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Introduction: This prospective cohort study aims to investigate the hearing dynamics and the changes in the central auditory pathways in infants with congenital cytomegalovirus (cCMV) infection., Materials and Methods: cCMV-infected neonates aged ≤3 weeks old were recruited and underwent clinical and laboratory tests to detect viremia and symptomatic infection, hearing examinations at three and six months of age, and radiological imaging of brain auditory pathways using diffusion tensor imaging., Results: From 26 eligible infants (52 ears), we detected symptomatic infection in nine (34.6%), viremia in 14 (14/25; 56.0%) and sensorineural hearing loss (SNHL) in 14 infants (53.8%). We observed 40 ears (76.9%) with unstable hearing thresholds, 17 (42.5%) of which fluctuated. Hearing fluctuation and progressivity were more common in symptomatic infection (66.7% vs. 14.7%, p<0.001; and 38.9% vs. 2.9%, p=0.002; respectively). A substantial proportion of ears had reduced fractional anisotropy (FA) in the medial geniculate body (59.1%), superior olivary nucleus (45.5%), trapezoid body (40.9%), auditory radiation (36.4%) and inferior colliculus (31.8%). Symptomatic infection was associated with an increased FA in the medial geniculate body (mean difference, MD: 0.12; 95% Confidence Intervals, 95%CI: 0.03, 0.22) and viremia in the inferior colliculus (MD: 0.09; 95%CI: 0.02, 0.16). An FA in the inferior colliculus of ≥0.404 had a sensitivity and specificity of 68.8% and 83.3% in predicting viremia (area under the curve 0.823; 95%CI: 0.633, 1.000, p=0.022)., Conclusion: SNHL along with its fluctuation and progression are common in cCMV-infected infants. cCMV infection may induce structural changes in the central auditory pathway.

Placental infection plays a central role in the pathogenesis of congenital human cytomegalovirus (HCMV) infections and is a cause of fetal growth restriction and pregnancy loss. HCMV can replicate in some trophoblast cell types, but it remains unclear how the virus evades antiviral immunity in the placenta and how infection compromises placental development and function. Human trophoblast stem cells (TSCs) can be differentiated into extravillous trophoblasts (EVTs), syncytiotrophoblasts (STBs), and organoids, and this study assessed the utility of TSCs as a model of HCMV infection in the first-trimester placenta. HCMV was found to non-productively infect TSCs, EVTs, and STBs. Immunofluorescence assays and flow cytometry experiments further revealed that infected TSCs frequently only express immediate early viral gene products. Similarly, RNA sequencing found that viral gene expression in TSCs does not follow the kinetic patterns observed during lytic infection in fibroblasts. Canonical antiviral responses were largely not observed in HCMV-infected TSCs and TSC-derived trophoblasts. Rather, infection dysregulated factors involved in cell identity, differentiation, and Wingless/Integrated signaling. Thus, while HCMV does not replicate in TSCs, infection may perturb trophoblast differentiation in ways that could interfere with placental function., Importance: Placental infection plays a central role in human cytomegalovirus (HCMV) pathogenesis during pregnancy, but the species specificity of HCMV and the limited availability and lifespan of primary trophoblasts have been persistent barriers to understanding how infection impacts this vital organ. Human trophoblast stem cells (TSCs) represent a new approach to modeling viral infection early in placental development. This study reveals that TSCs, like other stem cell types, restrict HCMV replication. However, infection perturbs the expression of genes involved in differentiation and cell fate determination, pointing to a mechanism by which HCMV could cause placental injury., Competing Interests: The authors declare no conflict of interest.

Human cytomegalovirus (HCMV) modulates numerous cellular pathways to facilitate infection. Iron is essential to many cellular processes and is often incorporated into proteins and enzymes involved in oxidative phosphorylation and DNA synthesis and repair, among others. Despite its prominent role in the cell, little is known about the regulation of iron metabolism during HCMV infection. Herein, we observe modulation of the transferrin receptor (TfR) during infection and a corresponding change in the cellular labile iron pool. TfR and the iron pool are increased early during infection and then return to mock levels at the late stages of infection. We identified the cellular ubiquitin ligase MARCH1 as an important regulator of TfR. MARCH1 plays a proviral role during infection, as its knockdown leads to a decrease in infectious titers. Knockdown of MARCH1 also leads to an increase in ROS, lipid peroxidation, and mitochondrial dysfunction. Inhibiting an early increase in TfR expression during infection also decreases virus production. These findings indicate the importance of tightly regulating iron metabolism during HCMV infection to facilitate efficient virus production. IMPORTANCE Iron is essential for cells, playing important roles in energy generation, DNA replication, and gene expression. During infection, HCMV alters many cellular processes to aid its replication. We found that iron levels are tightly regulated during infection and that dysregulation of iron levels alters the ability to produce infectious virions. We also found that HCMV inactivates many of the cellular safeguards put in place to deal with excess iron. Thus, infected cells become more susceptible to variations in iron levels, which could be exploited as a therapeutic strategy for dealing with HCMV infections.

Human cytomegalovirus (HCMV) has a large (∼235 kb) genome with more than 200 predicted open reading frames that exploits numerous cellular factors to facilitate its replication. A key feature of HCMV-infected cells is the emergence of a distinctive membranous cytoplasmic compartment termed the virion assembly compartment (vAC). Here, we report that host protein WD repeat domain 11 (WDR11) plays a key role in vAC formation and virion morphogenesis. We found that WDR11 was upregulated at both mRNA and protein levels during HCMV infection. At the late stage of HCMV replication, WDR11 relocated to the vAC and colocalized with markers of the trans-Golgi network (TGN) and vAC. Depletion of WDR11 hindered HCMV-induced membrane reorganization of the Golgi and TGN, altered vAC formation, and impaired HCMV secondary envelopment and virion morphogenesis. Further, motifs critical for the localization of WDR11 in TGN were identified by alanine-scanning mutagenesis. Mutation of these motifs led to WDR11 mislocation outside the TGN and loss of vAC formation. Taken together, these data indicate that host protein WDR11 is required for efficient viral replication at the stage of virion assembly, possibly by facilitating the remodeling of the endomembrane system for vAC formation and virion morphogenesis. IMPORTANCE During the late phase of human cytomegalovirus (HCMV) infection, the endomembrane system is dramatically reorganized, resulting in the formation of a unique structure termed the virion assembly compartment (vAC), which is critical for the assembly of infectious virions. The mechanism of HCMV-induced vAC formation is still not fully understood. In this report, we identified a host factor, WDR11, that plays an important role in vAC formation. Our findings argue that WDR11 contributes to the relocation of the Golgi and trans-Golgi network to the vAC, a membrane reorganization process that appears to be required for efficient virion maturation. The present work provides new insights into the vAC formation and HCMV virion morphogenesis and a potential novel target for antiviral treatment.

Congenital cytomegalovirus (cCMV) infection is the leading infectious cause of neurodevelopmental disorders. However, the neuropathogenesis remains largely elusive due to a lack of informative animal models. In this study, we developed a congenital murine CMV (cMCMV) infection mouse model with high survival rate and long survival period that allowed long-term follow-up study of neurodevelopmental disorders. This model involves in utero intracranial injection and mimics many reported clinical manifestations of cCMV infection in infants, including growth restriction, hearing loss, and impaired cognitive and learning-memory abilities. We observed that abnormalities in MRI/CT neuroimaging were consistent with brain hemorrhage and loss of brain parenchyma, which was confirmed by pathological analysis. Neuropathological findings included ventriculomegaly and cortical atrophy associated with impaired proliferation and migration of neural progenitor cells in the developing brain at both embryonic and postnatal stages. Robust inflammatory responses during infection were shown by elevated inflammatory cytokine levels, leukocyte infiltration, and activation of microglia and astrocytes in the brain. Pathological analyses and CT neuroimaging revealed brain calcifications induced by cMCMV infection and cell death via pyroptosis. Furthermore, antiviral treatment with ganciclovir significantly improved neurological functions and mitigated brain damage as shown by CT neuroimaging. These results demonstrate that this model is suitable for investigation of mechanisms of infection-induced brain damage and long-term studies of neurodevelopmental disorders, including the development of interventions to limit CNS damage associated with cCMV infection.

