Developed Cytomegalovirus Infection Research Articles

Epidemiology of Infections in Lung Transplant Recipients Treated With Belatacept.

Belatacept is a costimulatory blocker that can be used to prevent and treat rejection in lung transplant recipients (LuTRs). The epidemiology of infections in belatacept-treated LuTRs has not been systematically evaluated. We performed a single-center retrospective study of all adult LuTRs who received belatacept as prevention or treatment of antibody-mediated rejection (desensitization) or as part of maintenance immunosuppression from January 1, 2011, to June 30, 2022. We assessed the epidemiology of infections that occurred within 12 months following the first belatacept dose. Fifty-two LuTRs received at least one dose of belatacept as either desensitization (n = 32) or maintenance immunosuppression (n = 20). Among 45 patients who were cytomegalovirus (CMV) donor and/or recipient seropositive, nine (20%) developed CMV infection. Seven (77%) CMV infections occurred despite valganciclovir prophylaxis and four (44%) were associated with antiviral resistance. Three (6%) LuTRs developed Epstein-Barr virus (EBV) associated post-transplant lymphoproliferative disorder (PTLD). Twenty-five (48%) LuTRs developed 43 bacterial infections and five (10%) developed proven or probable invasive fungal disease. Incidence rates of viral, bacterial, and fungal infections were similar between the desensitization and maintenance groups: incidence rate ratios (95% confidence interval) were 0.70 (0.32-1.57), 1.31 (0.70-2.46), and 2.82 (0.31-25.2), respectively. Infection/PTLD prompted belatacept discontinuation in eight (15%) patients. In the first year after belatacept initiation, LuTRs commonly developed CMV infections, EBV+ PTLD, and bacterial infections. Multicenter collaborations are needed to better understand infection risks in LuTRs treated with belatacept.

Crushing obstacles: A case series on alternative letermovir administration in transplant recipients.

In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. 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.

Evolving trends in immunosuppression use and cytomegalovirus infection risk over the past decade in kidney transplantation.

The goal was to determine trends in immunosuppression use and its impact on cytomegalovirus (CMV) outcomes over the past 10 years. This was a single-center longitudinal cohort study of adult kidney recipients transplanted between Jan 2012 and June 2021. Baseline and follow-up data were gathered via chart abstraction and analyzed using univariate and multivariate analyses. Of 2392 kidney transplants conducted, 131 patients did not meet inclusion criteria. The mean age was 52 years, 41% were female, 57% were black, and 19% were CMV high-risk. The use of rabbit anti-thymocyte globulin (RATG) induction (odds ratio [OR] 1.6, 1.3-2.1), tacrolimus (FK) level >8ng/mL (OR 1.1, 1.09-1.11), CMV D+/R- rates (OR 1.06, 1.02-1.10), white blood cell count <3000 (OR 1.22, 1.18-1.26) and valganciclovir prophylaxis (OR 1.7, 1.6-1.9) have significantly increased over the past 10 years. Rejection rates (OR 0.86, 0.82-0.91) and BK viremia >2000 (OR 0.91, 0.91-0.98) have decreased. RATG induction (adjusted hazard ratio [aHR] 1.35, 1.2-1.5), FK >8ng/mL (aHR 3.5, 3.2-3.9), Belatacept conversion (aHR 2.5, 2.1-3.1), and rejection (aHR 1.8, 1.6-2.0) were significant risk factors for developing CMV infection, while mycophenolate mofetil <1500mg (aHR 0.52, 0.47-0.59), mammalian target of rapamycin inhibitor (mTORi) conversion (0.77, 0.56-0.89), cyclosporine-A conversion (aHR 0.68, 0.56-0.84) were associated with lower risk of CMV infection. Increasing use of potent immunosuppression coupled with higher CMV D+/R- F rates may be driving higher rates of CMV infection. Cyclosporine and mTORi conversion appears to be protective against CMV. A more individualized immunosuppression regimen based on infection risk merits consideration.

Analysis of the efficacy and prognostic factors of allogeneic hematopoietic stem cell transplantation in patients with myelodysplastic syndrome with blastomycosis and survival comparison of different subtypes after the WHO 2022 reclassification

