Valganciclovir in Infants with Hearing Loss and Clinically Inapparent Congenital Cytomegalovirus Infection: A Nonrandomized Controlled Trial.

OBJECTIVE: To assess the efficacy of valganciclovir in infants with hearing loss and clinically inapparent congenital cytomegalovirus infection (cCMV), as there is no consensus on treatment of this group. STUDY DESIGN: A nationwide, nonrandomized controlled trial, comparing 6 weeks of oral valganciclovir to no treatment in infants with cCMV, recruited after newborn hearing screening resulted in referral to an audiologist. The choice whether to treat was left to parents of subjects. Eligible subjects were full term infants aged <13 weeks with sensorineural hearing loss and diagnosed with cCMV through dried blood spot testing. The primary outcome, measured by linear and ordinal logistic regression, was change in best-ear hearing from baseline to follow-up at 18-22 months of age. RESULTS: Thirty-seven participants were included in the final analysis, of whom 25 were in the treatment group and 12 in the control group. The majority of subjects in both groups had neuroimaging abnormalities, which were mostly mild. Hearing deterioration was more likely in the control group compared with the treatment group (common OR 0.10, 95% CI 0.02-0.45, P = .003). Mean best-ear hearing deteriorated by 13.7 dB in the control group, compared with improvement of 3.3 dB in the treatment group (difference 17 dB, 95% CI 2.6 - 31.4, P = .02). CONCLUSIONS: We investigated treatment in children with hearing loss and clinically inapparent cCMV. Although our study was nonrandomized, it is the first prospective and controlled trial in this population. Valganciclovir-treated children with hearing loss and inapparent cCMV had less hearing deterioration at 18 through 22 months of age than control subjects. EUDRACT REGISTRY NUMBER: 2013-003068-30.

Epstein-Barr Viral Load Monitoring Strategy and the Risk for Posttransplant Lymphoproliferative Disease in Adult Liver Transplantation : A Cohort Study.

BACKGROUND: Primary infection with or reactivation of Epstein-Barr virus (EBV) can occur after liver transplant (LT) and can lead to posttransplant lymphoproliferative disease (PTLD). In pediatric LT, an EBV-DNA viral load (EBV VL) monitoring strategy, including the reduction of immunosuppression, has led to a lower incidence of PTLD. For adult LT recipients with less primary infection and more EBV reactivation, it is unknown whether this strategy is effective. OBJECTIVE: To examine the effect of an EBV VL monitoring strategy on the incidence of PTLD after LT in adults. DESIGN: Cohort study. SETTING: Two university medical centers in the Netherlands. PATIENTS: Adult recipients of first LT in Leiden between September 2003 and January 2017 with an EBV VL monitoring strategy formed the monitoring group (M1), recipients of first LT in Rotterdam between January 2003 and January 2017 without such a strategy formed the contemporary control group (C1), and those who had transplants in Leiden between September 1992 and September 2003 or Rotterdam between 1986 and January 2003 formed the historical control groups (M0 and C0, respectively). MEASUREMENTS: Influence of EBV VL monitoring on incidence of PTLD. RESULTS: After inverse probability of treatment weighting of the 4 groups to achieve a balance among the groups for important patient characteristics, differences within hospitals between the historical and recent era in cumulative incidences-expressed as the number of events per 1000 patients measured at 5-, 10-, and 15-year follow-up-showed fewer events in the contemporary era in both centers. This difference was considerably larger in the monitoring center, whereas the 95% CI included the null value of 0 for point estimates. LIMITATION: Retrospective, low statistical power, and incompletely balanced groups, and non-EBV PTLD cannot be prevented. CONCLUSION: Monitoring EBV VL may reduce PTLD incidence after LT in adults; larger studies are warranted. PRIMARY FUNDING SOURCE: None.

Primary sclerosing cholangitis and other risk factors for post-transplant lymphoproliferative disease after liver transplantation in adults.