Glioblastoma (GBM) is an aggressive primary central nervous system neoplasia with limited therapeutic options and poor prognosis. Following reports of cytomegalovirus (HCMV) in GBM tumors, the anti-viral drug Valganciclovir was administered and found to significantly increase the longevity of GBM patients. While these findings suggest a role for HCMV in GBM, the relationship between them is not clear and remains controversial. Treatment with anti-viral drugs may prove clinically useful; however, their results do not explain the underlying mechanism between HCMV infection and GBM progression. We hypothesized that HCMV infection would metabolically reprogram GBM cells and that these changes would allow for increased tumor progression. We infected LN-18 GBM cells and employed a Seahorse Bioanalyzer to characterize cellular metabolism. Increased mitochondrial respiration and glycolytic rates were observed following infection. These changes were accompanied by elevated production of reactive oxygen species and lactate. Due to lactate's numerous tumor-promoting effects, we examined the impact of paracrine signaling of HCMV-infected GBM cells on uninfected stromal cells. Our results indicated that, independent of viral transmission, the secretome of HCMV-infected GBM cells was able to alter the expression of key metabolic proteins and epigenetic markers. This suggests a mechanism of action where reprogramming of GBM cells alters the surrounding tumor microenvironment to be permissive to tumor progression in a manner akin to the Reverse-Warburg Effect. Overall, this suggests a potential oncomodulatory role for HCMV in the context of GBM.

Background & Aims: Recent non-malignant non-cirrhotic portal venous system thrombosis (PVT) is a rare condition. Among risk factors for PVT, cytomegalovirus (CMV) disease is usually listed based on a small number of reported cases. The aim of this study was to determine the characteristics and outcomes of PVT associated with CMV disease., Methods: We conducted a French multicenter retrospective study comparing patients with recent PVT and CMV disease ("CMV positive"; n = 23) to patients with recent PVT for whom CMV testing was negative ("CMV negative"; n = 53) or unavailable ("CMV unknown"; n = 297)., Results: Compared to patients from the "CMV negative" and "CMV unknown" groups, patients from the "CMV positive" group were younger, more frequently had fever, and had higher heart rate, lymphocyte count and serum ALT levels (p ≤0.01 for all). The prevalence of immunosuppression did not differ between the 3 groups (4%, 4% and 6%, respectively). Extension of PVT was similar between the 3 groups. Thirteen out of 23 "CMV positive" patients had another risk factor for thrombosis. Besides CMV disease, the number of risk factors for thrombosis was similar between the 3 groups. Heterozygosity for the prothrombin G20210A gene variant was more frequent in "CMV positive" patients (22%) than in the "CMV negative" (4%, p = 0.01) and "CMV unknown" (8%, p = 0.03) groups. Recanalization rate was not influenced by CMV status., Conclusions: In patients with recent PVT, features of mononucleosis syndrome should raise suspicion of CMV disease. CMV disease does not influence thrombosis extension nor recanalization. More than half of "CMV positive" patients have another risk factor for thrombosis, with a particular link to the prothrombin G20210A gene variant., Lay Summary: Patients with cytomegalovirus (CMV)-associated portal venous system thrombosis have similar thrombosis extension and evolution as patients without CMV disease. However, patients with CMV-associated portal venous system thrombosis more frequently have the prothrombin G20210A gene variant, suggesting that these entities act synergistically to promote thrombosis., Competing Interests: Conflict of interest Authors declare no conflict of interest related to the present study. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Introduction: Placental dysfunction triggers fetal growth restriction in congenital human cytomegalovirus (HCMV) infection. Studies suggest that HCMV infection interferes with the differentiation of human trophoblasts. However, the underlying mechanisms have not been clarified. This study investigated the impact of HCMV infection on gene transcriptomes in cytotrophoblasts (CTBs) associated with placental dysfunction., Methods: CTBs were isolated from human term placentas, and spontaneous syncytialization was observed in vitro. The transcriptome profiles were compared between CTB groups with and without HCMV infection by cap analysis gene expression sequencing. The effect of HCMV infection on trophoblast differentiation was evaluated by examining cell fusion status using immunocytochemical staining for desmoplakin and assessing the production of cell differentiation markers, including hCG, PlGF, and soluble Flt-1, using ELISA., Results: The expression of the genes categorized in the signaling pathways related to the cell cycle was significantly enhanced in CTBs with HCMV infection compared with uninfected CTBs. HCMV infection hindered the alteration of the gene expression profile associated with syncytialization. This suppressive effect under HCMV infection was concurrent with the reduction in hCG and PlGF secretion. Immunostaining for desmoplakin revealed that HCMV infection reduced the cell fusion of cultured CTBs. These findings imply that HCMV infection has a negative impact on syncytialization, which is indispensable for the maintenance of villous function., Discussion: HCMV infection interferes with gene expression profiles and functional differentiation of trophoblasts. Suppression of syncytialization may be a survival strategy for HCMV to expand infection and could be associated with placental dysfunction., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Cytomegaloviruses (CMVs) are among the largest pathogenic viruses in mammals. To enable replication of their long double-stranded DNA genomes, CMVs induce profound changes in cell cycle regulation. A hallmark of CMV cell cycle control is the establishment of an unusual cell cycle arrest at the G 1 /S transition, which is characterized by the coexistence of cell cycle stimulatory and inhibitory activities. While CMVs interfere with cellular DNA synthesis and cell division, they activate S-phase-specific gene expression and nucleotide metabolism. This is facilitated by a set of CMV gene products that target master regulators of G 1 /S progression such as cyclin E and A kinases, Rb-E2F transcription factors, p53-p21 checkpoint proteins, the APC/C ubiquitin ligase, and the nucleotide hydrolase SAMHD1. While the major themes of cell cycle regulation are well conserved between human and murine CMVs (HCMV and MCMV), there are considerable differences at the level of viral cell cycle effectors and their mechanisms of action. Furthermore, both viruses have evolved unique mechanisms to sense the host cell cycle state and modulate the infection program accordingly. This review provides an overview of conserved and divergent features of G 1 /S control by MCMV and HCMV.

The cGAS/STING/TBK1 (cyclic guanine monophosphate-AMP synthase/stimulator of interferon genes/Tank-binding kinase 1) innate immunity pathway is activated during human cytomegalovirus (HCMV) productive (lytic) replication in fully differentiated cells and during latency within incompletely differentiated myeloid cells. While multiple lytic-phase HCMV proteins neutralize steps along this pathway, none of them are expressed during latency. Here, we show that the latency-associated protein UL138 inhibits the cGAS/STING/TBK1 innate immunity pathway during transfections and infections, in fully differentiated cells and incompletely differentiated myeloid cells, and with loss of function and restoration of function approaches. UL138 inhibits the pathway downstream of STING but upstream of interferon regulatory factor 3 (IRF3) phosphorylation and NF-κB function and reduces the accumulation of interferon beta mRNA during both lytic and latent infections. IMPORTANCE While a cellular restriction versus viral countermeasure arms race between innate immunity and viral latency is expected, few examples have been documented. Our identification of the first HCMV latency protein that inactivates the cGAS/STING/TBK1 innate immune pathway opens the door to understanding how innate immunity, or its neutralization, impacts long-term persistence by HCMV and other latent viruses.