Objective: To evaluate the efficacy and prognostic factors of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with myelodysplastic syndrome accompanied by myelodysplasia (MDS-EB) and to compare the prognosis of different subtypes of patients classified by World Health Organization (WHO) 2022. Methods: A total of 282 patients with MDS-EB who underwent allo-HSCT at the Hematology Hospital of the Chinese Academy of Medical Sciences from October 2006 to December 2022 were included in the study. The WHO 2022 diagnostic criteria reclassified MDS into three groups: myelodysplastic tumors with type 1/2 of primitive cell proliferation (MDS-IB1/IB2, 222 cases), MDS with fibrosis (MDS-f, 41 cases), and MDS with biallelic TP53 mutation (MDS-biTP53, 19 cases). Their clinical data were retrospectively analyzed. Results: ① The median age of 282 patients was 46 (15-66) years, with 191 males and 91 females. Among them, 118 (42% ) and 164 (58% ) had MDS-EB1 and MDS-EB2, respectively. ②Among the 282 patients, 256 (90.8% ) achieved hematopoietic reconstruction after transplantation, with 11 (3.9% ) and 15 (5.3% ) having primary and secondary implantation dysfunctions, respectively. The cumulative incidence of acute graft-versus-host disease (GVHD) 100 days post-transplantation was (42.6±3.0) %, and the cumulative incidence of grade Ⅱ-Ⅳ acute GVHD was (33.0±2.8) %. The cumulative incidence of chronic GVHD 1 year post-transplantation was (31.0±2.9) %. Post-transplantation, 128 (45.4% ), 63 (22.3% ), 35 (12.4% ), and 17 patients (6.0% ) developed cytomegalovirus infection, bacteremia, pulmonary fungal infection, and Epstein-Barr virus infection. ③The median follow-up time post-transplantation was 22.1 (19.2-24.7) months, and the 3-year overall survival (OS) and disease-free survival (DFS) rates were 71.9% (95% CI 65.7% -78.6% ) and 63.6% (95% CI 57.2% -70.7% ), respectively. The 3-year non-recurrent mortality rate (NRM) is 17.9% (95% CI 13.9% -22.9% ), and the 3-year cumulative recurrence rate (CIR) is 9.8% (95% CI 6.7% -13.7% ). The independent risk factors affecting OS post-transplantation include monocyte karyotype (P=0.004, HR=3.26, 95% CI 1.46-7.29), hematopoietic stem cell transplantation complication index (HCI-CI) of ≥3 points (P<0.001, HR=2.86, 95% CI 1.72-4.75), and the occurrence of acute gastrointestinal GVHD of grade Ⅱ-Ⅳ (P<0.001, HR=5.94, 95% CI 3.50-10.10). ④The 3-year OS and DFS rates in the MDS-IB1/IB2 group post-transplantation were better than those in the MDS-biTP53 group [OS: 72.0% (95% CI 63.4% -80.7% ) vs 46.4% (95% CI 26.9% -80.1% ), P=0.020; DFS: 67.4% (95% CI 60.3% -75.3% ) vs 39.7% (95% CI 22.3% -70.8% ), P=0.015]. The 3-year CIR was lower than that of the MDS-biTP53 group [7.3% (95% CI 4.3% -11.4% ) vs 26.9% (95% CI 9.2% -48.5% ), P=0.004]. The NRM at 3 years post-transplantation in the MDS-IB1/IB2, MDS-f, and MDS-biTP53 groups were 16.7% (95% CI 12.1% -22.1% ), 20.5% (95% CI 9.4% -34.6% ), and 26.3% (95% CI 9.1% -47.5% ), respectively (P=0.690) . Conclusion: Allo-HSCT is an effective treatment for MDS-EB, with monomeric karyotype, HCI-CI, and grade Ⅱ-Ⅳ acute gastrointestinal GVHD as independent risk factors affecting the patient's OS. The WHO 2022 classification helps distinguish the efficacy of allo-HSCT in different subgroups of patients. Allo-HSCT can improve the poor prognosis of patients with MDS-f, but those with MDS-biTP53 have a higher risk of recurrence post-transplantation.

Risk factors and outcomes of cytomegalovirus infection in the intensive care unit.

Cytomegalovirus (CMV) infection has long been recognized as an important viral syndrome in the immunocompromised host. The disease is less well described in critically-ill patients. We evaluated the risk factors for the development of CMV infection in patients admitted to the intensive care unit (ICU). We also compared the outcomes of CMV infection in ICU patients to those of patients with hematological malignancies. This is a retrospective study composed of three arms: patients admitted to the ICU with infection (ICU + / CMV + arm), patients admitted to the ICU who did not develop CMV infection (ICU + / CMV- arm, and patients with hematological malignancies on the hematology ward without CMV infection (ICU - / CMV + arm). Patients who were admitted to ICU for surgical causes had a decreased risk of CMV infection. On the other hand, receiving corticosteroids and vasoactive drugs was associated with an increased risk of CMV infection with adjusted odds ratios (aOR) of 2.4 and 25.3, respectively. Mortality was higher in ICU + / CMV + patients compared to ICU - / CMV + patients. In the ICU + /CMV + population, male sex and being on mechanical ventilation after CMV infection were independent predictors of mortality (aOR 4.6 and 5.0, respectively). CMV infection in ICU patients is a potentially serious disease requiring close attention. The findings from our study help in identifying patients in the ICU at risk for CMV infection, thereby warranting frequent screening. Patients at high risk of death (male, on mechanical ventilation) should receive prompt treatment and intensive follow-up.

