Maribavir for treatment of cytomegalovirus infection in a liver-transplanted patient.

Cytomegalovirus infection (CMV) can be fatal for organ transplant recipients as shown in this case report. Maribavir is a recently approved drug, which can be used for therapy-refractory CMV infection or when other treatment options cannot be used. The patient in this case report was a CMV-infected liver transplant recipient, who developed a severe erythema and high CMV DNA during valganciclovir therapy. Toxic epidermal necrolysis was suspected. The patient was treated with maribavir, and both CMV DNA and the skin normalised. This case illustrates that maribavir is a useful alternative to other antiviral drugs for CMV infection.

Comparison of Whole Blood and Plasma for Monitoring Cytomegalovirus and Epstein-Barr Virus.

Monitoring Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infection after transplantation is recommended to enable preemptive therapy. However, the most suitable sample type remains unclear. Patients who underwent hematopoietic stem cell or liver transplantation were included in this study. Viral loads in sequential whole-blood and plasma samples were retrospectively analyzed. EBV DNA was detected more frequently in whole blood (55%) than in plasma (18%). The detection rate of CMV DNA was similar between the two sample types. The correlation of viral loads between the two sample types were 0.515 and 0.688 for EBV and CMV, respectively. Among paired samples in which EBV DNA was detected in whole blood, the plasma EBV detection rate was significantly higher in patients who underwent hematopoietic stem cell transplantation than in those who underwent liver transplantation. The viral DNA load in whole blood and plasma showed similar trends. The EBV detection rate was higher in whole blood, and a high correlation was observed between CMV DNA loads and whole blood and plasma. These results indicate that whole blood is more sensitive for monitoring both EBV and CMV, whereas plasma is a potential alternative sample for monitoring CMV.

Real-life use of letermovir prophylaxis for cytomegalovirus in heart transplant recipients.

INTRODUCTION: Cytomegalovirus (CMV) remains the predominant opportunistic infection following solid organ transplantation (SOT). While valganciclovir is the drug of choice for CMV prophylaxis, its utility can be compromised due to the risk of cytopenia. Letermovir, a novel agent approved for CMV prophylaxis in allogeneic hematopoietic stem cell transplant recipients and high-risk kidney transplant recipients, exhibits reduced toxicity. This study aims to present the practical application of letermovir as both primary and secondary prophylaxis against CMV in heart transplant recipients (HTR). METHODS: In this observational, retrospective, single-center study, we included all consecutive adult HTRs from June 2020 to January 2022 who were administered letermovir for CMV prophylaxis. We documented instances of CMV breakthrough infections, side effects related to letermovir, changes in neutropenia following the switch from valganciclovir to letermovir, and any drug interactions with the immunosuppressive regimen. RESULTS: The study comprised 10 patients: two received primary prophylaxis with letermovir due to a high risk of CMV infection (donor-positive, recipient-negative serostatus), and eight received it as secondary prophylaxis following a CMV infection. The median duration of letermovir administration was 8 months (range 3-12 months). No CMV breakthrough infections were reported while on prophylaxis. However, three patients experienced CMV breakthrough infections after discontinuing letermovir prophylaxis (30%). No significant side effects were observed, although one patient reported digestive intolerance. Among the nine patients on tacrolimus, six needed reduced doses after switching to letermovir. CONCLUSION: This real-life study appears to support the effectiveness of letermovir prophylaxis in HTR. Nonetheless, the risk of CMV infection post-treatment cessation is notable. Further drug monitoring and research on the efficacy of letermovir for CMV prophylaxis in SOT patients is warranted.

Non-Detection of HCMV Total Genomic DNA in Human Glioma Cells Genome.