Reducing the socioeconomic toll from age-related physical and mental morbidities requires better understanding of factors affecting healthy aging. While many environmental, lifestyle, and genetic factors affect healthy aging, this study addressed the influence of cytomegalovirus (CMV) infection and immunity on age-related inflammation and cognitive abilities. Healthy adults 70-90 years old were recruited into a prospective study investigating relationships between anti-CMV immunity, markers of inflammation, baseline measures of cognitive ability, and changes in cognitive ability over 18 months. Humoral and cellular responses against CMV, levels of inflammatory markers, and cognitive abilities were measured at study entry, with measurement of cognitive abilities repeated 18 months later. CMV-seropositive and -seronegative sub-groups were compared, and relationships between anti-CMV immunity, markers of inflammation, and cognitive ability were assessed. Twenty-eight of 39 participants were CMV-seropositive, and two had CMV-specific CD8 + T cell responses indicative of CMV immune memory inflation. No significant differences for markers of inflammation or measures of cognitive ability were observed between groups, and cognitive scores changed little over 18 months. Significant correlations between markers of inflammation and cognitive scores with interconnection between anti-CMV antibody levels, fractalkine, cognitive ability, and depression scores suggest areas of focus for future studies.

CMV causes mostly asymptomatic but lifelong infection. Primary infection or reactivation in immunocompromised individuals can be life-threatening. CMV viremia often occurs in solid organ transplant recipients and associates with decreased graft survival and higher mortality. Furthering understanding of impaired immunity that allows CMV reactivation is critical to guiding antiviral therapy and examining the effect of CMV on solid organ transplant outcomes. This study characterized longitudinal immune responses to CMV in 31 kidney transplant recipients with CMV viremia and matched, nonviremic recipients. Recipients were sampled 3 and 12 months after transplant, with additional samples 1 week and 1 month after viremia. PBMCs were stained for NK and T cell markers. PBMC transcriptomes were characterized by RNA-Seq. Plasma proteins were quantified by Luminex. CD8+ T cell transcriptomes were characterized by single-cell RNA-Seq. Before viremia, patients had high levels of IL-15 with concurrent expansion of immature CD56bright NK cells. After viremia, mature CD56dim NK cells and CD28-CD8+ T cells upregulating inhibitory and NK-associated receptors were expanded. Memory NK cells and NK-like CD28-CD8+ T cells were associated with control of viremia. These findings suggest that signatures of innate activation may be prognostic for CMV reactivation after transplant, while CD8+ T cell functionality is critical for effective control of CMV.

Introduction: Opportunistic infection with multiple pathogens currently has become less uncommon since the application of immunosuppressant or corticosteroid in non- Human immunodeficiency virus patients. However, the clinical diagnosis of the co-infection remains difficult since the uncertainty and deficiency of the microbiologic testing methods., Patient Concerns: A 66-year-old male patient was admitted to our hospital with chest stuffiness, shortness of breath and elevated body temperature., Diagnosis: He was diagnosed with the co-infection of Pneumocystis jiroveci and cytomegalovirus by metagenomic next-generation sequencing of bronchoalveolar lavage fluid after bronchoscopy., Interventions: The patient was empirically treated with broad-spectrum antibiotics, trimethoprim/ sulfamethoxazole and ganciclovir in the beginning of the admission., Outcomes: The condition of this patient was not improved even with the intervention at the early stage of the disease. His family requested discharge after 24 inpatient days., Lessons: This case highlights the application of metagenomic next-generation sequencing in the clinical diagnosis of pulmonary co-infection. Suitable prophylaxis, necessary clinical awareness and accurate diagnosis are indispensable for immunocompromised patients with pulmonary infection., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Whether donor (D+) or recipient (R+) cytomegalovirus (CMV) seropositivity is associated with functional impairment in liver transplant recipients is not known., Methods: Patients included adult liver transplant recipients in the Organ Procurement and Transplantation Network database transplanted over a five-year period from 1 January 2014-31 December 2018. Functional status in the database was assessed using Karnofsky performance scale. A logistic regression model that controlled for potential confounders was used to examine the association of CMV serostatus and functional status. Variables significantly associated with functional status ( p < 0.05) were then used to develop propensity score and propensity score matched analysis was conducted where each patient was compared with a matched-control with the same propensity score., Results: Among 30,267 adult liver transplant recipients, D+ or R+ patients had significantly lower functional status at last follow-up than the D-R- cohort (OR 0.88, 95% CI 0.80-0.96, p = 0.007). In propensity score matched model, D+ or R+ patients had significantly lower functional status than matched-controls ( p = 0.009). D+ or R+ CMV serostatus ( p = 0.018) and low functional level ( p < 0.001) were also independently associated with infections as cause-of-death., Conclusions: D+ or R+ liver transplant recipients had lower functional status and higher risk of deaths due to infections. Future studies are warranted to examine the mechanistic basis of these findings in the setting of transplantation.

Purpose: To determine distinguishing features of the clinical characteristics of anterior uveitis (AU) caused by herpes simplex virus (HSV), varicella-zoster virus (VZV), and cytomegalovirus (CMV)., Design: Retrospective, multicenter case series., Methods: Consecutive patients with herpetic AU examined at 11 tertiary centers in Japan between January 2012 and December 2017 and who were followed for ≥3 months were evaluated. Diagnosis was made by polymerase chain reaction (PCR) for HSV, VZV, or CMV in the aqueous humor, or classical signs of herpes zoster ophthalmicus., Results: This study enrolled 259 herpetic AU patients, including PCR-proven HSV-AU (30 patients), VZV-AU (50), and CMV-AU (147), and herpes zoster ophthalmicus (32). All HSV-AU and VZV-AU patients were unilateral, while 3% of CMV-AU patients were bilateral. Most HSV-AU and VZV-AU patients were sudden onset with an acute clinical course, while CMV-AU had a more insidious onset and chronic course. There were no significant differences for all surveyed symptoms, signs, and complications between HSV-AU and VZV-AU. However, significant differences were detected for many items between CMV-AU and the other two herpetic AU types. Ocular hyperemia and pain, blurring of vision, ciliary injection, medium-to-large keratic precipitates (KPs), cells and flare in the anterior chamber, and posterior synechia significantly more often occurred in HSV-AU and VZV-AU vs CMV-AU. In contrast, small KPs, coin-shaped KPs, diffuse iris atrophy, elevated intraocular pressure, and glaucoma surgery were significantly more frequent in CMV-AU vs HSV-AU and VZV-AU., Conclusion: This multicenter, retrospective study identified distinguishing features of HSV-AU, VZV-AU, and CMV-AU., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Cytomegalovirus (CMV) gastritis is occasionally reported in case reports and limited case series. Up to now, it is the largest and most comprehensive retrospective study of CMV gastritis., Methods: All patients who were histologically diagnosed with CMV gastritis at Linkou Chang Gung Memorial Hospital between January 2000 and April 2020 were included. Patients were divided into two groups according to immunity. Between-group differences in characteristics, manifestations, endoscopic features, prognostic factors, and outcomes were analyzed. The main endpoint was 3-month mortality., Results: A total of 54 patients (34 immunocompromised, 20 immunocompetent) were enrolled. Common presentations included gastrointestinal bleeding (35.2%), abdominal pain (33.3%) and fever (31.5%). The endoscopic features included ulcer (88.9%) and inflammation (11.1%). The 3-month mortality rate was 20.4% and overall mortality rate was 40.7%. Acute kidney injury was the only independent risk factor for 3-month mortality (OR 53.89, 95%CI 1.56-1861.73, p = 0.027). Anti-viral therapy and host immune status did not affect 3-month mortality., Conclusion: Both immunocompromised and immunocompetent patients with CMV gastritis have high mortality rates, without significant between-group differences. Acute kidney injury is the only independent predictive factor for 3-month mortality. Prevention of acute kidney injury may possibly improve the 3-month mortality rate., (Copyright © 2020 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Inflammatory cardiomyopathy, characterized by inflammatory cell infiltration into the myocardium and a high risk of deteriorating cardiac function, has a heterogeneous aetiology. Inflammatory cardiomyopathy is predominantly mediated by viral infection, but can also be induced by bacterial, protozoal or fungal infections as well as a wide variety of toxic substances and drugs and systemic immune-mediated diseases. Despite extensive research, inflammatory cardiomyopathy complicated by left ventricular dysfunction, heart failure or arrhythmia is associated with a poor prognosis. At present, the reason why some patients recover without residual myocardial injury whereas others develop dilated cardiomyopathy is unclear. The relative roles of the pathogen, host genomics and environmental factors in disease progression and healing are still under discussion, including which viruses are active inducers and which are only bystanders. As a consequence, treatment strategies are not well established. In this Review, we summarize and evaluate the available evidence on the pathogenesis, diagnosis and treatment of myocarditis and inflammatory cardiomyopathy, with a special focus on virus-induced and virus-associated myocarditis. Furthermore, we identify knowledge gaps, appraise the available experimental models and propose future directions for the field. The current knowledge and open questions regarding the cardiovascular effects associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are also discussed. This Review is the result of scientific cooperation of members of the Heart Failure Association of the ESC, the Heart Failure Society of America and the Japanese Heart Failure Society.

