Short- and long-term impact of vaccination against cytomegalovirus: a modeling study.

BACKGROUND: Infection with cytomegalovirus (CMV) is highly prevalent worldwide and can cause severe disease in immunocompromised persons and congenitally infected infants. The disease burden caused by congenital CMV infection is high, especially in resource-limited countries. Vaccines are currently under development for various target groups. METHODS: We evaluated the impact of vaccination strategies and hygiene intervention using transmission models. Model parameters were estimated from a cross-sectional serological population study (n=5179) and a retrospective birth cohort (n=31,484), providing information on the age- and sex-specific CMV prevalence and on the birth prevalence of congenital CMV (cCMV). RESULTS: The analyses show that vertical transmission and infectious reactivation are the main drivers of transmission. Vaccination strategies aimed at reducing transmission from mother to child (vaccinating pregnant women or women of reproductive age) can yield substantial reductions of cCMV in 20 years (31.7-71.4% if 70% of women are effectively vaccinated). Alternatively, hygiene intervention aimed at preventing CMV infection and re-infection of women of reproductive age from young children is expected to reduce cCMV by less than 2%. The effects of large-scale vaccination on CMV prevalence can be substantial, owing to the moderate transmissibility of CMV at the population level. However, as CMV causes lifelong infection, the timescale on which reductions in CMV prevalence are expected is in the order of several decades. Elimination of CMV infection in the long run is only feasible for a vaccine with a long duration of protection and high vaccination coverage. CONCLUSIONS: Vaccination is an effective intervention to reduce the birth prevalence of cCMV. Population-level reductions in CMV prevalence can only be achieved on a long timescale. Our results stress the value of vaccinating pregnant women and women of childbearing age and provide support for the development of CMV vaccines and early planning of vaccination scenarios and rollouts.

T and B Cell Markers in Dried Blood Spots of Neonates with Congenital Cytomegalovirus Infection: B Cell Numbers at Birth Are Associated with Long-Term Outcomes.

Congenital CMV infection (cCMV) is the most common congenital infection that can cause long-term impairment (LTI). The pathogenesis of LTI is not completely understood. Fetal immunity may play a role in controlling the infection and preventing LTI, although immune activation may also contribute to fetal immunopathology. In this study, we analyzed various molecular markers of T and B cell numbers in neonatal dried blood spots of 99 children with cCMV and 54 children without cCMV: δRec-ψJα signal joints on TCR excision circles, intron recombination signal sequence k-deleting element signal joints on Igκ-deleting recombination excision circles, genomic intron recombination signal sequence k-deleting element coding joint, genomic Vδ1-Jδ1, and Vδ2-Jδ1 rearrangements. Of this cohort, clinical symptoms at birth and LTI at 6 y of age were recorded. Neonates with cCMV had fewer TCR excision circles in their blood than non-infected controls. Furthermore, cCMV infection was associated with increased numbers of γδ T cells and B cells, and these numbers were positively correlated with CMV viral load in the dried blood spots. Infected children with a better long-term outcome had higher numbers of B cells at birth than those who developed LTI; no difference in B cell replication was observed. The potential protective role of B cells in controlling cCMV-related disease and the clinical value of this marker as a predictor of long-term outcome merit further evaluation.

Infectious reactivation of cytomegalovirus explaining age- and sex-specific patterns of seroprevalence.

Human cytomegalovirus (CMV) is a herpes virus with poorly understood transmission dynamics. Person-to-person transmission is thought to occur primarily through transfer of saliva or urine, but no quantitative estimates are available for the contribution of different infection routes. Using data from a large population-based serological study (n = 5,179), we provide quantitative estimates of key epidemiological parameters, including the transmissibility of primary infection, reactivation, and re-infection. Mixture models are fitted to age- and sex-specific antibody response data from the Netherlands, showing that the data can be described by a model with three distributions of antibody measurements, i.e. uninfected, infected, and infected with increased antibody concentration. Estimates of seroprevalence increase gradually with age, such that at 80 years 73% (95%CrI: 64%-78%) of females and 62% (95%CrI: 55%-68%) of males are infected, while 57% (95%CrI: 47%-67%) of females and 37% (95%CrI: 28%-46%) of males have increased antibody concentration. Merging the statistical analyses with transmission models, we find that models with infectious reactivation (i.e. reactivation that can lead to the virus being transmitted to a novel host) fit the data significantly better than models without infectious reactivation. Estimated reactivation rates increase from low values in children to 2%-4% per year in women older than 50 years. The results advance a hypothesis in which transmission from adults after infectious reactivation is a key driver of transmission. We discuss the implications for control strategies aimed at reducing CMV infection in vulnerable groups.

