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Human cytomegalovirus (HCMV) non-primary infections can occur in pregnant women and may result in congenital infection. Comprehensive studies investigating the frequency, characteristics, risk factors and immune response of non-primary infection in pregnancy are missing, while the rate of vertical transmission is not known.HCMV non-primary infection was investigated prospectively in 250 pregnant women. Blood and urine samples as well as saliva and vaginal swabs were collected at 13, 21 and 31 weeks of gestation and at delivery. HCMV-DNA and specific IgG and IgM levels were determined.Overall, 105/250 pregnant women (42.0%) developed non-primary infection. HCMV-DNA was detected more frequently in vaginal secretions (84/250 of the women, 33.6%) than in urine (35/250, 14.0%), saliva (26/250, 10.4%) and blood (7/250, 3.0%). The rate of HCMV non-primary infection increased significantly with the progression of pregnancy (from 12.9% in the first trimesters of gestation to 21.9% at delivery, p 0.01). IgM was detected in 25/250 of the women (10.0%), with no association with non-primary infection, while anti-gB IgG was significantly higher (p 0.01) in women with non-primary infection. Age and close contact with children were not associated with non-primary infection. No woman with non-primary infection transmitted the infection to the fetus (95% confidence interval of transmission rate: 0-3.5%).Although HCMV non-primary infection is frequent during pregnancy, the rate of congenital infection as a consequence of non-primary infection is likely to be ≤ 3.5%.

Cytomegalovirus (CMV) infection is one of the preeminent congenital viral infections, and despite its potential morbidity, uncertainty about its physiopathology, prevention and treatment remains until now. We report a case of a dichorionic and diamniotic twin pregnancy in which only one of the fetus had signs of being affected. The first twin had prenatal diagnosis of intrauterine growth restriction and hyperechogenic bowel, attributable to CMV infection, while there was no evidence of infection of the second one. Prenatal treatment was done with maternal administration of valacyclovir and postnatal treatment of the infected newborn with oral valganciclovir with normal neurodevelopment assessment at 12 months corrected age. In this case, maternal CMV infection was not equally transmitted to both fetuses, suggesting that there may be intrinsic fetal and placental factors influencing both transmission and the clinical features of the infection.

Cytomegalovirus (CMV) can cause recalcitrant recurrent keratouveitis and secondary glaucoma. We report a case of chronic recurrent anterior uveitis with secondary glaucoma presenting with acute visual loss and interface fluid 9 years after laser in situ keratomileusis. Based on clinical presentation, a viral aetiology was suspected. Aqueous tap was positive for CMV-DNA by real-time quantitative PCR of the aqueous humour. The patient was treated with systemic antivirals, topical corticosteroids and antiglaucoma medications. The interface fluid resorbed rapidly. The intraocular pressure (IOP) was controlled by trabeculectomy. There was no further corneal deterioration at 7-month follow-up and the IOP had also stabilised. We believe this is only the third reported case of CMV-related interface fluid syndrome. This case highlights the role of quantitative PCR analysis for establishing viral aetiology in recurrent unilateral hypertensive anterior uveitis and reports the unusual finding of interface fluid which resolved after starting systemic antiviral therapy.

Chronic infections and the subsequent immune response have recently been shown to be risk factors for cognitive decline and Alzheimer disease and related dementias (ADRD). While some studies have shown an association between cytomegalovirus (CMV), a chronic and highly prevalent infection, and cognition and/or ADRD, these studies have been limited by nonrepresentative and small samples. Using 2016 data on 5,617 adults aged 65 years or more from the Health and Retirement Study, we investigated the cross-sectional associations of both CMV serostatus and immunoglobulin G (IgG) antibody response with cognitive function using linear regression models adjusting for age, sex, race/ethnicity, and educational attainment. We further investigated potential effect-measure modification by educational attainment. Overall, both CMV seropositivity and higher IgG antibody response were associated with lower cognitive function, though the relationship was not statistically significant in adjusted models. Among participants with less than a high school diploma, CMV seropositivity and being in the first tertile of IgG response, relative to seronegative persons, were associated with lower scores on the Telephone Interview for Cognitive Status (−0.56 points (95% confidence interval: −1.63, 0.52) and −0.89 points (95% confidence interval: −2.07, 0.29), respectively), and the relationship was attenuated among those with higher education. Our results suggest that CMV may be a risk factor for cognitive impairment, particularly among persons with fewer educational resources.

Objectives Previous research has documented a consistent association between current socioeconomic status (SES) and cytomegalovirus (CMV). Early life is likely a critical period for CMV exposure and immune development, but less is known about early-life socioeconomic factors and CMV, particularly in older age populations. Using data from the Health and Retirement Study, we investigated the association between life course socioeconomic disadvantage and immune response to CMV among older adults. Methods Using ordered logit models, we estimated associations between several measures of socioeconomic disadvantage and the odds of being in a higher CMV Immunoglobulin G (IgG) response category in a sample of 8,168 respondents aged older than 50 years. Results We found a significant association between educational attainment and CMV IgG response. Those with less than a high school education had 2.00 (95% confidence interval [CI]: 1.67–2.40) times the odds of being in a higher CMV category compared to those with a college degree or greater. In addition, we also observed a significant association with parental education and CMV response. Individuals with parents having 8 years or less of schooling had 2.32 (95% CI: 2.00–2.70) times the odds of higher CMV response compared to those whose parents had greater than high school education. Discussion CMV IgG levels in older adults are associated with both early-life and adult SES. Life course socioeconomic disadvantage may contribute to disparities in immunological aging.

A 27-year-old immunocompetent woman presented to our clinic with redness, mild pain and blurring of vision in her left eye (LE) for 3 weeks with no preceding history of injury or contact lens wear. At presentation, her visual acuity was 20/20 and 20/60 in the right eye and LE, respectively. Slit

Cytomegalovirus (CMV) viremia is associated with a higher mortality rate and prolonged intensive care unit (ICU) stay for critically ill patients. CMV infection causes transient but substantial immunosuppression for transplant recipients, increasing risk of fungal infection. The association between CMV viremia and invasive pulmonary aspergillosis (IPA) for critically ill patients is still unknown.We retrospectively analyzed patients received bronchoalveolar lavage (BAL), galactomannan test, influenza survey and blood CMV viral load test in ICUs of a university hospital between April 2017 and May 2020. Independent risks for IPA were analyzed by multivariable logistic regression.A total of 136 patients were included. Twenty-one patients had IPA, 48 patients had CMV viremia and 22 patients had influenza. In a multivariable logistic regression model, patients with CMV viremia or influenza had higher IPA risk (adjusted odds ratio, 3.98 and 8.72; 95% CI, 1.26-12.60 and 2.64-28.82; p value = 0.019 and0.001, respectively.). Patients with detectable CMV in BAL fluid did not have higher IPA risk (crude odds ratio, 0.95; 95% CI, 0.33-2.79; p value = 0.933). After stratifying patients by CMV viral load, the IPA risk is higher for patients with higher viral loads. There is an additive synergistic effect on IPA risk between CMV viremia and influenza infection.For critically ill patients, CMV viremia is an independent risk factor of IPA. Patients with higher blood CMV viral loads have a higher risk of IPA. CMV viremia and influenza have an additive synergistic effect for IPA risk in critically ill patients.