Post-transplant lymphoproliferative disease (PTLD) is a rare but serious complication of liver transplantation (LT) with morbidity and mortality. The risk factors for PTLD in adults are ill-defined. This study aimed to assess the risk factors for PTLD after LT in adults. All adult LT recipients between 1986 and 2016 from 2 centers in the Netherlands were included, with follow-up until 2020. PTLD was diagnosed according to the World Health Organization (WHO) classification. Potential risk factors for PTLD were assessed using multivariate Cox regression analysis. A total of 1281 patients were included, of whom 29 (2.3%) developed PTLD. Results show that independent risk factors for PTLD after LT in adults were no Epstein-Barr virus load monitoring strategy, primary sclerosing cholangitis as an indication for LT, era (historic era linked to more intense long-term immunosuppression), and Epstein-Barr virus-seronegative recipient. No other independent risk factors were identified in this study. Of the 207 patients with primary sclerosing cholangitis as an indication for LT, 13 (6.3%) developed PTLD versus 16 out of 1074 (1.5%) patients with other underlying liver diseases (log-rank p <0.001). The yearly PTLD incidence was higher in the first year than in the later years after LT (2.4%/y vs. 0.6%/y) for primary sclerosing cholangitis, but not for other indications (0.16%/y). In Epstein-Barr virus-seronegative recipients PTLD occurred earlier after LT, while in 97% of seropositive recipients it could occur very late after LT.

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.

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.

The association between foodborne and orofecal pathogens and allergic sensitisation -- EuroPrevall study.

BACKGROUND: An inverse association between markers of exposure to foodborne and orofecal pathogens and allergic sensitization has been reported. However, the findings of epidemiological studies have not been consistent. This study investigated the relationship between antibodies to hepatitis A, Toxoplasma gondii and salmonella and allergic sensitization to food and aeroallergens in children from different geographical areas. METHODS: Specific IgE and/or skin prick testing against food and aeroallergens were measured in children from 6 to 12 years of age residing in Greece, the Netherlands, China, India and Russia. Seropositivity to the three pathogens was measured, and data on potential confounders were collected using questionnaire. RESULTS: Data from 800 children (126 from Athens; 248 from Utrecht; 110 from Hong Kong; 119 from urban Tomsk; and 197 from rural Tomsk) could be analysed. The highest percentage of positive serology to salmonella was found in Hong Kong (46.4%), to T. gondii in urban Tomsk (13.4%) and to hepatitis A in Athens (71.2%). Although not significant, T. gondii seropositivity tends to be negatively associated, and hepatitis A seropositivity tends to be positively associated with allergic sensitization. CONCLUSION: Inconsistent associations were observed between allergic sensitization to food and aeroallergens and markers of exposure to two common foodborne pathogens. The association with T. gondii tends to be negative, consistent with the 'hygiene hypothesis', but the association with hepatitis A tends to be positive. Taken together, there is no clear evidence that past exposure to foodborne and orofecal pathogens protects against allergic sensitization to food or aeroallergens.

The apparent paradox of maternal seropositivity as a risk factor for congenital cytomegalovirus infection: a population-based prediction model.

Because maternal seropositivity for CMV is associated with substantial protection against congenital CMV infection, prevention measures have focused mainly on seronegative pregnant women for decades. However, population-wide insight in the contribution of nonprimary infection (reactivation and/or re-infection with a different strain) on the most common sequela, hearing loss, is missing. A population-based prediction model was developed to estimate the proportion of congenital CMV-related hearing loss resulting from nonprimary maternal infection. Incorporated was a meta-analysis of the risk of hearing loss, calculating pooled proportions of children with hearing loss after nonprimary and primary infection. Subsequently, the model was applied for worldwide present population seroprevalences (range 30-95%). It was estimated that, for all population seroprevalences, nonprimary maternal infections are responsible for the majority of congenital CMV infections. This proportion increased with seroprevalence, ranging from 57% (95%CI 24-85%) to 96% (95% CI 88-99%) for seroprevalences of 30% to 95%. Our meta-analysis (six reports) showed that the risk of hearing loss after nonprimary infection was 11% (28/253 children, 95% CI 7-15%) versus 13% (50/385 children, 95% CI 10-16%) after primary infection. Incorporating this risk into our model, we estimated that nonprimary infections also accounted for the majority of CMV-related hearing loss. This proportion ranged from 53% (95% CI 13-86%) to 95% (95% CI 62-99%) for seroprevalences of 30% to 95%. Our data underline the worldwide contribution of nonprimary infections in causing CMV-related hearing loss. These results imply that prevention research such as vaccine and hygiene studies should not only be directed at seronegative but also seropositive pregnant women.

