Changing knowledge, attitudes and behaviours towards cytomegalovirus in pregnancy through film-based antenatal education: a feasibility randomised controlled trial of a digital educational intervention.

BACKGROUND: Congenital cytomegalovirus (CMV) is the most common congenital infection globally, however information about CMV is not routinely included in antenatal education in the United Kingdom. This feasibility study aimed to gather the essential data needed to design and power a large randomised controlled trial (RCT) to investigate the efficacy of a digital intervention in reducing the risk of CMV acquisition in pregnancy. In order to do this, we carried out a single-centre RCT, which explored the knowledge, attitudes and risk reduction behaviours in women in the intervention and treatment as usual groups, pre- and post-intervention. METHODS: CMV seronegative women living with a child less than four years old, receiving antenatal care at a single UK tertiary centre, were randomised to the digital intervention or 'treatment as usual' groups. Participants completed questionnaires before the digital intervention and after and at 34 gestational weeks, and responses within groups and between groups were compared using tailored randomisation tests. CMV serology was tested in the first trimester and at the end of pregnancy. RESULTS: Of the 878 women screened, 865 samples were analysed with 43% (n = 372) being CMV seronegative and therefore eligible to take part in the RCT; of these, 103 (27.7%) women were enrolled and 87 (84%) of these completed the study. Most participants (n = 66; 64%) were unfamiliar with CMV at enrolment, however at 34 gestational weeks, women in the intervention group (n = 51) were more knowledgeable about CMV compared to the treatment as usual group (n = 52) and reported engaging in activities that may increase the risk of CMV transmission less frequently. The digital intervention was highly acceptable to pregnant women. Overall, four participants seroconverted over the course of the study: two from each study group. CONCLUSIONS: A large multi-centre RCT investigating the efficacy of a CMV digital intervention is feasible in the United Kingdom; this study has generated essential data upon which to power such a study. This single-centre feasibility RCT demonstrates that a digital educational intervention is associated with increase in knowledge about CMV and can result in behaviour change which may reduce the risk of CMV acquisition in pregnancy. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03511274 , Registered 27.04.18, http://www.Clinicaltrials.gov.

Valganciclovir for symptomatic congenital cytomegalovirus disease.

BACKGROUND: The treatment of symptomatic congenital cytomegalovirus (CMV) disease with intravenous ganciclovir for 6 weeks has been shown to improve audiologic outcomes at 6 months, but the benefits wane over time. METHODS: We conducted a randomized, placebo-controlled trial of valganciclovir therapy in neonates with symptomatic congenital CMV disease, comparing 6 months of therapy with 6 weeks of therapy. The primary end point was the change in hearing in the better ear ("best-ear" hearing) from baseline to 6 months. Secondary end points included the change in hearing from baseline to follow-up at 12 and 24 months and neurodevelopmental outcomes, with each end point adjusted for central nervous system involvement at baseline. RESULTS: A total of 96 neonates underwent randomization, of whom 86 had follow-up data at 6 months that could be evaluated. Best-ear hearing at 6 months was similar in the 6-month group and the 6-week group (2 and 3 participants, respectively, had improvement; 36 and 37 had no change; and 5 and 3 had worsening; P=0.41). Total-ear hearing (hearing in one or both ears that could be evaluated) was more likely to be improved or to remain normal at 12 months in the 6-month group than in the 6-week group (73% vs. 57%, P=0.01). The benefit in total-ear hearing was maintained at 24 months (77% vs. 64%, P=0.04). At 24 months, the 6-month group, as compared with the 6-week group, had better neurodevelopmental scores on the Bayley Scales of Infant and Toddler Development, third edition, on the language-composite component (P=0.004) and on the receptive-communication scale (P=0.003). Grade 3 or 4 neutropenia occurred in 19% of the participants during the first 6 weeks. During the next 4.5 months of the study, grade 3 or 4 neutropenia occurred in 21% of the participants in the 6-month group and in 27% of those in the 6-week group (P=0.64). CONCLUSIONS: Treating symptomatic congenital CMV disease with valganciclovir for 6 months, as compared with 6 weeks, did not improve hearing in the short term but appeared to improve hearing and developmental outcomes modestly in the longer term. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT00466817.).

