Congenital cytomegalovirus (cCMV) infection can cause fluctuating hearing loss and vestibulopathy. The pathogenesis is unknown. This report describes a 13-year old boy with cCMV and severe hearing... Show moreCongenital cytomegalovirus (cCMV) infection can cause fluctuating hearing loss and vestibulopathy. The pathogenesis is unknown. This report describes a 13-year old boy with cCMV and severe hearing loss in the right ear since age 3, presenting with fluctuating hearing loss in the left ear and vestibular symptoms. 3D fluid attenuated inversion recovery (FLAIR) MRI showed endolymphatic hydrops in the acutely affected ear. This is the first description of a child with cCMV subjected to this imaging technique, raising the question whether endolymphatic hydrops could play a role in the development of late-onset symptoms and demonstrating the possibilities of this MRI sequence. Show less
HLA-matched allogeneic stem cell transplantation (alloSCT) is a potential curative therapy for patients with high-risk hematologic malignancies. The therapeutic effect of alloSCT is mediated by T... Show moreHLA-matched allogeneic stem cell transplantation (alloSCT) is a potential curative therapy for patients with high-risk hematologic malignancies. The therapeutic effect of alloSCT is mediated by T cells derived from the stem cell donor that have the potential to recognize and eliminate malignant cells of patient origin, better known as the graft-versus-leukemia effect. Besides, donor-derived T cells are of importance for the protection against viruses early after alloSCT. On the other hand, T cells of donor origin can also initiate harmful graft-versus-host disease if healthy cells of the patient are recognized. Therefore, the major challenge in the field of alloSCT is to find a balance between graft-versus-leukemia effect and viral protection versus graft-versus-host disease with the aim to reduce complications early after alloSCT. In this thesis, the manipulation of donor-derived T cells at different stages during the process of HLA-matched alloSCT was investigated: from in vitro T-cell depletion of the graft before infusion into the patient until adoptive T-cell therapy early after alloSCT to support anti-viral immunity and graft-versus-leukemia effect. Show less
Kleinherenbrink, W.; Baas, M.; Nakhsbandi, G.; Hesselink, D.A.; Roodnat, J.I.; Winter, B.C. de; ... ; Gelder, T. van 2021
Breakthrough cytomegalovirus (CMV) disease during valganciclovir prophylaxis is rare but may cause significant morbidity and even mortality. In order to identify patients at increased risk the... Show moreBreakthrough cytomegalovirus (CMV) disease during valganciclovir prophylaxis is rare but may cause significant morbidity and even mortality. In order to identify patients at increased risk the incidence of CMV disease was studied in a large population of renal transplant recipients who underwent a kidney transplantation in the Radboud University Medical Center between 2004 and 2015 (n = 1300). CMV disease occurred in 31/1300 patients. Multivariate binary linear regression analysis showed that delayed graft function (DGF) (p = 0.018) and rejection (p = 0.001) significantly and independently increased the risk of CMV disease, whereas CMV status did not. Valganciclovir prophylaxis was prescribed to 281/1300 (21.6%) high-risk patients (defined as CMV IgGseronegative recipients receiving a kidney from a CMV IgG-seropositive donor (D+/R-)). Of these 281 patients, 51 suffered from DGF (18%). The incidence of breakthrough CMV disease in D + /R- patients with DGF was much higher than in those with immediate function (6/51 (11.8%) vs 2/230, (0.9%), p = 0.0006 Fisher's exact test), despite valganciclovir prophylaxis. This higher incidence of CMV disease could not be explained by a higher incidence of rejection (and associated anti-rejection treatment) in patients with DGF. D + /R- patients with DGF are at increased risk of developing CMV disease despite valganciclovir prophylaxis. These findings suggest that underexposure to ganciclovir occurs in patients with DGF. Prospective studies evaluating the added value of therapeutic drug monitoring to achieve target ganciclovir concentrations in patients with DGF are needed. Show less
Rozhnova, G.; Kretzschmar, M.E.; Klis, F. van der; Baarle, D. van; Korndewal, M.J.; Vossen, A.C.; M. van boven 2020
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... Show moreBackground 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. Show less
Congenital ‘ToRCH’ infections have a low incidence in The Netherlands but diagnostic testing occurs frequently for a variety of different indications, some of which aren’t necessary. On the... Show moreCongenital ‘ToRCH’ infections have a low incidence in The Netherlands but diagnostic testing occurs frequently for a variety of different indications, some of which aren’t necessary. On the contrary, EV- and HPeV infections have a high incidence infants, but are frequently missed due to lack of testing. Furthermore, knowledge about follow-up after a proven infection with EV or HPeV is scarce.The aim of the first part of this thesis (part A) was to investigate the yield of performing diagnostic tests for ‘ToRCH’ infections in newborn infants with lenticulostriate vasculopathy (LSV) or small for gestational age (SGA). In the second part of this thesis (part B) the epidemiology and follow-up of Entero- (EV) and Human Parechovirus (HPeV) induced sepsis-like illness in neonates and young infants was studied.This thesis updates and nuances the indications for testing for both groups of pathogens and provides insight in the follow-up after a proven infection with EV or HPeV. Show less
Berg, S.P.H. van den; Pardieck, I.N.; Lanfermeijer, J.; Sauce, D.; Klenerman, P.; Baarle, D. van; Arens, R. 2019
Upon cytomegalovirus (CMV) infection, large T-cell responses are elicited that remain high or even increase over time, a phenomenon named memory T-cell inflation. Besides, the maintained robust T... Show moreUpon cytomegalovirus (CMV) infection, large T-cell responses are elicited that remain high or even increase over time, a phenomenon named memory T-cell inflation. Besides, the maintained robust T-cell response, CMV-specific T cells seem to have a distinctive phenotype, characterized by an advanced differentiation state. Here, we will review this special differentiation status by discussing the cellular phenotype based on the expression of CD45 isoforms, costimulatory, inhibitory and natural killer receptors, adhesion and lymphocyte homing molecules, transcription factors, cytokines and cytotoxic molecules. In addition, we focus on whether the differentiation state of CMV-specific CD8 T cells is unique in comparison with other chronic viruses and we will discuss the possible impact of factors such as antigen exposure and aging on the advanced differentiation status of CMV-specific CD8 T cells. Show less