Cytomegalovirus infection during daratumumab therapy in patients with newly diagnosed multiple myeloma.

The introduction of daratumumab has improved treatment outcomes for multiple myeloma (MM). However, infectious complications are a concern in patients receiving daratumumab. Although some reports have explored the association between daratumumab and cytomegalovirus (CMV) infection, most of these have focused on relapsed or refractory cases, and few describe patients with newly diagnosed MM (NDMM). In this study, we retrospectively analyzed CMV infections in 53 patients with NDMM who received daratumumab as induction therapy. CMV infection was defined as CMV antigenemia positivity. The median age at treatment initiation was 71years (range, 50-82years), and 50.9% of the patients were female. The median duration of daratumumab administration was 10.0months (range, 0.3-63.8months). Nine patients developed CMV infection, and the cumulative incidence rate at six months was 18.1% (95% confidence interval: 8.9-30.1%). One patient experienced CMV retinitis and required antiviral therapy, while the remaining eight patients did not require treatment and could be managed through observation. Few cases of CMV infection during daratumumab treatment for NDMM required treatment. However, the incidence of CMV infection was not negligible, suggesting that regular monitoring for CMV is worth considering to ensure more appropriate management during daratumumab treatment.

High-dimensional mass cytometry identified circulating natural killer T-cell subsets associated with protection from cytomegalovirus infection in kidney transplant recipients

Cytomegalovirus (CMV) infection is associated with poor kidney transplant outcomes. While innate and adaptive immune cells have been implicated in its prevention, an in-depth characterization of the in vivo kinetics of multiple cell subsets and their role in protecting against CMV infection has not been achieved. Here, we performed high-dimensional immune phenotyping by mass cytometry, and functional assays, on 112 serially collected samples from CMV seropositive kidney transplant recipients. Advanced unsupervised deep learning analysis was used to assess immune cell populations that significantly correlated with prevention against CMV infection and anti-viral immune function. Prior to infection, kidney transplant recipients who developed CMV infection showed significantly lower CMV-specific cell-mediated immune (CMI) frequencies than those that did not. A broad diversity of circulating cell subsets within innate and adaptive immune compartments were associated with CMV infection or protective CMV-specific CMI. While percentages of CMV (tetramer-stained)-specific T cells associated with high CMI responses and clinical protection, circulating CD3+CD8midCD56+ NK-T cells overall strongly associated with low CMI and subsequent infection. However, three NK-T cell subsets sharing the CD11b surface marker associated with CMV protection and correlated with strong anti-viral CMI frequencies in vitro. These data were validated in two external independent cohorts of kidney transplant recipients. Thus, we newly describe the kinetics of a novel NK-T cell subset that may have a protective role in post-transplantation CMV infection. Our findings pave the way to more mechanistic studies aimed at understanding the function of these cells in protection against CMV infection.

Utility of the Interferon-Gamma Enzyme-Linked Immunosorbent Spot Assay to Predict Risk of Cytomegalovirus Infection in Kidney Transplant Recipients.

Non-specific interferon-gamma (IFN-γ) enzyme-linked immunosorbent (ELISpot) responses after solid organ transplant (SOT) and their relationship with cytomegalovirus (CMV) reactivation have hardly been investigated. Adult kidney transplant (KT) recipients underwent measurement of IFN-γ-producing T cells using the ELISpot assay before and 1 month after transplantation. Data for CMV infection episodes were collected. Risk factors for post-transplant CMV infection, based on IFN-γ responses, were analyzed using a Cox proportional hazards model. A total of 93 KT recipients were enrolled in the study and 84 evaluable participants remained at 1 month post KT. Thirty-three (39%) recipients developed subsequent CMV infection within 6 months post-transplant. At 1-month post-transplant, IFN-γ-producing T cells with <250 spot-forming units (SFUs)/2.5 × 105 peripheral blood mononuclear cells (PBMCs) were significantly associated with CMV infection (HR 3.1, 95% CI 1.4-7.1, p = 0.007). On multivariable analysis, posttransplant IFN-γ-producing T cells with <250 SFUs/2.5 × 105 PBMCs remained independently associated with CMV infection (HR 3.1, 95% CI 1.2-7.8, p = 0.019). Conclusions: KT recipients with low IFN-γ-producing T cells measured by the ELISpot assay are more likely to develop CMV infection after transplantation. Therefore, measurement of nonspecific cell-mediated immunity ELISpot responses could potentially stratify recipients at risk of CMV infection (Thai Clinical Trials Registry, TCTR20210216004).

Cytomegalovirus infection during pregnancy.