Importance: The sensitivity of dried blood spots (DBS) to identify newborns with congenital cytomegalovirus (cCMV) infection has not been evaluated in screening studies using the current, higher-sensitivity methods for DBS processing., Objective: To assess the sensitivity of DBS polymerase chain reaction (PCR) for newborn screening for cCMV infection using saliva as the reference standard for screening, followed by collection of a urine sample for confirmation of congenital infection., Design, Setting, and Participants: This population-based cohort study took place at 5 newborn nurseries and 3 neonatal intensive care units in the Minneapolis/Saint Paul area in Minnesota from April 2016 to June 2019. Newborns enrolled with parental consent were screened for cCMV using DBS obtained for routine newborn screening and saliva collected 1 to 2 days after birth. Dried blood spots were tested for CMV DNA by PCR at both the University of Minnesota (UMN) and the US Centers for Disease Control and Prevention (CDC). Saliva swabs were tested by CMV DNA PCR at the UMN laboratory only. Newborns who screened positive by saliva or DBS had a diagnostic urine sample obtained by primary care professionals, tested by PCR within 3 weeks of birth. Analysis began July 2019., Exposures: Detection of CMV from a saliva swab using a PCR assay., Main Outcomes and Measures: Number of children with urine-confirmed cCMV and the proportion of them who were CMV positive through DBS screening., Results: Of 12 554 individuals enrolled through June 2019 (of 25 000 projected enrollment), 56 newborns were confirmed to have cCMV (4.5 per 1000 [95% CI, 3.3-5.7]). Combined DBS results from either UMN or CDC had a sensitivity of 85.7% (48 of 56; 95% CI, 74.3%-92.6%), specificity of 100.0% (95% CI, 100.0%-100.0%), positive predictive value (PPV) of 98.0% (95% CI, 89.3%-99.6%), and negative predictive value (NPV) of 99.9% (95% CI, 99.9%-100.0%). Dried blood spot results from UMN had a sensitivity of 73.2% (95% CI, 60.4%-83.0%), specificity of 100.0% (100.0%-100.0%), PPV of 100.0% (95% CI, 91.4%-100.0%), and NPV of 99.9% (95% CI, 99.8%-99.9%). Dried blood spot results from CDC had a sensitivity of 76.8% (95% CI, 64.2%-85.9%), specificity of 100.0% (95% CI, 100.0%-100.0%), PPV of 97.7% (95% CI, 88.2%-99.6%), and NPV of 99.9% (95% CI, 99.8%-99.9%). Saliva swab results had a sensitivity of 92.9% (52 of 56; 95% CI, 83.0%-97.2%), specificity of 99.9% (95% CI, 99.9%-100.0%), PPV of 86.7% (95% CI, 75.8%-93.1%), and NPV of 100.0% (95% CI, 99.9%-100.0%)., Conclusions and Relevance: This study demonstrates relatively high analytical sensitivity for DBS compared with previous studies that performed population-based screening. As more sensitive DNA extraction and PCR methods continue to emerge, DBS-based testing should remain under investigation as a potential low-cost, high-throughput option for cCMV screening.

Introduction: Polymerase chain reaction (PCR)-based testing of cerebrospinal fluid (CSF) samples has greatly facilitated the diagnosis of central nervous system (CNS) infections. However, the clinical significance of Epstein-Barr virus (EBV) DNA in CSF of individuals with suspected CNS infection remains unclear. We wanted to gain a better understanding of EBV as an infectious agent in immunocompetent patients with CNS disorders., Methods: We identified cases of EBV-associated CNS infections and reviewed their clinical and laboratory characteristics. The study population was drawn from patients with EBV PCR positivity in CSF who visited Pusan National University Hospital between 2010 and 2019., Results: Of the 780 CSF samples examined during the 10-year study period, 42 (5.4 %) were positive for EBV DNA; 9 of the patients (21.4 %) were diagnosed with non-CNS infectious diseases, such as optic neuritis, Guillain-Barré syndrome, and idiopathic intracranial hypotension, and the other 33 cases were classified as CNS infections (22 as encephalitis and 11 as meningitis). Intensive care unit admission (13/33 patients, 39.3 %) and presence of severe neurological sequelae at discharge (8/33 patients, 24.2 %) were relatively frequent. In 10 patients (30.3 %), the following pathogens were detected in CSF in addition to EBV: varicella-zoster virus (n = 3), cytomegalovirus (n = 2), herpes simplex virus 1 (n = 1), herpes simplex virus 2 (n = 1), Streptococcus pneumomiae (n = 2), and Enterococcus faecalis (n = 1). The EBV-only group (n = 23) and the co-infection group (n = 10) did not differ in age, gender, laboratory data, results of brain imaging studies, clinical manifestations, or prognosis; however, the co-infected patients had higher CSF protein levels., Conclusion: EBV DNA in CSF is occasionally found in the immunocompetent population; the virus was commonly associated with encephalitis and poor prognosis, and frequently found together with other microbes in CSF., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Cytomegalovirus (CMV) is a major infectious cause of death and disease after transplantation. We have previously demonstrated that the tissue-associated adaptive Vδ2neg γδ T cells are key effectors responding to CMV and associated with recovery, contrasting with their innatelike circulating counterparts, the Vγ9posVδ2pos T cells that respond to phosphoantigens but not to CMV. A third Vγ9negVδ2pos subgroup with adaptive functions has been described in adults. In the current study, we demonstrate that these Vγ9negVδ2pos T cells are also components of the CMV immune response while presenting with distinct characteristics from Vδ2neg γδ T cells. In a cohort of kidney transplant recipients, CMV seropositivity was the unique clinical parameter associated with Vγ9negVδ2pos T-cell expansion and differentiation. Extensive phenotyping demonstrated their substantial cytotoxic potential and activation during acute CMV primary infection or reinfection. In vitro, Vγ9negVδ2pos T cells responded specifically to CMV-infected cells in a T-cell receptor-dependent manner and through strong interferon γ production. Finally, Vγ9negVδ2pos T cells were the only γδ T-cell subset in which expansion was tightly correlated with the severity of CMV disease. To conclude, our results identify a new player in the immune response against CMV and open interesting clinical perspectives for using Vγ9negVδ2pos T cells as an immune marker for CMV disease severity in immunocompromised patients., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Xenotransplantation using pig organs has achieved survival times up to 195 days in pig orthotopic heart transplantation into baboons. Here we demonstrate that in addition to an improved immunosuppressive regimen, non-ischaemic preservation with continuous perfusion and control of post-transplantation growth of the transplant, prevention of transmission of the porcine cytomegalovirus (PCMV) plays an important role in achieving long survival times. For the first time we demonstrate that PCMV transmission in orthotopic pig heart xenotransplantation was associated with a reduced survival time of the transplant and increased levels of IL-6 and TNFα were found in the transplanted baboon. Furthermore, high levels of tPA-PAI-1 complexes were found, suggesting a complete loss of the pro-fibrinolytic properties of the endothelial cells. These data show that PCMV has an important impact on transplant survival and call for elimination of PCMV from donor pigs.