Characterising variation in five genetic loci of cytomegalovirus during treatment for congenital infection.

Cytomegalovirus (CMV) is the most common congenital infection in humans and a leading cause of sensorineural hearing loss. Ganciclovir (6 mg/kg twice daily for 42 days) has been shown to reduce hearing deterioration and is used in clinical practice. Vaccines and passive administration of antibody are being evaluated in randomized controlled trials in allograft candidates, women of childbearing age, and pregnant women with primary CMV infection. To help define genetic variation in each of the targets of these therapeutic interventions, we amplified and sequenced genes UL97 (site utilised for ganciclovir phosphorylation), UL55 (glycoprotein B (gB) vaccine target) and UL128, UL130, and UL131a (specific monoclonal antibody targets). Serial blood, saliva, and urine samples (total 120) obtained from nine infants with symptomatic congenital CMV treated with 42 days' ganciclovir were analyzed. All samples tested were UL97 wild type at baseline and none developed mutations during treatment, showing no selection of resistance. The prevalences of UL55 genotypes were 28% gB1, 22% gB2, 1% gB3, and mixed in 20% samples. No mutations were noted in UL128-131a. Phylogenetic tree analysis showed that sequences with variations were found in multiple body sites of individual patients, so there was no evidence of body site compartmentalization of particular strains of CMV. The significance of these results for changes in diagnostic practices and therapeutic interventions against CMV are discussed. J. Med. Virol. 89:502-507, 2017. © 2016 Wiley Periodicals, Inc.

Fifteen-minute consultation: diagnosis and management of congenital CMV.

Congenital cytomegalovirus (cCMV) infection can result in permanent neurological problems and is a potentially preventable cause of sensorineural hearing loss in the UK. There is an urgency to diagnose and assess cCMV as antiviral treatment and has only been shown to be effective if started in the first 4 weeks of life. A recent randomised controlled trial of 6 months of treatment using oral valganciclovir has shown modest benefit in preventing hearing deterioration and in improving some neurodevelopmental outcomes. Parents and clinicians need to make a timely and informed choice regarding antiviral treatment and ensure that relevant non-pharmaceutical interventions are considered. This paper brings together the current evidence regarding the diagnosis and treatment of cCMV, consensus from two paediatric infectious diseases centres and outlines research priorities.

Evaluating the feasibility of integrating salivary testing for congenital CMV into the Newborn Hearing Screening Programme in the UK.

UNLABELLED: Congenital cytomegalovirus (cCMV) accounts for 20% of all childhood sensorineural hearing loss (SNHL) but is not routinely tested for at birth. Valganciclovir has been shown to prevent hearing deterioration and improve neurocognitive outcomes if started in the first month of life. This study aimed to assess the feasibility of integrating testing for cCMV using salivary swabs into the Newborn Hearing Screening Programme (NHSP). Parents of newborns <22 days old in South West London, who were referred after their initial newborn hearing screen for further audiological testing, were approached by hearing screeners to obtain a saliva sample for CMV DNA polymerase chain reaction (PCR). Eighty percent (203/255) of newborns who were eligible had a saliva swab taken by the hearing screener. Over 99% of results were delivered within the first month of life. Two newborns were identified with cCMV and both seen on day 10 of life by the paediatric specialist. All saliva samples tested delivered a result using real-time PCR. CONCLUSION: It is feasible for hearing screeners to obtain saliva swabs to test for CMV DNA using real-time PCR in newborns referred after their initial hearing screen. Rapid diagnostic testing for cCMV needs a more detailed clinical and cost-effectiveness analysis.

Cytomegalovirus glycoprotein-B vaccine with MF59 adjuvant in transplant recipients: a phase 2 randomised placebo-controlled trial.