Cytomegalovirus (CMV) infection during pregnancy is a global silent problem. Additionally, it is the leading cause of congenital infections, non-genetic sensorineural hearing loss, and neurodevelopmental delays in infants. However, this has barely been recognized globally. This condition lacks adequate attention, which is further emphasized by the lack of awareness among healthcare workers and the general population. The impact of CMV infection is often overlooked because of the asymptomatic nature of its presentation in infected pregnant women and newborns, difficulty in diagnosis, and the perception that infants born to women with pre-existing antibodies against CMV have normal neonatal outcomes. This article highlights the latest information on the epidemiology, transmission, clinical manifestations, and development of CMV infection and its management. We reviewed the pathophysiology and clinical manifestations of CMV infection in pregnant women, diagnostic methods, including screening and prognostic markers, and updates in treatment modalities. Current advancements in research on vaccination and hyperimmunoglobulins with worldwide treatment protocols are highlighted.

Investigation of Ganciclovir Resistance in Cytomegalovirus Isolates by Phenotypic and Genotypic Methods

Ganciclovir-resistant cytomegalovirus (CMV) strains are reported following long-term antiviral agent use, especially for immune-suppressive patients. In this study, it was aimed to investigate the mutations in the UL97 gene of CMV, which causes ganciclovir (GCV) resistance by genotypic and phenotypic methods in patients who developed CMV infection following hematopoietic cell (HCT) or solid organ transplantation (SOT). Thirty patients who had HCT or SOT in Mediterranean University Hospital and developed CMV infection during routine follow-up with a viral load of CMV over 1000 copies/mL were included in the study. CMV DNA was analyzed by an automated system (Cobas Ampliprep/COBAS TaqMan CMV Test, Roche Diagnostics, Germany) quantitatively. DNA sequence analysis of the regions including codons 420-664 in the UL97 gene region was done by the Sanger sequencing method to detect mutations causing antiviral resistance and compared with defined mutations. In order to investigate antiviral resistance by phenotypic methods, heparinized blood samples of the patients were collected, 'buffy coat (leukocyte layer)' was inoculated into MRC-5 cells by centrifugation method and CMV growth in these cells was controlled with monoclonal antibodies when growth was detected, virus titer was determined and plaque reduction test was applied as recommended. It was determined that 22 of the 30 patients were HCT recipients and eight were SOT (five kidney, three liver) recipients. When the CMV serology pattern of the patients was evaluated before transplantation, 29 (96.7%) patients were found to be seropositive and one (3.3%) patient was found to be seronegative. Totally, nine CMV UL97 mutations were detected in seven (23.3%) pediatric patients who had HCT, including six seropositive and one seronegative case. In addition, one mutation (D605E) not known to cause GCV resistance was detected in a seronegative recipient and three previously unidentified mutations were detected (1474T, F499S, V559A) in a seronegative recipient. Five of the mutations defined were UL97 mutations with a defined clinical resistance against GCV in each of the five recipients (C603W, C592G, H520Q, M460V, A594T). In the plaque reduction test using 3 µM, 12 µM, 48 µM and 96 µM concentrations of GCV in CMV strains, the IC50 value was determined to be ≥ 8 µM for the five CMV strains, and the phenotypic presence of GCV resistance was shown. Clinical resistance associated with CMV UL97 mutation was detected in five (22.7%) of 22 patients who had HCT. GCV resistance was also demonstrated in these patients by phenotypic methods. No UL97 mutation was detected in the patients who had SOT.

Clinical characteristics and outcomes in CMV infection in intestinal transplant recipients: A single-center experience.

Cytomegalovirus (CMV) infection is one of the most common posttransplantation infections and has been associated with increased rejection and mortality. Data in intestinal transplants recipients are limited. This is a single-center, retrospective cohort study of all intestinal transplants performed between January 1, 2009, and August 31, 2020. We included recipients of all ages who were at risk of CMV infection. To identify the risk factors, we conducted at first univariate and multivariate analysis. For the multivariate analysis, we developed a logistic regression model based on the result of univariate analysis. Ninety five patients with a median age of 32 (interquartile range [IQR] 4, 50) were included. CMV donor seropositive/recipient seronegative were 17 (17.9%). Overall, 22.1% of the recipients developed CMV infection at a median time of 155 (IQR 28-254) days from transplant, including 4 CMV syndrome and 6 CMV end-organ disease. Overall, 90.4%, (19/21) developed DNAemia while on prophylaxis. Median peak viral load and time to negativity was 16 000 (IQR 1034-43 892) IU/mL and 56 (IQR 49-109) days, respectively. (Val)ganciclovir and foscarnet were utilized in 17 (80.9%) and 1 (4.76%) recipients, respectively. Recurrences of CMV DNAemia and graft rejection were observed in three and six recipients, respectively. Younger age was identified as a risk factor (p=.032, odds ratio 0.97, 95% confidence interval 0.95-0.99) to develop CMV DNAemia. A significant proportion of intestinal transplant recipients developed CMV infection while on prophylaxis. Better methods such as CMV cell mediated immunity guided prophylaxis should be used to prevent infections in this population.