Objective: We describe a patient with history of heart transplant on maintenance immunosuppression who presented with sigmoid colon perforation from cytomegalovirus (CMV) colitis and performed a systematic review of outcomes after perforated CMV colitis. Background: Cytomegalovirus enterocolitis is uncommon among solid organ transplant patients and can result in small or large bowel perforation. Methods: We systematically reviewed articles describing patients with CMV enterocolitis with small or large bowel perforations from PubMed, Embase, and Web of Science from database inception to February 2021. Results: Seventy-seven articles were identified containing 84 patients with perforated CMV enterocolitis. The most prevalent comorbid diagnosis was human immunodeficiency virus (HIV; 27 patients, 32%), and 37 patients (44%) were taking corticosteroids at time of presentation. The ileum was the most common location for a perforation (26 patients, 31%). Odds of survival were lower for patients with small bowel perforation (odds ratio [OR], 0.38; 95% confidence interval [CI], 0.14-0.98) and HIV/acquired immunodeficiency syndrome (AIDS; OR, 0.32; 95% CI, 0.11-0.88). Odds of survival were higher for patients with large bowel perforation (OR, 2.64; 95% CI, 1.03-7.09), radiographically diagnosed perforation (OR, 3.45; 95% CI, 1.12-11.60) and those who received a CMV antiviral (OR, 9.19; 95% CI, 3.26-28.48). Conclusions: Perforated CMV enterocolitis is uncommon even in immunocompromised hosts. Clinicians should maintain a high level of suspicion for CMV-induced bowel perforation in this population because antiviral treatment is associated with increased odds of survival.

Patients with established rheumatoid arthritis (RA) demonstrate altered immune responses to Epstein-Barr virus (EBV), but the presence and roles of EBV have not been fully explored during the pre-clinical disease period. This study was undertaken to determine if EBV infection, as evidenced by an altered anti-EBV antibody response, either plays an important role in driving the development of RA or is a result of expanded RA-related autoimmunity.A total of 83 subjects with RA according to the 1987 American College of Rheumatology (ACR) criteria and 83 age-, sex-, and race-matched control subjects without RA were included in our study. We collected sera from RA subjects and matched controls during the pre-RA and post-RA diagnosis periods and tested the sera for the presence of 5 anti-EBV antibodies (anti-EBV nuclear antigen 1 IgG isotype, anti-viral capsid antigen [anti-VCA] isotypes IgG and IgA, and anti-early antigen [EA] isotypes IgG and IgA), 7 RA-related autoantibodies (rheumatoid factor measured by nephelometry [RF-Neph] as well as isotype-specific IgA-RF, IgM-RF, and IgG-RF, and anti-cyclic citrullinated peptide [anti-CCP] antibodies, including anti-CCP2, anti-CCP3, and anti-CCP3.1), 22 cytokines/chemokines, 36 individual anti-citrullinated protein antibodies, and IgG-cytomegalovirus (CMV) antibodies. Random forest classification, mixed modeling, and joint mixed modeling were used to determine differences in anti-EBV antibody levels between RA subjects and controls.Random forest analysis identified the presence of preclinical EBV antibodies in the serum that differentiated RA subjects from controls without RA. Specifically, IgG-EA antibody levels were higher in RA subjects (mean ± SD 0.82 ± 0.72 international standardized ratio [ISR]) compared to controls (mean ± SD 0.49 ± 0.28 ISR). In subjects with RA, elevated serum IgG-EA levels in the preclinical period before seroconversion were significantly correlated with increased serum IgM-RF levels (P = 0.007), whereas this correlation was not seen in control subjects without RA (P = 0.15). IgG-CMV antibody levels did not differ between groups.Subjects whose serum IgG-EA antibody levels are elevated in the preclinical period will eventually develop RA, which suggests that EBV reactivation cycles are increased during the preclinical period of RA. A combination of RF and EBV reactivation may play an important role in the development of RA.

Congenital cytomegalovirus (cCMV) infection in the newborn can present with sensorineural hearing loss and microcephaly. The objectives of this study were to determine baseline knowledge of cCMV and the acceptability of an infographic about cCMV among a group of postpartum women. Participants completed a questionnaire assessing their perceptions of an infographic as well as their knowledge and risk behaviours for acquisition of CMV. Of all 140 respondents, 119 (85%) had no prior knowledge of cCMV, and all 12 women (8.6%) who viewed the infographic indicated that it was helpful. Our study also demonstrated that passive dissemination of an infographic in clinics results in limited viewership.

Both cytomegalovirus (CMV) viremia and disseminated nontuberculous mycobacterial (NTM) disease are common opportunistic infections in AIDS patients. Whether concurrent CMV viremia is associated with mortality in patients with AIDS and disseminated NTM disease is unknown. Subjects were patients with AIDS and disseminated NTM disease seen at a single center from January 2015 to April 2021. Data were retrospectively collected. Differences in demographics and clinical characteristics and hospitalization survival rates were compared between patients with disseminated NTM and with CMV viremia or not. Subjects were 113 AIDS patients with disseminated NTM who were seen at this Hospital from January 2015 to April 2021. Twenty-six of the patients had CMV viremia and 87 did not. The median age was 36 years (interquartile range [IQR] 29-42) and 108 patients were male (96%). The median CD4 count was 7 cells/µL (IQR 3-17). The median plasma CMV viral load was 9,245 IU/mL (IQR 3147-45725). The serum albumin of patients with CMV viremia was significantly lower than that of patients without CMV viremia (P = 0.03). Compared to patients without CMV viremia (81.6%), patients with CMV viremia had a significantly poorer prognosis (P = 0.01). Cox regression analysis indicated that the risk of a poor prognosis in patients with CMV viremia was 4.7 times higher than that in patients without CMV viremia (P = 0.003), and patients with CD8 more than 250/μL had a better prognosis (P = 0.02). CMV viremia increases the risk of a poor prognosis in patients with AIDS and a disseminated NTM infection. A routine CMV DNA test should be performed on patients with AIDS and disseminated NTM disease in order to reduce the risk of death.

Background: The current COVID-19 pandemic has attracted great attention from the medical world. In the past year, there have been reports of missed or delayed treatments for conditions that mimic COVID-19. The main symptoms caused by SARS-CoV-2, such as fever and cough, belong to different clinical conditions. It is of the utmost importance that the diagnostic thinking used to analyze data and information to reach a COVID-19 diagnosis does not overlook the plethora of different diagnoses related to these symptoms. Case report: The aim of this work is to present the clinical case of a patient having unrecognized HIV infection with a 4-week history of fever, cough, and hypoxia. When tests were allowed to highlight HIV-related immunodeficiency status, a CMV assay was performed in order to evaluate opportunistic pneumonia. Through this, diagnosis of HIV combined with CMV pneumonia was made, thus excluding COVID-19 respiratory insufficiency. Conclusion: The diagnosis of the two conditions in the COVID-19 era is challenging due to overlapping clinical and radiological features and limitations of current diagnostic assays. This causes clinical implications due to diagnostic delays.