BACKGROUND: Cytomegalovirus end-organ disease can be prevented by giving ganciclovir when viraemia is detected in allograft recipients. Values of viral load correlate with development of end-organ disease and are moderated by pre-existing natural immunity. Our aim was to determine whether vaccine-induced immunity could do likewise. METHODS: We undertook a phase-2 randomised placebo controlled trial in adults awaiting kidney or liver transplantation at the Royal Free Hospital, London, UK. Exclusion criteria were pregnancy, receipt of blood products (except albumin) in the previous 3 months, and simultaneous multiorgan transplantation. 70 patients seronegative and 70 seropositive for cytomegalovirus were randomly assigned from a scratch-off randomisation code in a 1:1 ratio to receive either cytomegalovirus glycoprotein-B vaccine with MF59 adjuvant or placebo, each given at baseline, 1 month and 6 months later. If a patient was transplanted, no further vaccinations were given and serial blood samples were tested for cytomegalovirus DNA by real-time quantitative PCR (rtqPCR). Any patient with one blood sample containing more than 3000 cytomegalovirus genomes per mL received ganciclovir until two consecutive undetectable cytomegalovirus DNA measurements. Safety and immunogenicity were coprimary endpoints and were assessed by intention to treat in patients who received at least one dose of vaccine or placebo. This trial is registered with ClinicalTrials.gov, NCT00299260. FINDINGS: 67 patients received vaccine and 73 placebo, all of whom were evaluable. Glycoprotein-B antibody titres were significantly increased in both seronegative (geometric mean titre 12,537 (95% CI 6593-23,840) versus 86 (63-118) in recipients of placebo recipients; p<0.0001) and seropositive (118,395; 64,503-217,272) versus 24,682 (17,909-34,017); p<0.0001) recipients of vaccine. In those who developed viraemia after transplantation, glycoprotein-B antibody titres correlated inversely with duration of viraemia (p=0.0022). In the seronegative patients with seropositive donors, the duration of viraemia (p=0.0480) and number of days of ganciclovir treatment (p=0.0287) were reduced in vaccine recipients. INTERPRETATION: Although cytomegalovirus disease occurs in the context of suppressed cell-mediated immunity post-transplantation, humoral immunity has a role in reduction of cytomegalovirus viraemia. Vaccines containing cytomegalovirus glycoprotein B merit further assessment in transplant recipients. FUNDING: National Institute of Allergy and Infectious Diseases, Grant R01AI051355 and Wellcome Trust, Grant 078332. SPONSOR: University College London (UCL).

Vestibular and balance dysfunction in children with congenital CMV: a systematic review.

OBJECTIVE: This systematic review evaluates vestibular and balance dysfunction in children with congenital cytomegalovirus (cCMV), makes recommendations for clinical practice and informs future research priorities. DESIGN: MEDLINE, Embase, EMCARE, BMJ Best Practice, Cochrane Library, DynaMed Plus and UpToDate were searched from inception to 20 March 2021 and graded according to Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) criteria. PATIENTS: Children with cCMV diagnosed within 3 weeks of life from either blood, saliva and/or urine (using either PCR or culture). INTERVENTION: Studies of vestibular function and/or balance assessments. MAIN OUTCOME MEASURES: Vestibular function and balance. RESULTS: 1371 studies were identified, and subsequently 16 observational studies were eligible for analysis, leading to an overall cohort of 600 children with cCMV. All studies were of low/moderate quality. In 12/16 studies, vestibular function tests were performed. 10/12 reported vestibular dysfunction in ≥40% of children with cCMV. Three studies compared outcomes for children with symptomatic or asymptomatic cCMV at birth; vestibular dysfunction was more frequently reported in children with symptomatic (22%-60%), than asymptomatic cCMV (0%-12.5%). Two studies found that vestibular function deteriorated over time: one in children (mean age 7.2 months) over 10 months and the other (mean age 34.7 months) over 26 months. CONCLUSIONS: Vestibular dysfunction is found in children with symptomatic and asymptomatic cCMV and in those with and without hearing loss. Audiovestibular assessments should be performed as part of neurodevelopmental follow-up in children with cCMV. Case-controlled longitudinal studies are required to more precisely characterise vestibular dysfunction and help determine the efficacy of early supportive interventions. PROSPERO REGISTRATION: CRD42019131656.

Antiviral therapy of CMV disease in children.