Clinical evaluation of viral acute respiratory tract infections in children presenting to the emergency department of a tertiary referral hospital in the Netherlands.

BACKGROUND: The relative incidence and clinical impact of individual respiratory viruses remains unclear among children presenting to the hospital emergency department with acute respiratory tract infection (ARTI). METHODS: During two winter periods, respiratory virus real-time multiplex PCR results were evaluated from children (< 18 years) presenting to the emergency department of a tertiary referral hospital with ARTI that had been sampled within 48 hours of hospital presentation. In an attempt to identify virus-specific distinguishing clinical features, single virus infections were correlated with presenting signs and symptoms, clinical findings and outcomes using multivariate logistic regression. RESULTS: In total, 274 children with ARTI were evaluated and most were aged < 3 years (236/274, 86%). PCR detected respiratory viruses in 224/274 (81.8%) children and included 162 (59%) single and 62 (23%) mixed virus infections. Respiratory syncytial virus (RSV) and human rhinovirus (HRV) single virus infections were common among children aged < 3 years, but proportional differences compared to older children were only significant for RSV (95% CI 1.3-15). Clinical differentiation between viral ARTIs was not possible due to common shared presenting signs and symptoms and the high frequency of mixed viral infections. We observed virus-associated outcome differences among children aged < 3 years. Oxygen treatment was associated with RSV (OR 3.6) and inversely correlated with FLU (OR 0.05). Treatment with steroids (OR 3.4) or bronchodilators (OR 3.4) was associated with HRV. Severe respiratory complications were associated with HRV (OR 3.5) and inversely correlated with RSV (OR 0.24). CONCLUSIONS: Respiratory viruses are frequently detected in young children presenting to the hospital emergency department with ARTI and require PCR diagnosis since presenting signs and symptoms are not discriminant for a type of virus. RSV and HRV bear a high burden of morbidity in the pediatric clinical setting.

Changing epidemiology of parvovirus B19 in the Netherlands since 1990, including its re-emergence after the COVID-19 pandemic.

Parvovirus B19V (B19V) infection during pregnancy can be complicated by potentially life-threatening fetal hydrops, which can be managed by intrauterine transfusion (IUT). This study investigates the long-term temporal patterns in the epidemiology of B19V and evaluates the impact on fetal hydrops, by combining data on B19V infections from the Dutch Sentinel Surveillance system in the period 1990 to 2023, Dutch blood banking data and hospital data on fetal hydrops. Using wavelet analysis, we identified annual epidemic cycles in the Netherlands in the period 1990-2019 and we identified superimposed multiannual cycles in the period 1990-2009. After 2009, no multiannual cycle could be identified, although the incidence fluctuated and correlates with number of IUT performed. As of 2020, weekly reports of B19V infection demonstrated a historically low incidence and B19V-DNA positive blood donors were nearly absent. From May 2020 to May 2023, no IUT for B19V-related hydrops was performed. In the spring of 2023, B19V infections re-emerged, reaching pre-pandemic epidemic levels. Due to the changes in B19V epidemiology over the last 30 years and the near-absence of B19V during the COVID-19 pandemic, the resulting low immunity levels may lead to rebound outbreaks. Alertness to severe complications such as fetal hydrops is warranted.

Persistence and antiviral resistance of varicella zoster virus in hematological patients.