Introduction Cytomegalovirus (CMV) is one of the most common and clinically significant viral infections following allogeneic hematopoietic cell transplantation (HCT). Currently available options for CMV prophylaxis and treatment present challenges related to side effects and cost. Methods In this retrospective medical record review, the incidence of clinically significant CMV infection (CMV disease or reactivation requiring preemptive treatment) following allogeneic HCT was compared in patients receiving valacyclovir 1 g three times daily versus acyclovir 400 mg every 12 h for viral prophylaxis. Results Forty-five patients who received valacyclovir were matched based on propensity scoring to 35 patients who received acyclovir. All patients received reduced-intensity conditioning regimens containing anti-thymocyte globulin. Clinically significant CMV infection by day + 180 was lower in the valacyclovir group compared to the acyclovir group (18% vs. 57%, p = 0.0004). Patients receiving valacyclovir prophylaxis also had less severe infection evidenced by a reduction in CMV disease, lower peak CMV titers, delayed CMV reactivation, and less secondary neutropenia. Conclusion Prospective evaluation of valacyclovir 1 g three times daily for viral prophylaxis following allogeneic HCT is warranted. Due to valacyclovir's favorable toxicity profile and affordable cost, it has the potential to benefit patients on a broad scale as an option for CMV prophylaxis.

Half of the world's population is at risk of arthropod-borne virus (arbovirus) infections. Several arbovirus infections have been associated with Guillain-Barré syndrome (GBS). We investigated whether arboviruses are driving GBS beyond epidemic phases of transmission and studied the antibody response to glycolipids. The protocol of the International Guillain-Barré syndrome Outcome Study (IGOS), an observational prospective cohort study, was adapted to a case-control design. Serum samples were tested for a recent infection with Zika virus (ZIKV), dengue virus (DENV), chikungunya (CHIKV) virus, hepatitis E virus, Epstein-Barr virus (EBV), cytomegalovirus (CMV), Campylobacter jejuni, and Mycoplasma pneumoniae, and for antibodies to glycolipids. Forty-nine patients were included from Brazil (63%), Argentina (14%), and Malaysia (22%). Evidence of a recent infection was found in 27/49 (55%) patients: C jejuni (n = 15, 31%), M pneumoniae (n = 5, 10%), CHIKV (n = 2, 4%), EBV (n = 1, 2%), C jejuni and M pneumoniae (n = 2, 4%), CMV and DENV (n = 1, 2%), and C jejuni and DENV (n = 1, 2%). In 22 patients, 35 paired controls were collected. Odds ratio for recent infections did not significantly differ between cases and controls. No typical anti-ganglioside antibody binding was associated with recent arbovirus infection. We conclude that arbovirus infections occur in GBS patients outside of epidemic viral transmission, although not significantly more than in controls. Broad infection and anti-ganglioside antibody serology are important to establish the most likely pathogenic trigger in GBS patients. Larger studies are necessary to determine the association between arboviruses and GBS.

Although antiviral prophylaxis has reduced cytomegalovirus (CMV) DNAemia and disease in seronegative solid organ transplant (SOT) recipients (R-) receiving seropositive donor organs (D+), its impact on CMV transmission is uncertain. Transmission, defined as CMV antigenemia/CMV DNAemia and/or seroconversion by year 2, and associated demographic risk factors were studied retrospectively in 428 D+/R- and 429 D-/R- patients receiving a SOT at our center. The cumulative transmission incidence was higher for lung (90.5%) and liver recipients (85.1%) than heart (72.7%), kidney (63.9%), and pancreas (56.2%) recipients (p .001) and was significantly lower in living (50.1%) versus deceased donor (77.4%, p .001) kidney recipients despite identical antiviral prophylaxis. In multivariate analysis, only allograft type predicted transmission risk (HR [CI] lung 1.609 [1.159, 2.234] and liver 1.644 [1.209, 2.234] vs kidney). For 53 D+ donating to1 R- with adequate follow-up, 43 transmitted to all, three transmitted to none, and seven transmitted inconsistently with lungs and livers always transmitting but donor-matched heart, kidney or kidney-pancreas allografts sometimes not. Kidney pairs transmitted concordantly. CMV transmission risk is allograft-specific and unchanged despite antiviral prophylaxis. Tracking transmission and defining donor factors associated with transmission escape may provide novel opportunities for more targeted CMV prevention and improve outcome analysis in antiviral and vaccine trials.

The cytomegalovirus (CMV) viral terminase inhibitor letermovir is approved for prophylaxis of CMV infection and disease in adult CMV-seropositive allogeneic hematopoietic stem cell transplantation recipients. In a phase III trial (NCT02137772), letermovir significantly reduced clinically significant CMV infection (CS-CMVi) rate vs. placebo through Week 24 (primary end point) and Week 14 (secondary end point) post transplantation. Here, exposure-response relationships were investigated using efficacy and selected safety end points from the phase III trial to inform the proposed clinical dose. Post hoc exposure estimates were derived from a population pharmacokinetic model. No significant exposure dependencies were found for CS-CMVi through Week 24 or Week 14 among letermovir-treated participants. Evaluated covariates had no impact on exposure-efficacy relationships and letermovir plasma exposure did not affect time of CS-CMVi onset. There was no dependence between adverse event incidence and letermovir exposure. These results support current dosing recommendations in several countries and regions, including the United States and European Union.

Introduction: Observational studies suggest that low-dose valganciclovir prophylaxis (450 mg daily for normal renal function) is as effective as and perhaps safer than standard-dose valganciclovir (900 mg daily) in preventing CMV infection among kidney transplant recipients. However, this practice is not supported by current guidelines due to concerns for breakthrough infection from resistant CMV, mainly in high-risk CMV donor-seropositive/recipient-seronegative kidney transplant recipients. Standard-dose valganciclovir is costly and possibly associated with higher incidence of neutropenia and BKV DNAemia. Our institution adopted low-dose valganciclovir prophylaxis for intermediate-risk (seropositive) kidney transplant recipients in January 2018. Research Question: To analyze the efficacy (CMV DNAemia), safety (BK virus DNAemia, neutropenia, graft loss, and death), and cost savings associated with this change. Design: We retrospectively compared the above outcomes between CMV-seropositive kidney transplant recipients who received low-dose and standard-dose valganciclovir, transplanted within our institution, between 1/19/2014 and 7/15/2019, using propensity score-adjusted competing risk analyses. We also compared cost estimates between the two dosing regimens, for 3 months of prophylaxis, and for different percentage of patient-weeks with normal renal function, using the current average wholesale price of valganciclovir. Results: We studied 179 CMV-seropositive kidney transplant recipients, of whom 55 received low-dose and 124 standard-dose valganciclovir. The majority received nonlymphocyte depleting induction (basiliximab). Low-dose valganciclovir was at least as effective and safe as, and more cost-saving than standard-dose valganciclovir. Conclusion: This single-center study contributes to mounting evidence for future guidelines to be adjusted in favor of low-dose valganciclovir prophylaxis in CMV-seropositive kidney transplant recipients.