New Perspectives in Cytomegalovirus After Transplant: The Role of Immunosuppressant Management.

New Perspectives in Cytomegalovirus After Transplant: The Role of Immunosuppressant Management.

Incidence and severity of cytomegalovirus infection in seropositive heart transplant recipients.

The frequency and significance of cytomegalovirus (CMV) infection in seropositive (R+) heart transplant recipients (HTR) is unclear, with preventative recommendations mostly extrapolated from other groups. We evaluated the incidence and severity of CMV infection in R+ HTR, to identify risk factors and describe outcomes. R+ HTR from 2010 to 2019 were included. Antiviral prophylaxis was not routinely used, with clinically guided monitoring the local standard of care. The primary outcome was CMV infection within one-year post-transplant; secondary outcomes included other herpesvirus infections and mortality. CMV infection occurred in 27/155 (17%) R+ HTR. Patients with CMV had a longer hospitalization (27 vs. 20 days, unadjusted HR 1.02, 95% CI 1.00-1.02, p=.01), higher rate of intensive care readmission (26% vs. 9%, unadjusted HR 3.46, 1.46-8.20, p=.005), and increased mortality (33% vs. 8%, unadjusted HR 10.60, 4.52-24.88, p<.001). The association between CMV and death persisted after adjusting for multiple confounders (HR 24.19, 95% CI 7.47-78.30, p<.001). Valganciclovir prophylaxis was used in 35/155 (23%) and was protective against CMV (infection rate 4% vs. 27%, adjusted HR .07, .01-.72, p=.025), even though those receiving it were more likely to have received thymoglobulin (adjusted OR 10.5, 95% CI 2.01-55.0, p=.005). CMV infection is common in R+ HTR and is associated with a high burden of disease and increased mortality. Patients who received valganciclovir prophylaxis were less likely to develop CMV infection, despite being at higher risk. These findings support the routine use of antiviral prophylaxis following heart transplantation in all CMV R+ patients.

A Single-Center Case Series of Successful Abdominal Organ Transplantation From SARS-CoV-2-infected Donors to Uninfected Recipients-Do We Need Rigorous Monitoring?

We analyzed 16 recipients (7 liver, 9 kidney) transplanted from SARS-CoV-2 nucleic acid test+ deceased donors from December 25, 2021, to February 28, 2022, who were followed-up for at least 90 d. Primary outcomes included coronavirus disease 2019-positivity, allograft loss, and all-cause mortality. Secondary outcomes included biopsy-proven rejection (BPAR), donor-specific antibodies, delayed graft function, and opportunistic infections. Unlike previous studies, we followed the recipients clinically with the intent to treat if they developed SARS-CoV-2 symptoms. All donors were SARS-CoV-2 polymerase chain reaction-positive 72 h before donation. No recipients developed SARS-CoV-2 infection. The nadir serum creatinine and estimated glomerular filtration rate were 1.33 mg/dL and 64 mL/min/1.732 m2 for kidney transplantation (KTx) respectively. The median alanine transaminase was 14.5 IU/L, aspartate aminotransferase 13 IU/L, and alkaline phosphatase 74 IU/L. Two KTx patients lost allograft, and 1 liver transplantation patient died with a failed allograft. However, this was unrelated to their SARS-CoV-2-positive donor status. One BPAR in the liver transplantation was treated with steroids. No donor-specific antibodies or BPAR were reported in the KTx. Six KTx patients experienced delayed graft function, and 4 are off dialysis. Two KTx patients developed cytomegalovirus infection because of an error in reporting the cytomegalovirus serostatus by the donor center. We did not do serial testing for SARS-CoV-2 by polymerase chain reaction, imaging, or cycle threshold score pre- or posttransplant for donor/recipient and had comparable outcomes with previous studies. Because of the low risk of transmission, serial testing might not be necessary and, thus, could be reciprocated at small-volume transplant centers.

The First ABO Incompatible Kidney Transplantation without Splenectomy in India - A Review at 12 Years.

The First ABO Incompatible Kidney Transplantation without Splenectomy in India - A Review at 12 Years.

Analysis of the effect of cytomegalovirus infection in clinical outcomes and prolonged duration of SARS-CoV-2 shedding in intensive care unit patients with COVID-19 pneumonia.

