Characterization of recurrent cytomegalovirus reactivations post allogenic stem cell transplantation in a population with high seropositivity.

OBJECTIVES: This study aimed to characterize incidences of CMV reactivations within one year post-allo-SCT and identify risk factors for CMV second reactivation episode in population with high seropositivity where first CMV reactivation episode deemed to be high. METHODS: This retrospective cohort study analyzed data from 359 allo-SCT patients aged 14 and older admitted to a tertiary academic hospital. Data on demographic and clinical factors, CMV serostatus, conditioning regimens, graft-versus-host disease prophylaxis, engraftment time, and CMV reactivations were collected. RESULTS: First and second CMV reactivations occurred in 88.9% and 18.4% of post-allo-SCT patients respectively. Patients were stratified into two groups based on primary disease necessitating allo-SCT, patients with malignant (Group 1) and non-malignant (Group 2) hematological disease. Factors associated with the second reactivation included cord blood as a stem cell source, human leukocyte antigen mismatch, acute graft-versus-host disease, and hematological malignancies. Patients with non-malignant hematological disease displayed better outcomes, including a higher rate of spontaneous clearance of first CMV reactivation (70% versus 49.4%) and lower rates of second CMV reactivation (9.6% versus 31%) than those with malignant hematological disease. The one-year overall survival rate was 87.7% (95.5% in non-malignant hematological disease and 78.13% in malignant hematological disease). CONCLUSION: Our findings are concordant with previous local study in regard to high rate of first CMV reactivation post-allo-SCT. It appears that patients with nonmalignant hematological disease had better outcomes, such as lower second CMV reactivation and higher survival rates compared to patients with malignant hematological disease. Further investigation is needed to identify other factors affecting recurrent CMV reactivations in allo-SCT in patients with malignant hematological disease.

Human cytomegalovirus microRNAs: strategies for immune evasion and viral latency.

Viruses use various strategies and mechanisms to deal with cells and proteins of the immune system that form a barrier against infection. One of these mechanisms is the encoding and production of viral microRNAs (miRNAs), whose function is to regulate the gene expression of the host cell and the virus, thus creating a suitable environment for survival and spreading viral infection. miRNAs are short, single-stranded, non-coding RNA molecules that can regulate the expression of host and viral proteins, and due to their non-immunogenic nature, they are not eliminated by the cells of the immune system. More than half of the viral miRNAs are encoded and produced by Orthoherpesviridae family members. Human cytomegalovirus (HCMV) produces miRNAs that mediate various processes in infected cells to contribute to HCMV pathogenicity, including immune escape, viral latency, and cell apoptosis. Here, we discuss which cellular and viral proteins or cellular pathways and processes these mysterious molecules target to evade immunity and support viral latency in infected cells. We also discuss current evidence that their function of bypassing the host's innate and adaptive immune system is essential for the survival and multiplication of the virus and the spread of HCMV infection.

Evaluation of T. gondii, rubella, and cytomegalovirus seroprevalences among female Syrian refugees in Sanliurfa, Turkiye.

INTRODUCTION: Since the Syrian Civil War began in 2011, the official number of refugees under temporary protection in Turkiye is reported to be 3,522,036 in 2023. Most of the Syrians living outside the refugee camps have worse conditions in terms of access to healthcare centers and social opportunities, compared to those living in camps. The Sanliurfa province hosts the third highest number of Syrians (370,291) in Turkiye. There are no data about the seroprevalence of Toxoplasma gondii (T. gondii), rubella (rub), or cytomegalovirus (CMV) among Syrian refugees in Sanliurfa. We aimed to investigate the seroprevalence of T. gondii, rub, and CMV infections among female Syrian refugees of reproductive age (15-49 years) living in Sanliurfa province. METHODOLOGY: A cross-sectional study was conducted in different districts of Sanliurfa. A total of 460 households were selected using the probability sampling method. One married female Syrian refugee aged between 15 and 49 years, was chosen in each household, leading to a sample size of 410 female Syrian refugees. The seropositivity of T. gondii, CMV, and rub IgM and IgG in blood samples were analyzed using enzyme immunoassays (Abbott Architect, Illinois, USA). RESULTS: The seropositivity rates of T. gondii, CMV, and rubella IgM and IgG were 4.4% and 59.8%; 3.9%; and 99%; and 1.9%, and 99.5%, respectively. CONCLUSIONS: A screening program should be implemented for T. gondii, CMV, and rub infections for Syrian refugees. Seronegative women should be vaccinated against rub and educated about the transmission and preventive routes of toxoplasmosis and CMV infection.