Background Postnatal infection with cytomegalovirus (CMV) in very-preterm and very-low-birth-weight infants, transmitted through breast milk (BM), is potentially associated with adverse outcomes. This study aimed to investigate the incidence and clinical significance of postnatal CMV infection in a tertiary neonatal intensive care unit. Methods Infants of CMV-seropositive mothers born in a neonatal intensive care unit in Melbourne, Australia, were observed for 14 weeks from birth in a prospective cohort study. Maternal BM and infant urine were tested weekly for CMV by culture and polymerase chain reaction, respectively. Clinical and laboratory data were collected and analyzed in relation to the infants' CMV infection status. Results Data from 65 infants of 56 CMV-seropositive mothers were available for analysis. Of these mothers, 88% (49/56) shed CMV in their BM. Of the 58 infants exposed to CMV-positive BM, 27 (47%) became urine polymerase chain reaction CMV-positive. There was no significant difference in gestational age, birth weight, incidence of bronchopulmonary dysplasia, or necrotizing enterocolitis between the CMV-positive and CMV-negative groups. However, CMV-positive infants had a longer length of hospital stay and more episodes of prolonged neutropenia. Of the CMV-positive infants, 30% (8/27) remained asymptomatic, 48% (13/27) had symptoms categorized as mild and 22% (6/27) as severe. Conclusions About half of preterm and very-low-birth-weight infants exposed to CMV-positive BM become infected, and a fifth develop significant clinical symptoms. Future studies should address the maternal and neonatal factors that determine the risk of mother-to-infant CMV transmission, as well as those leading to clinical deterioration and long-term sequelae.

OBJECTIVE Evaluation of relevance and feasibility of universal newborn congenital cytomegalovirus infection (cCMVI) screening in saliva. DESIGN Retrospective, population-based cohort study. SETTING Clamart, France, 2016-2020. POPULATION All neonates born consecutively in our level III maternity unit. METHODS CMV PCR in saliva for all neonates at birth, and, if positive, CMV PCR in urine to confirm or exclude cCMVI. Prospective and retrospective characterisation of maternal infections. ROC curve analysis to assess saliva PCR performances. Acceptability of screening among staff members evaluated by a survey. MAIN OUTCOME MEASURES Number of cCMVI neonates; number of expected and unexpected cCMVI. RESULTS Among 15 341 tested neonates, 63 had cCMVI (birth prevalence of 0.4%, 95% CI 0.3-0.5). In 50% of cases, maternal infection was a non-primary infection (NPI) during pregnancy. cCMVI was expected or suspected (maternal primary infection [PI], antenatal or neonatal signs) in 24/63 neonates (38%), and unexpected in 39/63 neonates (62%). The best CMV saliva threshold to predict cCMVI was 356 (2.55 log) copies/ml [95% CI 2.52 log-3.18 log], with an area under the ROC curve of 0.97. Over 90% of the 72 surveyed staff members reported that the screening was easy and quick. No parent refused the screening. CONCLUSIONS Universal screening for cCMVI with CMV PCR on saliva samples is feasible and highly acceptable to parents and healthcare providers. Over half (62%) of the cases had no prenatal/neonatal signs of cCMVI or a maternal history of CMV infection during pregnancy and would probably not have been diagnosed without universal screening. TWEETABLE ABSTRACT In 62% of congenital cytomegalovirus infection cases, only universal neonatal screening in saliva can detect infection.

Background Reactivation of viruses such as Epstein-Barr virus (EBV) and cytomegalovirus (CMV) are common in critically ill patients and have been described in patients with severe COVID-19. However, it is unclear whether these reactivations are associated with increased mortality and whether targeted treatments are beneficial. Methods In a retrospective single-center cohort study, patients with severe COVID-19 treated on our intensive care unit (ICU) were screened for EBV and CMV reactivation as detected by polymerase chain reaction. If present, patient characteristics, temporal connections to severe acute respiratory syndrome coronavirus 2 diagnosis and corticosteroid use, the use of targeted treatments as well as the course of disease and outcome were analyzed. As control group, non-COVID-19 patients with sepsis, treated within the same time period on our ICU, served as control group to compare incidences of viral reactivation. Results In 19 (16%) of 117 patients with severe COVID-19 treated on our ICU EBV reactivations were identified, comparable 18 (14%) of 126 in the non-COVID-19 control group ( P = .672). Similarly, in 11 (9%) of 117 patients CMV reactivations were identified, comparable to the 16 (13%) of 126 in the non-COVID-19 sepsis patients ( P = .296). The majority of EBV (58%) and CMV reactivations (55%) were detected in patients under systemic corticosteroid treatment. 7 (37%) of 19 patients with EBV reactivation survived the ICU stay, 2 (29%) of 7 patients with rituximab treatment and 5 (42%) of 12 patients without treatment ( P = .568). Five (50%) of 10 patients with CMV reactivation survived the ICU stay, 5 (83%) of 6 patients with ganciclovir treatment and 0 of 4 patients without treatment ( P = .048). Follow-up analysis in these patients showed that the initiation of treatment lead to decrease in viral load. Conclusion Critically ill patients with COVID-19 are at a high risk for EBV and CMV reactivations. Whether these reactivations are a cause of hyperinflammation and require targeted treatment remains uncertain. However, in patients with clinical deterioration or signs of hyperinflammation targeted treatment might be beneficial and warrants further studying.

Decreased cytomegalovirus (CMV)-specific immunity after hematopoietic cell transplantation (HCT) is associated with late CMV reactivation and increased mortality. Whether letermovir prophylaxis-associated reduction in viral exposure influences CMV-specific immune reconstitution is unknown. In a prospective cohort of allogeneic HCT recipients who received letermovir, we compared polyfunctional CMV-specific T-cell responses to those of controls who received PCR-guided preemptive therapy before the introduction of letermovir. Thirteen-color flow cytometry was used to assess T-cell responses at 3 months after HCT following stimulation with CMV immediate early-1 (IE-1) antigen and phosphoprotein 65 (pp65) antigens. Polyfunctionality was characterized by combinatorial polyfunctionality analysis of antigen-specific T-cell subsets. Use of letermovir and reduction of viral exposure were assessed for their association with CMV-specific T-cell immunity. Polyfunctional T-cell responses to IE-1 and pp65 were decreased in letermovir recipients and remained diminished after adjustment for donor CMV serostatus, absolute lymphocyte count, and steroid use. Among letermovir recipients, greater peak CMV DNAemia and increased viral shedding were associated with stronger CD8+ responses to pp65, whereas the CMV shedding rate was associated with greater CD4+ responses to IE-1. In summary, our study provided initial evidence that letermovir may delay CMV-specific cellular reconstitution, possibly related to decreased CMV antigen exposure. Evaluating T-cell polyfunctionality may identify patients at risk for late CMV infection after HCT.