Coronavirus disease 2019 (COVID-19) is a global outbreak disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Cytomegalovirus (CMV) infection can occur in critical COVID-19 patients and is associated with adverse clinical outcomes. The aim of this study was to explore the clinical characteristics and outcome of CMV infection in critical COVID-19 patients. This was a retrospective cohort study. From May to September 2021, SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR)-confirmed COVID-19 patients with intensive care unit (ICU) admission were enrolled. CMV infection was confirmed by PCR. Baseline characteristics, critical illness data and clinical outcomes were recorded and analyzed. Seventy-two RT-PCR-confirmed COVID-19 patients with ICU admission were included during the study period and 48 (66.7%) patients required mechanical ventilation (MV). Overall, in-hospital mortality was 19.4%. Twenty-one (29.2%) patients developed CMV infection. Patients with CMV infection had a higher likelihood of diabetes, higher lactate dehydrogenase and lactate levels, and higher proportions of MV, anticoagulant, and steroid use. Patients with CMV infection were associated with longer duration of SARS-CoV-2 shedding, longer ICU and hospital stay, and fewer ventilator-free days. The independent risk factor for development of CMV infection was a higher accumulative steroid dose. CMV infection adversely impacted the outcomes of critical COVID-19 patients, resulting in longer ICU stays, longer mechanical ventilation uses and prolonged shedding of SARS-CoV-2.

Absolute Lymphocyte Count as a Marker for Cytomegalovirus Infection After Heart Transplantation.

Previous studies indicate an association between reduced absolute lymphocyte count (ALC) and cytomegalovirus (CMV) infection after solid organ transplantation and have therefore highlighted the potential of ALC as a simple tool to predict CMV infection in transplant patients. This study aimed to examine the utility of ALC as a valuable marker for CMV infection in heart transplant patients. Clinical information and ALC data of all adult patients who received orthotopic heart transplantation at the Medical University of Vienna between January 2004 and May 2019 were collected. We performed a multivariable Cox regression model that incorporates repeated measurements of ALC as a time-varying continuous factor in 2 ways, first as continuous logarithmic factor considering a 50% decrease of ALC levels and second as binary factor using a threshold of 610 cells/μL. One hundred fifty-eight (39%) patients developed CMV infection over the course of 2 y. Patients with lymphopenia were shown to be at higher risk of developing CMV infection both in the continuous approach (HR [per 50% reduction] 1.29; confidence interval [CI], 1.09-1.53; P = 0.003) and the binary approach with a cutoff of 610 cells/μL (HR 1.74; CI, 1.20-2.51; P = 0.003). This study demonstrated a strong association between reduced ALC and the development of CMV infection after heart transplantation. ALC value monitoring could provide an additional tool to assess individualized CMV risk after solid organ transplantation.

Analysis of risk factors and prognosis of cytomegalovirus infection post umbilical cord blood stem cell transplantation in children with primary immunodeficiency diseases

Objective: To investigate the risk factors and outcomes of cytomegalovirus (CMV) infection post umbilical cord blood stem cell transplantation (UCBT) in children with primary immunodeficiency diseases (PID). Methods: Clinical data of 143 PID children who received UCBT in the Children's Hospital of Fudan University from January 2015 to June 2020 were collected retrospectively. CMV-DNA in the plasma was surveilled once or twice a week within 100 days post-UCBT. According to the CMV-DNA test results, children were divided into the CMV-infected group and the CMV-uninfected group. The incidence and risk factors of CMV infection were analyzed. At 1-month post-UCBT, the absolute lymphocyte count, ratio of lymphocyte subsets and immunoglobulin levels were compared between those whose CMV infection developed 1-month later post-UCBT and those not. Mann-Whitney U test and chi-squared test were used for comparision between groups. Kaplan-Meier survival analysis was used to analyze the impact of CMV infection on survival. Results: Among 143 patients, there were 113 males and 30 females, with a age of 14 (8, 27) months at UCBT. Chronic granulomatosis disease (n=49), very-early-onset inflammatory bowel disease (n=43) and severe combined immunodefiency (n=29) were the three main kinds of PID. The rate of CMV infection was 21.7% (31/143), and the time of infection occurring was 44 (31, 49) days post-UCBT. The incidence of recurrent CMV infection was 4.2% (6/143) and refractory CMV infection was 4.9% (7/143).There was no significant difference in the first time CMV-DNA copy and peak CMV-DNA copy during treatment between the recurrent CMV infection group and the non-recurrent CMV infection group (32.8 (18.3, 63.1)×106 vs. 22.5 (13.2, 31.9)×106 copies/L, Z=-0.95, P=0.340;35.2 (20.2, 54.6)×106 vs. 28.4 (24.1, 53.5)×106copies/L, Z=-0.10, P=0.920), so were those between the refractory CMV infection group and non-refractory CMV infection group (21.8 (13.1, 32.2)×106 vs. 25.9 (14.2, 12.2)×106copies/L, Z=-1.04, P=0.299; 47.7 (27.9, 77.6)×106 vs. 27.7 (19.7,51.8)×106copies/L, Z=-1.49, P=0.137). The CMV-infected group accepted more reduced-intensity conditioning (RIC) regimen than the CMV-uninfected group (45.2% (14/31) vs. 25.0% (28/112), χ2=4.76, P<0.05). The rate of CMV-seropositive recipients and Ⅱ-Ⅳ acute graft versus host diseases (aGVHD) are significantly higher in the CMV-infected group than the CMV-uninfected group (100% (31/31) vs. 78.6% (88/112), 64.5% (20/31) vs. 26.8% (30/112), χ2=7.98,15.20, both P<0.05). The follow-up time was 31.6 (13.2, 45.9) months, CMV infection had no effect on overall survival (OS) rate (χ2=0.02, P=0.843). There was significant difference in the survival rate among three groups of refractory CMV infection, non-refractory CMV infection and the CMV-uninfected (4/7 vs.95.8% (23/24) vs. 86.6% (97/112), χ2=5.91, P=0.037), while there was no significant difference in the survival rate among three groups of recurrent CMV infection, non-recurrent CMV infection and the CMV-uninfected (5/6 vs. 88.0% (22/25) vs. 86.6% (97/112), χ2=0.43, P=0.896). Children who developed CMV infection after 30 days post-UCBT had lower absolute count and rate of CD4+ T cells and immunoglobulin G (IgG) level than those in the CMV-uninfected group (124.1 (81.5, 167.6) ×106 vs. 175.5 (108.3, 257.2) ×106/L, 0.240 (0.164, 0.404) vs. 0.376 (0.222, 0.469), 9.3 (6.2, 14.7) vs. 13.6 (10.7, 16.4) g/L, Z=-2.48, -2.12,-2.47, all P<0.05), but have higher rate of CD8+T cells than those in CMV-uninfected group (0.418 (0.281, 0.624) vs. 0.249 (0.154, 0.434), Z=-2.56, P=0.010). Conclusions: RIC regimen, grade Ⅱ-Ⅳ aGVHD and CMV-seropositive recipients are the main risk factors associated with CMV infection in PID patients post-UCBT. Survival rate of children with refractory CMV infection after UCBT is reduced. Immune reconstitution in children after UCBT should be regularly monitored, and frequency of CMV-DNA monitoring should be increased for children with delayed immune reconstitution.