AIM: To demonstrate if the human cytomegalovirus (HCMV) genome, that is involved in the pathogenesis of gliomas, is part of the genomic DNA of glioma cells or not. MATERIAL AND METHODS: The study included U87MG glioblastoma cell culture and tumor samples from glioma patients. The genomic DNA of tumor samples and U87MG cells were extracted and real-time quantitative PCR was used to assess the presence of the human cytomegalovirus genomic DNA. RESULTS: Consequently, HCMV positivity was not detected in the tumor and cell line genomic DNA under the aforementioned experimental conditions. CONCLUSION: We found that the genomic DNA of all the samples was negative for HCMV genomic DNA. Thus, HCMV could not be detected in human glioma tumors and we put forward that HCMV genomic DNA was not incorporated into the genomic DNA of glioma cells. Thus, total viral DNA is not involved in the pathogenesis of glioma; however, small viral particles or specific genes might be incorporated into the genomic DNA of glioma cells, leading to cancer development. This prompts further studies for verification.

OUTCOMES OF INFECTIOUS PANUVEITIS ASSOCIATED WITH SIMULTANEOUS MULTI-POSITIVE OCULAR FLUID POLYMERASE CHAIN REACTION.

PURPOSE: To evaluate features of infectious panuveitis associated with multiple pathogens detected by ocular fluid sampling. METHODS: Single-center, retrospective, consecutive case series of patients with aqueous/vitreous polymerase chain reaction testing with >1 positive result in a single sample from 2001 to 2021. RESULTS: Of 1,588 polymerase chain reaction samples, 28 (1.76%) were positive for two pathogens. Most common pathogens were cytomegalovirus (n = 16, 57.1%) and Epstein-Barr virus (n = 13, 46.4%), followed by varicella zoster virus (n = 8, 28.6%), Toxoplasma gondii (n = 6, 21.4%), herpes simplex virus 2 (n = 6, 21.4%), herpes simplex virus 1 (n = 6, 21.4%), and Toxocara (n = 1, 3.6%). Mean initial and final visual acuity (logarithm of the minimum angle of resolution) were 1.3 ± 0.9 (Snellen ∼20/400) and 1.3 ± 1.1 (Snellen ∼20/400), respectively. Cytomegalovirus-positive eyes (n = 16, 61.5%) had a mean final visual acuity of 0.94 ± 1.1 (Snellen ∼20/175), whereas cytomegalovirus-negative eyes (n = 10, 38%) had a final visual acuity of 1.82 ± 1.0 (Snellen ∼20/1,320) ( P < 0.05). Main clinical features included intraocular inflammation (100%), retinal whitening (84.6%), immunosuppression (65.4%), retinal hemorrhage (38.5%), and retinal detachment (34.6%). CONCLUSION: Cytomegalovirus or Epstein-Barr virus were common unique pathogens identified in multi-PCR-positive samples. Most patients with co-infection were immunosuppressed with a high rate of retinal detachment and poor final visual acuity. Cytomegalovirus-positive eyes had better visual outcomes compared with cytomegalovirus-negative eyes.

Rethinking human cytomegalovirus latency reservoir.

Human cytomegalovirus (HCMV) is a prevalent herpesvirus, infecting the majority of the human population. Like other herpesviruses, it causes lifelong infection through the establishment of latency. Although reactivation from latency can cause significant morbidity and mortality in immunocompromised hosts, our understanding of HCMV latency and how it is maintained remains limited. Here, we discuss the characterized latency reservoir in hematopoietic cells in the bone marrow and the gaps in our knowledge of mechanisms that facilitate HCMV genome maintenance in dividing cells. We further review clinical evidence that strongly suggests the tissue origin of HCMV reactivation, and we outline similarities to murine cytomegalovirus where latency in tissue-resident cells has been demonstrated. Overall, we think these observations call for a rethinking of HCMV latency reservoirs and point to potential sources of HCMV latency that reside in tissues.

Expanded targeted screening for congenital cytomegalovirus infection.

