Alemtuzumab is a potent lymphocyte-depleting immunotherapy used in solid organ transplan-tation (SOT), that is increasingly being applied in diverse lymphoproliferative disorders (LPDs). However, a significant toxicity limiting expanded usage is cytomegalovirus (CMV) infection, for which standardized preventive strategies exist in SOT but not in LPDs due to a poor understanding of infection risk in this population, with early LPD studies largely limited to stem cell transplantation. Using one of the most diverse arrays of LPDs studied to date, our retrospective cohort study of non-transplant patients receiving alemtuzumab over a ten-year period at a large regional cancer center examines the incidence and clinical profile of infected patients. Among 24 patients, we identified a composite CMV infection rate of 42% with a symptomatic rate of 21%. We also noted significant variations in preventive strategies, which alongside a high infection rate presents an opportunity to improve outcomes through further work in standardization.

OBJECTIVE: To explore Cytomegalovirus (CMV) antigen-specific multi-cytokine immune responses in patients with rheumatic disease (RD) under different CMV infection status.
METHODS: A total of 60 RD patients in our center from March 2023 to August 2023 were enrolled. The patients were divided into latent CMV infection and active CMV infection, the latter was classified as subclinical CMV infection or CMV disease based on presence or absence of symptoms related to CMV. Whole blood was collected and stimulated with QuantiFERON-CMV antigen. The levels of IFN-γ, TNF-α, IL-2, IL-4, IL-6, IL-10, IL-17 and CXCL-2 in supernatant were measured by Luminex Assays. The receiver operating characteristic curve was used to evaluate the diagnostic accuracy of cytokine for distinguishing different CMV infection status.
RESULTS: The proportion of patients with severe lymphopenia was lowest in the latent CMV infection group, while there were no significant differences in medication usage in different CMV infection status. After stimulation with QF-CMV antigens, the levels of IFN-γ, TNF-α and IL-2 in the CMV disease group were significantly lower than those in the latent CMV infection group. CMV antigen-specific IFN-γ, TNF-α levels and severe lymphopenia together provided the best discriminatory performance for distinguishing between latent and either active CMV infection patients (AUC = 0.854) or CMV disease patients (AUC = 0.935).
CONCLUSIONS: Noninvasive peripheral blood biomarkers (the combination of CMV antigen-specific IFN-γ, TNF-α levels and severe lymphopenia) may have the potential to diferentiate different status of CMV infection in RD population.

Emergence of drug resistance is rare after use of letermovir (LMV) as prophylaxis for post-transplant cytomegalovirus (CMV) infection. In a recent study involving renal transplant recipients, no known LMV resistance mutations were detected in those receiving LMV prophylaxis. However, uncharacterized viral amino acid substitutions were detected in LMV recipients by deep sequencing in viral subpopulations of 5%-7%, at codons previously associated with drug resistance: UL56 S229Y (n = 1), UL56 M329I (n = 9) and UL89 D344Y (n = 5). Phenotypic analysis of these mutations in a cloned laboratory CMV strain showed that S229Y conferred a 2-fold increase in LMV EC50, M329I conferred no LMV resistance, and D344Y knocked out viral viability that was restored after the nonviable clone was reverted to wild type D344. As in previous CMV antiviral trials, the detection of nonviable mutations, even in multiple study subjects, raises strong suspicion of genotyping artifacts and encourages the use of replicate testing for authentication of atypical mutation readouts. The non-viability of UL89 D344Y also confirms the biologically important locus of the D344E substitution that confers resistance to benzimidazole CMV terminase complex inhibitors, but does not feature prominently in LMV resistance.

