Search Results (143)

Cytomegalovirus (CMV) is the most common infectious cause of congenital malformations, often presenting with atypical clinical findings. Fetal damage is most severe following primary maternal infection during the first trimester of pregnancy, with the likelihood of transmission increasing with pregnancy advancement. CMV damage may continue to intensify during the early postnatal years. In this narrative review we summarized publications from the last 30 years addressing the epidemiology, diagnosis, prevention and treatment of CMV in pregnancy, with a special emphasis on embryonic and fetal damage. Substantial progress has been made in the diagnosis and treatment of CMV infection during pregnancy, warranting a reconsideration of current clinical approaches. Assessment of viral load enables prediction of fetal infection; its reduction by maternal treatment with valacyclovir may lower both the rate and severity of transmission. Confirmed fetal infection can be diagnosed by amniocentesis and viral DNA detection. Clinical manifestations in infants may be evident at birth (cCMV) or gradually emerge during the first years. The most common fetal damage is hearing loss alongside a variety of brain lesions resulting in significant neurological deficits, including intellectual impairment. Brain involvement is diagnosed by ultrasound or magnetic resonance imaging (MRI). Pharmacological treatment with ganciclovir or valganciclovir, if initiated early after birth, can slow the progression of hearing loss and may ameliorate other neurological and neurodevelopmental deficits. As of today, there is no approved CMV vaccine for prevention. The mRNA-1647’s vaccine, currently in phase 3 clinical trial, appears promising. These advances underscore the need for screening pregnant women in the first trimester and newborn infants of mothers suspected of having CMV infection. Neurodevelopmental follow up for several years, including hearing and visual assessment, is advised in all infants positive for CMV. Infants with clinical manifestations should be offered treatment as early as possible following diagnosis of cCMV. Full article

The emergence of drug-resistant cytomegalovirus (CMV) complicates viral response to therapy. We present two cases of solid organ transplant (SOT) recipients, highlighting the reversion of UL97 mutations associated with val(ganciclovir) resistance. Patient 1, a heart transplant recipient, initially received pre-emptive treatment with val(ganciclovir), followed by foscarnet for recurrent CMV episodes. Mutations A594V in the UL97-kinase gene and V715M in the UL54-polymerase gene were detected. He developed CMV colitis and was then treated with maribavir. After discontinuing val(ganciclovir), genotyping revealed no resistance mutations. Following CMV DNA suppression, secondary prophylaxis with letermovir and val(ganciclovir) was initiated. Patient 2, a double-lung transplant recipient, experienced several CMV episodes. Initially treated with val(ganciclovir), he developed the L595S mutation in the UL97 kinase gene, conferring resistance. Therapy was then switched to foscarnet, which was suspended due to renal failure, and then to maribavir. Subsequently, the H411Y mutation in the UL97 was detected, conferring maribavir resistance, while val(ganciclovir) mutation was no longer detectable. He was then treated with val(ganciclovir) and letermovir, achieving undetectable CMV DNA, and then continued letermovir alone as prophylaxis. Detecting gene mutations that confer drug resistance is crucial for managing antiviral therapy when virological response is lacking. In our cases, the reversion of (va)ganciclovir-resistance mutations occurred after drug withdrawal, a previously unreported finding. Full article

Background: Cytomegalovirus (CMV) remains a formidable complication in small bowel transplantation (SBT) due to the graft’s high immunogenicity and profound immunosuppression required, with refractory disease representing a particularly devastating challenge. Case: We report an 18-year-old male who underwent SBT, complicated by recurrent acute rejection episodes requiring intensive immunosuppression. He developed refractory CMV disease, marked by non-response to first line therapy with ganciclovir—despite the absence of genotypic resistance—necessitating sequential use of foscarnet, dual antivirals, CMV immunoglobulin, and novel agents (maribavir and letermovir). Discussion: This case illustrates the multifactorial drivers of refractory CMV disease in SBT recipients, including donor–recipient serostatus mismatch, profound immunosuppression through T-cell-depleting induction, corticosteroid exposure, and biologic therapy. It highlights the distinction between refractory and resistant CMV, and the role of combination antiviral strategies including novel agents to achieve disease control. Outcomes remain dismal despite aggressive and innovative therapies, underscoring the limited efficacy of interventions in the context of severe immunologic compromise. Conclusions: Refractory CMV enteritis in SBT exemplifies the extreme difficulty of balancing viral control with rejection management. Despite exhausting antiviral strategies, survival remains poor. Highlights: Refractory CMV enteritis is a significant challenge in small bowel transplant recipients due to intense immunosuppression. Persistent CMV disease may occur despite antiviral prophylaxis and the absence of resistant gene mutations. Combination antiviral strategies, including maribavir, demonstrated significant clinical improvement. Profound immunosuppression required to manage acute graft rejection episodes complicates antiviral management and disease clearance. Despite best efforts in CMV management in this population, outcomes may still be compromised by unrelated or compounding factors. Full article

