Prophylactic therapy using epigenetic agents for RUNX1::RUNXT1-positive high-risk AML after Allo-HSCT.

Disease recurrence is the leading cause of treatment failure in patients with RUNX1::RUNXT1-positive acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Post-transplant maintenance therapy, guided by monitoring minimal residual disease (MRD), is commonly administered; however, relapse rates remain high. This prospective study aimed to assess the effectiveness and safety of epigenetic agents as prophylactic therapy in patients with RUNX1::RUNXT1-positive AML. Thirty high-risk patients received prophylactic therapy (n = 17 and n = 13 in the chidamide and AZA groups, respectively) between January 2019 and July 2023. 34 high-risk patients who received preemptive treatment due to molecular relapse were included in the analysis. The two-year relapse-free survival (RFS) and overall survival (OS) were significantly higher in the prophylactic group compared to the preemptive group (82.82% vs. 51.38%, P = 0.014; 86.42% vs. 56.16%, P = 0.025, respectively); 2-year cumulative incidence of relapse rates were 13.8% and 36.40%, respectively (P = 0.037). In conclusion, prophylactic therapy with epigenetic agents may improve long-term prognosis and is well-tolerated in patients with RUNX1::RUNXT1-positive high-risk AML. Timely post-transplant prophylactic therapy may be more effective than preemptive therapy based on positive MRD results.

Impact of Primary Letermovir Prophylaxis Versus Preemptive Antiviral Therapy for Cytomegalovirus on Economic and Clinical Outcomes after Hematopoietic Cell Transplantation.

Preemptive therapy (PET) historically has been the primary strategy to reduce early-onset cytomegalovirus (CMV) reactivation after allogeneic hematopoietic cell transplantation (HCT) but is associated with antiviral-associated toxicities and increases in healthcare resource utilization and cost. Despite its high cost, letermovir (LTV) prophylaxis has largely supplanted PET due to its effectiveness and tolerability. Direct comparisons between LTV and PET approaches on economic and clinical outcomes after allogeneic HCT remain limited. Objective: To compare total cost of care (inpatient and outpatient) between LTV prophylaxis and PET through day+180 after allogeneic HCT. Adult allogeneic CMV seropositive (R+) HCT recipients who initiated LTV <30 days after HCT between 01/01/18 and 12/31/18 were matched 1:1 to allogeneic CMV R+ HCT recipients between 01/01/15 and 12/31/17 (PET cohort). Patients were grouped into high-risk (HR) or standard-risk (SR) for CMV to compare the LTV and PET cohorts. Direct costs for each patient's index HCT admission and all subsequent inpatient and outpatient care through day+180 after HCT were determined and converted into 2021 US dollars and then to Medicare proportional dollars (MPD). A secondary analysis using 2019 average wholesale price was conducted to specifically evaluate anti-CMV medication costs. There were a total of 176 patients with 54 HR CMV pairs and 34 SR CMV pairs. No differences in survival between LTV and PET for both HR and SR CMV groups were observed. The rate of clinically significant CMV infection decreased for both HR CMV (11/54, 20.4% versus 38/54, 70.4%, P < .001) and SR CMV (1/34, 2.9% versus 12/34, 35.3%, P < .001) patients who were given LTV prophylaxis with corresponding reductions in val(ganciclovir) and foscarnet (HR CMV only) use. Among HR CMV patients, LTV prophylaxis was associated with reductions in CMV-related readmissions (3/54, 5.6% versus 18/54, 33.3%, P < .001) and outpatient visits within the first 100 days after HCT (20 versus 25, P = .002), and a decreased median total cost of care ($36,018 versus $75,525, P < .001) in MPD was observed. For SR CMV patients on LTV, a significant reduction in the median inpatient cost ($15,668 versus $27,818, P < .001) was found, but this finding was offset by a higher median outpatient cost ($26,145 versus $20,307, P = .030) that was not CMV-driven. LTV prophylaxis is highly effective in reducing clinically significant CMV reactivations for both HR and SR HCT recipients. In this study, LTV prophylaxis was associated with a decreased total cost of care for HR CMV patients through day+180. Specifically, reductions in CMV-related readmissions, exposure to CMV-directed antiviral agents, and outpatient visits in the first 100 days after HCT were observed. SR CMV patients receiving LTV prophylaxis benefited by having a reduced inpatient cost of care due to lowered room and pharmacy costs.