An early diagnosis and intervention for congenital cytomegalovirus infection can reduce long-term disability; however, the introduction of universal neonatal screening has been controversial worldwide. The present study clarified the outcome of a targeted screening protocol for detecting congenital cytomegalovirus infection based on suggestive perinatal conditions. In addition, the positive rate was compared to those from the reported studies and the validity of the targeted screening criteria was discussed. A total of 2121 newborn infants were admitted to our hospital between October 2018 and October 2021. Cytomegalovirus DNA was examined by the isothermal nucleic acid amplification method for urine samples from newborns with any of the following: microcephaly, abnormal ultrasound findings in the brain and visceral organs, repeated failure in neonatal hearing screening, suspicious maternal cytomegalovirus infection during pregnancy, and other abnormal findings suggestive of congenital cytomegalovirus infection. Among 2121 newborns, 102 (4.8%) were subject to the urine cytomegalovirus DNA test based on the abovementioned criteria. Of them, three were cytomegalovirus DNA-positive. According to the protocol, the cytomegalovirus DNA-positive rates were 0.14% among the total enrollment of 2121 newborns and 2.9% (3/102) among the targeted newborns. This protocol may overlook congenital cytomegalovirus infection that is asymptomatic or exhibits inapparent clinical manifestations only at birth; however, it is feasible and helps lead to the diagnosis of congenital cytomegalovirus infection that may otherwise be overlooked.

Risk Factors for Hearing Loss at Birth in Newborns With Congenital Cytomegalovirus Infection.

Importance: With a prevalence between 0.2% and 6.1% of all live births, congenital cytomegalovirus (cCMV) infection is a major cause of congenital nonhereditary sensorineural hearing loss. Despite the large amount of research on cCMV-related hearing loss, it is still unclear which newborns are at risk of hearing loss. Objective: To identify independent risk factors for cCMV-related congenital hearing loss and predictors of hearing loss severity at birth. Design, Setting, and Participants: This cross-sectional study of newborns with cCMV infection used data included in the Flemish CMV registry that was collected from 6 secondary and tertiary hospitals in Flanders, Belgium, over 15 years (January 1, 2007, to February 7, 2022). Data were analyzed March 3 to October 19, 2022. Patients were included in the study after confirmed diagnosis of cCMV infection and known hearing status at birth. Patients who presented with other possible causes of sensorineural hearing loss were excluded. Main Outcomes and Measures: Primary outcome was hearing status at birth. Clinical, neurological, and laboratory findings along with the timing of seroconversion and blood viral load were separately considered as risk factors. Binary logistic regression was performed to identify independent risk factors for congenital hearing loss in newborns with cCMV. Effect sizes were measured using Hedges g, odds ratio, or Cramer V. Results: Of the 1033 newborns included in the study (553 of 1024 [54.0%] boys), 416 (40.3%) were diagnosed with symptomatic cCMV infection and 617 (59.7%) with asymptomatic cCMV infection. A total of 15.4% of the patients (n = 159) presented with congenital hearing loss; half of them (n = 80 [50.3%]) had isolated hearing loss. The regression model revealed 3 independent risk factors for congenital hearing loss: petechiae at birth (adjusted odds ratio [aOR], 6.7; 95% CI, 1.9-23.9), periventricular cysts on magnetic resonance imaging (MRI; aOR, 4.6; 95% CI, 1.5-14.1), and seroconversion in the first trimester (aOR, 3.1; 95% CI, 1.1-9.3). Lower viral loads were seen in patients with normal hearing compared with those with congenital hearing loss (median [IQR] viral load, 447.0 [39.3-2345.8] copies per milliliter of sample [copies/mL] vs 1349.5 [234.3-14 393.0] copies/mL; median difference, -397.0 [95% CI, -5058.0 to 174.0] copies/mL). Conclusions and Relevance: Findings of this cross-sectional study suggest that newborns with cCMV infection and petechiae at birth, periventricular cysts on MRI, or a seroconversion in the first trimester had a higher risk of congenital hearing loss. Clinicians may use these risk factors to counsel parents in the prenatal and postnatal periods about the risk of congenital hearing loss. Moreover, linking clinical features to hearing loss may provide new insights into the pathogenesis of cCMV-related hearing loss. The importance of viral load as a risk factor for congenital hearing loss remains unclear.

Cytopathological analysis of bronchoalveolar lavage fluid in patients with and without HIV infection.