BACKGROUND: Varicella zoster virus (VZV) infections are a relevant cause of morbidity and mortality in hematological patients and especially in hematopoietic stem cell transplant (HSCT) recipients. The present study aimed to investigate the prevalence and clinical significance of viral persistence and antiviral resistance by systematically analyzing all episodes of VZV diagnosed in our laboratory in pediatric and adult hematological patients between 2007 and 2010. METHODS: Patient charts were reviewed to document patient and disease characteristics. VZV loads were determined in all available clinical samples from the day of diagnosis and thereafter. Persistent VZV infection was defined as a VZV infection that lasted at least 7 days. Analysis of resistance was performed in all patients with persistent VZV infection by sequence analysis of viral thymidine kinase and DNA polymerase genes. RESULTS: In total, 89 episodes occurred in 87 patients, of whom 65 were recipients of an allogeneic HSCT. Follow-up samples were available in 54 episodes. Persistent VZV was demonstrated in 32 of these episodes (59%). Complications occurred in 16 of the persistent episodes (50%) vs 2 of 22 nonpersistent episodes (9%). Mutations possibly associated with resistance were found in 27% of patients with persistent VZV, including patients with treatment-unresponsive dermatomal zoster that progressed to severe retinal or cerebral infection. CONCLUSIONS: In hematological patients, VZV-related complications occur frequently, especially in persistent infections. Antiviral resistance is a relevant factor in persistent infections and needs to be investigated in various affected body sites, especially when clinical suspicion of treatment failure arises.

How to use... neonatal TORCH testing.

Toxoplasma gondii, rubella, cytomegalovirus and herpes simplex virus have in common that they can cause congenital (TORCH) infection, leading to fetal and neonatal morbidity and mortality. During the last decades, TORCH screening, which is generally considered to be single serum testing, has been increasingly used inappropriately and questions have been raised concerning the indications and cost-effectiveness of TORCH testing. The problems of TORCH screening lie in requesting the screening for the wrong indications, wrong interpretation of the single serum results and in case there is a good indication for diagnosis of congenital infection, sending in the wrong materials. This review provides an overview of the pathogenesis, epidemiology and clinical consequences of congenital TORCH infections and discusses the indications for, and interpretation of, TORCH screens.

Vaccine value profile for cytomegalovirus.

Cytomegalovirus (CMV) is the most common infectious cause of congenital malformation and a leading cause of developmental disabilities such as sensorineural hearing loss (SNHL), motor and cognitive deficits. The significant disease burden from congenital CMV infection (cCMV) led the US National Institute of Medicine to rank CMV vaccine development as the highest priority. An average of 6.7/1000 live births are affected by cCMV, but the prevalence varies across and within countries. In contrast to other congenital infections such as rubella and toxoplasmosis, the prevalence of cCMV increases with CMV seroprevalence rates in the population. The true global burden of cCMV disease is likely underestimated because most infected infants (85-90 %) have asymptomatic infection and are not identified. However, about 7-11 % of those with asymptomatic infection will develop SNHL throughout early childhood. Although no licensed CMV vaccine exists, several candidate vaccines are in development, including one currently in phase 3 trials. Licensure of one or more vaccine candidates is feasible within the next five years. Various models of CMV vaccine strategies employing different target populations have shown to provide substantial benefit in reducing cCMV. Although CMV can cause end-organ disease with significant morbidity and mortality in immunocompromised individuals, the focus of this vaccine value profile (VVP) is on preventing or reducing the cCMV disease burden. This CMV VVP provides a high-level, comprehensive assessment of the currently available data to inform the potential public health, economic, and societal value of CMV vaccines. The CMV VVP was developed by a working group of subject matter experts from academia, public health groups, policy organizations, and non-profit organizations. All contributors have extensive expertise on various elements of the CMV VVP and have described the state of knowledge and identified the current gaps. The VVP was developed using only existing and publicly available information.

Rapid genotyping of cytomegalovirus in dried blood spots by multiplex real-time PCR assays targeting the envelope glycoprotein gB and gH genes.