Assessment of the impact of cytomegalovirus seropositivity on blood parameters in renal hemodialysis patients.

End-stage renal disease (ESRD) patients are considered immunocompromised, putting them at high risk for infections, including cytomegalovirus (CMV). CMV can affect hematological parameters, causing further complications in ESRD patients. This study intended to determine the seropositivity of CMV infection in hemodialysis patients and its effect on different blood parameters in ESRD patients to help decrease the overall dialysis associated morbidity and mortality. Blood samples were collected from 45 ESRD patients and 45 controls. A complete blood count was performed using an automated cell counter. CMV-specific IgM and IgG levels were measured using immunochemistry testing. The seropositivity for CMV-IgG was 42.2% in ESRD patients which was significantly higher than in control group (22.2%) (p=0.042). The seropositivity for CMV-IgM was 6.7% in ESRD patients with no difference with the control group (4.4%). The prevalence of anemia was significantly higher in CMV seropositive (77.3%) compared to CMV seronegative (47.8%) ESRD patients. Other studied blood parameters were not different between CMV seronegative and seropositive ESRD patients. In conclusion, CMV infection is a significant concern for dialysis patients and can affect hematological parameters, leading to further complications. Early detection and treatment of CMV infection and monitoring of CMV IgM and IgG levels are critical to prevent further complications and improve clinical outcomes.

TTV and CMV viral load dynamics: Which emerges first during immunosuppression?

Novel biomarkers reflecting the degree of immunosuppression in transplant patients are required to ensure eventual personalized equilibrium between rejection and infection risks. With the above aim, Torque Teno Virus (TTV) viremia was precisely examined in a large cohort of transplanted immunocompromised patients (192 hematological and 60 solid organ transplant recipients) being monitored for Cytomegalovirus reactivation. TTV load was measured in 2612 plasma samples from 448 patients. The results revealed a significant increase in TTV viral load approximately 14 days following CMV reactivation/infection in solid organ transplant (SOT) patients. No recognizable difference in TTV load was noted among hematological patients during the entire timeframe analyzed. Furthermore, a temporal gap of approximately 30 days was noted between the viral load peaks reached by the two viruses, with Cytomegalovirus (CMV) preceding TTV. It was not possible to establish a correlation between CMV reactivation/infection and TTV viremia in hematological patients. On the other hand, the SOT patient cohort allowed us to analyze viral kinetics and draw intriguing conclusions. Taken together, the data suggest, to our knowledge for the first time, that CMV infection itself could potentially cause an increase in TTV load in the peripheral blood of patients undergoing immunosuppressive therapy.

Asymptomatic cytomegalovirus gastritis in an immunocompetent COVID-19 patient: A case report.

A number of complications are associated with COVID-19 due to reduced immunity. Of these, opportunistic infections are of great significance because of their atypical presentation and low detection rates. Co-infection of various parts of the gastrointestinal system with cytomegalovirus (CMV) is a common occurrence in COVID- 19 patients. Dysphagia and odynophagia are the main complaints of oesophagitis caused by CMV. Colitis due to CMV presents with melena, diarrhoea, or constipation. However, gastritis due to the same agent can be asymptomatic or associated with atypical symptoms like fever and epigastric pain. Cytomegalovirus gastritis can be fatal if not detected early. Hence, continued monitoring of routine baseline investigations is imperative until the complete resolution of COVID-19, as prompt diagnosis improves the outcomes.

Cytomegalovirus vaccine vector-induced effector memory CD4 + T cells protect cynomolgus macaques from lethal aerosolized heterologous avian influenza challenge.