Long-term impairment attributable to congenital cytomegalovirus infection: a retrospective cohort study.

AIM: This study aimed to estimate long-term impairment attributable to congenital cytomegalovirus infection (cCMV). METHOD: This nationwide cohort study retrospectively assessed cCMV in children born in 2008 in the Netherlands, testing 31 484 stored neonatal dried blood spots. Extensive medical data of cCMV-positive children (n=133) and matched cCMV-negative comparison children (n=274) up to 6 years of age were analysed. RESULTS: Moderate to severe long-term impairment was diagnosed in 24.8% (33 out of 133) of all cCMV-positive children (53.8% in symptomatic, 17.8% in asymptomatic), compared with 12.0% (33 out of 274) of cCMV-negative children. Sensorineural hearing loss was seen only in five cCMV-positive children (3.8%). Developmental delays were diagnosed more often in cCMV-positive children than cCMV-negative children: motor (12.0% vs 1.5%), cognitive (6.0% vs 1.1%), and speech-language (16.5% vs 7.3%). Long-term impairment in multiple domains was more frequent in symptomatic (19.2%) and asymptomatic (8.4%) cCMV-positive children than cCMV-negative children (1.8%). INTERPRETATION: Children with cCMV were twice as likely to have long-term impairment up to the age of 6 years, especially developmental delays and sensorineural hearing loss, than cCMV-negative comparison children, with a risk difference of 12.8%. These insights into the risk of cCMV-associated impairment can help optimize care and stimulate preventive measures. WHAT THIS PAPER ADDS: Congenital cytomegalovirus infection (cCMV) leads to impairment in 25% of cases. Fifty per cent of children with cCMV symptoms at birth have long-term impairment. The risk difference of moderate to severe long-term impairment between children with and without cCMV is 13%, attributable to cCMV. cCMV leads to motor, cognitive, and speech-language developmental delay in children.

Influence of obesity on nocturnal oxygen saturation in young children.

UNLABELLED: Obesity is increasing worldwide and it is accompanied by major health effects. In adults and school-aged children, obesity is associated with decreased respiratory function, which may lead to disturbed sleeping and subsequently difficulties in concentration and behavioural disorders. The evidence for the association between obesity and decreased respiratory function in younger children is scarce. To explore the association between body weight and nocturnal respiratory function in young children, 1 to 3 years old, nocturnal pulse oximetry was performed at home. Children with tonsillar hypertrophy were excluded. Percentage of time with oxygen saturation (SpO(2)) <95 % was measured and its association with body mass index (BMI) for age z scores was analysed. Pulse oximetric data of 51 children, including 18 children with a BMI for age above +2 standard deviations, were obtained for this study. Linear regression analysis, correction for gender and parental smoking, showed a positive association between the natural logarithm of SpO(2) <95 % and BMI for age z score [regression coefficient (ß) 0.19, 95 % confidence interval 0.00-0.39]. CONCLUSION: In young children, higher body weight is associated with a decrease in nocturnal oxygen saturation.

Healthcare costs attributable to congenital cytomegalovirus infection.

OBJECTIVE: Congenital cytomegalovirus infection (cCMV) can cause symptoms at birth as well as long-term impairment. This study estimates cCMV-related healthcare costs in the Netherlands in early childhood. DESIGN, SETTING AND PATIENTS: In a nationwide retrospective cohort study, 156 children with cCMV were identified by testing 31 484 neonatal dried blood spots for cCMV. Use of healthcare resources in the first 6 years of life by children with cCMV and a matched cCMV-negative control group were analysed. Mean costs per child were calculated by multiplying healthcare resource use by its reference prices. EXPOSURE: Children with cCMV were compared with cCMV-negative children. MAIN OUTCOME MEASURES: The average total healthcare costs per child were based on the average costs for hospital admissions and consultations by healthcare providers. RESULTS: Mean healthcare costs of children with cCMV (€6113, n=133) were higher than children without cCMV (€3570, n=274), although statistically not significant, with a mean difference of €2544 (95% CI €-451 to €5538). The costs of children with long-term impairment were two times higher in children with cCMV (€17 205) compared with children without cCMV (€8332). CONCLUSIONS: Children with cCMV, especially those with long-term impairment and those symptomatic at birth, accrue higher healthcare costs than cCMV-negative children in the first 6 years of life, although this is not statistically significant. This economic impact is of importance in the evaluation of preventive measures against cCMV. TRIAL REGISTRATION NUMBER: NTR3582.

Neonatal screening parameters in infants with congenital Cytomegalovirus infection.