BACKGROUND: Human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) infection can lead to a broad spectrum of lung diseases, including infectious diseases and tumors. Recently, with the wide application of bronchoscopes and cytopathology of bronchoalveolar lavage fluid (BALF), the diagnostic efficiency of lung diseases has improved. The present study focuses on analyzing the cytopathologic characteristics of BALF in the diagnosis of HIV/AIDS-related lung disease and comparing the lung disease spectrum between HIV and HIV-uninfected patients. METHODS: BALF specimens were collected from 2211 patients. Using ThinPrep liquid-based technology, the cytologic smears were prepared by staining with Hematoxylin and Eosin (HE), Gomori's methenamine silver (GMS), and Periodic Acid Schiff (PAS), acid-fast and immunocytochemical (ICC) staining. Real-time PCR was used to detect cytomegalovirus (CMV) and Mycobacterium tuberculosis (M. tuberculosis) in the remaining BALF. PCR-reverse dot hybridization was used for mycobacterial species identification. RESULTS: From the 2211 BALF specimens, 1768 (79.96%) were specimens from HIV-infected patients, and 443 (20.04%) were speciments from HIV-uninfected patients. The HIV-infected patients with a median age of 38.5 ± 11.3 years were markedly younger than the HIV-uninfected patients (52.9 ± 14.9 years) (p < 0.01). We found that 1635 (92.5%) HIV-infected patients were males, showing a prominently higher proportion than those without HIV infection (71.1%) (p < 0.01). Meanwhile, 1045 specific lesions were found in 1768 HIV-infected patients (59.1%), including 1034 cases of infectious diseases and 11 neoplastic lesions, also exhibiting a distinctly higher proportion compared to the HIV-uninfected patients (12.2%) (p < 0.001). For the HIV-infected group, a distinctly higher proportion of single infection lesions (724/1768, 41%) was noted than the HIV-uninfected group (14/443, 3.2%) (p < 0.001). Among single infection lesions, the most common was Cytomegalovirus(CMV) infection (20.9%) for the HIV-infected group, followed by Pneumocystis jiroveci(PJ) (13.0%), Fungal (3.5%), and Mycobacterial infections (3.4%), of which M. tuberculosis infection accounted for 3.1%. Double infections (300/1768, 17.0%) and Triple infections (10/1768, 0.6%) were found only among the patients with HIV. The malignancies among HIV-infected patients included adenocarcinomas (0.22%), small cell carcinomas (0.2%), squamous cell carcinomas (0.1%), and diffuse large B-cell lymphoma (0.1%). HIV-infected patients exhibited a significantly lower incidence of neoplastic lesions (0.6% vs. 9.0%) than the HIV-uninfected patients (p < 0.001). CONCLUSIONS: There was a significant difference in the spectrum of lung diseases between HIV-infected and non-infected patients diagnosed by BALF cytopathology.

Optimal duration of antiviral treatment in patients with gastrointestinal cytomegalovirus disease at a low and high risk of relapse.

ABSTRACT: We evaluated the association between antiviral treatment duration and relapse of gastrointestinal (GI) cytomegalovirus (CMV) disease by analyzing the risk factors for relapse.Patients who were diagnosed with GI CMV disease at a tertiary hospital from January 2008 to April 2019 were retrospectively enrolled. Patients with relapsed disease were those with a recurrence of GI CMV disease at least 4 weeks after the initial antiviral treatment.Of 238 participants, including 145 (51.9%) with upper and 93 (48.1%) with lower GI CMV diseases, 27 (11.3%) had experienced relapses. The difference in antiviral treatment duration between the relapsed and nonrelapsed GI CMV groups was not significant (median days, 21.0 vs 17.0, P = .13). Multivariate analysis revealed that hematologic malignancy (odds ratio, 3.73; P = .026) and ulcerative colitis (odds ratio, 4.61; P = .003) were independent risk factors for relapse. Participants with at least one of these risk factors and those with no independent risk factors were classified under the high- (relapse rate, 25.9%) and low-risk of relapse groups (relapse rate, 6.7%), respectively. Accordingly, we further stratified 180 (75.6%) and 58 (24.4%) participants under the low- and high-risk of relapse groups, respectively. There was no significant difference in relapse rates between the high- and low-risk groups according to antiviral treatment duration.Approximately 10% of the participants experienced relapses after antiviral treatment, with hematologic malignancy and ulcerative colitis featuring as risk factors. Therefore, prolonged antiviral treatment might not be helpful in preventing GI CMV disease relapse.

