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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 lg 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. (C) 2022 The Authors. Published by Elsevier Ltd.

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. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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. © 2013 John Wiley & Sons, Ltd.

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%Cl 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%Cl 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%Cl 1.1-4.6). This association was strongest for regions with more than 30% non-Western immigrants (OR 3.3, 95%Cl 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. J. Med. Virol. 83: 1777-1782, 2011. (C) 2011 Wiley-Liss, Inc.

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. Copyright (C) 2011 John Wiley & Sons, Ltd.

Ned Tijdschr Med Microbiol 2011;19 (1): 28-32

Mondelinge presentaties van het Nederlands Congres Volksgezondheid 2011, Duurzaam Gezond gehouden 6 en 7 april De Meervaart Amsterdam

Ned Tijdschr Med Microbiol 2011;19 (1): 10-13

Ned Tdschr voor Allergie en Astma 2011; 11 (1):13-23

Background: Congenital infections are associated with a wide spectrum of clinical symptoms, including lenticulostriate vasculopathy (LSV). Objective: To determine the relationship between LSV and congenital infections, as diagnosed by TORCH serology and viral culture for cytomegalovirus (CMV). Methods: All neonates with LSV admitted to our neonatal intensive-care unit from 2004 to 2008 were included in the study. Results of maternal and neonatal TORCH testing were evaluated. Results: During the study period, cranial ultrasound scans were performed in 2,088 neonates. LSV was detected in 80 (4%) neonates. Maternal and/or neonatal serological TORCH tests were performed in 73% (58/80) of cases. None of the mothers or infants (0 of 58) had positive IgM titres for Toxoplasma, rubella, CMV or herpes simplex virus. Additional urine culture for CMV was performed in 38 neonates. None of the infants (0 of 38) had a positive CMV urine culture test. Conclusions: Routinely applied efforts to diagnose congenital infections in cases presenting with LSV have a poor yield. Routine TORCH screening in neonates with LSV cases should only be regarded as mandatory once well-designed studies demonstrate a clear diagnostic benefit. Copyright (C) 2009 S. Karger AG, Basel

Background: Norovirus, Rotavirus group A, Astrovirus, Sapovirus and Adenovirus serotypes 40 and 41, are common causes of gastroenteritis. Conventional diagnosis of these causative agents is based on antigen detection and electron microscopy. Objective: To improve the diagnostic possibilities for viral gastroenteritis, two internally controlled multiplex real-time PCRs have been developed. Study design: Individual real-time PCRs were developed and optimized for the specific detection of Norovirus genogroup I, Norovirus genogroup II, Rotavirus group A, Astrovirus, Adenovirus group F and Sapovirus. Subsequently, the PCRs were combined to two multiplex PCR reactions. The multiplex assays were clinically evaluated using 239 fecal samples submitted to our laboratory over a 1-year period for the routine detection of Rotavirus and/or Adenovirus antigens using the Vikia (R) Rota/Adeno test (bioMerieux, Boxtel, The Netherlands). Results: In general, the multiplex real-time PCR assays showed comparable sensitivity and specificity to the individual assays. Aretrospective clinical evaluation showed increased pathogen detection in samples from 14% using conventional methods to 45% using PCR. Subsequently, the assay was implemented as a routine diagnostic tool. From September 2007 up to December 2009, 486 positive results were obtained in 1570 samples (31%) analyzed. Norovirus genogroup II was found the most frequently (61.1%), followed by Adenovirus (9.9%), Rotavirus (9.3%), Astrovirus (6.0%), Norovirus genogroup I (3.3%) and Sapovirus (0.4%). Conclusions: Two internally controlled multiplex real-time PCR assays for the simultaneous detection of Astrovirus, Adenovirus group F, Rotavirus, Norovirus genogroups I and II and Sapovirus have shown significant improvement in the diagnosis of viral gastroenteritis. (C) 2010 Elsevier B. V. All rights reserved.