Congenital Cytomegalovirus infection (cCMV) is the most common cause of congenital infections worldwide that can cause long-term impairment (LTI). The metabolic alterations due to cCMV are largely unknown. This study aims to assess the metabolites included in the neonatal screening in relation to cCMV and cCMV outcome, allowing the identification of prognostic markers for clinical outcome. Essential amino acids, hormones, carnitines and enzymes from Dried Blood Spots (DBS) were analyzed of 102 children with cCMV and 179 children without cCMV, and they were related to symptoms at birth and LTI at 6years of age. In this cohort, the neonatal screening parameters did not change in relation to cCMV, nor to symptoms at birth or LTI. However, metabolic changes were observed in children born preterm, with lower concentrations of essential amino acids in premature infants with cCMV compared to premature controls. Finally, a higher concentration of palmytoilcarnitine (C16) in the group with higher viral load was observed. Though these data demonstrate limitations in the use of neonatal screening data as predictors for long-term cCMV outcome, the metabolism of preterm neonates with cCMV merits further evaluation.

Congenital Cytomegalovirus Infection: Child Development, Quality of Life and Impact on Daily Life.

Congenital cytomegalovirus (cCMV) infection is the most common congenital infection worldwide and can lead to long-term impairments such as developmental delay. It is currently unknown how this affects the daily life of children and their parents. Children For this study, children with cCMV were identified by testing stored dried blood spots of 31,484 five-year-old children born in 2008 in the Netherlands. Parents of 133 children with cCMV and 274 children without cCMV participated and filled in questionnaires on the child's development, the child's and parents' quality of life, care provided for the children and consequences of cCMV on daily life. School performance reports at 6 years of age were also investigated. Children with cCMV had delays in general and expressive language development more often, and they attended physical therapists more frequently than children without cCMV. School performance of children with cCMV and symptoms at birth was poorer than that of cCMV-negative children with similar symptoms at birth. The quality of life of children with long-term impairment was lower in children with cCMV than those without cCMV. Parents of children with cCMV and long-term impairments reported more physical and concentration problems than parents of children without cCMV. These findings indicate that cCMV has a considerable impact not only on the child's development and school performance but also on the daily life of children and their parents. The care for children with cCMV should therefore include support for motor and speech-language development as well as family-centered care.

Clinical pathways for inborn errors of metabolism: warranted and feasible.

Inborn errors of metabolism (IEMs) are known for their low prevalence and multidisciplinary care mostly founded on expert opinion. Clinical pathways are multidisciplinary tools to organise care which provide a clear route to the best care and improve communication. In 2010 the Dutch Society for Children and Adults with an Inborn Error of Metabolism (VKS) initiated development of clinical pathways for inborn errors of metabolism. In this letter to the editor we describe why it is warranted to develop clinical pathways for IEMs and shortly discuss the process of development for these pathways in the Netherlands.

Relation between abdominal obesity, insulin resistance and left ventricular hypertrophy diagnosed by electrocardiogram and magnetic resonance imaging in hypertensive patients.

Obesity is related to left ventricular hypertrophy (LVH). Whether LVH on electrocardiography (ECG-LVH) is a result of increased cardiac electrical activity or due to increased left ventricular mass (LVM) remains to be determined. The aims of the present study were to investigate the relation between obesity and ECG-LVH and LVM by magnetic resonance imaging (MRI-LVM) in patients with hypertension and to investigate the relation of insulin resistance (IR) and LVH. Patients with hypertension (n = 421) were evaluated using Sokolow-Lyon voltage, Cornell voltage, and cardiac magnetic resonance imaging. Waist circumference was used as a measure of abdominal obesity. Linear regression analysis revealed an inverse relation (adjusted ß = -0.02, 95% confidence interval -0.02 to -0.01) between waist circumference and Sokolow-Lyon voltage, indicating a decrease of 0.02 mV per 1-cm increase in waist circumference. There was a positive relation between waist circumference and MRI-LVM (ß = 0.49, 95% confidence interval 0.32 to 0.67). Patients in the highest quartile of LVM had a worse metabolic profile than patients with the Sokolow-Lyon voltage criterion. The relations of IR with ECG-LVH and MRI-LVM were similar to those of waist circumference in relation to ECG-LVH and MRI-LVM. In conclusion, there is an inverse relation between waist circumference and ECG-LVH and a positive relation between waist circumference and MRI-LVM. This study indicates that obesity has a different relation to voltage criteria for LVH compared to anatomic criteria for LVH, supporting the hypothesis that IR decreases electrocardiographic voltages, despite an increase in MRI-LVM. The clinical implication is that especially in patients with IR, Sokolow-Lyon voltage is low in contrast to high MRI-LVM.