Risk factors and outcomes of cytomegalovirus infection in children post cord blood transplantation with focus on impact of graft-versus-host disease and immunosuppressants.

Cytomegalovirus (CMV) infection remains an important cause of morbidity and mortality post cord blood transplantation (CBT). It has been suggested that the graft-versus-host disease (GVHD) and immunosuppressants have an impact on CMV infection. This study evaluated the incidence, outcomes, and risk factors of CMV infection, while focusing on GVHD and the use of immunosuppressants, in 103 children who had received CBT. Among the patients, 92.2% were positive for CMV serology, while CMV antigenemia was observed in 68.9% and CMV disease developed in 26.2%. CMV enterocolitis was the most common, followed by retinitis and pneumonia. Patients with positive CMV serology and grade II to IV GVHD were independently associated with CMV antigenemia. Recurrent CMV antigenemia was observed significantly more frequently in patients with extensive chronic GVHD. Patients with CMV disease showed significantly worse overall survival, relapse-free survival, and non-relapse mortality than those without CMV disease. In conclusion, CMV infection is common post-CBT in countries with a high rate of CMV seropositivity in the general population and is related to worse outcomes. GVHD severity is associated with the development and recurrence of CMV infection. Thus, efforts need to be made to prevent CMV infection in children post-CBT.

Leaning towards Cytomegalovirus serological screening in pregnancy to prevent congenital infection: a cost-effectiveness perspective.

OBJECTIVE: To assess the cost-effectiveness of prenatal detection of congenital cytomegalovirus (cCMV) following maternal primary infection in the first trimester within standard pregnancy follow-up or involving population-based screening (serological testing at 7 and 12 weeks of gestation), with or without secondary prevention (valaciclovir) in maternal CMV primary infection. DESIGN: Cost-effectiveness study from the perspective of the French national health insurance system. SETTING: Cost-effectiveness based on previously published probability estimates and associated plausible ranges hypothetical population of 1,000,000 pregnant women. POPULATION: Hypothetical population of 1,000,000 pregnant women. METHODS: Cost-effectiveness of detecting fetal cCMV in terms of the total direct medical costs involved and associated expected outcomes. MAIN OUTCOME MEASURES: Detection rates and clinical outcomes at birth. RESULTS: Moving to a population-based approach for targeting fetal CMV infections would generate high monetary and organizational costs while increasing detection rates from 15% to 94%. This resource allocation would help implementing horizontal equity according to which individuals with similar medical needs should be treated equally. Secondary prevention with valaciclovir had a significant effect on maternal-fetal CMV transmission and clinical outcomes in newborns, with a 58% decrease of severely infected newborns for a 3.5% additional total costs. Accounting for women decision-making (amniocentesis uptake and termination of pregnancy in severe cases) did not impact the cost-effectiveness results. CONCLUSIONS: These findings could fuel thinking on the opportunity of developing clinical guidelines to rule identification of cCMV infection and administration of in-utero treatment. These findings could fuel the development of clinical guidelines on the identification of congenital CMV infection and the administration of treatment in utero. TWEETABLE ABSTRACT: CMV serological screening followed by valaciclovir prevention may prevent 58% to 71% of severe cCMV cases for 38 € per pregnancy.

Universal newborn screening for congenital cytomegalovirus infection: feasibility and relevance in a French type-III maternity cohort.

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.

Infant Botulism: Checklist for Timely Clinical Diagnosis and New Possible Risk Factors Originated from a Case Report and Literature Review.

Infant botulism is a rare and underdiagnosed disease caused by BoNT-producing clostridia that can temporarily colonize the intestinal lumen of infants less than one year of age. The diagnosis may be challenging because of its rareness, especially in patients showing atypical presentations or concomitant coinfections. In this paper, we report the first infant botulism case associated with Cytomegalovirus coinfection and transient hypogammaglobulinemia and discuss the meaning of these associations in terms of risk factors. Intending to help physicians perform the diagnosis, we also propose a practical clinical and diagnostic criteria checklist based on the revision of the literature.

Production- and Purification-Relevant Properties of Human and Murine Cytomegalovirus.