Understanding the relationship between infection and stroke has taken on new urgency in the era of the coronavirus disease 2019 (COVID-19) pandemic. This association is not a new concept, as several infections have long been recognized to contribute to stroke risk. The association of infection and stroke is also bidirectional. Although infection can lead to stroke, stroke also induces immune suppression which increases risk of infection. Apart from their short-term effects, emerging evidence suggests that poststroke immune changes may also adversely affect long-term cognitive outcomes in patients with stroke, increasing the risk of poststroke neurodegeneration and dementia. Infections at the time of stroke may also increase immune dysregulation after the stroke, further exacerbating the risk of cognitive decline. This review will cover the role of acute infections, including respiratory infections such as COVID-19, as a trigger for stroke; the role of infectious burden, or the cumulative number of infections throughout life, as a contributor to long-term risk of atherosclerotic disease and stroke; immune dysregulation after stroke and its effect on the risk of stroke-associated infection; and the impact of infection at the time of a stroke on the immune reaction to brain injury and subsequent long-term cognitive and functional outcomes. Finally, we will present a model to conceptualize the many relationships among chronic and acute infections and their short- and long-term neurological consequences. This model will suggest several directions for future research.

Objectives: To assess neurological sequelae and growth in the first 12 months of life in a cohort of congenital cytomegalovirus (cCMV) infected infants compared to cCMV uninfected infants., Study Design: This was a prospective matched cohort study conducted in Soweto, South Africa where forty-six confirmed cCMV cases were matched on HIV-exposure, gender and gestational age (±two weeks) to 84 cCMV-uninfected controls in a 1:2 ratio. Cases and controls were followed up until 12 months of age to assess anthropometry, hearing and neurodevelopmental outcomes., Results: Thirty-four (73.9%) cCMV cases and 74 (88.1%) controls, completed all assessments at 12 months age. At 12 months, one cCMV case had died, none of the children in either group had SNHL and neurodevelopmental delay was present in a similar percentage of cCMV cases (n = 2; 6%) and controls (n = 1, 4%; OR 1.09, 95% CI 0.04-27.84, p = 0.958). Anthropometry did not differ between cases and controls overall throughout the follow up period. HIV-exposed cases had smaller head circumference for age at 6 and 12 months when compared with HIV-exposed controls., Conclusion: By 12 months of age, there was no evidence of a difference in neurological sequelae between cCMV infected South African children and cCMV uninfected children in this study. Further follow-up is warranted to detect late-onset hearing loss and neurodevelopmental delay beyond 12 months of age., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: Shabir Madhi reports grants from the National Research Foundation, South Africa during the conduct of the study and grants and personal fees from the Bill and Melinda Gates Foundation, grants from Pfizer, GlaxoSmithKline, Sanofi and Mivervax outside the submitted work. Suresh Boppana reports personal fees from Merck and grants from Meridian Biosciences outside the submitted work. All other authors have declared that no competing interests exist. This does not alter our adherence to PLOS ONE policies on sharing data and materials outside the submitted work. All other authors have declared that no competing interests exist.

Despite multiple studies, the role of cytomegalovirus [CMV] infection in exacerbating the severity of inflammation in ulcerative colitis [UC], and its response to treatment, remain debatable. Additionally, the optimal diagnostic tests for CMV infection in the setting of UC relapse, and timing of antiviral treatment initiation, remain unclear. The challenge faced by gastroenterologists is to differentiate between an acute UC flare and true CMV colitis. It seems that the presence of CMV colitis, as defined by the presence of intranuclear or intracellular inclusion bodies on haematoxylin and eosin [H&E] staining and/or positive immunohistochemistry [IHC] assay on histology, is associated with more severe colitis. Patients with CMV infection and acute severe colitis are more resistant to treatment with corticosteroids than non-infected patients. This refractoriness to steroids is related to colonic tissue CMV viral load and number of inclusion bodies [high-grade CMV infection] which may have a pronounced effect on clinical outcomes and colectomy rates. Whereas many studies showed no effect for antiviral treatment on colectomy rates in CMV-infected UC patients, there was a significant difference in colectomy rates of patients with high-grade infection who received anti-viral therapy compared with those who did not receive treatment. It was therefore proposed that high-grade CMV disease indicates that the virus is acting as a pathogen, whereas in those with low-grade CMV disease, the severity of IBD itself is more likely to influence outcome. The different algorithms that have been put forward for the management of patients with UC and concomitant CMV infection are discussed., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Practitioners need validated strategies for teaching children with significant multiple disabilities (e.g., cognitive, motor, and sensory disability) to use tangible symbols for expressive communication. This single-case experimental design study replicated the positive effect of an adapted protocol for teaching Phase 1 of the Picture Exchange Communication System (PECS) using tangible symbols and extended it to a younger group (4-7 years old) of learners with multiple disabilities. It also tested the effect of an adapted protocol for Phase 2 of PECS to incorporate use of a single switch speech-generating device to gain the attention of an adult communication partner. Two of three students who reached mastery in Phase 1 also reached mastery in Phase 2 and may have generalized requesting behavior from the interventionist (i.e., researchers) to their classroom teacher. Results add to the growing evidence base that shows that the adapted PECS Phase 1 procedures are a promising practice for learners with multiple disabilities, including sensory impairment, and provide preliminary evidence for a more efficient and effective approach to adapting PECS Phase 2 than previously studied for this group of learners. Directions for future research and recommendations for practice are provided.

We previously showed that CMV-induced CD4 + CD27 - CD28 - T cells have regulatory (Treg) function. Here we sought to identify the target/s and the mechanistic underpinning/s of this effect. CMV-induced CD4 + CD27 - CD28 - were sorted from CMV-stimulated PBMC and added to CMV-stimulated autologous PBMC cultures. Transwell experiments showed that the CMV-induced Treg mechanism of action required cell-to-cell contact. CMV-Treg significantly decreased proliferation of autologous CMV-stimulated CD8 + and, to a lesser extent, CD4 + T cells; reduced activation and increased apoptosis of CD4 + and CD8 + T cells; and increased apoptosis and expression of CTLA-4, T cell-inhibitory ligand, on dendritic cells. There was no effect on monocytes. Anti-PD-1, but not anti-CTLA-4, mAb-treatment increased proliferation of CD8 + T cells and decreased apoptosis of CD4 + and CD8 + T cells. Our data indicated that CD8 + T cells were the main target of CMV-specific Treg, which induced apoptosis of their targets using the PD-1 pathway., Competing Interests: Declaration of competing interest AW receives research grants from Merck & Co. Inc., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Blood monocytes mediate the hematogenous dissemination of human cytomegalovirus (HCMV) in the host. However, monocytes have a short 48-hour (h) lifespan and are not permissive for viral replication. We previously established that HCMV infection drives differentiation of monocytes into long-lived macrophages to mediate viral dissemination, though the mechanism was unclear. Here, we found that HCMV infection promoted monocyte polarization into distinct macrophages by inducing select M1 and M2 differentiation markers and that Akt played a central role in driving differentiation. Akt's upstream positive regulators, PI3K and SHIP1, facilitated the expression of the M1/M2 differentiation markers with p110δ being the predominant PI3K isoform inducing differentiation. Downstream of Akt, M1/M2 differentiation was mediated by caspase 3, whose activity was tightly regulated by Akt in a temporal manner. Overall, this study highlights that HCMV employs the PI3K/SHIP1/Akt pathway to regulate caspase 3 activity and drive monocyte differentiation into unique macrophages, which is critical for viral dissemination.