Background/Objectives: Cytomegalovirus (CMV) is an opportunistic pathogen, complicating acute severe ulcerative colitis (ASUC), and its role in ASUC prognosis remains a debate. This study aims to report the rates and identify predictors for colectomy at 12 months, following an episode of ASUC with concomitant CMV colonic infection. Methods: This is a retrospective cohort study of patients with ASUC and CMV colonic infection confirmed by PCR or Immunohistochemistry. Baseline clinical, biochemical, endoscopic and disease-related characteristics were recorded. Patients were followed-up for 12 months to calculate the one-year colectomy rate. Predictors of colectomy were identified via multivariate logistic regression. Results: Forty-five cases of CMV colonic infection in 37 patients with ASUC were recorded [66.7% men, mean age: 47.0 years (SD = 18.5)]. At diagnosis, 20% were on monotherapy with advanced treatment and 37.8% on advanced treatment plus corticosteroids and/or immunomodulators. Twenty-three (51.1%) were receiving corticosteroids, while 17.8% did not receive any immunosuppressive agent. Forty (88.9%) patients were treated with ganciclovir and valganciclovir and one (2.2%) with foscarnet for at least 21 days. Eleven patients (24.4%) required colectomy, two (4.4%) during their initial hospitalization and nine (20%) during the follow-up period. The recurrence of CMV was recorded in nine (20.9%) cases, three of which required colectomy. Patients with hemoglobin < 12 g/dL (p = 0.023) and patients on vedolizumab at diagnosis (p = 0.050) had a higher probability of colectomy. Conclusions: We report a 25% one-year colectomy rate in our cohort with ASUC and superimposed CMV colonic infection. At baseline, anemia and vedolizumab treatment were associated with a higher probability of colectomy. Full article

Postnatal cytomegalovirus (pCMV) infection is typically asymptomatic in term infants but poses significant risks to very preterm and very low birth weight (VLBW) infants. The primary mode of transmission of pCMV is breast milk from seropositive mothers. Here, we present the case of a 29-week preterm female who contracted pCMV and began to manifest symptoms at day of life (DOL) 50. She developed respiratory compromise, massive ascites, and was extremely ill. The patient was managed with ganciclovir (GCV), intravenous immunoglobulins (IVIG), and percutaneous drainage of the ascites. She gradually improved and was discharged after a 5-month neonatal intensive care unit (NICU) stay. After presenting the case, we review the clinical manifestations of pCMV, and particularly its less well-recognized gastrointestinal manifestations, including ascites. We then outline guidelines for treatment and prevention. Clinicians should consider pCMV in VLBW and extremely premature infants presenting with thrombocytopenia, colitis, or ascites, especially in the second and third months of life. Full article

Cytomegalovirus (CMV) represents the most prevalent cause of congenital viral infection in newborns and the leading non-genetic etiology of sensorineural hearing loss (SNHL) in children. Notably, only 10–15% of congenitally infected infants possibly present with classic clinical symptoms at birth, including Small for gestational age, Microcephaly, Petechiae or purpura, Blueberry muffin rash, Jaundice, Hepatomegaly, Splenomegaly and abnormal neurologic signs. In contrast, approximately 90% of infected neonates exhibit no apparent symptoms initially. Current research predominantly focuses on symptomatic cases due to their severe acute presentations and high rates of long-term sequelae (40–60%), including SNHL and neurodevelopmental impairments. However, significant controversy persists regarding the management of asymptomatic infants. Emerging evidence reveals that 8–15% of asymptomatic carriers develop Late-onset Hearing Loss (LOHL) beyond the neonatal period. Additionally, 5–10% may manifest neurodevelopmental abnormalities including mild intellectual disability, learning difficulties, or motor coordination disorders. Crucially, given the substantial population of asymptomatic cCMV cases, these delayed complications account for 30–40% of all cCMV-related long-term morbidity, underscoring their considerable public health impact. This review synthesizes current evidence and controversies regarding cCMV-related SNHL in asymptomatic or mildly symptomatic children, with a focus on screening, diagnostic classification, and antiviral management gaps, to heighten clinical awareness of this underrecognized cause of hearing loss. Full article