Following allogeneic stem cell transplantation (alloSCT), most patients experience a period of profound and prolonged T cell deficiency due to the immune suppression and/or T cell depletion (TCD... Show moreFollowing allogeneic stem cell transplantation (alloSCT), most patients experience a period of profound and prolonged T cell deficiency due to the immune suppression and/or T cell depletion (TCD). In this period the patients are at risk for developing infectious complications by reactivation of endogenous herpes like viruses cytomegalovirus (CMV), Epstein-Barr virus (EBV) and varicella zoster virus (VZV). Reactivation of endogenous CMV is the most frequently occurring herpes virus reactivation following alloSCT. Approximately 60% of alloSCT recipients are seropositive for CMV and are therefore at risk for endogenous reactivation of latent CMV. CMV reactivation can lead to potentially fatal CMV disease, comprising CMV pneumonitis, CMV colitis or CMV encephalitis. The aim of this thesis was to evaluate factors that influence the incidence of CMV disease after TCD alloSCT. These factors include the conditioning regimen, serostatus of the donor, pharmacological intervention following alloSCT and adoptive T cell transfer for treatment of refractory CMV reactivation or CMV disease. Show less
Heiden, P. van der; Marijt, E.; Falkenburg, F.; Jedema, I. 2018
In this thesis, new insights in the complex and intertwined relationship between viral infections, T cells and natural killer cells after allogeneic HSCT in children are provided and discussed.... Show moreIn this thesis, new insights in the complex and intertwined relationship between viral infections, T cells and natural killer cells after allogeneic HSCT in children are provided and discussed. Patients are at high risk of viral complication during the T cell deficient period early after HSCT. When viral infections occur, interventions to bridge the period until the recovery of antiviral T cell immunity are of great importance to improve the clinical outcome after HSCT. Besides antiviral medication and the use of adoptive immunotherapy, NK cells may play a role in the protection against viruses when T cells are not available to perform their task. Show less
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... Show moreThe 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. Show less
Congenital cytomegalovirus infection (cCMV) may lead to symptoms at birth and long-term consequences. We present a nationwide, retrospective cohort study on the outcome of cCMV up to age 6 years.... Show moreCongenital cytomegalovirus infection (cCMV) may lead to symptoms at birth and long-term consequences. We present a nationwide, retrospective cohort study on the outcome of cCMV up to age 6 years. For this study we identified cCMV, using polymerase chain reaction, by analysing dried blood spots, which are taken shortly after birth for neonatal screening. The group of children with cCMV were compared to a group of children who were cCMV negative at birth. Data were collected about their health and development up to age 6 years. Parents of 73 693 children were invited to participate, and 32 486 (44.1%) gave informed consent for testing of their child's dried blood spot for CMV. Of the 31 484 dried blood spots tested, 156 (0.5%) were positive for cCMV. Of these, four (2.6%) children had been diagnosed with cCMV prior to this study. This unique retrospective nationwide study permits the estimation of long-term sequelae of cCMV up to the age of 6 years. The birth prevalence of cCMV in this study was 0.5%, which is in line with prior estimates. Most (97.4%) children with cCMV had not been diagnosed earlier, indicating under-diagnosis of cCMV. Show less
T cell responses are highly critical for the control of numerous pathogenic infections. For proper T cell activation, several signals are required, including antigen presentation, interactions... Show moreT cell responses are highly critical for the control of numerous pathogenic infections. For proper T cell activation, several signals are required, including antigen presentation, interactions mediated via costimulatory receptor/ligand pairs, and cytokine signaling. There are many different costimulatory receptors that upon interaction with specific ligands promote T cell expansion and differentiation. This diverse repertoire of costimulatory molecules, suggests that each costimulatory receptor/ligand interaction has a unique function, nonetheless all interactions impact T cell expansion. It is unclear which signals are essential in a given situation and whether costimulatory molecules have unique or overlapping functions. Besides costimulatory signals, also IL-2 signals and type I IFNs promote T cell expansion. In this thesis, we assess how costimulatory signals, IL-2 and type I IFNs affect virus-specific immunity and determine whether these signals work in a cooperative manner. More understanding of the combined impact of signals that promote T cell expansion and differentiation could be valuable for improving current vaccination settings and immunotherapies. Show less
The research described in this thesis aims to study determinants of the course and outcome of treatment of herpesvirus infections in immunocompromised patients. Both viral factors, such as... Show moreThe research described in this thesis aims to study determinants of the course and outcome of treatment of herpesvirus infections in immunocompromised patients. Both viral factors, such as antiviral resistance, and patient factors, including immunological parameters, were investigated. Techniques to study antiviral resistance were optimized for use in a clinical diagnostic setting. The aim of this research is to improve and facilitate management of herpesvirus infections in immunocompromised patients. Show less
