplant recipients. This study assessed the association between neutropenia and short-term healthcare resource utilization (HCRU) and clinical events for adults receiving valganciclovir and/or ganciclovir prophylaxis post-kidney transplantation in the United States.

Adult kidney transplant recipients from 2012 to 2020 who received valganciclovir and/or ganciclovir prophylaxis were identified in the TriNetX database. Patients with a neutropenia event during the 1-year post-kidney transplant were identified as cases and those without were identified as controls. Cases and controls were matched 1:1 on patient characteristics in the 1-year period before the kidney transplant. HCRU and clinical event rates in the year following the first neutropenia event were compared between the cases and controls.

Of 3564 identified case-control pairs, the average age was 52 years and 59.57% were male. Cases had higher HCRU in the first year after neutropenia than controls, characterized by 1.40-, 1.28-, and 1.33-times higher rates of inpatient, outpatient, and emergency department visits (all p < 0.001). Cases also had higher incident rates for cytomegalovirus-related events, use of granulocyte colony stimulating factor, and opportunistic infections (all adjusted incident rate ratios >1 with p < 0.01), and greater risks of death, graft loss, and acute graft rejection (all adjusted hazard ratios >1 with p < 0.001).

Higher HCRU and clinical burden were observed within the first year following post-transplant neutropenia. New options for cytomegalovirus prophylaxis that are less likely to induce neutropenia are needed to improve patient outcomes.

Valganciclovir (ValG) is the most widely used drug for cytomegalovirus (CMV) prophylaxis in kidney transplant recipients (KTRs). However, it is associated with dose-limiting side effects and considerable costs. Some centers have identified valacyclovir (ValA) as an economically attractive alternative with a lower risk of bone marrow suppression. The comparative effectiveness of these two drugs is not well-established. This study aims to compare the efficacy and safety of ValA and ValG for CMV prophylaxis in KTRs.

Searches were conducted of the Medline, Cochrane, Web of Science, Embase, and Ovid databases. Endpoints encompassed the incidence of CMV disease, CMV viremia, acute rejection, leukopenia/neutropenia, and other infections, including BK polyomavirus and non-CMV herpesviruses (HVs). Risk ratios (RRs) with 95% confidence intervals (CIs) were pooled using a random-effects model.

Six studies, comprising 888 patients (438 receiving ValA), were included. The groups were comparable in CMV viremia incidence (RR, 0.70; 95% CI, 0.31-1.57; P=0.4) and the development of CMV disease (RR, 0.74; 95% CI, 0.09-5.97; P=0.8). No significant differences in acute rejection rates were observed (RR, 0.97; 95% CI, 0.50-1.91; P=0.8). However, the rate of leukopenia/neutropenia was significantly lower in the ValA group (RR, 0.57; 95% CI, 0.42-0.77; P<0.01). No significant differences were noted for BK viremia (RR, 0.67; 95% CI, 0.24-1.87; P=0.4) or other HV infections (RR, 1.43; 95% CI, 0.61-3.38; P=0.4).

The drugs demonstrate comparable efficacy in preventing CMV infection following kidney transplantation. However, ValA may have a lower impact on bone marrow suppression.

Kidney transplantation is the preferred treatment for patients with advanced chronic kidney disease and end-stage kidney disease, offering superior quality of life and survival compared to dialysis. This manuscript provides an updated overview of post-transplant care, highlighting recent advancements and current practices to assist generalists in managing these patients. It covers key areas such as immunosuppression strategies, drug interactions, and the management of transplant-specific acute kidney injury. The focus includes the use of sodium-glucose cotransporter-2 inhibitors and cell-free DNA monitoring for evaluating allograft health and immune-mediated injury. The manuscript reviews the fundamentals of immunosuppression, including both induction and maintenance therapies, and underscores the importance of monitoring kidney function, as well as addressing hypertension, diabetes, and infections. It also provides recommendations for vaccinations and cancer screening tailored to kidney transplant recipients and emphasizes lifestyle management strategies, such as exercise and sodium intake, to reduce post-transplant complications.

Patients undergoing solid organ and hematopoietic stem cell transplantation are at risk of opportunistic pathogenic infections that increase morbidity and mortality. Universal antiviral prophylaxis improves the outcomes in this context. Therapeutic drug monitoring of antiviral drugs is not universally recommended but may be necessary in certain complex or polymorbid patients. The authors aimed to develop and validate a high-performance liquid chromatography-tandem mass spectrometry method to simultaneously quantify ganciclovir, acyclovir, and letermovir in human serum.