Cytomegalovirus (CMV) remains an important cause of morbidity and mortality in infants and children. The main burden of disease occurs in congenital infection, postnatal infection in premature infants and in older immunocompromised children (now predominantly following transplantation) in developed countries. In lower income countries, CMV is a major co-pathogen in human immunodeficiency virus [HIV]-infected infants. Antiviral treatment options remain very limited. The guanosine analogue ganciclovir (GCV) was first used in children over 20 years ago, but the optimal dose, duration and route of administration remain poorly evidence based. In particular there are very limited data in premature infants and older children. Direct comparison studies between the intravenous ganciclovir and the oral valyl-ester valganciclovir (VGCV) have not been performed. CMV disease is important, but not very common and there remains a need to identify useful surrogate markers of successful antiviral therapy to facilitate clinical trials. Cidofovir and foscarnet have very significant toxicity. No other anti-CMV agent has successfully completed phase III studies. There remain few other antiviral agents effective against CMV on the horizon. This chapter reviews the current clinical spectrum of CMV disease in childhood and the evidence base for both GCV and VGCV use in clinical practice. It also discusses the antiviral studies currently being performed and those that need to be performed.

Congenital Cytomegalovirus Infection: A Narrative Review of the Issues in Screening and Management From a Panel of European Experts.

Maternal primary and non-primary cytomegalovirus (CMV) infection during pregnancy can result in in utero transmission to the developing fetus. Congenital CMV (cCMV) can result in significant morbidity, mortality or long-term sequelae, including sensorineural hearing loss, the most common sequela. As a leading cause of congenital infections worldwide, cCMV infection meets many of the criteria for screening. However, currently there are no universal programs that offer maternal or neonatal screening to identify infected mothers and infants, no vaccines to prevent infection, and no efficacious and safe therapies available for the treatment of maternal or fetal CMV infection. Data has shown that there are several maternal and neonatal screening strategies, and diagnostic methodologies, that allow the identification of those at risk of developing sequelae and adequately detect cCMV. Nevertheless, many questions remain unanswered in this field. Well-designed clinical trials to address several facets of CMV treatment (in pregnant women, CMV-infected fetuses and both symptomatic and asymptomatic neonates and children) are required. Prevention (vaccines), biology and transmission factors associated with non-primary CMV, and the cost-effectiveness of universal screening, all demand further exploration to fully realize the ultimate goal of preventing cCMV. In the meantime, prevention of primary infection during pregnancy should be championed to all by means of hygiene education.

Maternal type of CMV infection and sequelae in infants with congenital CMV: Systematic review and meta-analysis.

Cytomegalovirus (CMV) is the most common congenital infection. Intrauterine transmission may occur following primary (PI) or non-primary (NPI) maternal infection and result in both neonatal symptomaticdisease and long-term complications.The aim of the present systematic review and meta-analysis was the qualitative and quantitative comparison of neonatal symptomatic disease and long-term sequelae of congenitally CMV infected children born following maternal PI or NPI. Articles from MEDLINE and SCOPUS databases were systematically reviewed. Articles describing neonatal symptoms and/or long-term sequelae in infants and children with cCMV born to mothers following PI and NPI were eligible.From eligible articles, data on the prevalence of neonatal symptoms, sensorineural hearing loss (SNHL) or neurologic sequelae in children born following PI and NPI were extracted and statistically analyzed. Maternal infection status did not influence neonatal symptomatic disease (pooled Odds Ratio (OR) 0.83, 95 % CI [0.55; 1.27], p=0.397). Additionally, the two groups of cCMV infected children had similar risk of developing SNHL, bilateral SNHL or other neurologic outcomes. Importantly, these findings remained as such, when newborns identified through universal screening were separately analyzed. Finally, when data on symptomatic and/or asymptomatic newborns were evaluated alone, maternal type was not associated with outcomes examined. Considering available data, the universal screening of all newborns for CMV infection may be discussed as a perspective. The systematic review and meta-analysis were registered in PROSPERO (Prospero registration number: CRD42019125179).

Use of stored dried blood spots for retrospective diagnosis of congenital CMV.