BACKGROUND: In a phase 3 trial, letermovir was non-inferior to valganciclovir for CMV disease prophylaxis in CMV-seronegative (R-) kidney transplant recipients (KTRs) who received a kidney from a CMV-seropositive donor (D+). Genotypic antiviral resistance and CMV glycoprotein B (gB) genotype are reported.
METHODS: Plasma samples with detectable CMV DNA were sequenced for presence of known letermovir and valganciclovir resistance-associated amino acid substitutions (RASs) encoded by CMV gene regions (UL51, UL56, UL89, UL54, UL97) and prevalence of gB (UL55) genotypes (gB1-gB5).
RESULTS: 84 of 292 participants in the letermovir and 93 of 297 in the valganciclovir group had evaluable data for ≥1 gene target. Letermovir RASs were not detected in participants who received letermovir prophylaxis; however, 3 had valganciclovir RASs (pUL97). Twelve participants in the valganciclovir group had valganciclovir RASs (pUL54, pUL97); and 1 who did not receive letermovir during the trial also had letermovir RASs (pUL56). All but 1 participant responded to valganciclovir treatment irrespective of breakthrough CMV DNAemia or frequency of RASs. gB1 was the most frequent genotype across all participants and subgroups.
CONCLUSIONS: Letermovir RASs were not detected in the letermovir group, supporting a low risk for development of resistance with letermovir prophylaxis in CMV D+R- KTRs.
BACKGROUND: ClinicalTrials.gov: NCT03443869, EudraCT: 2017-001055-30.

OBJECTIVE: 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).
CONCLUSIONS: 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.

Cytomegalovirus (CMV) has been linked with increased cardiovascular risk and monocyte activation in people living with HIV (PLWH). This cross-sectional study aimed to compare CMV immunoglobulin G (IgG) levels between combined antiretroviral therapy (cART)-treated PLWH versus ART-naïve PLWH and those without HIV, and to investigate their associations with biomarkers of endothelial injury and carotid atherosclerosis, in Gaborone, Botswana. All participants were between 30 and 50 years old. Carotid intimal media thickness (cIMT) and biomarkers of endothelial injury and monocyte activation were also assessed. The association between quantitative CMV IgG and cardiovascular disease risk was assessed in multivariate logistic regression analysis. The results showed that the mean CMV IgG level among ART-naïve participants was significantly higher than both the cART group and controls. However, CMV IgG levels did not differ significantly between the controls and cART groups. Among PLWH, CMV IgG levels were associated with ICAM-1 levels and cIMT. Increases in CMV IgG among ART-naïve participants were significantly associated with increases in log VCAM-1. In conclusion, CMV IgG levels are elevated among PLWH in sub-Saharan Africa, and higher levels are associated with biomarkers of endothelial injury and cIMT. Future research should investigate the long-term impact of elevated CMV IgG among PLWH.

One-third of humanity harbors a lifelong infection with Toxoplasma gondii, and probably about 80% are infected with human cytomegalovirus (CMV). This study aims to delineate the associations between toxoplasmosis and cognitive abilities and compare these to the associations with CMV. We evaluated the cognitive performance of 557 students, who had been examined for Toxoplasma and CMV infections, using intelligence, memory, and psychomotor tests. The results indicated cognitive impairments in seropositive individuals for both pathogens, with variations in cognitive impact related to sex and the Rh factor. Specifically, Toxoplasma infection was associated with lower IQ in men, whereas CMV was predominantly associated with worse performance by women when testing memory and reaction speeds. Analysis of the antibody concentrations indicated that certain Toxoplasma-associated cognitive detrimental effects may wane (impaired intelligence) or worsen (impaired reaction times) over time following infection. The findings imply that the cognitive impairments caused by both neurotropic pathogens are likely due to pathological changes in the brain rather than from direct manipulative action by the parasites.