A stable isotopically labeled internal standard was used for each antiviral drug. Compounds were extracted by protein precipitation, evaporation, and reconstitution in an aqueous mobile phase. Samples were analyzed using reverse-phase chromatography with subsequent detection by electrospray ionization in the positive ion mode on a triple quadrupole mass spectrometer (run time: 6.5 minutes).

Analytical curves for ganciclovir and acyclovir exhibited linearity within 0.1-25 mg/L (R2 > 0.993), whereas for letermovir, the linear range was 0.01-2 mg/L (R2 = 0.999). Matrix effects were not observed. Intraday and interday precision and accuracy were within ±15%. A therapeutic drug monitoring-guided strategy was explored to optimize preemptive antiviral drug therapy in 3 cohorts of transplant recipients. Seventy-nine samples from 35 patients were quantified, revealing median trough concentrations of 0.2 mg/L for ganciclovir (n = 21), 0.28 mg/L for acyclovir (n = 26), and 0.29 mg/L for letermovir (n = 32).

This method has been successfully applied in clinical settings and allows reliable and accurate drug-level measurements.

Human cytomegalovirus (CMV) remains an important pathogen, especially for immunocompromised patients such as solid organ and hematopoietic stem cell recipients. Viral genomic mutations conferring drug resistance are an important impediment to effective CMV management and frequently lead to use of alternative antiviral drugs to treat CMV disease.

Results from 1459 de-identified patient samples with both UL54 and UL97 sequencing results were analyzed for ganciclovir (GCV) and maribavir (MBV) resistance mutations. Genomic sequencing was performed by the Sanger method and resistance mutations were identified by comparison to CMV reference strain AD169.

Ganciclovir resistance was identified in 379 of 1459 (25.98%) of the samples tested, with most resistance-conferring mutations present in viral gene UL97. A total of 121 of 1459 (8.29%) samples had MBV resistance mutations, and 84 (69.42%) of the 121 samples with MBV resistance also had GCV resistance mutations. Of the 84 samples with resistance to both MBV and GCV, 35 (41.67%) had a single UL97 mutation conferring resistance to both drugs, either C480F or F342Y. The overall prevalence of C480F was increased relative to an earlier analysis of samples from this reference laboratory.

Although a high prevalence of CMV resistance mutations was identified, this must be taken in the context of healthcare providers submitting samples from patients with suspected CMV resistance. Most MBV-resistant samples were also resistant to GCV, suggesting that use of MBV as an alternative to GCV may benefit from genotypic resistance testing to achieve the effective control of CMV disease.

Letermovir is used primarily for cytomegalovirus (CMV) prophylaxis in select hematopoietic cell or solid organ transplant recipients. The manufacturer has provided no guidance on whether letermovir can be crushed and administered via enteral tube. This study aimed to assess whether letermovir tablets could be manipulated (eg, through crushing) for enteral tube administration.

This was a retrospective, single-center review of patients who received crushed letermovir tablets administered via enteral tube for at least 7 days, between April 2018 and August 2023. Data collection focused on demographics, transplant history, treatment characteristics associated with letermovir, and diagnosis of CMV viremia or disease.

Fourteen patients met the inclusion criteria for the review and received crushed letermovir for a median of 19 days (range, 7 to 42 days). All patients were on letermovir as CMV prophylaxis, the majority of whom were lung transplant recipients. On the basis of CMV serostatus at the time of transplantation, 50% of patients were classified as being at high risk and the other 50% were in the intermediate-risk category for CMV disease. One patient developed low-level viremia with a CMV viral load of 254 IU/mL. No patients developed CMV infection or disease while receiving crushed letermovir.

On the basis of this case series, manipulation of letermovir immediate-release tablets was proven to be safe and effective for patients. Crushing letermovir for administration via enteral tube should be considered as an option for patients who cannot tolerate administration via the oral route.

Liver transplantation (LT) is a well-established therapy for patients with decompensated cirrhosis and early-stage hepatocellular carcinoma. Liver transplantation activity varies sharply across Latin American (LATAM) countries due to differences in resources, expertise, and funding and local attitudes toward organ donation and transplantation. This current guidance of postoperative care after LT is the first position paper of the Latin American Association for the Study of the Liver (ALEH) Special Interest Group (SIG), drawing evidence-based recommendations regarding immediate and long-term postoperative care of LT recipients, taking into consideration their applicability in Latin America.

Cytomegalovirus (CMV) infection is a frequent complication after kidney transplantation (KT) and has various effects on recipient and graft survival. Although guidelines recommend anti-viral prophylaxis with ganciclovir or valganciclovir, there is a demand for alternative regimen for CMV prevention. We investigated the effects of a 3-month valacyclovir-based prophylaxis on CMV infection and clinical outcomes in KT recipients using a nationwide cohort.