Genotyping of cytomegalovirus (CMV) is useful to examine potential differences in the pathogenicity of strains and to demonstrate coinfection with multiple strains involved in CMV disease in adults and congenitally infected newborns. Studies on genotyping of CMV in dried blood spots (DBS) are rare and have been hampered by the small amount of dried blood available. In this study, two multiplex real-time PCR assays for rapid gB and gH genotyping of CMV in DBS were developed. Validation of the assays with 39 CMV-positive plasma samples of transplant recipients and 21 urine specimens of congenitally infected newborns was successful in genotyping 100% of the samples, with gB1 and gB3 being the most prevalent genotypes. Multiple gB and gH genotypes were detected in 36% and 33% of the plasma samples, respectively. One urine sample from a newborn with symptomatic congenital CMV was positive for gB1 and gB2. DBS of congenitally infected newborns (n = 41) were tested using 9 µl of dried blood, and genotypes were detected in 81% (gB) and 73% (gH) of the samples, with gB3 being the most prevalent genotype. No clear association of specific genotypes with clinical outcome was observed. In conclusion, the CMV gB and gH PCR assays were found to be rapid, sensitive for detecting mixed infections, and suitable for direct usage on DBS. These assays are efficient tools for genotyping of CMV in DBS of congenitally infected newborns.

Implementing neonatal screening for congenital cytomegalovirus: addressing the deafness of policy makers.

Congenital cytomegalovirus (CMV) infection is an important public health problem with approximately 7 in 1,000 newborns infected and consequently at risk for hearing impairment. Newborn hearing screening will fail to detect this hearing impairment in approximately half of the cases because late onset hearing loss is frequent. Hearing impairment has profound impact on cognitive and social development of children and their families, determining most of the disease burden of congenital CMV infection. The potential value of newborn screening for congenital CMV is increasingly discussed. To date, many experts acknowledge the benefit of antiviral treatment in the prevention of hearing deterioration in newborns with neurological symptoms, and the benefit of early identification of late-onset hearing impairment by means of extensive audiological follow up of infected infants. These opinions imply that the potential of newborn screening for CMV would lie in the identification of the large proportion of asymptomatic congenitally infected newborns at risk for developing late-onset hearing loss. Experience with postnatal antiviral treatment of symptomatic newborns is encouraging, but has not been studied in asymptomatic congenitally infected newborns. A large-scale study on the safety and effectiveness of combined screening and antiviral therapy for congenital CMV infection is the necessary next step to take and should not be delayed.

Cytomegalovirus seropositivity is associated with glucose regulation in the oldest old. Results from the Leiden 85-plus Study.

BACKGROUND: Cytomegalovirus (CMV) infection has been reported to contribute to the pathogenesis of type 1 diabetes and post-transplantation diabetes. However, CMV infection has not been evaluated as a possible risk factor for type 2 diabetes. Our aim was to investigate potential associations between CMV seropositivity, CMV IgG antibody level and glucose regulation in the oldest old. RESULTS: CMV seropositive subjects were more likely to have type 2 diabetes (17.2% vs 7.9%, p = 0.016), had a higher level of HbA1c (p = 0.014) and higher non-fasting glucose (p = 0.024) in the oldest olds. These associations remained significant after adjustment for possible confounders. CMV IgG antibody level was not significantly associated with glucose regulation (all p > 0.05). CONCLUSIONS: In the oldest old, CMV seropositivity is significantly associated with various indicators of glucose regulation. This finding suggests that CMV infection might be a risk factor for the development of type 2 diabetes in the elderly.

Evaluation of a personalized, dose-sparing revaccination strategy in hepatitis B vaccine non-responders.

OBJECTIVES: The detection of low levels of antibodies against HBsAg (anti-HBs) below 10 IU/L in non-responders after a primary hepatitis B vaccination, is associated with seroconversion after revaccination. We compared the diagnostic performance of four anti-HBs assays in non-responders in their ability to differentiate between absence or presence of low levels of anti-HBs and propose a revaccination strategy guided by anti-HBs titres. METHODS: Non-responders were revaccinated with Fendrix 20 µg at 0, 1 and 2 months. Anti-HBs titres were determined by Abbott Architect, Diasorin Liaison, Roche Cobas and Siemens ADVIA Centaur. Inter-assay agreement was evaluated with Cohen's Kappa (k) in baseline samples between zero-responders without detectable antibodies and poor-responders with detectable antibodies < 10 IU/L. Seroconversion rates and geometric mean titres were analysed at 0, 1 and 3 months. A titre-based strategy (one revaccination dose and anti-HBs measurement followed by two more revaccination doses if required) was compared with the standard revaccination series of 3 doses. RESULTS: 57 participants were included in the analysis. k was ≥ 0.65 for all assays except ADVIA (k ≤ 0.41). After one revaccination dose all assays detected a mean seroconversion rate in zero-responders of 42.9%, compared to 85.1% in poor-responders. The difference between zero- and poor-responders in seroconversion rate per assay was significant (p < 0.05). After three revaccination doses the mean seroconversion rate was 88.2% in zero-responders and 98.5% in poor-responders (p > 0.286 per assay). A titre-based strategy reduced the amount of revaccinations by 17% compared with the standard. CONCLUSIONS: All assays demonstrated a comparable difference in seroconversion rate between zero- and poor-responders after one revaccination dose. The revaccination strategy could be optimised by differentiation between zero- and poor-responders followed by a titre-guided schedule.