There is a large unmet need for a prophylactic vaccine against human cytomegalovirus (HCMV) to combat the ubiquitous infection that is ongoing with this pathogen. A vaccination against HCMV could protect immunocompromised patients and prevent birth defects caused by congenital HCMV infections. Moreover, cytomegalovirus (CMV) has a number of features that make it a very interesting vector platform for gene therapy. In both cases, preparation of a highly purified virus is a prerequisite for safe and effective application. Murine CMV (MCMV) is by far the most studied model for HCMV infections with regard to the principles that govern the immune surveillance of CMVs. Knowledge transfer from MCMV and mice to HCMV and humans could be facilitated by better understanding and characterization of the biological and biophysical properties of both viruses. We carried out a detailed investigation of HCMV and MCMV growth kinetics as well as stability under the influence of clarification and different storage conditions. Further, we investigated the possibilities to concentrate and purify both viruses by ultracentrifugation and ion-exchange chromatography. Defective enveloped particles were not separately analyzed; however, the behavior of exosomes was examined during all experiments. The effectiveness of procedures was monitored using CCID50 assay, Nanoparticle tracking analysis, ELISA for host cell proteins, and quantitative PCR for host cell DNA. MCMV generally proved to be more robust in handling. Despite its greater sensitivity, HCMV was efficiently (100% recovery) purified and concentrated by anion-exchange chromatography using QA monolithic support. The majority of the host genomic DNA as well as most of the host cell proteins were removed by this procedure.

Current practices of management of maternal and congenital Cytomegalovirus infection during pregnancy after a maternal primary infection occurring in first trimester of pregnancy: Systematic review.

INTRODUCTION: Congenital CMV infection is the first worldwide cause of congenital viral infection but systematic screening of pregnant women and newborns for CMV is still debated in many countries. OBJECTIVES: This systematic review aims to provide the state of the art on current practices concerning management of maternal and congenital CMV infection during pregnancy, after maternal primary infection (PI) in first trimester of pregnancy. DATA SOURCES: Electronically searches on databases and hand searches in grey literature. STUDY ELIGIBILITY CRITERIA AND PARTICIPANTS: Primary outcome was listing biological, imaging, and therapeutic management interventions in two distinct populations: population 1 are pregnant women with PI, before or without amniocentesis; population 2 are pregnant women with congenitally infected fetuses (after positive amniocentesis). Secondary outcome was pregnancy outcome in population 2. RESULTS: Out of 4,134 studies identified, a total of 31 studies were analyzed, with 3,325 pregnant women in population 1 and 1,021 pregnant women in population 2, from 7 countries (Belgium, France, Germany, Israel, Italy, Spain and USA). In population 1, ultrasound (US) examination frequency was 0.75/month, amniocentesis in 82% cases, maternal viremia in 14% and preventive treatment with hyperimmune globulins (HIG) or valaciclovir in respectively 14% and 4% women. In population 2, US examination frequency was 1.5/month, magnetic resonance imaging (MRI) in 44% cases at 32 weeks gestation (WG), fetal blood sampling (FBS) in 24% at 28 WG, and curative treatment with HIG or valaciclovir in respectively 9% and 8% patients. CONCLUSIONS: This systematic review illustrates management of maternal and congenital CMV during pregnancy in published and non-published literature, in absence of international consensus. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019124342.

Frequency and natural course of congenital cytomegalovirus-associated hearing loss in children.

BACKGROUND: Congenital cytomegalovirus-associated hearing loss (cCMV-associated HL) is a common cause of congenital or early-onset deafness. Although cCMV infection has been reported to lead to various types of HL, the natural course of cCMV-associated HL over a long period is not yet known. OBJECTIVES: To investigate the clinical phenotype of cCMV-associated HL in the largest study to date. METHODS: Thirty-one CMV-positive children, diagnosed by examining CMV DNA extracted from their dried umbilical cords retrospectively, were divided into unilateral and bilateral HL groups, and their hearing ability was evaluated using pure-tone audiometry and auditory steady-state response over time. RESULTS: Thirteen patients (41.9%) had unilateral HL and 18 (58.1%) had bilateral HL. In most cases of unilateral cCMV-associated HL, the ear with better hearing maintained a normal hearing threshold. Notably, in most cases of both unilateral and bilateral HL, the ear with worse hearing ultimately showed severe to profound HL. CONCLUSION: Our findings revealed that the natural course of cCMV-associated HL was different between the cases of unilateral and bilateral HL, as well as between the ears with better or worse hearing in all cases. These findings indicate that accurate diagnosis could enable proper follow-up and management of cCMV-associated HL in children.