424.9: Real-World Treatment Patterns and Outcomes For Cytomegalovirus Infection and Disease in Hematopoietic Stem Cell Transplant Recipients in Selected Countries Outside of North America and Europe: A Systematic Review

Background: There is a paucity of real-world data on treatments used for cytomegalovirus (CMV) in hematopoietic stem cell transplant (HSCT) recipients, which differ across countries, outside of developed markets. To address this knowledge gap, a systematic review was conducted to evaluate current treatment patterns for CMV infection and disease following HSCT in selected countries outside of North America and Europe and describe related outcomes. Methods: Information sources (search period: 01 Jan. 2011 – 21 Jul. 2021) included indexed literature (Ovid® MEDLINE and Embase, Cochrane Database of Systematic Reviews and World Health Organization database Global Index Medicus), conference abstracts, pragmatic searches of the grey literature and snowballing of references lists of retained studies. Observational studies of interest included HSCT recipients (any age) who developed CMV infection or disease in 15 selected countries in Asia-Pacific, Latin America, Russia, and the Middle East. Outcomes of interest were treatment patterns for CMV infection and CMV disease, proportion of patients (pts) with resistant and refractory CMV including definitions, treatment-related outcomes and adverse events (AEs). The protocol was registered in PROSPERO (CRD42020205559). Results: Out of 25 retained studies (33 to 475 pts), most included allogeneic HSCT recipients (n=21, 84.0%) and adult pts (n=20, 80.0%). In HSCT recipients, pre-emptive therapy with intravenous ganciclovir (IV GCV) and/or valganciclovir (VGCV) is the conventional first-line (1L) approach for CMV infection prevention, with a median treatment duration of 14-24 days (5 studies). GCV IV was also the conventional treatment for CMV disease (5 studies), with treatment lasting 12-30 days (3 studies). Neutropenia was observed in 30.0% and 39.8% pts treated with GCV and, in 3 studies, neutropenia, myelosuppression, and nephrotoxicity led to GCV discontinuation, respectively, in 13.6%, 10.0%, and 2.3% of pts. In 3 studies, up to 10.0% of pts had second-line (2L) treatment with foscarnet, due to GCV-related myelosuppression. The reported proportion of pts with resistant CMV (definition not specified) ranged between 0% and 7.7% (5 studies; Figure 1). These pts received foscarnet or cidofovir as 2L therapy for a mean duration of 14 days (no data on AEs reported). In 3 studies, estimates of refractory CMV were 2.9%, 13.0%, and 49.4% (latter estimate reported in 39 pts, of whom 56.0% had recurrent CMV). Conclusion: In selected countries outside of North America and Europe, conventional therapeutic options for pre-emptive and treatment of CMV infection and CMV disease following HSCT were IV GCV and VGCV. However, premature treatment discontinuation occurred in up to 1 in 8 pts, highlighting an unmet need with current standard of care. Real-world outcomes in pts with refractory CMV (with or without resistance) were scarce and warrants further investigation in this patient population, including therapeutic management.This review was funded by Takeda International AG – Singapore Branch. S-YC has served as a consultant for Takeda Pharmaceutical, and has received research support and payment for lectures from Merck Sharp & Dohme, Pfizer and Gilead. WD has no conflicts of interest to disclose. CMM has received honoraria from Takeda and MSD (advisory board, speaker, educational events, meetings). IS is an employee of Takeda Pharmaceuticals India Pvt Ltd. AS and DD are employees of Takeda International AG – Singapore Branch and hold stock options. MS has received grants from F2G, Gilead, Merck and personal fees from Gilead, Pfizer, Takeda and Roche for work outside of this research. Literature retrieval, analysis and medical writing support were provided by Aurore Bergamasco, Camille Goyer, and Yola Moride of Yolarx Consultants and funded by Takeda International AG – Singapore Branch.