Background: Congenital infections are associated with a wide variety of clinical symptoms, including subependymal cysts (SEC). Objective: To determine the co-occurrence of SEC and congenital infections, as diagnosed by TORCH serologic tests and/or cytomegalovirus (CMV) urine culture. Methods: We performed a retrospective study of all neonates admitted to our neonatal intensive care unit from 1998 to 2009 in whom SEC were detected on cranial ultrasound and TORCH serologic tests and/or CMV urine cultures were performed. Results: Fifty-nine neonates fulfilled the inclusion criteria. TORCH serologic tests were performed in 69% (41/59) of cases. Urine CMV culture was performed in 68% (40/59) of cases. None of the neonates tested positive for IgM Toxoplasma gondii, Rubella and Herpes simplex virus. Positive CMV IgM titers and/or a positive urine CMV culture were detected in 2% (1/59) of neonates. Conclusion: The co-occurrence of TORCH congenital infections in infants with SEC is rare. Routine TORCH screening in neonates with SEC does not seem warranted. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

The involvement of TNF-alpha in the release of soluble TNF receptors was assessed in mice, treated with anti-CD3 monoclonal antibodies. After treatment with three different anti-CD3 mAb, we simultaneously studied serum levels of TNF-alpha, soluble TNF receptor P55 and P75. All three anti-CD3 mAb triggered the release of both of the soluble TNF receptors, whereas only one of the anti-CD3 mAb triggered TNF-alpha release. These data demonstrate that in our model soluble TNF receptor release is independent of TNF-alpha release.

In dit proefschrift geven we een wetenschappelijke basis voor het opzetten van een severe acute respiratory infections (SARI) surveillance systeem in Nederland. Met behulp van pilotstudies onderzochten we de essentiële voorwaarden voor een duurzaam SARI surveillance systeem in Nederland.

Cytomegalovirus (CMV) infection is a worldwide common infection that in a considerable proportion of individuals remains unnoticed. The congenital CMV infection (cCMV) can induce a variety of clinical manifestations at birth (symptoms at birth), and of permanent long-term impairments (LTI). Of the total of infected neonates at birth, 13% are symptomatic at birth, and half of them will develop LTI. However, 13% of the asymptomatic neonates will still develop the same LTI. Therefore, a quite high percentage of neonates will develop LTI. This thesis aimed to identify prognostic markers, for short- and long-term clinical outcome, and correlates of protection, for future vaccine development. In order to identify such biomarkers, a retrospective nationwide cohort of children with (n=125) and without (n=263) cCMV was used. The findings of this thesis allowed us to get more insights into cCMV pathogenesis, and into the potential processes leading to immune dysfunction, and therefore to a worse clinical outcome. Several approaches have been used to explore prognostic markers. The neonatal immune markers, through DNA quantification of the most common TCR and BCR rearrangements from DBS, together with the maternal-child HLA background, through typing DNA from buccal swabs, seemed to be quite promising for prognostic markers.

The phenotype and functionality that CD8+ T cells acquire upon encountering their cognate antigen depend on many factors that are controlled by the nature of the pathogen The acquired phenotypical and functional characteristics determine the potential of the CD8+ T cells to form bona fide memory populations that are able to expand upon secondary challenge. We investigated factors that control CD8+ T cell differentiation. We have shown that the height of the viral dose greatly impacts the immunological outcome by affecting the magnitude of the response and the phenotype and function of the (memory) CD8+ T cells that are induced. The acquired phenotype and functions determine the capacity to expand upon re-encounter with the same pathogen and we have shown that the IL-2 producing capacity of CD8+ T cells functions as a crucial determinant of CD8+ T cell expansion potential. Although we addressed only a small fraction of all variables involved in the induction and maintenance of antigen-specific T cell populations our observations and insights gathered by others already provide a basis for rational immunotherapeutic treatment design, however, for fine-tuning of therapy-induced immune responses aspects about e.g. the timing and cooperating signals still need to be understood in more detail.

This thesis describes the consequences of congenital cytomegalovirus infection in Dutch children up to six years of age. The first chapter is a general introduction on this topic. The second chapter discusses the seroprevalence of cytomegalovirus infection in the Netherlands. The third chapter describes the design of the CROCUS-study, which was used to investigate the long-term consequences of congenital cytomegalovirus infection. In chapter four the clinical consequences of congenital cytomegalovirus infection are discussed. Chapter five elaborates about the consequences of congenital cytomegalovirus infection on the child development and the quality of life of children and their parents. In the sixth chapter the cost of illness of congenital cytomegalovirus infection is calculated. The last chapter is a general discussion on the long-term consequences of congenital cytomegalovirus infection.