Mannose-binding lectin and ficolin-2 gene polymorphisms predispose to cytomegalovirus (re)infection after orthotopic liver transplantation.

BACKGROUND & AIMS: The lectin pathway of complement activation is a crucial effector cascade of the innate immune response to pathogens. Cytomegalovirus (CMV) infection occurs frequently in immunocompromised patients after orthotopic liver transplantation (OLT). Single-nucleotide polymorphisms (SNPs) in the lectin pathway genes determine their liver-derived protein level and functional activity. We examined the association between these SNPs and the risk for CMV infection in OLT. METHODS: OLT patients (n = 295) were genotyped for recipient and donor SNPs in mannose-binding lectin (MBL2), Ficolin-2 (FCN2) and MBL-associated serine protease (MASP2) genes. RESULTS: Combined analysis of independently associated variant MBL2 [HR 1.65, p<0.02] and wild-type FCN2 [1.85; p<0.02] SNPs in the donor liver showed an increased risk of CMV infection for either and both risk genotypes [HR 2.02 and HR 3.26, respectively, p = 0.004], especially in CMV Donor-/Recipient+ (D-/R+) patients [HR 4.7 and HR 10.0, respectively, p = 0.01]. A genetic donor-recipient mismatch for MBL2 and FCN2 increased the CMV risk independently, also combined [HR 5.35; p<0.001], particularly in CMV D-/R+ patients [HR 16.6; p = 0.009]. Multivariate Cox analysis showed a consistent stepwise increase in CMV infection risk with the gene profile of the donor [up to HR 2.77; p<0.005] and the combined MBL2 and FCN2 donor-recipient mismatch profile [up to HR 4.57; p<0.001], independent from donor-recipient CMV serostatus, also at higher CMV (re)infection cut-off values. CONCLUSIONS: MBL2 and FCN2 risk alleles of donor liver and recipient constitute independent risk factors for CMV infection after OLT. Patients with these risk genes probably need intensified CMV monitoring and anti-viral therapy.

Congenital cytomegalovirus infection in the Netherlands: birth prevalence and risk factors.

Congenital cytomegalovirus (CMV) infection is the most common congenital viral infection worldwide. The sequela encountered most frequently is hearing impairment, affecting approximately one out of five infants congenitally infected. Data on the birth prevalence and risk factors of congenital CMV infection in the Netherlands are scarce. The aim of this study was to determine the birth prevalence of congenital CMV in the Netherlands. A sample of 6,500 dried blood spots (DBS) from infants born in the Netherlands was tested anonymously for CMV DNA. The sample was stratified by the number of live births in different regions of the Netherlands of the year 2007. Additionally, on a regional level, risk factors for congenital CMV were analyzed. The birth prevalence of congenital CMV in the Netherlands was 0.54% (35/6,433, 95%CI 0.36-0.72). Congenital CMV infection was significantly higher in regions with more than 15% young children (0-5 years) compared with regions with a lower proportion of young children (OR 5.9, 95%CI 1.4-25.2). Congenital CMV infection was significantly higher in regions with more than 30% immigrants compared with regions with a lower proportion of immigrants (OR 2.2, 95%CI 1.1-4.6). This association was strongest for regions with more than 30% non-Western immigrants (OR 3.3, 95%CI 1.5-7.5). Based on the knowledge of the natural history of congenital CMV infection, approximately 1,000 children are born with congenital CMV infection in the Netherlands annually, of whom eventually approximately 180 children (0.1% of all newborns) will be affected by long term sequelae, with hearing loss being the symptom encountered most frequently.