424.8: Real-World Treatment Patterns and Outcomes For Cytomegalovirus Infection and Disease in Solid Organ Transplant Recipients in Selected Countries Outside North America and Europe: A Systematic Review

Background: In Europe and North America, ganciclovir (GCV) and valganciclovir (VGCV) constitute the standard of care for the management of cytomegalovirus (CMV) infection and disease in solid organ transplant (SOT) recipients. As practices vary across countries due to differences in access to health care or resources, a systematic review was undertaken to evaluate treatment patterns for CMV infection and disease post-SOT in selected countries outside of Europe and North America and describe related outcomes. Methods: Information sources (search period: 01 Jan. 2011 – 21 Jul. 2021) included literature search (Ovid® MEDLINE and Embase, Cochrane Database of Systematic Reviews and World Health Organization database Global Index Medicus), pragmatic searches of the grey literature, and snowballing of references lists. Observational studies that included SOT (any organ) recipients (any age) who developed CMV infection or disease in 15 selected countries in Asia-Pacific, Latin America, Russia and the Middle East and reported on the outcomes of interest (treatment patterns for CMV infection and CMV disease, proportion of patients (pts) with resistant and/or refractory CMV including definitions, treatment-related outcomes and adverse events, AEs) were included. The protocol was registered in PROSPERO (CRD42020205559). Results: A total of 23 studies (18 to 1,620 pts), most (87.0%, n=20) conducted in adults (≥ 18 years), were included (kidney: n=19 [82.6%]; liver: n=3 [13.0%]; mixed SOTs: n=1 [4.3%]). In studies reporting on preventive strategies used for CMV (n=4), similar proportions of pts receiving prophylaxis and pre-emptive therapy were found (45% to 58.7% pts and 41.3% to 56.3% pts, respectively). Intravenous (IV) GCV and VGCV were the preferred first-line (1L) treatments for both prevention (IV GCV: 77.8%-100% pts, VGCV: 44.4%-99.2% pts) and treatment (IV GCV: 77.8%-100% pts) of CMV infection and disease. In 3 studies, the treatment duration for CMV disease was between 12 and 90 days. In pediatric pts who received GCV as pre-emptive therapy after prophylaxis, time to viremia clearance was 3.5 months. Rates of CMV resistance were reported in 3 studies (Figure 1). No data on risk factors for CMV resistance nor on pts with refractory CMV were found. Hematological AEs (i.e., thrombocytopenia, leucopenia, neutropenia, anemia) were reported in up to 25% of pts receiving IV GCV, as prophylaxis or pre-emptive therapy (Figure 1). Data stratified according to treatment strategy were not available. Conclusion: The conventional 1L treatment for both prevention and treatment of CMV was IV GCV or VGCV. However, as identified studies reported that 1 in 4 pts experience hematological AEs with these therapies, there remains an unmet need for this patient population. Data on the proportion and management of SOT pts with resistant and/or refractory CMV remains scarce in countries outside of Europe and North America.This review was funded by Takeda International AG – Singapore Branch. JC has received grants from Takeda company. MS has received grants from F2G, Gilead, Merck and personal fees from Gilead, Pfizer, Takeda and Roche for work outside of this research. IS is an employee of Takeda Pharmaceuticals India Pvt Ltd. AS and DD are employees of Takeda International AG – Singapore Branch and hold stock options. HT has received research grants to conduct clinical trials from Novartis, Pfizer, BMS, Natera, and Astra Zeneca. Literature retrieval, analysis and medical writing support were provided by Aurore Bergamasco, Camille Goyer, and Yola Moride of Yolarx Consultants and funded by Takeda International AG – Singapore Branch.