How Immunosenescence and Inflammaging May Contribute to Hyperinflammatory Syndrome in COVID-19.

Aging is characterized by the dynamic remodeling of the immune system designated "immunosenescence," and is associated with altered hematopoiesis, thymic involution, and lifelong immune stimulation by multitudinous chronic stressors, including the cytomegalovirus (CMV). Such alterations may contribute to a lowered proportion of naïve T-cells and to reduced diversity of the T-cell repertoire. In the peripheral circulation, a shift occurs towards accumulations of T and B-cell populations with memory phenotypes, and to accumulation of putatively senescent and exhausted immune cells. The aging-related accumulations of functionally exhausted memory T lymphocytes, commonly secreting pro-inflammatory cytokines, together with mediators and factors of the innate immune system, are considered to contribute to the low-grade inflammation (inflammaging) often observed in elderly people. These senescent immune cells not only secrete inflammatory mediators, but are also able to negatively modulate their environments. In this review, we give a short summary of the ways that immunosenescence, inflammaging, and CMV infection may cause insufficient immune responses, contribute to the establishment of the hyperinflammatory syndrome and impact the severity of the coronavirus disease 2019 (COVID-19) in elderly people.

Association between Epstein-Barr virus and periodontitis: A meta-analysis.

PURPOSE: Previous studies have found that Epstein-Barr virus (EBV) is associated with periodontitis, though some controversy remains. This meta-analysis aimed to clarify and update the relationship between EBV and periodontitis as well as clinical parameters. METHODS: A comprehensive search was conducted in the PubMed and Scopus databases in December 2020. Original data were extracted according to defined inclusion and exclusion criteria. Outcomes were analyzed, including overall odds ratios (ORs) and 95% confidence intervals (CIs). A random-effects model was used, and publication bias was assessed by Egger's and Begg's tests. Sensitivity analysis was used to evaluate the stability of the outcome. RESULTS: Twenty-six studies were included in the present meta-analysis, involving 1354 periodontitis patients and 819 healthy controls. The included studies mostly showed high quality. The overall quantitative synthesis for the association between EBV and periodontitis was an increased odds ratio when subgingival EBV was detected OR = 7.069, 95% CI = 4.197-11.905, P<0.001). The results of subgroup analysis suggested that the association of EBV with periodontitis was significant in Asian, European, and American populations (P<0.001; P = 0.04; P = 0.003, respectively) but not in African populations (P = 0.29). Subgroup analysis by sample type showed that subgingival plaque (SgP), tissue and gingival crevicular fluid GCF were useful for EBV detection (P<0.001). EBV detection amplification methods included nested PCR, multiplex PCR and PCR (P<0.001; P = 0.05, P<0.001, respectively), but EBV detection by real-time PCR and loop-mediated isothermal amplification presented no significant result (P = 0.06; P = 0.3, respectively). For the clinical parameters of periodontitis, pocket depth (PD) and bleeding of probing (BOP) percentages were higher in the EBV-positive sites than in the EBV-negative sites (MD 0.47 [0.08, 0.85], P = 0.02; MD 19.45 [4.47, 34.43], P = 0.01). CONCLUSIONS: A high frequency of EBV detection is associated with an increased risk of periodontitis. The EBV association was particularly significant in all populations except in African populations. Subgigival plaque (SgP), tissue and GCF were not significantly different useful material for detecting EBV in periodontitis. Nested PCR and multiplex PCR are reliable methods for this purpose. In the presence of EBV, PD and BOP are reliable clinical parameters for gingival inflammation. However, some caution in such interpretation is justified due to heterogeneity among studies. A suggested extension could assess the parallel influence of other human herpesviruses.