BACKGROUND: Cytomegalovirus-specific T-cell-mediated immunity (CMV-CMI) protects from CMV infection in allogeneic hematopoietic cell transplantation (allo-HCT), but to date, there is no validated measure of CMV immunity for this population.
METHODS: In this prospective, observational, pilot study, CMV T-cell responses were evaluated monthly and at onset of graft-versus-host disease (GVHD) or CMV infection in CMV-seropositive allo-HCT recipients using a commercial flow cytometry assay, the CMV inSIGHT T-Cell Immunity Panel (CMV-TCIP). The primary endpoint was the time to first positive CMV-TCIP, defined as percentage of interferon-γ-producing CD4+ or CD8+ CMV-specific T cells >0.2%. Letermovir was prescribed from day +10 to ≥100.
RESULTS: Twenty-eight allo-HCT recipients were enrolled. The median time to first positive CMV-TCIP result was earlier for CD4+ (60 days [interquartile range, IQR 33‒148]) than for CD8+ T cells (96 days [IQR 33‒155]) and longer for haploidentical and mismatched transplant recipients (77 and 96 days, respectively) than for matched donors (45 and 33 days, respectively). CD4+ and CD8+ CMV-CMI recovery was sustained in 10/10 (100%) and 10/11 (91%) patients, respectively, without GVHD, whereas CD4+ and/or CD8+ CMV-CMI was lost in 4/6 and 2/6 patients, respectively, with GVHD requiring steroids. As a predictor of clinically significant CMV infection in patients with low-level CMV reactivation, the sensitivity and negative predictive value of CMV-TCIP were 90% and 87.5%, respectively, for CD4+ CMV-TCIP and 66.7% and 62.5%, respectively, for CD8+ CMV-TCIP.
CONCLUSIONS: There was significant variability in time to CMV-CMI recovery post-HCT, with slower recovery after haploidentical and mismatched HCT. CD4+ CMV-CMI may protect against CS-CMVi, but immunity may be lost with GVHD diagnosis and treatment.

OBJECTIVE: The objective of this study was to assess the role of T-lymphocyte immune responses in newborns with congenital cytomegalovirus (CMV) infection (cCMV) and their potential association with the development of long-term sequelae.
METHODS: A multicenter, prospective study from 2017 to 2022 was conducted across 8 hospitals in Spain. Blood samples were collected within the first month of life from neonates diagnosed with cCMV. Intracellular cytokine staining was employed to evaluate the presence of CMV-specific interferon-gamma (IFN-γ)-producing CD8+ and CD4+ T lymphocytes (CMV-IFN-γ-CD8+/CD4+) using flow cytometry. The development of sequelae, including hearing loss and neurologic impairment, was assessed during follow-up.
RESULTS: In total, 64 newborns were included; 42 infants (65.6%) had symptomatic cCMV. The median age at the last follow-up visit was 25.3 months (IQR 20.1-34.4). Eighteen infants had long-term sequelae (28.1%), predominantly hearing loss (20.3%) and neurologic disorders (15.6%). No relationship was observed between total count or percentage of CMV-specific IFN-γ-CD8+ or CD4+ lymphocytes and long-term sequelae. Multivariable analysis demonstrated an association between lower total lymphocyte count and long-term sequelae (aOR 0.549, 95% CI: 0.323-0.833), which requires further study.
CONCLUSIONS: CMV-specific IFN-γ-CD4+ and CD8+ T-lymphocyte responses in neonates with cCMV were not predictive of long-term sequelae.

BACKGROUND: Valganciclovir (valG), a cytomegalovirus (CMV) prophylactic agent, has dose-limiting side effects. The tolerability and effectiveness of valacyclovir (valA) as CMV prophylaxis is unknown.
METHODS: We conducted a randomized, open-label, single-center trial of valA versus valG for all posttransplant CMV prophylaxis in adult and pediatric kidney recipients. Participants were randomly assigned to receive valA or valG. Primary endpoints were the incidence of CMV viremia and side-effect related drug reduction with secondary assessment of incidence of EBV viremia.
RESULTS: Of the 137 sequential kidney transplant recipients enrolled, 26 % were positive and negative for CMV antibody in donor and recipient respectively. The incidence of CMV viremia (4 of 71 [6 %]; 8 of 67 [12 %] P = 0.23), time to viremia (P = 0.16) and area under CMV viral load time curve (P = 0.19) were not significantly different. ValG participants were significantly more likely to require side-effect related dose reduction (15/71 [21 %] versus 1/66 [2 %] P = 0.0003). Leukopenia was the most common reason for valG dose reduction and granulocyte-colony stimulating factor was utilized for leukopenia recovery more frequently (25 % in valG vs 5 % in valA: P = 0.0007). Incidence of EBV viremia was not significantly different.
CONCLUSIONS: ValA has significantly less dose-limiting side effects than valG. In our study population, a significant increase in CMV viremia was not observed, in adults and children after kidney transplant, compared to valG.
BACKGROUND: NCT01329185.