Relationship between Contingent Negative Variation and afterimage duration in migraine patients.

Background: Abnormalities in electrocortical parameters and persistence of afterimage after visual stimulation are known to occur in migraine patients. The results of studies on Contingent Negative Variation (CNV) and afterimage persistence in migraine patients suggest a link between these two phenomena and a connection to the pathomechanism of migraine. Objectives: To date, no studies have investigated both afterimage duration and CNV parameters in the same subjects. The aim of this study was to investigate the relationship between the early component of CNV (iCNV) and the duration of the afterimage in migraine patients. Methods: Sixty seven migraine patients from the headache center of the University of Rostock Medical Center were examined for iCNV amplitude, iCNV habituation and afterimage duration. The subjects also completed questionnaires developed for this study and the MIDAS (Migraine Disability Assessment) questionnaire. Results: Associations were found between iCNV amplitude and afterimage duration and between habituation capacity and afterimage duration. A deficit in habituation capacity correlated with a significantly prolonged afterimage duration. Increased iCNV amplitude and prolonged afterimage duration were also significantly correlated. Conclusion: Conclusions about the pathophysiology of migraine can be drawn from the results of this study. The results support the hypothesis of cortical hyperexcitability as a consequence of a low pre-activation level, which may be a possible contributory cause of migraine. Furthermore, they allow assessment of whether the afterimage examination, which is easier and quicker to perform than the CNV examination, can be used as a diagnostic tool or as a parameter to monitor the course of therapy in people with migraine.

Efficacy and safety of preemptive therapy for cytomegalovirus end-organ disease in people living with HIV: a systematic review and meta-analysis.

INTRODUCTION: Cytomegalovirus end-organ-disease (CMV EOD) is still a major cause of debilitating illness in people living with HIV, especially in developing countries. OBJECTIVE: To evaluate the efficacy and safety of preemptive therapy against CMV EOD in HIV-positive adults with CMV viremia. METHODS: Systematic review of clinical trials by searching electronic databases and clinical trial registries, screening and selection of references, data extraction and assessment of risk of bias. The results were presented in a narrative synthesis. Aggregated analyzes for dichotomous outcomes were reported as odds ratios with 95 % Confidence Intervals. RESULTS: Four RTC were included. A reduction in the risk of CMV EOD with preemptive therapy was found OR=0.49 (95 % CI 0.31‒0.76). We did not identify significant differences for all-cause mortality, adverse events, and withdrawal of the therapy secondary to adverse events. CONCLUSIONS: Preemptive therapy could be a potential option for preventing CMV EOD in people living with HIV.

Does therapeutic drug monitoring (TDM) of trough concentrations suffice for optimizing preemptive therapy with ganciclovir of cytomegalovirus infections in non-renal solid organ transplant recipients?

OBJECTIVES: The aim of this study is to explore the relationship between ganciclovir exposure and clinical efficacy and/or safety in non-renal solid organ transplant (SOT) recipients receiving preemptive therapy with ganciclovir/valganciclovir and undergoing therapeutic drug monitoring (TDM)-guided dosing optimization. METHODS: Non-renal SOT recipients admitted to IRCCS Azienda Ospedaliero-Universitaria of Bologna receiving preemptive therapy with ganciclovir or valganciclovir for active cytomegalovirus (CMV) infection and who underwent at least one TDM were included. Desired ganciclovir Cmin range was set at 1-3 mg/L, and average ganciclovir trough concentrations (Cmin ) were calculated for each patient. Reduced CMV viral load below the lower limit of quantification (LLQ) at 30 days and occurrence of myelotoxicity were selected as the primary outcome. Univariate analysis was performed by comparing patients with average Cmin below or above 1 or 3 mg/L. Receiver operating characteristic (ROC) curve analysis was performed to identify the average ganciclovir Cmin cut-off predictive for clinical efficacy or toxicity. RESULTS: Twenty-nine out of 89 retrieved patients met the inclusion criteria, with a median (interquartile [IQR]) baseline CMV viral load of 27,163 copies/mL (IQR 13 159.75-151 340.25 copies/mL). Reduced CMV viral load below the LLQ at 30 days was found in 17 patients (58.6%). No difference was found in the primary outcome between patients showing average Cmin below or above 1 mg/L (100.0% vs. 53.8%; p = .25) and/or 3 mg/L (65.2% vs. 33.3%; p = .20). ROC analysis did not allow to identify an average Cmin cut-off predictive of clinical efficacy or toxicity. CONCLUSIONS: No clear relationship between ganciclovir Cmin and neither CMV eradication nor safety issues was identified.