An influenza vaccine approach that overcomes the problem of viral sequence diversity and provides long-lived heterosubtypic protection is urgently needed to protect against pandemic influenza viruses. Here, to determine if lung-resident effector memory T cells induced by cytomegalovirus (CMV)-vectored vaccines expressing conserved internal influenza antigens could protect against lethal influenza challenge, we immunize Mauritian cynomolgus macaques (MCM) with cynomolgus CMV (CyCMV) vaccines expressing H1N1 1918 influenza M1, NP, and PB1 antigens (CyCMV/Flu), and challenge with heterologous, aerosolized avian H5N1 influenza. All six unvaccinated MCM died by seven days post infection with acute respiratory distress, while 54.5% (6/11) CyCMV/Flu-vaccinated MCM survived. Survival correlates with the magnitude of lung-resident influenza-specific CD4 + T cells prior to challenge. These data demonstrate that CD4 + T cells targeting conserved internal influenza proteins can protect against highly pathogenic heterologous influenza challenge and support further exploration of effector memory T cell-based vaccines for universal influenza vaccine development.

Clinical characteristics and outcomes of immunocompromised critically ill patients with cytomegalovirus end-organ disease: a multicenter retrospective cohort study.

BACKGROUND: Cytomegalovirus (CMV) infection in patients with cellular immune deficiencies is associated with significant morbidity and mortality. However, data on CMV end-organ disease (CMV-EOD) in critically ill, immunocompromised patients are scarce. Our objective here was to describe the clinical characteristics and outcomes of CMV-EOD in this population. METHODS: We conducted a multicenter, international, retrospective, observational study in adults who had CMV-EOD and were admitted to any of 18 intensive care units (ICUs) in France, Israel, and Spain in January 2010-December 2021. Patients with AIDS were excluded. We collected the clinical characteristics and outcomes of each patient. Survivors and non-survivors were compared, and multivariate analysis was performed to identify risk factors for hospital mortality. RESULTS: We studied 185 patients, including 80 (43.2%) with hematologic malignancies, 55 (29.7%) with solid organ transplantation, 31 (16.8%) on immunosuppressants, 16 (8.6%) with solid malignancies, and 3 (1.6%) with primary immunodeficiencies. The most common CMV-EOD was pneumonia (n = 115, [62.2%] including 55 [47.8%] with a respiratory co-pathogen), followed by CMV gastrointestinal disease (n = 64 [34.6%]). More than one organ was involved in 16 (8.8%) patients. Histopathological evidence was obtained for 10/115 (8.7%) patients with pneumonia and 43/64 (67.2%) with GI disease. Other opportunistic infections were diagnosed in 69 (37.3%) patients. Hospital mortality was 61.4% overall and was significantly higher in the group with hematologic malignancies (75% vs. 51%, P = 0.001). Factors independently associated with higher hospital mortality were hematologic malignancy with active graft-versus-host disease (OR 5.02; 95% CI 1.15-27.30), CMV pneumonia (OR 2.57; 95% CI 1.13-6.03), lymphocytes < 0.30 × 109/L at diagnosis of CMV-EOD (OR 2.40; 95% CI 1.05-5.69), worse SOFA score at ICU admission (OR 1.18; 95% CI 1.04-1.35), and older age (OR 1.04; 95% CI 1.01-1.07). CONCLUSIONS: Mortality was high in critically ill, immunocompromised patients with CMV-EOD and varied considerably with the cause of immunodeficiency and organ involved by CMV. Three of the four independent risk factors identified here are also known to be associated with higher mortality in the absence of CMV-EOD. CMV pneumonia was rarely proven by histopathology and was the most severe CMV-EOD.

Cellular immunity against cytomegalovirus and risk of infection after kidney transplantation.

Introduction: Cytomegalovirus (CMV) infection remains a challenge following kidney transplantation (KTx). Currently, CMV-IgG serostatus at transplantation is used to individualize CMV preventive strategies. We assessed the clinical utility of CMV-IGRA for predicting CMV infection following KTx. Methods: We performed a nationwide prospective cohort study from August 2016 until December 2022. Data from all adult KTx recipients in Norway, n=1,546 (R+; n=1,157, D+/R-; n=260, D-/R-; 129), were included with a total of 3,556 CMV-IGRA analyses (1,375 at KTx, 1,188 at eight weeks, 993 one-year after KTx) and 35,782 CMV DNAemia analyses. Results: In R+ recipients CMV-IGRA status, measured at any of the time-points, could not identify any differential risk of later CMV infection. D+/R- recipients remaining CMV-IGRA negative 1-year after transplantation (regardless of positive CMV DNAemia and/or CMV IgG status at that time) had increased risk of developing later CMV infection compared to D+/R- recipients who had become CMV-IGRA positive (14% vs. 2%, p=0.01). Conclusion: Knowledge of pre-transplant CMV-IGRA status did not provide additional information to CMV-IgG serostatus that could improve current post-transplant CMV treatment algorithms. However, D+/R- recipients with a persisting negative CMV-IGRA one-year after transplantation remained at increased risk of experiencing later CMV infection. Therefore we advocate post-transplant CMV-IGRA monitoring in these patients.