Overall, 2,584 KT recipients from 20 transplant centers registered with the Korean Organ Transplantation Registry between May 2014 and December 2019 were analyzed in this study. The recipients were divided into valacyclovir prophylaxis and non-prophylaxis groups, a 1:3 propensity score matching was performed, and 1,036 recipients (291 and 745 in the prophylaxis and non-prophylaxis groups, respectively) were analyzed. The impact of valacyclovir-based prophylaxis on CMV after KT, other clinical outcomes, and the risk factors for CMV infection development were investigated.

The prophylaxis group showed a lower incidence of CMV infection and rejection compared to the non-prophylaxis group (3.64 vs. 10.25 events/100 person-years and 1.85 vs. 7.27 events/100 person-years, respectively). Valacyclovir prophylaxis, donor age, deceased donor, length of hospitalization after KT, anti-thymocyte globulin use, and CMV serological mismatch between the donor and recipient were independent risk factors for CMV infection after KT.

Valacyclovir prophylaxis after KT significantly reduced CMV infection and rejection. We suggest that valacyclovir could be considered as an alternative strategy for CMV prophylaxis after KT. However, our study has limitations, including its retrospective design, variability in valacyclovir dosing and CMV monitoring, and unassessed confounding factors. Further prospective studies with standardized protocols and larger cohorts are needed to validate our findings.

Rituximab (RIT) induction therapy is widely used for desensitization against ABO-incompatible living-donor kidney transplants (KT). However, the efficacy of valganciclovir (VGCV) prophylaxis against cytomegalovirus (CMV) disease and infection in KT recipients (KTRs) following RIT induction remains unclear.

The current multicenter retrospective study included 213 KTRs who received low-dose RIT induction between 1998 and 2021, across 6 facilities included in the Michinoku Renal Transplant Network (MRTN). VGCV dosage varied from 450 mg/day (twice weekly) to 900 mg/day (daily), with treatment durations of 3-12 months. The primary and secondary endpoints were the incidence of CMV disease and infection, respectively.

The incidence of CMV disease was significantly higher in the VGCV group (23.5%; 16 patients) than in the non-VGCV group (5.5%; 8 patients) (p < 0.01). The incidence of CMV infection was 54.5% (79 patients) in the non-VGCV group and 48.5% (33 patients) in the VGCV group, with no significant difference (p = 0.42). In the subgroup of CMV-seronegative KTRs receiving allografts from CMV-seropositive donors (CMV IgG (D + /R-)), 18 out of 24 KTRs received VGCV prophylaxis, of whom 10 (55.6%) developed CMV disease. Within this subgroup, only 4 KTRs received VGCV with the standard protocol (900 mg daily for 6 months), and none developed CMV disease.

Insufficient VGCV prophylaxis does not reduce the incidence of CMV disease in KTRs following low-dose RIT induction. Despite concerns about leukopenia due to RIT and VGCV, in KTRs with CMV IgG (D + /R-) serostatus, VGCV prophylaxis with a standard protocol may be advisable.

While access and outcomes disparities for African American (AA) kidney transplant recipients are documented, there are limited studies assessing medication access disparities in transplantation. Cytomegalovirus (CMV) causes severe complications for transplant recipients, and we aimed to understand differences in access to CMV prophylaxis valganciclovir and its impact on CMV infection rates in AA transplant recipients.

This single-center, retrospective longitudinal cohort study examined high-risk (CMV serostatus D+/R-) adult kidney transplant recipients between June 1, 2010, and May 31, 202, through EMR abstraction. Standard univariate comparative statistics were employed alongside binary logistic regression for multivariable modeling.

During the 10 year period, 418 kidney transplant recipients were included, with 179 (42.8%) identified as AA and 239 as non-AA. There were significant differences in mean age (p = 0.001) and private versus Medicaid insurance status (p < 0.001). AAs experienced higher death-censored graft loss rates (10.6% AA vs. 5.0% non-AA, p = 0.031). CMV infection rate, opportunistic infection rate, leukopenia incidence, and death did not differ significantly between AA and non-AA patients. AA patients were 42% less likely to receive valganciclovir out-of-pocket cost assistance compared to non-AA patients (OR 0.58, [0.379-0.892], p = 0.013). When incorporating age, Medicaid status, and donor marginality in a multivariable model, the impact of AA race on utilizing assistance programs became statistically non-significant (OR 0.70, [0.448-1.094], p = 0.118).

AAs were significantly less likely to leverage assistance programs or utilize personal resources to access valganciclovir. This disparity was partially explained by age, insurance status, and donor type. Despite this, CMV infection rates were similar between AA and non-AA cohorts.