Preemptive Therapy in Cryptococcosis Adjusted for Outcomes.

Cryptococcosis is one of the most serious opportunistic diseases in patients living with HIV. For this reason, early diagnosis and appropriate treatment are important. OBJECTIVES: The aim of the study was to understand the development of patients diagnosed with cryptococcosis by detection of Cryptococcus antigen in serum by lateral flow assay (CrAg LFA) without nervous system involvement and with treatment in accordance with the results. MATERIALS AND METHODS: A retrospective, longitudinal, analytical study was performed. Seventy patients with cryptococcosis initially diagnosed by serum CrAg LFA without meningeal involvement between January 2019 and April 2022 were analyzed for medical records. The treatment regimen was adapted to the results of blood culture, respiratory material, and pulmonary tomography imaging. RESULTS: Seventy patients were included, 13 had probable pulmonary cryptococcosis, 4 had proven pulmonary cryptococcosis, 3 had fungemia, and 50 had preemptive therapy without microbiological or imaging findings compatible with cryptococcosis. Among the 50 patients with preemptive therapy, none had meningeal involvement or cryptococcosis recurrences to date. CONCLUSION: Preemptive therapy avoided progression to meningitis in CrAg LFA-positive patients. Preemptive therapy with dose adjustment of fluconazole in patients with the mentioned characteristics was useful despite the use of lower doses than recommended.

Clinical implantation of 92 VACStents in the upper gastrointestinal tract of 50 patients-applicability and safety analysis of an innovative endoscopic concept.

Introduction: Endoscopic vacuum therapy (EVT) has emerged as a promising treatment option for upper gastrointestinal wall defects, offering benefits such as evacuation of secretions and removal of wound debris by suction, and reduction and healing of wound cavities to improve clinical outcomes. In contrast, covered stents have a high rate of migration and lack functional drainage, while endoluminal EVT devices obstruct the GI tract. The VACStent is a novel device that combines the benefits of EVT and stent placement. Its design features a fully covered Nitinol-stent within a polyurethane sponge cylinder, enabling EVT while maintaining stent patency. Methods: This study analyzes the pooled data from three different prospective study cohorts to assess the safe practicality of VACStent placement, complete leak coverage, and effective suction-treatment of esophageal leaks. By pooling the data, the study aims to provide a broader base for analysis. Results: In total, trans-nasal derivation of the catheter, suction and drainage of secretion via vacuum pump were performed without any adversity. In the pooled study cohort of 92 VACStent applications, the mean stent indwelling time was 5.2 days (range 2-8 days) without any dislocation of the device. Removal of the VACStent was done without complication, in one case the sponge was lost but subsequently fully preserved. Minor local erosions and bleeding and one subsequent hemostasis were recorded unfrequently during withdrawal of the device (5.4%, 5/92) but no perforation or pressure ulcer. Despite a high heterogeneity regarding primary disease and pretreatments a cure rate of 76% (38/50 patients) could be achieved. Discussion: In summary, insertion and release procedure was regarded as easy and simple with a low potential of dislocation. The VACStent was well tolerated by the patient while keeping the drainage function of the sponge achieving directly a wound closure by continuous suction and improving the healing process. The implantation of the VACStent provides a promising new procedure for improved clinical treatment in various indications of the upper gastrointestinal wall, which should be validated in larger clinical studies.Clinical Trial Registration: Identifier [DRKS00016048 and NCT04884334].

Risk factors of cytomegalovirus infection after pediatric liver transplantation and effectiveness of preemptive therapy.