Identification and Characterization of Antigen-Specific T-Cells in Viral Infections.

Identification and characterization of CD8+ T-cells is important to determine their role in protecting and clearing viral infections. Here we provide details of the peptide-MHC (pMHC) tetramers-based approach to identify antigen-specific T-cells in human and murine samples. This method provides ex vivo quantification and functional characterization of T-cells reactive to specific viral antigens derived from CMV and rotavirus in human blood and in murine intestinal lamina propria samples, respectively.

Pre-Transplant Frequencies of FoxP3+CD25+ in CD3+CD8+ T Cells as Potential Predictors for CMV in CMV-Intermediate Risk Kidney Transplant Recipients.

Cytomegalovirus (CMV) infection detrimentally influences graft survival in kidney transplant recipients, with the risk primarily determined by recipient and donor serostatus. However, recipient CD8+ T cells play a crucial role in CMV control. The optimal preventive strategy (prophylaxis vs. pre-emptive treatment), particularly for seropositive (intermediate risk) recipients, remains uncertain. We investigated CD8+ T cell subpopulation dynamics and CMV occurrence (DNAemia ≥ 100 IU/mL) in 65 kidney transplant recipients, collecting peripheral blood mononuclear cells before (T1) and 1 year after transplantation (T2). Comparing the two timepoints, we found an increase in granulocyte, monocyte and CD3+CD8+ T cells numbers, while FoxP3+CD25+, LAG-3+ and PD-1+ frequencies were reduced at T2. CMV DNAemia occurred in 33 recipients (55.8%) during the first year. Intermediate risk patients were disproportionally affected by posttransplant CMV (N = 29/45, 64.4%). Intermediate risk recipients developing CMV after transplantation exhibited lower leukocyte, monocyte, and granulocyte counts and higher FoxP3+CD25+ frequencies in CD3+CD8+ T cells pre-transplantation compared to patients staying CMV negative. Pre-transplant FoxP3+CD25+ in CD3+CD8+ T cells had the best discriminatory potential for CMV infection prediction within the first year after transplantation (AUC: 0.746). The FoxP3+CD25+ CD3+CD8+ T cell subset may aid in selecting intermediate risk kidney transplant recipients for CMV prophylaxis.

Evaluation of Frequency of CMV Replication and Disease Complications Reveals New Cellular Defects and a Time Dependent Pattern in CVID Patients.

PURPOSE: Common Variable Immunodeficiency (CVID) is characterized by hypogammaglobulinemia and failure of specific antibody production due to B-cell defects. However, studies have documented various T-cell abnormalities, potentially linked to viral complications. The frequency of Cytomegalovirus (CMV) replication in CVID cohorts is poorly studied. To address this gap in knowledge, we set up an observational study with the objectives of identifying CVID patients with active viraemia (CMV, Epstein-Barr virus (EBV)), evaluating potential correlations with immunophenotypic characteristics, clinical outcome, and the dynamic progression of clinical phenotypes over time. METHODS: 31 CVID patients were retrospectively analysed according to viraemia, clinical and immunologic characteristics. 21 patients with non CVID humoral immunodeficiency were also evaluated as control. RESULTS: Active viral replication of CMV and/or EBV was observed in 25% of all patients. CMV replication was detected only in CVID patients (16%). CVID patients with active viral replication showed reduced HLA-DR+ NK counts when compared with CMV-DNA negative CVID patients. Viraemic patients had lower counts of LIN-DNAMbright and LIN-CD16+ inflammatory lymphoid precursors which correlated with NK-cell subsets. Analysis of the dynamic progression of CVID clinical phenotypes over time, showed that the initial infectious phenotype progressed to complicated phenotypes with time. All CMV viraemic patients had complicated disease. CONCLUSION: Taken together, an impaired production of inflammatory precursors and NK activation is present in CVID patients with active viraemia. Since "Complicated" CVID occurs as a function of disease duration, there is need for an accurate evaluation of this aspect to improve classification and clinical management of CVID patients.

