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Background Antiviral prophylaxis is recommended in cytomegalovirus (CMV)-seropositive kidney transplant (KT) recipients receiving antithymocyte globulin (ATG) as induction. An alternative strategy of premature discontinuation of prophylaxis after CMV-specific cell-mediated immunity (CMV-CMI) recovery (immunoguided prevention) has not been studied. Our aim was to determine whether it is effective and safe to discontinue prophylaxis when CMV-CMI is detected and to continue with preemptive therapy. Methods In this open-label, noninferiority clinical trial, patients were randomized 1:1 to follow an immunoguided strategy, receiving prophylaxis until CMV-CMI recovery or to receive fixed-duration prophylaxis until day 90. After prophylaxis, preemptive therapy (valganciclovir 900 mg twice daily) was indicated in both arms until month 6. The primary and secondary outcomes were incidence of CMV disease and replication, respectively, within the first 12 months. Desirability of outcome ranking (DOOR) assessed 2 deleterious events (CMV disease/replication and neutropenia). Results A total of 150 CMV-seropositive KT recipients were randomly assigned. There was no difference in the incidence of CMV disease (0% vs 2.7%; P = .149) and replication (17.1% vs 13.5%; log-rank test, P = .422) between both arms. Incidence of neutropenia was lower in the immunoguided arm (9.2% vs 37.8%; odds ratio, 6.0; P < .001). A total of 66.1% of patients in the immunoguided arm showed a better DOOR, indicating a greater likelihood of a better outcome. Conclusions Prophylaxis can be prematurely discontinued in CMV-seropositive KT patients receiving ATG when CMV-CMI is recovered since no significant increase in the incidence of CMV replication or disease is observed. In cytomegalovirus (CMV)-seropositive kidney transplant recipients receiving ATG induction, immunoguided prevention is not inferior to prophylaxis to prevent CMV complications. Prophylaxis can be prematurely discontinued after CMV-cell-mediated immunity recovery with no significant increase in the incidence of CMV replication or disease.

New reliable biomarkers are needed to improve individual risk assessment for post-transplant infection, acute graft rejection and other immune-related complications after solid organ transplantation (SOT) and allogeneic hematopoietic stem cell transplantation (allo-HSCT). One promising strategy relies on the monitoring of replication kinetics of virome components as functional surrogate for the net state of immunosuppression. Torque Teno Virus (TTV) is a small, non-enveloped, circular, single-stranded DNA anellovirus with no attributable pathological effects. A major component of the human blood virome, TTV exhibits various features that facilitate its application as immune biomarker: high prevalence rates, nearly ubiquitous distribution, stable viral loads with little intra-individual variability, insensitivity to antiviral drugs, and availability of commercial PCR assays for DNA quantification. The present review summarizes the available studies supporting the use of post-transplant TTV viremia to predict patient and graft outcomes after SOT and allo-HSCT. Taken together, this evidence suggests that high or increasing TTV DNA levels precede the occurrence of infectious complications in the SOT setting, whereas low or decreasing viral loads are associated with the development of acute rejection. The interpretation in allo-HSCT recipients is further complicated by complex interplay with the underlying disease, conditioning regimen, and timing of recovery of lymphocyte counts, although TTV kinetics may act as a marker of immunological reconstitution at the early post-transplant period. The standardization of PCR methods and reporting units for TTV DNAemia and the results from ongoing interventional trials evaluating a TTV load-guided strategy to adjust immunosuppressive therapy are achievements expected in the coming years.

BACKGROUND: Torque teno virus, the major member of the genus Alphatorquevirus, is an emerging biomarker of the net state of immunosuppression after kidney transplantation. Genetic diversity constitutes a main feature of the Anelloviridae family, although its posttransplant dynamics and clinical correlates are largely unknown.; METHODS: The relative abundance of Alphatorquevirus, Betatorquevirus, and Gammatorquevirus genera was investigated by high-throughput sequencing in plasma specimens obtained at various points during the first posttransplant year (n = 91 recipients). Total loads of all members of the Anelloviridae family were also quantified by an "in-house" polymerase chain reaction assay targeting conserved DNA sequences (n = 195 recipients). In addition to viral kinetics, clinical study outcomes included serious infection, immunosuppression-related adverse event (opportunistic infection and cancer)' and acute rejection.; RESULTS: Alphatorquevirus DNA was detected in all patients at every point, with an increase from pretransplantation to month 1. A variable proportion of recipients had detectable Betatorquevirus and Gammatorquevirus at lower frequencies. At least 1 change in the predominant genus (mainly as early transition to Alphatorquevirus predominance) was shown in 35.6% of evaluable patients. Total anelloviruses DNA levels increased from baseline to month 1, to peak by month 3 and decrease thereafter, and were higher in patients treated with T-cell depleting agents. There was a significant albeit weak-to-moderate correlation between total anelloviruses and TTV DNA levels. No associations were found between the predominant Anelloviridae genus or total anelloviruses DNA levels and clinical outcomes.; CONCLUSIONS: Our study provides novel insight into the evolution of the anellome after kidney transplantation. Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.