Postnatal cytomegalovirus (pCMV) infection is a common viral infection typically occurring within the first months of life. pCMV refers to postnatal acquisition of CMV rather than postnatal manifestations of antenatal or perinatal acquired CMV. pCMV is usually asymptomatic in term infants, but can cause symptomatic disease in preterm (gestational age <32 weeks) and very low birth weight (<1500 g) infants resulting in sepsis, pneumonia, thrombocytopaenia, neutropaenia, hepatitis, colitis and occasionally death. There are significant uncertainties regarding the management of premature infants with pCMV disease which is in part due to our limited understanding of the natural history of this disease. This review describes the current epidemiology and clinical manifestations of pCMV disease which should alert clinicians to test for CMV and also outlines a strategy to manage the condition., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

The critical consequences of human cytomegalovirus (HCMV) infection in the transplant population and in congenitally infected infants, the limited treatment options for HCMV, and the rise of resistant mutants toward existing therapies has fueled the search for new anti-HCMV agents. A pp28-luciferase recombinant HCMV was used as a reporter system for high-throughput screening of HCMV inhibitors. Approximately 400 000 compounds from existing libraries were screened. Subsequent validation assays using resynthesized compounds, several virus strains, and detailed virology assays resulted in the identification of five structurally unique and selective HCMV inhibitors, active at sub to low micromolar concentrations. Further characterization revealed that each compound inhibited a specific stage of HCMV replication. One compound was also active against herpes simplex virus (HSV1 and HSV2), and another compound was active against Epstein-Barr virus (EBV). Drug combination studies revealed that all five compounds were additive with ganciclovir or letermovir. Future studies will focus on optimization of these new anti-HCMV compounds along with mechanistic studies.

To examine whether autotaxin (ATX) in the aqueous humor causes elevated intraocular pressure (IOP) in patients with Posner-Schlossman syndrome (PSS). ATX and transforming growth factor beta (TGF-β) in the aqueous humor were quantified in PSS patients. The expression of ATX and TGF-β in cytomegalovirus (CMV)-infected-human trabecular meshwork (hTM) cells was examined. Biological changes in hTM cells and monkey Schlemm's canal endothelial (SCE) cells cultured in the conditioned medium of CMV-infected hTM cells were analyzed. The expression of ATX and TGF-β1 was upregulated in the aqueous humor of CMV-positive PSS patients, and the level of ATX in the aqueous humor was positively correlated with IOP. CMV infection upregulated ATX and TGF-β1 in hTM cells. The conditioned medium induced fibrotic changes in hTM cells and reduced SCE permeability, which was attenuated by an ATX inhibitor, a lysophosphatidic acid receptor antagonist, and a Rho kinase inhibitor. ATX in the aqueous humor induced by CMV infection may trigger elevated IOP. Modulating ATX activity may be a novel treatment modality for PSS.

Background: Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infection are common in early childhood. CMV infection favours a T-helper-1 and EBV infection a T-helper-2 cell response, possibly leading to disbalanced T-helper cell response, and subsequent risk of asthma or atopy., Objective: To study the associations of EBV and CMV with lung function, asthma and inhalant allergic sensitization at school age., Methods: This study among 3546 children was embedded in a population-based prospective cohort. At age 6 years, serum IgG levels against EBV and CMV were measured by ELISA. At age 10 years, lung function was measured by spirometry, asthma by questionnaire and inhalant allergic sensitization by skin prick test., Results: Unadjusted models showed that seropositivity for EBV was associated with a higher FEV 1 and FEF 75 (Z-score difference (95% CI): 0.09 (0.02, 0.16) and 0.09 (0.02, 0.15)), while seropositivity for CMV was not. Specific combinations of viruses showed that seropositivity for EBV was only associated with FEV 1 and FEF 75 in the presence of seropositivity for CMV (0.12 (0.04, 0.20)) and 0.08 (0.01, 0.15)). Seropositivity for CMV in the absence of seropositivity for EBV was associated with an increased risk of inhalant allergic sensitization (OR (95% CI): 1.31 (1.02, 1.68)). All effect estimates attenuated into non-significant mainly after adjustment for child's ethnicity. Seropositivity for EBV or CMV was not associated with asthma., Conclusions and Clinical Relevance: Associations of EBV and CMV infections in early childhood with school-age lung function and inhalant allergic sensitization are explained by ethnicity, or sociodemographic and lifestyle-related factors., (© 2020 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)

The widespread use of combination antiretroviral therapies (cART) has converted the prognosis of HIV infection from a rapidly progressive and ultimately fatal disease to a chronic condition with limited impact on life expectancy. Yet, HIV-infected patients remain at high risk for critical illness due to the occurrence of severe opportunistic infections in those with advanced immunosuppression (i.e., inaugural admissions or limited access to cART), a pronounced susceptibility to bacterial sepsis and tuberculosis at every stage of HIV infection, and a rising prevalence of underlying comorbidities such as chronic obstructive pulmonary diseases, atherosclerosis or non-AIDS-defining neoplasms in cART-treated patients aging with controlled viral replication. Several patterns of intensive care have markedly evolved in this patient population over the late cART era, including a steady decline in AIDS-related admissions, an opposite trend in admissions for exacerbated comorbidities, the emergence of additional drivers of immunosuppression (e.g., anti-neoplastic chemotherapy or solid organ transplantation), the management of cART in the acute phase of critical illness, and a dramatic progress in short-term survival that mainly results from general advances in intensive care practices. Besides, there is a lack of data regarding other features of ICU and post-ICU care in these patients, especially on the impact of sociological factors on clinical presentation and prognosis, the optimal timing of cART introduction in AIDS-related admissions, determinants of end-of-life decisions, long-term survival, and functional outcomes. In this narrative review, we sought to depict the current evidence regarding the management of HIV-infected patients admitted to the intensive care unit.

This paper aimed to evaluate whether human cytomegalovirus (HCMV) infection in extravillous cytotrophoblasts (EVT) could shift the balance between regulatory T (Treg) and T-helper type 17 (Th17) cells in vitro. In this study, primary EVT isolated from first trimester placental tissues were infected with HCMV, and conditional media were harvested after cultivation for 72 h. T lymphocytes were cultured in the presence or absence of HCMV-infected conditional media. The frequencies of Th17 or Treg cells from HCMV group were significantly lower or higher than those from the control group, with the expression of corresponding key cytokines at both messenger ribonucleic acid and secretion levels, respectively. The ratio of Treg to Th17 cells was significantly lower in HCMV group than that in control group ( P < 0.01). In conclusion, tiled Th17/Treg balance at maternal-fetal interface exists after HCMV infection.