Infections with cytomegalovirus (CMV) can result in increased morbidity and mortality in immunocompromised patients. The pUL97 kinase is a critical enzyme in the regulation of CMV replication. Although it does not phosphorylate deoxynucleosides, this enzyme is involved in the first phosphorylation step of ganciclovir (GCV), a viral DNA polymerase inhibitor. In contrast, maribavir (MBV) is a specific inhibitor of pUL97 kinase activity. In this paper, we analyzed the already-reported amino acid changes, conferring resistance to MBV and cross-resistance to GCV, in the pUL97 protein structure, predicted with AlphaFold2. Docking experiments suggest that MBV is a dual-site inhibitor, targeting ATP binding and substrate phosphorylation. Substitutions that confer resistance to MBV only may directly or indirectly alter the shape of the cavity in the vicinity of the invariant K355 in the putative ATP binding site, without affecting the viral growth. The most frequently encountered T409M substitution may correspond to a gatekeeper mutation. Substitutions that induce cross-resistance to MBV and GCV may directly or indirectly affect the environment of D456 and N461 residues in the catalytic loop, with reduced viral replicative capacity. These results have implications for the clinical use of MBV as well as for the design of novel pUL97 kinase inhibitors. Full article

Cytomegalovirus (CMV) colitis, a complication in patients with inflammatory bowel disease (IBD), particularly ulcerative colitis (UC), is a significant diagnostic and therapeutic challenge due to its overlap with IBD flares. CMV reactivation in IBD is driven by chronic inflammation, compromised immune function, and use of immunosuppressive agents like corticosteroids. Risk factors include older age, pancolitis, and severe disease. Diagnosis hinges on endoscopy and histology, with tissue biopsy and immunohistochemistry as the gold standard. Quantitative tissue PCR may aid in differentiating latent from active infection. CMV colitis exacerbates IBD symptoms, prolongs hospitalization, and increases colectomy rates. Antiviral therapy, primarily ganciclovir, improves outcomes in patients with corticosteroid-refractory UC. Treatment focuses on tapering corticosteroids, optimizing biologic therapies such as infliximab, and a careful application of antivirals tailored to disease severity and viral load. Further research is needed to refine diagnostic thresholds and treatment strategies to mitigate CMV’s impact on IBD prognosis. Early identification and individualized management are critical to improving clinical outcomes and reducing morbidity. Full article

Background: Cytomegalovirus (CMV) infection is the most common and serious congenital infection, with universal screening in pregnancy, standardized therapy, and a vaccine still lacking. Study design: In the 1990s, we noted that intravenous ganciclovir did not cure some children with severe sequelae due to congenital cytomegalovirus (CMV) infection. Therefore, we performed an open randomized trial using intravenous foscarnet as an alternative to intravenous ganciclovir in 24 infants (12 in each therapy group), all with severe neurological manifestations due to congenital CMV infection. Nine and five infants, belonging to the foscarnet or ganciclovir group, respectively, had abnormal hearing. One infant in each group also had chorioretinitis. Concomitantly, 12 CMV-infected infants with similar manifestations, who did not receive any therapy, were used as controls. The results of short-term (2 years) and long-term (7–29 years, mean 22.2) follow-up are reported herein. Short-term results: Neurological outcomes were normal in five of the twelve children who were treated with foscarnet, compared to nine of the twelve children given ganciclovir. None of the untreated children were healthy. There was a statistically significant difference (p = 0.023) between the treated and untreated children. Hearing was normal in four of the twelve children treated with foscarnet, seven of the twelve children treated with ganciclovir, and two untreated children. Long-term-results: Two children in both therapy groups died before the age of 17 years, and six untreated children died between 7 and 26 years of age. Neurological outcomes were normal in three of the ten children treated with foscarnet, in two of the ten treated with ganciclovir, and in none of the untreated children. Hearing was normal in two children treated with foscarnet, in six children treated with ganciclovir, and in one untreated child. Conclusions: Intravenous ganciclovir and foscarnet were found to be safe at long-term follow-up and appeared to be capable of mitigating the neurological and auditory consequences of congenital CMV disease at the short-term follow-up. However, there was progressive worsening of the symptomatology in all three groups, with a statistically significant increase in the number of deaths (p = 0.035) among 4 of the 24 children in the therapy groups and 6 of the 12 untreated children. Full article