To estimate graft function after kidney transplantation during active herpesviruses or superinfection Materials and methods. The study included 32 patients (men 21, women 11) with end-stage chronic kidney disease. The median age was 43 years. Cytomegalovirus (CMV), EpsteinBarr virus (EBV) and human herpes virus 6 (HHV-6) DNAs were screened by RT-PCR in the donor's transplant biopsy, and recipients peripheral blood and urine after kidney transplantation (KT) on 0, 1, 2, 4, 6, 12 months. Antiviral antibodies (IgM and IgG) were also screened by Enzyme-linked immunoassay analysis (ELISA) along with PCR. The 500 or less copies of viral DNA per 105 nuclear cells or 1 ml of urine was considered as low, more than 1000 copies high.On the first month after KT CMV DNA was detected in 50% of pts., EBV DNA in 40% and HHV-6 DNA in 33%. During first year after KT two or three viruses simultaneously were found in 12 recipients: CMV, EBV, and HHV-6 were detected in 5 recipients; CMV and EBV in 4 patients; CMV and HHV-6 in 2 pts; EBV and HHV-6 in 1 pt. Graft dysfunction was observed in 9 patients with a high concentration of viral DNA of one, two or three viruses simultaneously. An upraise of the concentration of virus DNA (CMV, EBV and HHV 6) was detected primarily in the urine, while in the blood its concentration was less than 500 cop or undetectable. Renal dysfunction was not observed on the background of low concentrations of viral DNA in urine and blood. However, with an increase of DNA concentration, an impaired graft function in 8 of 12 patients appeared. Low viral DNA level proved to be a background for another virus activation or bacterial/fungal superinfection.Graft dysfunction occurs at high viral DNA levels detection during mono-or superinfection. Low viral load can serve as a background for another virus activation and/or bacterial/fungal superinfection.Цель. Оценить функцию почечного трансплантата при сочетанной герпесвирусной инфекции. Материалы и методы. В исследование включены 32 пациента (мужчин 21, женщин 11) с хронической болезнью почек терминальной стадии (ХБПС5). Медиана возраста 43 года. Методом иммуноферментного анализа определяли противовирусные иммуноглобулины, методом полимеразной цепной реакции концентрацию ДНК цитомегаловируса, вируса Эпштейна-Барр (ВЭБ) и вируса герпеса человека 6-го типа (ВГЧ-6) в периферической крови, моче у реципиента до и через 1, 2, 4, 6 мес, 1 год после трансплантации аллогенной почки (ТАП) и в биоптате трансплантата донора. Концентрация ДНК менее 500 коп/105 клеток или в 1 мл мочи считалась низкой, более 1000 коп высокой. Результаты. В 1-й месяц после ТАП выявлена ДНК ЦМВ в 50% случаев, ДНК ВЭБ в 40% и ДНК ВГЧ-6 в 33%. У 12 реципиентов обнаружены одновременно маркеры двух или трех вирусов. Из них у 5 реципиентов ДНК ЦМВ, ВЭБ и ВГЧ-6, у 4 ДНК ЦМВ и ВЭБ, у 2 ДНК ЦМВ и ВГЧ-6, у 1 ВЭБ и ВГЧ-6. Повышение концентрации ДНК выявлялось прежде всего в моче, при этом в крови концентрация оставалась низкой или вообще не определялась. У 9 пациентов наблюдалось нарушение функции трансплантата при высокой концентрации ДНК одного или сразу двух/трех вирусов в моче. При низкой вирусной нагрузке как в моче, так и в крови не отмечалась дисфункция трансплантата, но у 8 из 12 реципиентов на фоне низкой концентрации одного вируса выявлялось повышение концентрации другого или присоединение бактериальной, грибковой инфекции. Заключение. Высокая концентрация ДНК в моче одного или нескольких герпесвирусов указывает на дисфункцию почечного трансплантата. Низкая вирусная нагрузка может служить фоном для присоединения другой вирусной и бактериальной инфекции.

Background The primary aim of this study was to analyze the survival of patients undergoing lung transplant (LT) with cytomegalovirus (CMV)-positive serologies at the time of transplantation, according to the presence of CMV events and according to the severity of these events. The secondary objective was to assess whether there are differences in the incidence of chronic lung allograft dysfunction (CLAD) according to the presence of these events. Methods This was an observational, single-center, retrospective study. The inclusion criterion for the study was having undergone LT at the Hospital Universitario 12 de Octubre from October 2008 to February 2019. Survival was calculated using the Kaplan-Meier method and compared using the log-rank test. The incidence of CLAD was compared using the χ2 test. Results Inclusion criteria were met by 239 LTs. In terms of survival, no difference was found between patients with and without CMV events (log-rank P = .52), with mean survival of 3223 ± 164 days and 3024 ± 146 days, respectively. Nor did we find a difference when stratifying patients according to no CMV events, infection, syndrome, and disease (log-rank P = .6). There was also no difference in the incidence of CLAD between patients with and without CMV events (P > .178). Conclusion In patients with positive CMV serology, the development of CMV events, including severe disease, does not seem to influence survival. The incidence of CLAD also is not increased by the presence of CMV events.

Immunosuppressive therapy reduces the risk for allograft rejection but leaves recipients susceptible to infections. Cytomegalovirus (CMV) is one of the most frequent causes for infection after transplantation and increases the risk for allograft rejection. As lung transplant recipients (LTRs) need to be under immunosuppression for life, they are a vulnerable group. To determine the potential association between the development of CMV infection and the calcineurin inhibitor (CNI) blood levels within previous 90 days, a retrospective review of LTRs was performed. Data from recipients who underwent a lung transplantation (LTx) at our center from January 2011 to December 2018 were collected. The studied recipients, after case/control matching, included 128 CMV-infection cases. The median time from the transplant to the first positive CMV viral load was 291.5 days. In our study, more patients were treated with tacrolimus (91.9%) than with cyclosporine (8.1%). Drug blood levels at selected timepoints showed no statistically significant difference between cases and controls. However, we found that CMV infection was more frequent in the donor-seropositive/recipient-seronegative group, interstitial lung disease (ILD) recipients, LTRs who underwent basiliximab induction, cyclosporine treated recipients, and LTRs with lymphopenia (at the time of CMV infection and 90 days before). In this review of LTRs, no association between the CNI blood level and CMV infection was seen, although other immunity-related factors were found to be influencing, i.e., basiliximab induction, cyclosporine treatment, and lymphopenia.

Abdominal pain in an immunocompromised patient represents a common clinical scenario that may have uncommon causes. Evaluation relies first on identifying the immunocompromise, whether due to congenital immunodeficiencies, malignancy, hematopoietic stem cell transplant, solid organ transplant, or human immunodeficiency virus/acquired immunodeficiency syndrome. Based on this determination, the emergency physician may then build a focused differential of pathophysiologic possibilities. Careful evaluation is necessary given the absence of classic physical examination findings, and liberal use of laboratory and cross-sectional imaging is prudent. Conservative evaluation and disposition of these high-risk patients is important to consider.

Background Citomegalovirus (CMV) infects approximately 1% of live newborns. About 10% of the infants affected by congenital CMV infection are symptomatic at birth and up to 60% of these infants will develop permanent neurological disabilities. Depending on gestational age (GA) at the time of infection, the involvement of central nervous system (CNS) can lead to malformations of cortical development, calcifications, periventricular white matter lesions and cysts, ventriculomegaly and cerebellar hypoplasia. Case presentation We report the MRI findings in a Caucasian female born at 32 weeks of post-menstrual age with post-birth diagnosis of congenital CMV infection showing an unusual and peculiar marked T2 hyperintensity of the inner part of olfactory bulbs in addition to the CMV related diffuse brain involvement. Despite the known extensively described fetal and neonatal Magnetic Resonance Imaging (MRI) findings in CMV infected fetuses and newborns, any in vivo MRI depiction of olfactory system damage have never been reported so far. Nevertheless, in murine studies CMV is known to infect the placenta during pregnancy showing particular tropism for neural stem cells of the olfactory system and previous neuropathologic study on CMV infected human fetal brains from 23 to 28 weeks of GA reported damage in the olfactory bulbs (OB) consisting in disseminated cytomegalic cells, inflammation, necrosis and neuronal and radial glial cell loss. Therefore, we assume an OB involvement and damage in congenital CMV infection. Conclusion To our knowledge this is the first in vivo MRI evidence of OB damage in a newborn with congenital CMV infection that may give new insights on CMV infection.