BACKGROUND: Cytomegalovirus (CMV) infection is the most common infection following pediatric liver transplantation (LT). Preemptive therapy (PET) is an approach to initiate antiviral treatment for asymptomatic early CMV viremia detected by surveillance testing. However, data on CMV infection after PET are scarce, and the optimal cut-off remains controversial. This study aimed to evaluate the incidence, risk factors, and consequences of CMV infection in pediatric LT using 2 different viral load (VL) cut-offs. METHODS: We retrospectively reviewed patients aged 0-18 years who underwent LT at Ramathibodi Hospital between March 2001 and August 2020. Demographic data, CMV infection, CMV treatment, and consequences of CMV infection were collected. CMV viremia was monitored by a quantitative nucleic acid amplification test. Clinical outcomes were compared after starting antiviral therapy at a low (>400 but <2000 IU/mL) and a high VL cut-off (≥2000 IU/mL). RESULTS: A total of 126 patients were included. CMV infection was 71% (90/126), with an incidence rate of 5.5 per 1000 patient-day. Higher tacrolimus and prednisolone dosages were associated with CMV infection with an adjusted hazard ratio of 1.2 (95%CI 1.0-1.4, p = .02) and 2.4 (95%CI 1.9-3.4, p < .001), respectively. The consequences of CMV infection did not differ significantly for the low and high CMV VL cut-off groups. CONCLUSION: CMV infection in LT recipients is common and is associated with higher tacrolimus and corticosteroid dosage. Additionally, using the CMV VL cut-off at 2000 IU/mL to initiate antiviral therapy is practical and effective in preventing CMV disease.

Preemptive endoluminal vacuum therapy with the VACStent-A pilot study to reduce anastomotic leakage after Ivor Lewis hybrid esophagectomy.

Introduction: Endoscopic treatment by vacuum therapy (EVT) or covered stents has emerged as an improved treatment option for upper gastrointestinal wall defects and is regarded as an improved treatment option for anastomotic leakage (AL) after esophagectomy. However, endoluminal EVT devices may lead to obstruction of the GI tract; and a high rate of migration and missing functional drainage has been shown for covered stents. The recently developed VACStent, a combination of a fully covered stent within a polyurethane sponge cylinder may overcome these issues allowing EVT while stent passage is still open. Initial clinical applications have demonstrated efficacy, practicability and safety in the treatment of esophageal leaks (AL). Methods: In this pilot study, 9 patients with high-risk anastomosis after neoadjuvant therapy undergoing hybrid esophagectomy received the VACStent in a preemptive setting for the assessment of the reduction of the AL rate, postoperative morbidity and mortality. Results: Technical success of the application of the VACStent® was achieved in all interventions. One patient experienced anastomotic leakage 10 days after esophagectomy and was successfully treated with two consecutive VACStents and a VAC Sponge. In summary, mortality in-hospital was 0% and anastomotic healing was uneventful without septic episodes. No severe device-related adverse events (SADE) nor significant local bleeding or erosion could be observed. Oral intake of liquids or food was documented in all patients. The device handling was regarded uncomplicated. Discussion: The preemptive application of the VACStent offers a promising new option for improved clinical treatment avoiding of critical situations in hybrid esophagectomy, which should be validated in a large clinical study.

Real-world effectiveness of preemptive therapy (PET) for cytomegalovirus (CMV) disease prevention in CMV high-risk donor seropositive/recipient seronegative (D+R-) liver transplant recipients (LTxR).

BACKGROUND: Despite superiority of preemptive therapy (PET) compared to universal prophylaxis for prevention of cytomegalovirus (CMV) disease in the CAPSIL randomized trial among CMV D+R- liver transplant recipients (LTxRs), real-world effectiveness may be lower because of logistical concerns about feasibility of PET. METHODS: We retrospectively assessed PET as standard clinical care at a single transplant center among 50 consecutive adult CMV D+R- LTxRs undergoing a first liver transplant between 4/4/2019 and 5/18/2021 and compared outcomes and adherence to those randomized to PET in the CAPSIL study (N = 100). The primary outcome was CMV disease and secondary outcomes were biopsy-confirmed acute allograft rejection, retransplant, invasive fungal infections, and death, all assessed by 1-year post-transplant. Exploratory outcomes included virologic parameters and measures of adherence to protocol-specified CMV qPCR monitoring. RESULTS: Baseline characteristics were similar between groups. The cumulative incidence of CMV disease at 1-year post-transplant was 4/50 (8%) versus 9/100 (9%) in the real-world and CAPSIL cohorts, respectively, p = 1.0. The rate of breakthrough CMV disease during the 100-day PET period was low (2/50 [4%]) and similar to the PET cohort from the CAPSIL study (3/100 [3%]).  All secondary and exploratory outcomes were not significantly different between the real-world and CAPSIL PET cohorts. CONCLUSIONS: In this first reported study of real-world PET, the feasibility and effectiveness for CMV disease prevention and for other clinical outcomes in CMV D+R- LTxRs were similar to those reported with PET in a clinical trial. Additional studies to confirm feasibility and generalizability in other settings are warranted.