Reinfection With Severe Acute Respiratory Syndrome Coronavirus 2 Without Recurrence of Multisystem Inflammatory Syndrome in Children.

Multisystem inflammatory syndrome in children is a rare, potentially life-threatening postinfectious complication in children after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. It is currently unknown if multisystem inflammatory syndrome in children (MIS-C) can recur upon reinfection with SARS-CoV-2. Here, we report on a former MIS-C patient who was reinfected with SARS-CoV-2 without recurrence of MIS-C.

Serological response to three alternative series of hepatitis B revaccination (Fendrix, Twinrix, and HBVaxPro-40) in healthy non-responders: a multicentre, open-label, randomised, controlled, superiority trial.

BACKGROUND: Serological non-response can be present after hepatitis B vaccination in healthy adults. We aimed to establish which of three revaccination regimens is most effective at inducing protective immunity METHODS: Healthy adults (aged 18-80 years) from 16 Dutch centres (13 public health services, two university hospitals, and one travel clinic) were included in this multicentre, parallel group, randomised, controlled, superiority trial. The inclusion criterion was vaccine non-response (hepatitis B surface antibody [anti-HBs] titre <10 IU/L) after a primary series with three doses of one type of recombinant vaccine against hepatitis B virus (either HBVaxPro-10 or Engerix-B at months 0, 1, and 6). Participants were individually randomly assigned (1:1:1:1) to a vaccination series of repeated initial vaccination (HBVaxPro 10 µg or Engerix-B 20 µg) as the control, or to Twinrix 20 µg, Fendrix 20 µg, or HBVaxPro 40 µg. We used a web-based randomisation programme, stratified by centre, with a block size of four. Participants and centres were unmasked to assignment after randomisation. Laboratory staff and investigators were masked to vaccine-group assignment. All revaccination schedules were identical, with intramuscular vaccinations at 0, 1, and 2 months. Anti-HBs was measured at 0, 1, 2, and 3 months. The primary outcome was the percentage of responders (anti-HBs titres ≥10 IU/L) at 3 months. Immunogenicity and safety analyses were based on an intention-to-vaccinate analysis, the immunogenicity analysis with last observation carried forward for missing data, and the Bonferroni and the Benjamini-Hochberg method were applied to correct for multiple testing. The trial was registered in the Dutch National Trial Register and inclusion has been stopped (identifier NL3011; EudraCT-number 2011-005627-40). FINDINGS: The participants were recruited between Nov 1, 2012, and Sept 1, 2017. 480 participants were randomly assigned and included in intention-to-vaccinate analyses: 124 (26%) to control, 118 (25%) to Twinrix, 114 (24%) to HBVaxPro-40, and 124 (26%) to Fendrix. At month 3 the percentage of responders was 83 (67%) of 124 (95% CI 57·9-75·1 in the control group, 94 (80%) of the 118 (71·3-86·5) in the Twinrix group, 95 (83%) of 114 (75·2-89·7) in the HBVaxPro-40 group, and 108 (87%) of 124 (79·9-92·4) in the Fendrix group. Compared with the control group, the percentage of responders was superior for the HBVaxPro-40 group (adjusted difference 21·6% [95% CI 10·4-32·7], p=0·0204 [Bonferroni corrected p value]) and the Fendrix group (26·3% [15·4-37·3], p=0·0006), but not the Twinrix group (25·0% [13·0-37·0]; p=0·0846). One serious adverse event occurred (herpes zoster ophthalmicus) in the Fendrix group, which was not attributed to the vaccine. INTERPRETATION: Revaccinating healthy non-responders with Fendrix or HBVaxPro-40 resulted in significantly higher proportions of responders and therefore indication for these vaccines should be expanded to enable revaccination of non-responders. FUNDING: National Institute for Public Health and the Environment.