BACKGROUND Risk factors, virological parameters, and outcomes associated with HHV-6 viremia in high-risk donor CMV-seropositive and recipient CMV-seronegative (D+R-) liver transplant recipients in the current era are incompletely defined. METHODS The study population consisted of patients in the preemptive therapy (PET) arm of a randomized, controlled trial of PET versus valganciclovir prophylaxis for CMV prevention in D+R- liver transplant recipients. Weekly blood samples through 100 d in the PET group were tested for HHV-6 viremia using a real-time quantitative polymerase chain reaction. Assessments included virological characteristics and relationship with CMV, risk factors, and impact of HHV-6 viremia with outcomes through 12 mo posttransplant. RESULTS HHV-6 viremia at any level developed in 42% (40 of 96). Older patient age (P = 0.03), longer hospitalization (P = 0.015), and ICU stay at transplantation (P = 0.029) were significantly associated with high-grade viremia. Concurrent HHV-6 and CMV viremia was associated with earlier onset of HHV-6 viremia (P = 0.004), higher HHV-6 area under the curve (P = 0.043), and higher peak HHV-6 viral load (P = 0.006) versus HHV-6 viremia alone. High-grade viremia was independently associated with biopsy-proven rejection within 12 mo (P = 0.045) posttransplant. CONCLUSIONS Among D+R- liver transplant recipients receiving valganciclovir as PET, high-grade HHV-6 viremia was associated with increased age and critical illness in ICU at time of transplant and was independently associated with allograft rejection.

PURPOSEPatients with relapsed or refractory T-cell acute lymphoblastic leukemia (r/r T-ALL) have few options and poor prognosis. The aim was to assess donor-derived anti-CD7 chimeric antigen receptor (CAR) T-cell safety and efficacy in patients with r/r T-ALL.METHODSIn this single-center, phase I trial, we administered anti-CD7 CAR T cells, manufactured from either previous stem-cell transplantation donors or new donors, to patients with r/r T-ALL, in single infusions at doses of 5 × 105or 1 × 106(±30%) cells per kilogram of body weight. The primary end point was safety with efficacy secondary.RESULTSTwenty participants received infusions. Adverse events including cytokine release syndrome grade 1-2 occurred in 90% (n = 18) and grade 3-4 in 10% (n = 2), cytopenia grade 3-4 in 100% (n = 20), neurotoxicity grade 1-2 in 15% (n = 3), graft-versus-host disease grade 1-2 in 60% (n = 12), and viral activation grade 1-2 in 20% (n = 4). All adverse events were reversible, except in one patient who died through pulmonary hemorrhage related to fungal pneumonia, which occurred at 5.5 months, postinfusion. Ninety percent (n = 18) achieved complete remission with seven patients proceeding to stem-cell transplantation. At a median follow-up of 6.3 months (range, 4.0-9.2), 15 remained in remission. CAR T cells were still detectable in five of five patients assessed in month 6, postinfusion. Although patients' CD7-positive normal T cells were depleted, CD7-negative T cells expanded and likely alleviated treatment-related T-cell immunodeficiency.CONCLUSIONAmong 20 patients with r/r T-ALL enrolled in this trial, donor-derived CD7 CAR T cells exhibited efficient expansion and achieved a high complete remission rate with manageable safety profile. A multicenter, phase II trial of donor-derived CD7 CAR T cells is in progress ( NCT04689659 ).

Post-transplant cytomegalovirus (CMV) disease can be almost completely avoided by current infection control procedures. However, CMV reactivation occurs in more than half of patients, and some patients can develop clinically resistant CMV infections. Whether resistance is due to the host's immune status or a viral resistance mutation is challenging to confirm. Therefore, a prospective observational analysis of refractory CMV infection was conducted in 199 consecutive patients who received allogeneic hematopoietic stem cell transplantation at a single institution. Among them, 143 (72%) patients received anti-CMV drugs due to CMV reactivation, and only 17 (8.5%) exhibited refractory CMV infection. These patients had clinically refractory infection. However, viral genome analysis revealed that only one patient exhibited a mutation associated with the anti-CMV drug resistance. Clinical resistance was mainly correlated with host immune factors, and the incidence of resistance caused by gene mutations was low at the early stage after a transplantation.

CMV infection is a significant complication after solid organ transplantation. We used single cell TCR αβ sequencing to determine how memory inflation impacts clonality and diversity of the CMV-responsive CD8 and CD4 T cell repertoire in the first year after transplantation in human subjects. We observed CD8 T cell inflation but no changes in clonal diversity, indicating homeostatic stability in clones. In contrast, the CD4 repertoire was diverse and stable over time, with no evidence of CMV-responsive CD4 T cell expansion. We identified shared CDR3 TCR motifs among patients but no public CMV-specific TCRs. Temporal changes in clonality in response to transplantation and in the absence of detectable viral reactivation suggest changes in the repertoire immediately after transplantation followed by an expansion with stable clonal competition that may mediate protection.

PURPOSE: The higher prevalence of cognitive impairment/ dementia among cancer survivors is likely multifactorial. Since both exposures to cytomegalovirus (CMV) and inflammation are common among elderly cancer survivors, we evaluated their contribution towards dementia. METHODS: Data from 1387 cancer survivors and 7004 participants without cancer in the 2016 wave of the Health and Retirement Study (HRS) was used in this study. Two inflammatory biomarkers, C-reactive protein (CRP) and neutrophil–lymphocyte ratio (NLR), were used to create an inflammation score. We used survey logistic regression adjusted for survey design parameters. RESULTS: CMV seropositivity was not associated with cognitive impairment among cancer survivors (p = 0.2). In addition, inflammation was associated with elevated odds of cognitive impairment (OR = 2.2, 95% CI [1.2, 4.2]). Cancer survivors who were both CMV seropositive and had increased inflammation had the highest odds of cognitive impairment compared to those who were CMV seronegative and had low inflammation (OR = 3.8, 95% CI [1.5, 9.4]). The stratified analysis among cancer survivors showed this association was seen only among cancer survivors in whom the cancer was diagnosed within three years of measurement of inflammation score and CMV serostatus (OR = 18.5; 95% CI [6.1, 56.1]). CONCLUSION: The CMV seropositivity and high inflammation was associated with higher cognitive impairment among cancer survivors. The stronger associations seen among cancer survivors diagnosed within the last three years suggest that strategies to reduce CMV activation and inflammation during or immediately after cancer treatment may be important in reducing the prevalence of cognitive impairment/ dementia among cancer survivors.

Background The antiviral resistance of cytomegalovirus (CMV) infections is associated with mutations in the CMV UL54 and UL97 gene regions and is a serious problem in immunocompromised patients. However, the molecular epidemiology of UL54 and UL97 in Taiwan is unclear. Methods We conducted a retrospective study of patients with CMV infections between January and December 2016 in two tertiary hospitals, one regional hospital in Taiwan. CMV DNAemia was confirmed by elevated CMV DNA titers. Then the regions of the UL54 and UL97 mutations were amplified by PCR and sequenced. Results Of 729 patients with CMV syndrome, 112 CMV DNAemia patients were enrolled. Twelve novel variants in UL54 (P342S, S384F, K434R, S673F, T754M, R778H, C814S, M827I, G878E, S880L, E888K, and S976N) and one novel variant in UL97 (M615T) were discovered. UL97 antiviral resistance mutations (L595S, M460I, and M460V) were found in four patients (3.6%). In the drug resistance strains, the mutation events occurred after 83–150 days of therapy, and drug resistance was also observed in these patients. The following high frequency variants were observed: D605E in UL97 and A885T, N898D, V355A, N685S, and A688V in UL54. Conclusion The results demonstrate that the positive rate of CMV DNAemia was 15.3% (112/729) among the patients with clinical CMV infection symptoms. The proportion of antiviral resistance CMV strains within CMV DNAemia patients was 3.6%. With the information of polymorphism incidence in the UL54 and UL97 patients from our study, determination of the genetic profile of UL54 and UL97 among immunocompromised populations with refractory CMV infection is recommended.