Magnesium Sulfate Reduces Carrageenan-Induced Rat Paw Inflammatory Edema Via Nitric Oxide Production.

Background: Magnesium is an antagonist of the N-methyl-D-aspartate receptor. This study aimed to investigate the anti-edematous effect of magnesium sulfate (MS) in different protocols of use and the possible mechanism of its action. Methods: In a rat model of carrageenan-induced paw inflammation, the anti-edematous activity of MS was assessed with a plethysmometer. The effects of the nonselective inhibitor (L-NAME), selective inhibitor of neuronal (L-NPA) and inducible (SMT) nitric oxide synthase on the effects of MS were evaluated. Results: MS administered systemically before or after inflammation reduced edema by 30% (5 mg/kg, P < .05) and 55% (30 mg/kg, P < .05). MS administered locally (.5 mg/paw, P < .05) significantly prevented the development of inflammatory edema by 60%. L-NAME, intraperitoneally administered before MS, potentiated (5 mg/kg, P < .05) or reduced (3 mg/kg, P < .05), while in the highest tested dose L-NPA (2 mg/kg, P < .01) and SMT (.015 mg/kg, P < .01) reduced the anti-edematous effect of MS. Conclusions: Magnesium is a more effective anti-edematous drug in therapy than for preventing inflammatory edema. The effect of MS is achieved after systemic and local peripheral administration and when MS is administered as a single drug in a single dose. This effect is mediated at least in part via the production of nitric oxide.

Population Pharmacokinetic and Pharmacodynamic Analysis of Valganciclovir for Optimizing Preemptive Therapy of Cytomegalovirus Infections in Kidney Transplant Recipients.

This study aimed to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model of valganciclovir for preemptive therapy of cytomegalovirus (CMV) infection in kidney transplant patients. A population PK/PD model was developed with Monolix. Ganciclovir concentrations and CMV viral loads were obtained retrospectively from kidney transplant patients receiving routine clinical care. Ten thousand Monte Carlo simulations were performed with the licensed dosages adjusted for renal function to assess the probability of attaining a viral load target of ≤290 and ≤137 IU/mL. Fifty-seven patients provided 343 ganciclovir concentrations and 328 CMV viral loads for PK/PD modeling. A one-compartment pharmacokinetic model coupled with an indirect viral turnover growth model with stimulation of viral degradation pharmacodynamic model was devised. Simulations showed that 1- and 2-log10 reduction of CMV viral load mostly occurred between a median of 5 to 6 and 12 to 16 days, respectively. The licensed dosages achieved a probability of reaching the viral load target ≥90% at days 35 to 49 and 42 to 56 for the thresholds of ≤290 and ≤137 IU/mL, respectively. Simulations indicate that in patients with an estimated glomerular filtration rate of 10 to 24 mL/min/1.73m2, a dose increase to 450 mg every 36 h may reduce time to optimal viral load target to days 42 and 49 from a previous time of 49 and 56 days for the thresholds of ≤290 and ≤137 IU/mL, respectively. Currently licensed dosages of valganciclovir for preemptive therapy of CMV infection may achieve a viral load reduction within the first 2 weeks, but treatment should continue for ≥35 days to ensure viral load suppression.

Cytomegalovirus infection and disease in pediatric liver transplantation: Burden of disease under a preemptive therapy approach.