Reexploring cytomegalovirus serology in allogeneic hematopoietic cell transplantation.

PURPOSE OF REVIEW: Discuss the recent evidence on cytomegalovirus (CMV) serology in allogeneic hematopoeic cell transplant (HCT) recipients. RECENT FINDINGS: Whereas the role CMV-specific cellular mediated immunity has recently emerged as an important factor of CMV DNAemia posttransplant, the value of CMV serology has remained unchanged through decades, associated with donor selection and posttransplant prophylactic and monitoring strategies. In this review, we describe and discuss the emerging reports on the association between the magnitude of pretransplant CMV immunoglobulin G (IgG) titer and the posttransplant incidence of CMV DNAemia, as CMV IgG titer could become an additional tool in CMV risk assessment in the future. SUMMARY: Pretransplant recipient CMV serology may have significant implications in posttransplant CMV reactivation in allogeneic HCT recipients.

Potential relationship between cytomegalovirus and immunosenescence: Evidence from observational studies.

Immunosenescence (IS) occurs as a natural outcome of ageing and may be described as a decline in immune system flexibility and adaptability to sufficiently respond to new, foreign antigens. Potential factors that may precipitate IS include persistent herpesvirus infections, such as cytomegalovirus (CMV). Here, we conducted a review of the literature evaluating the potential association between CMV and IS. Twenty-seven epidemiologic studies that included direct comparisons between CMV-seropositive and CMV-seronegative immunocompetent individuals were analysed. The majority of these studies (n = 20) were conducted in European populations. The strength of evidence supporting a relationship between CMV, and various IS-associated immunologic endpoints was assessed. T-cell population restructuring was the most prominently studied endpoint, described in 21 studies, most of which reported a relationship between CMV and reduced CD4:CD8 T-cell ratio or modified CD8+ T-cell levels. Telomere length (n = 4) and inflammageing (n = 3) were less frequently described in the primary literature, and the association of these endpoints with CMV and IS was less pronounced. An emergent trend from our review is the potential effect modification of the CMV-IS relationship with both sex and age, indicating the importance of considering various effector variables when evaluating associations between CMV and IS. Our analysis revealed plausible mechanisms that may underlie the larger epidemiologic trends seen in the literature that support the indirect effect of CMV on IS. Future studies are needed to clarify CMV-associated and IS-associated immunologic endpoints, as well as in more diverse global and immunocompromised populations.

Efficacy and safety of adoptive T-cell therapy in treating cytomegalovirus infections post-haematopoietic stem cell transplantation: A systematic review and meta-analysis.

Cytomegalovirus (CMV) infection poses significant risks in allogeneic haematopoietic stem cell transplant (allo-HSCT) recipients. Despite advances in antiviral therapies, issues such as drug resistance, side effects, and inadequate immune reconstitution remain. This systematic review and meta-analysis aim to evaluate the efficacy and safety of adoptive cell therapy (ATC) in managing CMV infections in allo-HSCT recipients. Adhering to preferred reporting items for systematic reviews and meta-analyses guidelines, we conducted a comprehensive database search through July 2023. A systematic review and meta-analysis were conducted on studies involving HSCT patients with CMV infections treated with ATC. The primary outcome was the response rate to ATC, and secondary outcomes included adverse events associated with ATC. The Freeman-Tukey transformation was applied for analysis. In the meta-analysis of 40 studies involving 953 participants, ATC achieved an overall integrated response rate of 90.16%, with a complete response of 82.59% and a partial response of 22.95%. ATC source, HLA matching, steroid intake, and age group markedly influenced response rates. Donor-derived T-cell treatments exhibited a higher response rate (93.66%) compared to third-party sources (88.94%). HLA-matched patients demonstrated a response rate of 92.90%, while mismatched patients had a lower rate. Children showed a response rate of 83.40%, while adults had a notably higher rate of 98.46%. Adverse events were minimal, with graft-versus-host disease occurring in 24.32% of patients. ATC shows promising response rates in treating CMV infections post-HSCT, with an acceptable safety profile. However, to establish its efficacy conclusively and compare it with other antiviral treatments, randomised controlled trials are essential. Further research should prioritise such trials over observational and one-arm studies to provide robust evidence for clinical decision-making.