The diagnosis of congenital cytomegalovirus infection cannot be made with certainty in children presenting after the perinatal period, unless stored early samples are available for diagnostic testing. This has led to uncertainty in confirming the overall contribution of CMV to hearing loss and neurodevelopmental impairment. The use of dried blood spots (DBSs) to retrospectively diagnose infection in children with compatible symptoms may be helpful diagnostically although there are ongoing uncertainties regarding the stability of viral DNA in cards, the risk of contamination between cards, and sensitivity and specificity in a clinical setting. This report aims to address these areas and evaluate the use of DBS testing in our hands in the United Kingdom to date. Results from testing artificially prepared cards and cards from three populations of children suggest a high specificity for congenital CMV infection and a good sensitivity for cases where sensorineural hearing loss is caused by congenital CMV.

Neonatal listeriosis in the UK 2004-2014.

OBJECTIVE: To define the clinical features and outcomes of neonatal listeriosis, and identify the maternal risk factors to seek scope for improvement. METHODS: Neonatal listeriosis was identified prospectively from a United Kingdom neonatal infection surveillance network (neonIN) between 2004 and 2014. The participating neonatal units completed a study-specific proforma. RESULTS: The incidence of neonatal listeriosis was 3.4 per 100,000 live births. Of the 21 cases identified, 19 were confirmed with a median gestational age of 33 weeks and a median birth weight of 1960 g. The majority had clinical features (95%, 18/19), presented within the first 24 h (95%, 18/19), and received penicillin empirically (94%, 18/19). The neonatal case-fatality rate was 21% (24% if probable cases were included). A proportion of mothers were investigated (60%, 12/18) and diagnosed with listeriosis (58%, 7/12); 32% (6/19) were treated with antibiotics but only 33% (6/12) included penicillin. DISCUSSION: Despite its rarity and the prompt and appropriate use of antibiotics neonatal listeriosis has a high case-fatality rate. There is room for improvement in the adherence to the empiric antibiotic choice for puerperal sepsis, according to the national guidelines as this, would target listeriosis. Strategies should be in place to prevent pregnancy-associated listeriosis in higher risk population.

First estimates of the potential cost and cost saving of protecting childhood hearing from damage caused by congenital CMV infection.

BACKGROUND: Congenital cytomegalovirus (cCMV) is an important cause of childhood deafness, which is modifiable if diagnosed within the first month of life. Targeted screening of infants who do not pass their newborn hearing screening tests in England is a feasible approach to identify and treat cases to improve hearing outcome. AIMS: To conduct a cost analysis of targeted screening and subsequent treatment for cCMV-related sensorineural hearing loss (SNHL) in an, otherwise, asymptomatic infant, from the perspective of the UK National Health Service (NHS). METHODS: Using data from the newborn hearing screening programme (NHSP) in England and a recent study of targeted screening for cCMV using salivary swabs within the NHSP, we estimate the cost (in UK pounds (£)) to the NHS. The cost of screening (time, swabs and PCR), assessing, treating and following up cases is calculated. The cost per case of preventing hearing deterioration secondary to cCMV with targeted screening is calculated. RESULTS: The cost of identifying, assessing and treating a case of cCMV-related SNHL through targeted cCMV screening is estimated to be £6683. The cost of improving hearing outcome for an infant with cCMV-related SNHL through targeted screening and treatment is estimated at £14 202. CONCLUSIONS: The costs of targeted screening for cCMV using salivary swabs integrated within NHSP resulted in an estimate of cost per case that compares favourably with other screening programmes. This could be used in future studies to estimate the full economic value in terms of incremental costs and incremental health benefits.

Feasibility and acceptability of targeted screening for congenital CMV-related hearing loss.