BACKGROUND: CMV remains a frequent complication after liver transplantation. Few studies exist in children reporting the epidemiology and outcomes of CMV after LT with current prevention strategies. Our goal is to report the incidence of CMV infection and disease in pediatric LT recipients under preemptive therapy, identify risk factors, complications, and adverse reactions to treatment. METHODS: All pediatric LT recipients from a single center (1998-2018) were included. Antigenemia pp65 (1998-2003) and QNAT or both were used to inform preemptive therapy. Cutoff value for starting treatment was Agpp65 > 10 + cells/200 000 or QNAT >1500 copies/ml or any value in high-risk recipients (D+/R-). RESULTS: One hundred eighteen LT were analyzed. CMV infection was detected in 67% of patients, only 44 (37%) required treatment, and 5 (4%) developed CMV disease. All patients responded well to treatment, and no graft or patients were lost to CMV effects. There were no differences in mortality, CMV indirect effects, or other complications between those who required treatment and those who did not. Thirty-two percent of the patients who received antivirals developed an adverse hematological reaction. Risk factors associated with CMV infection requiring treatment were D+/R- (OR 13.9, p = .01) and fulminant hepatitis (OR 4.8, p = .02). CONCLUSIONS: Preemptive therapy for CMV in children is safe and effective, yields low CMV infection rates that require treatment, and minimal rates of CMV disease, without increasing CMV-related complications. Using this strategy, 63% of our patients did not receive treatment. Therefore, drug exposure, adverse reactions, and resistance risk were minimized.

The Ten Most Common Questions on Cytomegalovirus Infection in Hematopoietic Stem Cell Transplant Patients.

With the rising number of patients undergoing hematopoietic stem cell transplantation (HSCT), clinicians are more likely to encounter infectious complications in immunocompromised hosts, particularly cytomegalovirus (CMV) infection. Besides the high mortality of CMV end-organ disease, patients with detectable CMV viremia may have worse outcomes and decreased survival even in the absence of end-organ disease. In view of the implications on morbidity and mortality, clinicians should maintain a high index of suspicion and initiate antiviral drugs promptly when CMV infection is confirmed. High-risk patients should be identified in order to provide optimal management. Additionally, novel antiviral agents with a good safety profile and minor adverse events are now available for prophylaxis in high-risk patients and for treatment of resistant or refractory CMV infection. The following review provides concise, yet comprehensive, guidance on the burden and risk factors of CMV in this population, as well as an update on the latest evidence for the management of CMV infection.

Optimizing the treatment of cytomegalovirus infection in allo-HSCT recipients.

INTRODUCTION: Cytomegalovirus (CMV) infection continues to negatively impact the prognosis after allogeneic hematopoietic stem cell transplantation (allo-HSCT), even with active monitoring and preemptive strategies. Recent progress in pharmacology, immunotherapy, and vaccines has improved the strategy of CMV management. AREAS COVERED: We summarized recent advances in managing CMV infection post allo-HSCT, including diagnosis, prophylaxis, and treatment. In this review, we mainly focused on approaches that have optimized or might optimize the management of CMV infection after allo-HSCT. EXPERT OPINION: In our opinion, optimized management covers aspects including the serial monitoring of CMV-DNA and CMI, an accurate diagnosis, effective prophylaxis, and a rational preemptive therapy integrating antiviral drugs and cell therapies. Strategies based on the understanding of CMV pathogenesis and CMV-related immune reconstitution after allo-HSCT will be a direction in future studies.

Efficacy and safety of preemptive therapy for cytomegalovirus end-organ disease in people living with HIV: a systematic review and meta-analysis

ABSTRACT Introduction: Cytomegalovirus end-organ-disease (CMV EOD) is still a major cause of debilitating illness in people living with HIV, especially in developing countries. Objective: To evaluate the efficacy and safety of preemptive therapy against CMV EOD in HIV-positive adults with CMV viremia. Methods: Systematic review of clinical trials by searching electronic databases and clinical trial registries, screening and selection of references, data extraction and assessment of risk of bias. The results were presented in a narrative synthesis. Aggregated analyzes for dichotomous outcomes were reported as odds ratios with 95 % Confidence Intervals. Results: Four RTC were included. A reduction in the risk of CMV EOD with preemptive therapy was found OR=0.49 (95 % CI 0.31-0.76). We did not identify significant differences for all-cause mortality, adverse events, and withdrawal of the therapy secondary to adverse events. Conclusions: Preemptive therapy could be a potential option for preventing CMV EOD in people living with HIV.

Probable posttransplant lymphoproliferative disorder after pediatric living donor liver transplantation: Is a biopsy still needed?