Background Increasing evidence suggests that infection with the nonpathogenic human pegivirus type 1 (HPgV-1) exerts a clinical benefit in human immunodeficiency virus (HIV) patients, which could be attributable to immunomodulatory effects. Whether this impact can be extrapolated to kidney transplantation (KT) remains largely unknown. Methods We measured plasma HPgV-1 RNA by real-time polymerase chain reaction targeting the 5 ' untranslated region at various points (pretransplantation, day 7, months 1, 3, 6, and 12) in 199 KT recipients. Study outcomes included posttransplant serious infection, immunosuppression-related adverse event (opportunistic infection and/or de novo cancer), and acute graft rejection. Results HPgV-1 infection was demonstrated in 52 (26.1%) patients, with rates increasing from 14.7% at baseline to 19.1% by month 12 (p-value = .071). De novo infection occurred in 13.8% of patients with no detectable HPgV-1 RNA before transplantation. Double-organ (liver-kidney or kidney-pancreas) transplantation (odds ratio [OR]: 5.62; 95% confidence interval [CI]: 1.52-20.82) and donation after brain death (OR: 2.21; 95% CI: 1.00-4.88) were associated with posttransplant HPgV-1 infection, whereas pretransplant hypertension was protective (OR: 0.23; 95% CI: 0.09-0.55). There were no significant differences in the incidence of study outcomes according to HPgV-1 status. Plasma HPgV-1 RNA levels at different points did not significantly differ between patients that subsequently developed outcomes and those remaining free from these events. No correlation between HPgV-1 RNA and immune parameters or torque teno virus DNA load was observed either. Conclusion Unlike patients living with HIV, HPgV-1 infection does not seem to influence patient or graft outcomes after KT.

The immune system plays a key role in the host defense against viral pathogens. A signaling cascade is activated upon infection involving a variety of molecules such as pattern-recognition receptors (PRRs), interleukins or antiviral interferons. Long-term immunosuppression after solid organ transplantation (SOT) mainly abrogates adaptive T-cell-mediated responses, thus highlighting the relative contribution of innate immunity. Single-nucleotide polymorphisms (SNPs) within genes coding for PRRs or soluble mediators have been associated with differential susceptibility to viral infections among SOT recipients. A protective effect against cytomega-lovirus (CMV) infection or disease has been attributed to certain SNPs in TLR9 or IFNL3 genes, whereas the opposite effect has been attributed to genetic polymorphisms in TLR2, MBL2, DC-SIGN, IL10 or IFNG. The presence of SNPs in other molecules not directly involved in innate or adaptive immune responses such as aquaporins or pregnane X appear to modulate the risk of CMV or BK polyomavirus infection, respectively. Little information is available on the genetic determinants of the post-transplant susceptibility to herpesviruses causing clinical infection (herpes simplex virus or varicella zoster virus) or the replication kinetics of components of the human blood virome used as immune surrogates (Torque teno virus). The present review critically summarizes the current knowledge on how SNP genotyping would be useful to stratify SOT recipients according to the in-dividual risk of viral infection and proposes next research steps. Genetic susceptibility testing may improve personalized medicine and contribute to minimize the risk of viral infection after SOT.

[This corrects the article DOI: 10.1093/ofid/ofab250.].