Background/Objectives: Multi-lumen devices that limit physicochemical incompatibilities (PCIs) are frequently used in neonatal intensive care units where premature infants receive numerous infusions. The aim of the study was to investigate a PCI that occurred despite the use of a device of this type (EDELVAISS^® Multiline NEO, Doran International, Toussieu, France). Case Summary: A 7-week-old preterm infant received ganciclovir at therapeutic dosage for cytomegalovirus (CMV) infection. After the fifth administration of ganciclovir, a PCI occurred, leading to a white precipitate. The peripheral inserted central catheter (PICC) (PREMICATH^®2Fr, Vygon, Ecouen, France) had to be replaced. Laboratory reproduction of the administrations during 72 h, nuclear magnetic resonance (NMR) analysis and particle counting were carried out to analyse the occurrence of events leading to PCIs. The precipitate was linked to a PCI of parenteral nutrition associated with a dilution error of ganciclovir (omission of a 10-fold dilution step, resulting in ganciclovir being administered at 30 mg/L instead of 3 mg/L). Due to the presence of lipids in the parenteral nutrition, visual detection of the white precipitate was difficult. Conclusions: Multi-lumen infusion devices limit but do not prevent the occurrence of PCIs, particularly in the event of a preparation error. Despite the use of this type of device, great vigilance is still required, particularly with regard to prescription analysis and reconstitution procedures. Full article

Adenovirus (AdV) infections can lead to significant morbidity and increased mortality in immunocompromised populations such as hematopoietic stem cell and solid organ transplant recipients. This review evaluates currently available and emerging therapies for AdV infections. Cidofovir, while most commonly used, is limited by its variable efficacy and nephrotoxicity. This led to the development of brincidofovir, which has a better safety profile and great in vitro potency against AdV. The use of ribavirin and ganciclovir has been reported in the literature, but their use is limited due to inconsistent efficacy. Immune-based approaches, such as adoptive T-cell therapy, have shown promise in achieving viral clearance and improving survival but remain constrained by challenges related to manufacturing complexity and risks of graft-versus-host disease. This review underscores the need for standardized treatment protocols as well as comparative studies to identify optimal dosing and timing to initiate treatment. Future research should focus on individualized treatment approaches and the development of novel therapeutic agents to address the unmet clinical needs of AdV management. Full article

Background: Human cytomegalovirus (CMV) remains an important pathogen, especially for immunocompromised patients such as solid organ and hematopoietic stem cell recipients. Viral genomic mutations conferring drug resistance are an important impediment to effective CMV management and frequently lead to use of alternative antiviral drugs to treat CMV disease. Methods: Results from 1459 de-identified patient samples with both UL54 and UL97 sequencing results were analyzed for ganciclovir (GCV) and maribavir (MBV) resistance mutations. Genomic sequencing was performed by the Sanger method and resistance mutations were identified by comparison to CMV reference strain AD169. Results: Ganciclovir resistance was identified in 379 of 1459 (25.98%) of the samples tested, with most resistance-conferring mutations present in viral gene UL97. A total of 121 of 1459 (8.29%) samples had MBV resistance mutations, and 84 (69.42%) of the 121 samples with MBV resistance also had GCV resistance mutations. Of the 84 samples with resistance to both MBV and GCV, 35 (41.67%) had a single UL97 mutation conferring resistance to both drugs, either C480F or F342Y. The overall prevalence of C480F was increased relative to an earlier analysis of samples from this reference laboratory. Conclusions: Although a high prevalence of CMV resistance mutations was identified, this must be taken in the context of healthcare providers submitting samples from patients with suspected CMV resistance. Most MBV-resistant samples were also resistant to GCV, suggesting that use of MBV as an alternative to GCV may benefit from genotypic resistance testing to achieve the effective control of CMV disease. Full article