BACKGROUND: Congenital cytomegalovirus (cCMV) is the most common non-genetic cause of sensorineural hearing loss (SNHL) in children. Ganciclovir has been shown to prevent the continued deterioration in hearing of children with symptomatic cCMV, but some children with cCMV-related SNHL are unidentified in the neonatal treatment period. Neonatal cCMV screening provides an opportunity to identify infants with cCMV-related SNHL who might benefit from early treatment. OBJECTIVES: To assess the feasibility (ability to take samples before 3 weeks of age and clinical assessment by 30 days of age) and acceptability (maternal anxiety) of targeted CMV testing of infants who are 'referred' for further audiological testing after routine newborn hearing screening programme (NHSP). METHODS: Parents of infants who have 'no clear responses' on routine NHSP before 22 days of life in London and North East England were approached. Salivary and urine samples were tested by CMV PCR. At recruitment and 3 months, the short form Spielberger State-Trait Anxiety Inventory measured maternal anxiety. RESULTS: 411 infants were recruited. 99% (407/411) returned a sample; 98% (404/411) successfully yielded a CMV result, 6 had cCMV, all diagnosed on salivary samples taken <22 days of age (1.5%; 95% CI 0.6% to 3.2%). Only 50% returned urine samples compared with 99% returning salivary samples (p<0.001). Using saliva swabs 98% were successfully screened for CMV within 3 weeks. All positive screening CMV results were known by day 23, and 5/6 infants with cCMV were assessed within 31 days. Anxiety was not increased in mothers of infants screened for cCMV. CONCLUSIONS: Targeted salivary screening for cCMV within the NHSP is feasible, acceptable and detects infants with cCMV-related SNHL who could benefit from early treatment.

Ganciclovir treatment in children: evidence of subtherapeutic levels.

Ganciclovir (GCV) is used to treat babies and older children with cytomegalovirus-related disease. Treatment courses are generally derived from adult studies and there are few data relating to the pharmacokinetics of GCV in children. In adults, low trough GCV levels have been associated with treatment failure and virological resistance. Data regarding suitable drug levels for use in therapeutic drug monitoring (TDM) in the paediatric age group do not currently exist. In this study, anonymised data for all GCV levels sent to the UK Antibiotic Reference Laboratory from 1 November 1999 to 31 March 2007 were reviewed and analysed by age group. In total, 339 specimens were received from 129 patients; 192 specimens were from patients aged <18 years. There were significantly more trough GCV levels <0.5 mg/L in those aged <6 months and 6-12 months compared with adults (64.8% and 53.9%, respectively, vs. 15.9%; P<0.001). Those aged 5-18 years also had significantly more trough samples with levels <0.5 mg/L (80.0% vs. 15.9%; P<0.001). There was a significant difference between median peak GCV levels in those aged <6 months and adults (4.8 mg/L vs. 5.7 mg/L, respectively; P=0.047). In conclusion, GCV levels associated with treatment failure and considered subtherapeutic in adult patients were observed more often in specimens from paediatric patients. These lower levels may have implications for dosing in the paediatric age group, particularly during periods of rapid change in renal function such as the neonatal period. Clinicians should be aware of the relatively low drug exposure noted in this study and consider TDM and increasing drug dose where virological response is poor.

Managing congenital syphilis again? The more things change ...

PURPOSE OF REVIEW: Untreated syphilis may have profound adverse effects on pregnancy outcome, resulting in spontaneous abortion, stillbirth, premature delivery or perinatal death, or can result in significant morbidity during infancy, childhood or adolescence. In this article, we review current strategies for the management of maternal and congenital syphilis nationally and in resource-poor settings. RECENT FINDINGS: Since 1998, a dramatic increase in syphilis diagnoses has been documented among women of child-bearing age in the UK and elsewhere. The low prevalence of congenital syphilis in many developed countries may have led to complacency, hindering modern-day management of this historically important condition. Follow-up studies indicate that present antenotal and postnatal interventions could be improved. This conclusion extends to resource-poor settings endemic for syphilis in which rapid diagnostic techniques are currently being validated. SUMMARY: A stringent follow-up of pregnant women with syphilis before delivery and a proactive approach to identifying and treating exposed neonates born to such patients are needed.

Advances in the antiviral therapy of herpes virus infection in children.

Herpes viruses are ubiquitous and primary infections, with many of these viruses common during childhood. In general, children tolerate primary infection well, with only mild symptoms, but in the immunocompromised, including the newborn, infection can be associated with serious morbidity and mortality. Drug treatment for many of the herpes infections is available but is often associated with serious side effects. In the pediatric age group, treatment is further hindered by a lack of information on suitable dosing regimes, unavailability of oral solutions and a lack of clinical trials specifically investigating response to treatment in this group of patients. This article will review current evidence regarding the pharmacokinetics and dosing of the most commonly used antiherpetic agents and will look specifically at the treatment of the more common herpes virus infections in children.