Background: An association between productive cytomegalovirus infection and atherosclerosis was shown recently in several trials, including a previous study of ours. However, the mechanism involved in this association is still under investigation. Here, we addressed the interaction between productive cytomegalovirus infection and endothelial function in patients with ST-elevation myocardial infarction (STEMI)., Methods: We analyzed the presence of cytomegaloviral DNA in plasma and endothelial function in 33 patients with STEMI and 33 volunteers without cardiovascular diseases, using real-time polymerase chain reaction (PCR) and a noninvasive test of flow-mediated dilation., Results: Both the frequency of presence and the load of cytomegaloviral DNA were higher in plasma of patients with STEMI than those in controls. This difference was independent of other cardiovascular risk factors (7.38 [1.36-40.07]; P = 0.02). The results of the flow-mediated dilation test were lower in patients in STEMI than in controls (5.0% [2.65%-3.09%] vs 12. %5 [7.5%-15.15%]; P = 0.004) and correlated negatively with the cytomegaloviral DNA load (Spearman R = -0.407; P = 0.019) independently of other cardiovascular risk factors., Conclusions: Productive cytomegalovirus infection in patients with STEMI correlated negatively with endothelial function independently of other cardiovascular risk factors. The impact of cytomegalovirus on endothelial function may explain the role of cytomegalovirus in cardiovascular prognosis., (Published by Elsevier Inc.)

The incidence of infectious complications, compared with the general population and the pre-transplant status of the recipient, increases substantially following kidney transplantation, causing significant morbidity and mortality. The potent immunosuppressive therapy given to prevent graft rejection in kidney transplant recipients results in an increased susceptibility to a wide range of opportunistic infections including bacterial, viral and fungal infections. Over the last five years, several advances have occurred that may have changed the burden of infectious complications in kidney transplant recipients. Due to the availability of direct-acting antivirals to manage donor-derived hepatitis C infection, this has opened the way for donors with hepatitis C infection to be considered in the donation process. In addition, there have been the development of medications targeting the growing burden of resistant cytomegalovirus, as well as the discovery of the potentially important role of the gastrointestinal microbiota in the pathogenesis of post-transplant infection. In this narrative review, we will discuss these three advances and their potential implications for clinical practice., Competing Interests: Samuel Chan is supported by the Australian National Health and Medical Research Council (NHMRC) Postgraduate Scholarship, the Microba recipient grant, the Metro South Research Support Scheme, and the Royal Australasian College of Physicians NHMRC Research Excellence top-up award. Furthermore, Dr Chan is a current recipient of the 2018 Sir Gustav Nossal NHMRC Postgraduate Scholarship award. David Johnson has received consultancy fees, research grants, speaker’s honoraria and travel sponsorships from Baxter Healthcare and Fresenius Medical Care. He has received consultancy fees from Astra Zeneca and travel sponsorships from Amgen. He is a current recipient of an Australian NHMRC Practitioner Fellowship. Carmel Hawley is the recipient of research grants paid to her institution from Baxter Healthcare and Fresenius Medical Care and from Otsuka, Janssen and GlaxoSmithKLline for trial steering committee activities, paid to her institution. Nicole Isbel has received consultancy fees and speaker’s honoraria from Alexion Pharmaceuticals, Novo Nordisk and Amgen. The remaining authors have no conflicts of interest to declare with respect to the context and scope of this manuscript.

Ulcerative colitis has hypercoagulable state and high risk of thrombosis; so mucosal disturbance of microcirculation may be mediate and amplify the inflammation of ulcerative colitis. A 56-year-old female patient was admitted in hospital for discontinuously mucous bloody stool for more than 1 year. Ulcerative colitis was determined after colonoscopy and pathologic examination. Mesalazine was effective during the year, but her symptoms recurred three times due to her bad compliance. One month before admission, the patient had severe recurrence after mesalazine withdrawal. At this time, the result of quantitative fluorescence PCR of colonic histic CMV-DNA was 1.6 × 10 4  copies/mL positive, CMV colitis was accompanied. After 4 weeks of ganciclovir and 6 weeks of mesalazine usage and nutrition support, the symptoms of diarrhea and abdominal cramp did not improve; stool frequency was more than twenty times a day. Probe-based confocal laser endomicroscopy revealed local microcirculation disturbance. Papaverine 90-mg slow drip for at least 10 h a day was added. The symptoms dramatically disappeared after 3 days of papaverine treatment. The patient had yellow mushy stool 2-3 times a day. Pathological findings showed diffuse submucosal hemorrhage and transparent thrombosis in capillaries. Treatment of microcirculatory disturbance in severe UC is a promising adjuvant therapy. Confocal laser endomicroscopy may be an effective method for microcirculation judgment.

Human cytomegalovirus (CMV) is a double-stranded DNA virus that can cause widespread severe infection in immunocompromised individuals but is more typically a subclinical infection in immunocompetent individuals. Rarely, it can cause a serious infection in immunocompetent individuals. Here, we describe a 36-year-old otherwise healthy male who presented with fever, cough and malaise who was diagnosed with CMV pneumonia. He made a rapid recovery after initiation of ganciclovir and has been doing well on follow-up visits. We performed a comprehensive review of CMV pneumonia in immunocompetent individuals and have summarised the prior 16 reported cases of CMV pneumonia in immunocompetent patients. This article highlights the importance of considering CMV as a cause of pneumonia even in immunocompetent individuals, especially when the more common causes have been excluded. Early diagnosis allows prompt treatment and potentially complete recovery., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Cytomegalovirus (CMV) may no longer be the menace that plagues stem cell transplant outcomes, owing to marked improvements in transplantation techniques and methods of prophylaxis. However, it still remains a common and morbid problem for recipients of stem cell transplant and patients with certain hematologic malignancies. This article discusses the epidemiology and risk factors of CMV infection and disease, associated morbidity and mortality, diagnosis, and clinical features of clinical syndromes associated with CMV and the principles of management of CMV, with special attention to resistant CMV as it pertains to infectious disease specialists., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Common variable immunodeficiency syndrome (CVID) is a heterogeneous disorder characterised by diminished levels of IgG, IgA and/or IgM, and recurrent bacterial infections. Sinopulmonary infections are most commonly reported followed by gastrointestinal (GI) infections. GI tract represents the largest immune organ with abundance of lymphoid cells, its involvement can manifest variably ranging from asymptomatic involvement to florid symptoms and signs. Diffuse nodular lymphoid hyperplasia (DNLH) of the GI tract is characterised by numerous small polypoid nodules of variable size in the small intestine, large intestine or both. It is commonly seen in association to immunodeficiency states such as CVID, IgA deficiency and chronic infections due to Giardia lamblia and Helicobacter pylori and cryptosporidiosis. Repetitive antigenic stimulation leads to lymphoid hyperplasia. We herein describe a case of DNLH of the intestine and another case of duodenal cytomegalovirus (CMV) infection associated with CVID., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Although earlier studies have shown that antiviral treatment regimens using valganciclovir (VGCV) improved hearing function in some infants with congenital cytomegalovirus (CMV) infection; its efficacy on the severity of hearing dysfunction is unclear. We conducted a prospective study among 26 infants with congenital CMV infections from 2009 to 2018. Oral VGCV (32 mg/kg/day) was administered for 6 weeks (November 2009 to June 2015; n = 20) or 6 months (July 2015 to March 2018, n = 6). Hearing function was evaluated by measuring the auditory brainstem response before VGCV treatment and at 6 months. Hearing dysfunction, defined as a V-wave threshold >40 dB, was categorized into: most severe, ≥91 dB; severe, 61⁻90 dB; and moderate, 41⁻60 dB. Hearing improvement was defined as a decrease of ≥20 dB from the pretreatment V-wave threshold. Of 52 ears in 26 infants with congenital CMV infection, 29 (56%) had hearing dysfunction, and of 29 ears, 16 (55%) improved after VGCV treatment. Although, 16 (84%) of 19 ears with moderate or severe hearing dysfunction improved after treatment ( p < 0.001), 10 ears with the most severe form did not. In conclusion, VGCV treatment is effective in improving moderate and severe hearing dysfunction in infants with congenital CMV infection.