REIPI/ESGICH/ESGBIS/INCREMENT-SOT Group., There are scarce data on the efficacy of ertapenem in the treatment of bacteremia due to extended-spectrum-beta-lactamase (ESBL)-producing Enterobacterales (ESBL-E) in kidney transplant (KT) recipients. We evaluated the association between treatment with ertapenem or meropenem and clinical cure in KT recipients with nonsevere bacteremic urinary tract infections (B-UTI) caused by ESBL-E. We performed a registered, retrospective, international (29 centers in 14 countries) cohort study (INCREMENT-SOT, NCT02852902). The association between targeted therapy with ertapenem versus meropenem and clinical cure at day 14 (the principal outcome) was studied by logistic regression. Propensity score matching and desirability of outcome ranking (DOOR) analyses were also performed. A total of 201 patients were included; only 1 patient (treated with meropenem) in the cohort died. Clinical cure at day 14 was reached in 45/100 (45%) and 51/101 (50.5%) of patients treated with ertapenem and meropenem, respectively (adjusted OR 1.29; 95% CI 0.51 to 3.22; P = 0.76); the propensity score-matched cohort included 55 pairs (adjusted OR for clinical cure at day 14, 1.18; 95% CI 0.43 to 3.29; P = 0.74). In this cohort, the proportion of cases treated with ertapenem with better DOOR than with meropenem was 49.7% (95% CI, 40.4 to 59.1%) when hospital stay was considered. It ranged from 59 to 67% in different scenarios of a modified (weights-based) DOOR sensitivity analysis when potential ecological advantage or cost was considered in addition to outcome. In conclusion, targeted therapy with ertapenem appears as effective as meropenem to treat nonsevere B-UTI due to ESBL-E in KT recipients and may have some advantages., This work was supported by Plan Nacional de I+D+i 2013‐2016 and Instituto de Salud Carlos III (ISCIII), Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0001, RD16/0016/0002, RD16/0016/0008; RD16/0016/00010) and was cofinanced by the European Development Regional Fund “A way to achieve Europe,” Operative program Intelligent Growth 2014‐2020; ESCMID Study Group for Infections in Compromised Hosts (ESGICH grant to J.M.A.); Sociedad Andaluza de Trasplante de Órgano Sólido (SATOT grant to L.M.-M.); ESCMID Study Group for Bloodstream Infections and Sepsis (ESGBIS); and ESCMID Study Group for Antimicrobial Resistance Surveillance (ESGARS). B.G.-G. (PI 18/01849) and E.P.-N. (PI 16/01631) have received research funds from the Spanish Ministry of Science and Innovation, ISCIII; M.F.-R. holds a research contract “Miguel Servet” (CP 18/00073) from the Spanish Ministry of Science and Innovation, ISCIII.

Invasive fusariosis has a global increasing incidence and has emerged as a severe infection in nonneutropenic patients., Invasive fusariosis (IF) is associated with severe neutropenia in patients with concurrent hematologic conditions. We conducted a retrospective observational study to characterize the epidemiology of IF in 18 Spanish hospitals during 2000–2015. In that time, the frequency of IF in nonneutropenic patients increased from 0.08 cases per 100,000 admissions in 2000–2009 to 0.22 cases per 100,000 admissions in 2010–2015. Nonneutropenic IF patients often had nonhematologic conditions, such as chronic cardiac or lung disease, rheumatoid arthritis, history of solid organ transplantation, or localized fusariosis. The 90-day death rate among nonneutropenic patients (28.6%) and patients with resolved neutropenia (38.1%) was similar. However, the death rate among patients with persistent neutropenia (91.3%) was significantly higher. We used a multivariate Cox regression analysis to characterize risk factors for death: persistent neutropenia was the only risk factor for death, regardless of antifungal therapy.

Current guidelines recommend against systematic screening for or treating asymptomatic bacteriuria (AB) among kidney transplant (KT) recipients, although the evidence regarding episodes occurring early after transplantation or in the presence of anatomical abnormalities is inconclusive. Oral fosfomycin may constitute a good option for the treatment of posttransplant AB, particularly due to the emergence of multidrug-resistant (MDR) uropathogens. Available clinical evidence supporting its use in this specific setting, however, remains scarce. We performed a retrospective study in 14 Spanish institutions from January 2005 to December 2017. Overall, 137 episodes of AB diagnosed in 133 KT recipients treated with oral fosfomycin (calcium and trometamol salts) with a test-of-cure urine culture within the first 30 days were included. Median time from transplantation to diagnosis was 3.1 months (interquartile range [IQR], 1.1 to 10.5). Most episodes (96.4% [132/137]) were caused by Gram-negative bacteria (GNB), and 56.9% (78/137) were categorized as MDR (extended-spectrum beta-lactamase-producing Enterobacterales [20.4%] and carbapenem-resistant GNB [2.9%]). Rate of microbiological failure at month 1 was 40.1% (95% confidence interval [CI], 31.9% to 48.9%) for the whole cohort and 42.3% (95% CI, 31.2% to 54.0%) for episodes due to MDR pathogens. Previous urinary tract infection (odds ratio [OR], 2.42; 95% CI, 1.11 to 5.29; P value = 0.027) and use of fosfomycin as salvage therapy (OR, 8.31; 95% CI, 1.67 to 41.35; P value = 0.010) were predictors of microbiological failure. No severe treatment-related adverse events were detected. Oral fosfomycin appears to be a suitable and safe alternative for the treatment (if indicated) of AB after KT, including those episodes due to MDR uropathogens.