Posttransplant lymphoproliferative disorder (PTLD) is a complication of solid organ transplantation and is associated with Epstein-Barr virus (EBV). Recently, EBV-related PTLD was defined as probable PTLD or proven PTLD. Probable PTLD involves significant lymphadenopathy, hepatosplenomegaly, or other end-organ manifestations, without a histological diagnosis, together with significant EBV DNAemia. Proven PTLD is the detection of EBV-encoded proteins in a tissue specimen, together with symptoms and/or signs originating from the affected organ. Probable PTLD after pediatric liver transplantation has not been well documented. Therefore, here, we aimed to describe cases of five pediatric patients with probable PTLD after liver transplantation, who were successfully treated with preemptive immunosuppression reduction with or without rituximab. All five patients (age range, 1-4 years; two girls and three boys) had EBV DNAemia. Three patients developed probable PTLD within 12 months of transplantation. Further, three patients had a significantly high EBV viral load, but the other two patients with lymphadenopathy and end-organ manifestation had a relatively low EBV viral load. Early onset pediatric PTLD with significant EBV DNAemia is almost universally EBV-related. Biopsy was not performed in any patient due to the relative inaccessibility of the lesion and young age of the patients. If the patient's symptoms are too mild, if excisional biopsy is too difficult to perform, or if the patient is too sick to undergo an invasive procedure, initiating preemptive treatment without a histological diagnosis could be the treatment option.

Antiviral prophylaxis or preemptive therapy for cytomegalovirus after liver transplantation?: A systematic review and meta-analysis.

Background: To conduct a meta-analysis with the aim of comparing the outcomes of antiviral prophylaxis and preemptive therapy for the prevention of cytomegalovirus (CMV) infection in liver transplant (LT) recipients. Methods: We searched databases for qualified studies up until March 2022. Finally, a meta-analysis was carried out using a fixed-effect or random-effect model based on the heterogeneity. Results: With a total of 1834 LT patients, the pooled incidence of CMV infection and CMV disease in the overall LT recipients using antiviral prophylaxis and preemptive therapy were 24.7% vs. 40.4% and 6.4% vs. 9.4%, respectively. Our meta-analysis exhibited a significant reduction in the incidence of CMV infection due to antiviral prophylaxis when compared to preemptive therapy in the high-risk group (OR: 6.67, 95% CI: 1.73, 25.66; p = 0.006). In contrast, there was a significant reduction in the incidence of late-onset of CMV disease in preemptive therapy compared to antiviral prophylaxis in the high-risk group (OR: 0.29, 95% CI: 0.12, 0.74; p = 0.009). However, the incidence of CMV disease, allograft rejection, graft loss, drug related adverse effects, opportunistic infections and mortality did not differ significantly between both the interventions (all p> 0.05). Conclusions: We found the use of antiviral prophylaxis, compared with preemptive therapy, is superior in controlling CMV infection and prolonging the time to CMV disease in LT recipients without an increased risk of opportunistic infections, allograft rejection, graft loss, drug related adverse effects, development of drug resistance, and mortality.

Adenovirus Infection in Pediatric Hematopoietic Cell Transplantation: A Challenge Still Open for Survival.

Human Adenovirus (HAdV) infection occurs in 14−16% of patients in the early months after pediatric hematopoietic cell transplantation (HCT) and this correlates with a higher risk of developing HAdV disease and overall 6-month mortality. The main risk factors for HAdV infection are T-cell depletion of the graft by ex vivo CD34+ selection or in vivo use of alemtuzumab or anti-thymocyte serum, the development of grade III-IV graft versus host disease (GVHD), the type of donor (unrelated donor, cord blood, haploidentical, or HLA mismatched parent), and severe lymphopenia (<0.2 × 109/L). The prevention of HAdV disease is based on early intervention with antivirals in the asymptomatic patient when the permitted viral load threshold in the blood (≥102−3 copies/mL) and/or in the stool (109 copies/g stool) is exceeded. Cidofovir, a monophosphate nucleotide analog of cytosine, is the primary drug for preemptive therapy, used at 5 mg/kg/week for 2 weeks followed by 3−5 mg/kg every 2 weeks. The alternative schedule is 1 mg/kg every other day (three times/week). Enhancing virus-specific T-cell immunity in the first months post-HCT by donor-derived or third-party-derived virus-specific T cells represents an innovative and promising way of intervention, applicable both in prevention and therapeutic settings.