A 62-year-old immunocompetent woman was admitted with cytomegalovirus (CMV) infection, pulmonary embolism, splenic vein thrombosis and monoclonal gammopathy of undetermined significance (MGUS). Anticoagulation therapy was started. Two months later, seroconversion of CMV IgM to IgG was observed, while the monoclonal protein was no longer detectable. This suggests a relationship between acute CMV infection, transient MGUS and thrombosis. In accordance with current best practice guidelines for provoked venous thromboembolism (VTE), anticoagulation therapy could be discontinued after 3 months instead of 6 for unprovoked VTE, thereby reducing unnecessary time at risk of bleeding complications. While the relationships between CMV and both MGUS and thrombosis have been described independently, we are first to describe these three conditions occurring simultaneously.Furthermore, we provide a systematic review on the relation between CMV, MGUS and thrombosis., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Although cytomegalovirus is one of the most prevalent viral pathogens on the globe, in immunocompetent individuals infected with cytomegalovirus usually no specific antiviral therapy is required. In the case of impaired T-cell mediated immunity, however, latent infection can reactivate and occasionally a viral disease with organ involvement develops. The number of actually available anti-cytomegalovirus drugs is low, for prophylaxis or treatment ganciclovir, valganciclovir, foscarnet or cidofovir can be administered. The clinical use of these drugs is primarily hampered by their toxicity. In search for new treatment options, only letermovir, a terminase complex inhibitor compound showed appropriate activity and tolerability. In a placebo-controlled clinical trial on prophylactic letermovir in stem cell transplant patients, administration of the active compound resulted in a significant decrease in human cytomegalovirus reactivations as well as in prolonged survival. No toxicity affecting clinical use has been observed. For management of patients being at high risk for cytomegalovirus reactivation, appropriate antiviral strategy should be followed. Antiviral prophylaxis or diagnostics-guided pre-emptive therapy seem to be the most suitable options. Orv Hetil. 2019; 160(10): 363-369.

In developed countries, cytomegalovirus (CMV)-infected newborns are at high risk of developing sensorineural handicaps such as hearing loss, requiring extensive follow-up. However, early prognostic tools for auditory damage in children are not yet available. In the fetus, CMV infection leads to early olfactory bulb (OB) damage, suggesting that olfaction might represent a valuable prognosis for neurological outcome of this viral infection. Here, we demonstrate that in utero CMV inoculation causes fetal infection and growth retardation in mice of both sexes. It disrupts OB normal development, leading to disproportionate OB cell layers and rapid major olfactory deficits. Olfaction is impaired as early as day 6 after birth in both sexes, long before the emergence of auditory deficits. Olfactometry in males reveals a long-lasting alteration in olfactory perception and discrimination, particularly in binary mixtures of monomolecular odorants. Although sensory inputs to the OB remain unchanged, hallmarks of autophagy are increased in the OB of 3-postnatal week-old mice, leading to local neuroinflammation and loss of neurons expressing tyrosine hydroxylase and calbindin. At the cellular level, we found CMV-infected cells and an increased number of apoptotic cells scattered throughout the OB layers, whereas cell proliferation in the neurogenic subventricular zone was decreased. These cellular observations were long-lasting, persisting up to 16 weeks after birth in both males and females and thus providing a mechanism supporting olfactory loss. Despite obvious differences in neurogenesis between human and mouse, these findings offer new strategies aimed at early detection of neurological dysfunctions caused by congenital infections. SIGNIFICANCE STATEMENT In developed countries, congenital cytomegalovirus (CMV)-infected newborns are at high risk of developing sensory handicaps such as hearing loss, thus requiring prolonged follow-up. In this study, we describe for the first time the functional impact of congenital CMV infection on the olfactory system and its associated sense of smell. We demonstrate that a mouse model of congenital CMV infection shows defects in olfactory bulb (OB) normal development and pronounced olfactory deficits affecting acuity and discrimination of odorants. These major olfactory deficits occur long before the emergence of auditory deficits through the upregulation of OB autophagy inducing local neuroinflammation and altered neuron content. Our findings provide new opportunities for designing olfactory means to monitor the possible neurological outcome during congenital CMV infection., (Copyright © 2018 the authors 0270-6474/18/3810425-14$15.00/0.)

Background: Studies on human cytomegalovirus (HCMV) and Epstein-Barr virus (EBV) have focused primarily on the immunosuppressed population. Few studies have considered immunocompetent and not severely immunocompromised patients. We determined the infection rates of HCMV and EBV, their risk factors and their influence on liver function in patients with HBV-related acute-on-chronic liver failure (ACLF)., Methods: Patients infected with ACLF-based hepatitis B virus (HBV) from 1 December 2016 to 31 May 2018 were enrolled in our study and were divided into infected and uninfected groups. The risk factors for HCMV and EBV infection and their influence on liver function were analysed., Results: A total of 100 hospitalized patients with ACLF due to HBV infection were enrolled in this study. Of these patients, 5% presented HCMV deoxyribonucleic acid (DNA) and 23.0% presented EBV DNA. An HBV DNA count of < 1000 IU/mL increased the occurrence of HCMV infection (P = 0.003). Age, especially older than 60 years, was a risk factor for EBV infection (P = 0.034, P = 0.033). HCMV-infected patients had lower alanine aminotransferase (ALT) levels; albumin levels and Child-Pugh scores in EBV-infected patients were higher than those in uninfected patients., Conclusions: HCMV and EBV were detected in patients with ACLF caused by HBV infection. Lower replication of HBV (HBV DNA < 1000 IU/mL) may increase the probability of HCMV infection; age, especially older than 60 years of age, was a risk factor for EBV infection. HCMV infection may inhibit HBV proliferation and did not increase liver injury, while co-infection with EBV may influence liver function and may result in a poor prognosis.

Interleukin-1β (IL-1β) is a key effector of the inflammasome complex in response to pathogens and danger signals. Although it is well known that assembly of the inflammasome triggers proteolytic cleavage of the biologically inactive precursor pro-IL-1β into its mature secreted form, the mechanism by which human cytomegalovirus (HCMV) regulates IL-1β production via the inflammasome is still poorly understood. Here, we show that the infection of human foreskin fibroblasts (HFFs) with a mutant HCMV lacking the tegument protein pp65 (v65Stop) results in higher expression levels of mature IL-1β compared to its wild-type counterpart, suggesting that pp65 mediates HCMV immune evasion through downmodulation of IL-1β. Furthermore, we show that enhanced IL-1β production by the v65Stop mutant is due in part to induction of DNA binding and the transcriptional activity of NF-κB. Lastly, we demonstrate that HCMV infection of HFFs triggers a non-canonical IL-1β activation pathway where caspase-8 promotes IL-1β maturation independently of caspase-1. Altogether, our findings provide novel mechanistic insights into the interplay between HCMV and the inflammasome system and raise the possibility of targeting pp65 to treat HCMV infection.

We describe a case of an adult with dermatomyositis (DM) who presents with a rash, high fevers, tachycardia and hypotension, initially concerning for an infectious aetiology or a DM flare. She was found to have cytomegalovirus viraemia which improved after starting valganciclovir. After extensive workup and lack of improvement with broad-spectrum antimicrobial therapy, intravenous immunoglobulin and steroids, the patient was diagnosed with macrophage activation syndrome after bone marrow biopsy and levels of soluble CD25 (soluble interleukin (IL)-2 receptor) and IL2 were obtained. Unfortunately, despite therapy with dexamethasone, anakinra and etoposide, the patient decompensated and the patient's family opted for comfort care. The patient subsequently expired in the intensive care unit., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2018. No commercial re-use. See rights and permissions. Published by BMJ.)