Expansion of effector memory Vδ2neg γδ T cells associates with cytomegalovirus reactivation in allogeneic stem cell transplant recipients.

Background: Cytomegalovirus (CMV) reactivation is a significant concern following allogeneic stem cell transplantation. While previous research has highlighted the anti-CMV reactivation effect of γδ T cells in immunocompromised transplant patients, their characterization in recipients at high risk of CMV reactivation remains limited. Methods: This study focused on D+/R+ recipients (where both donor and recipient are CMV seropositive) at high risk of CMV reactivation. We analyzed 28 patients who experienced CMV recurrence within 100 days post-allogeneic hematopoietic stem cell transplantation, along with 36 matched recipients who did not experience CMV recurrence. Clinical data from both groups were compared, and risk factors for CMV reactivation were identified. Additionally, CMV viral load was measured, and flow cytometric analysis was conducted to assess changes in peripheral blood γδ T cell proportions, subpopulation distribution, and differentiation status. We also analyzed the CDR3 repertoire of the TCR δ chain in different γδ T cell subsets. Functional analysis was performed by measuring the lysis of CMV-infected cells upon stimulation. Results: CMV reactivation post-transplantation was associated with acute graft-versus-host disease (aGvHD) and reactivation of non-CMV herpesviruses. Notably, CMV reactivation led to sustained expansion of γδ T cells, primarily within the Vδ2neg γδ T cell subpopulation, with a trend toward differentiation from Naive to effector memory cells. Analysis of the δ chain CDR3 repertoire revealed a delay in the reconstitution of clonal diversity in Vδ2neg γδ T cells following CMV reactivation, while Vδ2pos T cells remained unaffected. Upon stimulation with CMV-infected MRC5 cells, the Vδ2neg γδ T cell subpopulation emerged as the primary effector cell group producing IFN-γ and capable of lysing CMV-infected cells. Moreover, our findings suggest that NKG2D is not necessary involved in Vδ2neg γδ T cell-mediated anti-CMV cytotoxicity. Conclusion: This study provides novel insights into the role of γδ T cells in the immune response to CMV reactivation in transplantation recipients at high risk of CMV infection. Specifically, the Vδ2neg γδ T cell subpopulation appears to be closely associated with CMV reactivation, underscoring their potential role in controlling infection and reflecting CMV reactivation in HSCT patients.

Serum signature of antibodies to Toxoplasma gondii, rubella virus, and cytomegalovirus in females with bipolar disorder: A cross-sectional study.

BACKGROUND AND AIM: Immunity alterations have been observed in bipolar disorder (BD). However, whether serum positivity of antibodies to Toxoplasma gondii (T gondii), rubella, and cytomegalovirus (CMV) shared clinical relevance with BD, remains controversial. This study aimed to investigate this association. METHODS: Antibody seropositivity of IgM and IgG to T gondii, rubella virus, and CMV of females with BD and controls was extracted based on medical records from January 2018 to January 2023. Family history, type of BD, onset age, and psychotic symptom history were also collected. RESULTS: 585 individuals with BD and 800 healthy controls were involved. Individuals with BD revealed a lower positive rate of T gondii IgG in the 10-20 aged group (OR = 0.10), and a higher positive rate of rubella IgG in the 10-20 (OR = 5.44) and 20-30 aged group (OR = 3.15). BD with family history preferred a higher positive rate of T gondii IgG (OR = 24.00). Type-I BD owned a decreased positive rate of rubella IgG (OR = 0.37) and an elevated positive rate of CMV IgG (OR = 2.12) compared to type-II BD, while BD with early onset showed contrast results compared to BD without early onset (Rubella IgG, OR = 2.54; CMV IgG, OR = 0.26). BD with psychotic symptom history displayed a lower positive rate of rubella IgG (OR = 0.50). LIMITATIONS: Absence of male evidence and control of socioeconomic status and environmental exposure. CONCLUSIONS: Differential antibody seropositive rates of T gondii, rubella, and cytomegalovirus in BD were observed.