Letermovir is a new antiviral drug approved for the prophylaxis of CMV infection in allogeneic stem cell transplants. The aim of the study was to assess the therapeutic efficacy of letermovir in difficult to treat CMV infections in lung transplant recipients. All lung transplant recipients between March 2018 and August 2020, who have been treated with letermovir for ganciclovir-resistant or refractory CMV infection were included in the study and analysed retrospectively. In total, 28 patients were identified. CMV disease was present in 15 patients (53.6%). In 23 patients (82.1%), rapid response was noticed, and CMV-viral load could be significantly decreased (>1 log10 ) after a median of 17 [14-27] days and cleared subsequently in all of these patients. Five patients (17.9%) were classified as non-responder. Thereof, development of a mutation of the CMV UL56 terminase (UL-56-Gen: C325Y) conferring letermovir resistance could be observed in three patients (60%). Common side effects were mild and mostly of gastrointestinal nature. Mild adjustments of the immunosuppressive drugs were mandatory upon treatment initiation with letermovir. In addition to other interventions, letermovir was effective in difficult to treat CMV infections in lung transplant recipients. However, in patients with treatment failure mutation conferring letermovir, resistance should be taken into account.

Human cytomegalovirus (HCMV) is an important opportunistic pathogen in allogeneic haematopoietic stem cell transplant (HSCT) recipients. High-throughput sequencing of target-enriched libraries was performed to characterise the diversity of HCMV strains present in this high-risk group. Forty-four HCMV-DNA-positive plasma specimens (median viral input load 321 IU per library) collected at defined time points from 23 HSCT recipients within 80 days of transplantation were sequenced. The genotype distribution for 12 hypervariable HCMV genes and the number of HCMV strains present (i.e. single- vs. multiple-strain infection) were determined for 29 samples from 16 recipients. Multiple-strain infection was observed in seven of these 16 recipients, and five of these seven recipients had the donor (D)/recipient (R) HCMV-serostatus combination D + R + . A very broad range of genotypes was detected, with an intrahost composition that was generally stable over time. Multiple-strain infection was not associated with particular virological or clinical features, such as altered levels or duration of antigenaemia, development of acute graft-versus-host disease or increased mortality. In conclusion, despite relatively low viral plasma loads, a high frequency of multiple-strain HCMV infection and a high strain complexity were demonstrated in systematically collected clinical samples from this cohort early after HSCT. However, robust evaluation of the pathogenic role of intrahost viral diversity and multiple-strain infection will require studies enrolling larger numbers of recipients. Supplementary Information The online version contains supplementary material available at 10.1007/s00430-021-00722-5.

Despite the development of efficient anti–human immunodeficiency virus-1 (HIV-1) therapy, HIV-1 associated pathogens remain a major clinical problem. Human cytomegalovirus (CMV) is among the most common HIV-1 copathogens and one of the main causes of persistent immune activation associated with dysregulation of the immune system, cerebrovascular and cardiovascular pathologies, and premature aging. Here, we report on the development of dual-targeted drugs with activity against both HIV-1 and CMV. We synthesized seven compounds that constitute conjugates of molecules that suppress both pathogens. We showed that all seven compounds exhibit low cytotoxicity and efficiently inhibited both viruses in cell lines. Furthermore, we chose a representative compound and demonstrated that it efficiently suppressed replication of HIV-1 and CMV in human lymphoid tissue ex vivo coinfected with both viruses. Further development of such compounds may lead to the development of dual-targeted anti-CMV/HIV-1 drugs.

Background Glioblastoma multiforme is the most invasive and lethal form of brain cancer with unclear etiology. Our study aimed to investigate the molecular prevalence of human cytomegalovirus (HCMV) and Epstein-Barr virus (EBV) infections in patients with glioblastoma multiforme (GBM). Methods This case-control study was conducted on 42 FFPE brain tumor samples from GBM patients and 42 brain autopsies from subjects without neurological disorders. The presence of EBV and HCMV DNA was determined, using PCR and nested-PCR assays, respectively. Results HCMV DNA was detected in 3 out of 42 (7.1%) of GBM samples and was absent from the control group (p = 0.07). Importantly, EBV DNA was detected in 9 out of 42 (21.4%) brain tissue specimens of GBM subjects, but again in none of the control group (p = 0.001). Conclusion Our findings indicate that infection with EBV is associated with GBM.

Objectives To analyze the impact of bilateral cochlear implantation (CI) on perceptual and linguistic development in hearing-impaired children with congenital Cytomegalovirus (CMV) infection. Patients and method A retrospective study was performed for the period 1991-2016 in a pediatric CI reference center. Closed Set Word (CSW) recognition scores, Categories of Auditory Performance (CAP) and linguistic level on the MT Lenormand scale (MTL) were compared between bilateral (Bi) and unilateral (Uni) groups 12, 24 and 36 months after first CI (CI-1). Results 84 patients with congenital CMV infection who underwent CI were included, in 2 groups: sequential or simultaneous bilateral CI (Bi) (N = 20), and unilateral CI (Uni) (N = 64). Twelve, 24 and 36 months after CI-1, CSW scores were 35.56%, 64.52% and 82.93% in Uni and 60.3%, 85% (P = 0.0084*), and 100% (P = 0.00085*) in Bi. CAP scores 12, 24 and 36 months after CI-1 were 2.57, 3.85 and 4.3 in Uni and 3.91 (P = 0.0068*), 5.00 (p = 0.029*) and 5.50 (P = 0.051*) in Bi. MTL linguistic level scores at 12, 24 and 36 months were 0.72, 1.25 and 1.65 in Uni, and 1.72, 3 (P = 0.033) and 3.11 (P = 0.045) in Bi. These significantly better scores in Bi at 24 and 36 months after CI-1 were also found on analysis of subgroups with no associated neurologic disorder (P = 0.046* and P = 0.032*), no associated psychiatric pathology (P = 0.0055* and P = 0.0073*), and no other associated disorder (P = 0.0018* and P = 0.035*), and for all subgroups together (P = 0.0036 and P = 0.037). Conclusion Bilateral CI is a faster way than unilateral CI for patients with congenital CMV infection to achieve structured fluent oral language. 50% of the series showed cerebral abnormalities on MRI, without difference between groups. This was not in itself predictive of poor progression of oral communication, unless associated with major neurologic disorder. Some children made little or no use of their CI in the medium term.