The occurrence and severity of periodontitis (PD) tend to increase with age, and yet the underlying mechanisms remain unclear. Immune senescence is known to be triggered in mice and humans as they age. Experimental PD in mice has been shown to induce senescence biomarkers p16 ^INK4a and p21, dysfunction of antigen-presenting cells (APCs), and activation of the senescence-associated secretory phenotype (SASP). However, the causal links of senescence to experimental PD are not yet established. This study aims to elucidate the role of senescence in experimental PD at a causal level. The P16-3MR mouse model harbors the p16^INK4a (Cdkn2a) promoter, driving in vivo expression of synthetic Renilla luciferase, monomeric red fluorescent protein (mRFP), and herpes simplex virus-1 thymidine kinase (HSV-TK). This facilitates in vivo identification of p16 ^INK4a activation at the cellular level and the consequences of selective elimination of p16^INK4a-positive cells by ganciclovir (GCV) treatment. Mice were treated with/without GCV for two weeks during ligature-induced PD. In vivo bioluminescence imaging quantified p16^INK4a activation, while Western blot and immunofluorescence analyses assessed key senescence and inflammatory markers (p16, p21, p53, Cyclin D1, p-H2A.X, IL17, and IL1β). Alveolar bone volume was analyzed by micro-CT and histomorphometry. Our findings demonstrate that clearance of senescent cells in mice subjected to experimental PD alleviates inflammation and mitigates bone loss. These results suggest a causal role for senescence in PD pathology, raising the future prospect of senolytic agents for therapeutic intervention in PD. Full article

Background/Objectives: Human cytomegalovirus (HCMV) DNAemia remains a significant concern for transplant recipients, largely due to mutations in the viral genome that may lead to antiviral-resistant strains. Mutations in the UL97 gene are frequently associated with resistance to ganciclovir (GCV), highlighting the importance of early mutation detection to effectively manage viremia. This study aimed to optimize a Sanger sequencing protocol for analyzing GCV resistance-linked mutations in the HCMV UL97 gene from plasma samples of transplant patients treated at Hospital de Clínicas de Porto Alegre, Rio Grande do Sul, Brazil. Methods: A nested-PCR approach combined with a touchdown PCR method was employed to enhance the sensitivity and specificity of the sequencing analysis. Results: The study sample included various transplants, encompassing solid organ and bone marrow recipients. Among 16 sequenced samples, 8 exhibited nucleotide substitutions resulting in amino acid changes. Notably, the A594V and C603W mutations, associated with GCV resistance, were identified in four samples. Additionally, three mutations with unknown phenotypic impact (P509L, A628T, and H662Y) and two viral polymorphisms (N510S and D605E) were detected. Furthermore, double peaks in the Sanger electropherograms, indicative of mixed viral populations of HCMV were observed in seven samples. Conclusions: The optimized Sanger sequencing protocol provides a cost-effective solution for detecting GCV resistance mutations in HCMV UL97 among transplant recipients. This approach could improve the understanding of HCMV strain dynamics and serve as a valuable tool for long-term patient monitoring, particularly within resource-constrained settings such as the public health systems of middle-income countries. Full article

Cytomegalovirus (CMV) infection in solid organ transplant (SOT) and hematopoietic cell transplant (HCT) recipients may increase the risk of rejection or allograft dysfunction, other infection(s), and morbidity and mortality. Treatment can be challenging due to medication-associated toxicities. Maribavir (MBV) is a promising option for the treatment of resistant or refractory (R/R) CMV infection in lieu of foscarnet (FOS), which has long been the recommended therapy for (val)ganciclovir-resistant infection. This was a single-center retrospective study of clinical outcomes of patients who received MBV compared to a control group who received FOS for an episode of CMV infection. Each cohort consisted of 27 episodes of CMV infection. Twenty patients in the MBV cohort and from the FOS cohort cleared the infection, with five and three patients developing MBV or FOS resistance, respectively. There were no statistically significant differences in failure of therapy as evidenced by persistent DNAemia (p = 0.56) or development of antiviral resistance (p = 0.24). In conclusion, MBV was as effective as FOS for the treatment of R/R CMV infection and was better tolerated without increased risk of antiviral resistance. Full article