BACKGROUND: Ganciclovir is the mainstay of therapy for the prophylaxis and treatment of Cytomegalovirus. However, therapy with this antiviral agent is hindered by side effects such as myelosuppression, which often leads to therapy cessation. Underdosing, as an attempt to prevent side effects, can lead to drug resistance and therapy failure. Therapeutic drug monitoring (TDM) has been used to overcome these problems. The purpose of this narrative review was to give an overview of ganciclovir TDM, available assays, population pharmacokinetic models, and discuss the current knowledge gaps. METHODS: For this narrative review, a nonsystematic literature search was performed on the PubMed database in April 2021. The following search terms were used: ganciclovir, valganciclovir, pharmacokinetics, pharmacodynamics, population pharmacokinetics, therapeutic drug monitoring, bioassay, liquid chromatography coupled with tandem mass spectrometry, liquid chromatography, chromatography, spectrophotometry, and toxicity. In addition, the reference lists of the included articles were screened. RESULTS: The most common bioanalysis method identified was liquid chromatography coupled with tandem mass spectrometry. There are different models presenting ganciclovir IC50; however, establishing a pharmacokinetic/pharmacodynamic target for ganciclovir based on preclinical data is difficult because there are no studies combining dynamic drug exposure in relation to inhibition of viral replication. The data on ganciclovir TDM show large interindividual variability, indicating that TDM may play a role in modifying the dose to reduce toxicity and prevent treatment failure related to low concentrations. The main hurdle for implementing TDM is the lack of robust data to define a therapeutic window. CONCLUSIONS: Although the pharmacokinetics (PK) involved is relatively well-described, both the pharmacodynamics (PD) and pharmacokinetic/pharmacodynamic relationship are not. This is because the studies conducted to date have mainly focused on estimating ganciclovir exposure, and owing to the limited therapeutic options for CMV infections, future studies on ganciclovir are warranted. ispartof: THERAPEUTIC DRUG MONITORING vol:44 issue:1 pages:138-147 ispartof: location:United States status: published

Purpose of review Cytomegalovirus (CMV) infection and disease are well described in the setting of secondary immunodeficiency. Less is known about CMV in the context of primary immunodeficiencies (PIDs), where inborn errors in one or more arms of the immune system result in variable degrees of CMV susceptibility. Recent findings PID presents unique challenges in the diagnosis and management of CMV disease. The clinical presentation of CMV in PID is often severe, accelerated by underlying immune dysregulation and iatrogenic immunosuppression. Here we describe the clinical significance of CMV infection in PID, the key components of immune defence against CMV and how these are affected in specific PIDs. CMV disease is under-recognized as a complication of common variable immunodeficiency (CVID). High rates of CMV end-organ disease, mortality, development of CMV resistance and prolonged antiviral use have been observed in individuals with CVID. Summary We recommend that clinicians tailor their approach to the individual based on their underlying immune deficit and maintain a high index of suspicion and low threshold for treatment. More research is required to improve stratification of CMV risk in PID, develop new diagnostic tools and manage end-organ disease in this cohort.

Cytomegalovirus (CMV) is the most frequent cause of congenital infection all over the world. Its prevalence ranges from 0.2 to 2.2%. Transmission from children to their pregnant mothers is a well-known risk factor, particularly if they attend a childcare centre. This study aims to compare the prevalence of CMV congenital infection (CMV_CI) in Portugal (Lisbon) between two studies, performed respectively in 2019 and 2020. In the 2019 study, performed in two hospitals, we found a 0.67% CMV_CI prevalence, using a pool strategy previously tested with saliva samples. In the 2020 study, using the same pool approach in four hospitals (the previous and two additional), and based on 1277 samples, the prevalence was 0.078%.Conclusion: The close temporal coincidence with COVID-19 lockdown suggests that these measures may have had a significant impact on this reduction, although other explanations cannot be ruled-out. What is Known: • Cytomegalovirus is the leading cause of congenital infection. • Behavioural measures decrease cytomegalovirus seroconversion in pregnant women. What is New: • From 2019 to 2020 there was a significant reduction in the prevalence of congenital CMV infection. info:eu-repo/semantics/publishedVersion

Objective To evaluate the correlation of neonatal parameters with late-onset sensorineural hearing loss (SNHL) and vestibular dysfunction in individuals with congenital cytomegalovirus (cCMV) infection using the National Health Insurance Research Database (NHIRD) in Taiwan. Design Retrospective cohort study. Setting The whole Taiwanese population. Participants Patients with related diagnostic codes and examinations in their records were regarded as having cCMV infection. Each subject in that group was matched to 10 control individuals with noncongenital CMV infection on the basis of several neonatal parameters, including low gestational age, low birth weight, low Apgar score, maternal history of CMV infection and prolonged cCMV infection. A total of 5893 and 58 930 participants were enrolled in the study and control groups, respectively. Main outcome measures The main outcomes were the development of SNHL and the development of vestibular dysfunction within one year after birth as reflected by diagnostic codes and specific examinations. Cox proportional hazard regression was used to calculate the adjusted hazard ratio (HR) and 95% confidence interval (CI) of each primary outcome between the two groups. Results Overall, 109 and 397 episodes of SNHL developed in the study group and the control group, respectively, and the study group demonstrated a significantly higher incidence of SNHL (adjusted HR: 2.56; 95% CI: 2.07-3.18). In addition, similar incidence rates of vestibular dysfunction were found in the study group and the control group, with 7 and 90 events, respectively (adjusted HR: 0.77; 95% CI: 0.36-1.67). In subgroup analyses, a higher incidence of SNHL was correlated with lower gestational age (GA) (adjusted HR: 2.09; 95% CI: 1.29-3.39), lower birth weight (BW) (adjusted HR: 2.05; 95% CI: 1.28-3.30) and prolonged cCMV infection (adjusted HR: 3.92; 95% CI: 1.95-7.88). Conclusions Low GA, low BW and a long disease course are significantly correlated with late-onset SNHL in cCMV infection.

Adoptive transfer of in vitro expanded, chimeric antigen receptor (CAR)-redirected CD19-specific T cells can induce dramatic disease regression in patients with leukemia and lymphomas. However, the full potential of this emerging modality is hampered in some cancer settings by a significant rate of therapeutic failure arising from the attenuated engraftment and persistence of CAR-redirected T cells, and tumor relapse following adoptive transfer. Here, we discuss an advanced strategy that facilitates post-infusion in vivo boosting of CAR T cells via CMV vaccination, to mediate durable remission of B cell malignancies by engrafting a CAR molecule onto a CMV-specific T cell. We also discuss a feasible and unique platform for the generation of the CMV-CD19CAR T cells for clinical application. This new approach would overcome multiple challenges in current CAR T cell technology including: short T cell persistence, limited duration of response, and inability to re-stimulate T cells after relapse or persistent disease.

AIM To evaluate and describe results of aetiological investigations offered to a population level cohort of babies who had confirmed permanent hearing loss after they either (i) failed universal neonatal hearing screening or (ii) passed newborn screening but were detected with a permanent hearing loss in early childhood. METHODS Descriptive analysis of results of investigations offered to neonates and young children in whom permanent hearing loss was detected as part of a statewide newborn hearing screening programme. A total of 306 285 newborns were screened between 2013 and 2017. The failed screening results were confirmed by a diagnostic audiological assessment battery. Medical evaluation for the identification of the cause of the hearing loss was performed by a paediatrician or otolaryngologist, investigations were ordered using a stepwise approach, and aetiology was assigned using a coding scheme. RESULTS Permanent hearing loss was confirmed in 967 children (0.3%). Data were available for 873. An aetiological factor was identified or presumed in 61.3% of cases. Genetic causes were present in 26.8% and structural causes were present in 24.9% of cases. Congenital cytomegalovirus was present in 4.4%. CONCLUSIONS Use of a coding scheme is feasible at a population level and allows collation of data from multiple sites and will allow outcome mapping and service planning.