Publications by authors named "Ann C Vossen"

49 Publications

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

Authors:
Ganna Rozhnova Mirjam E Kretzschmar Fiona van der Klis Debbie van Baarle Marjolein Korndewal Ann C Vossen Michiel van Boven

BMC Med 2020 07 2;18(1):174. Epub 2020 Jul 2.

Center for Infectious Disease Control, National Institute of Public Health and the Environment, Bilthoven, The Netherlands.

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.
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http://dx.doi.org/10.1186/s12916-020-01629-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331215PMC
July 2020

Diagnosis of intrauterine parvovirus B19 infection at birth - Value of DNA detection in neonatal blood and dried blood spots.

Authors:
Anne Russcher Anja Enders Caroline S de Brouwer Dick Oepkes Ralph Hahn Martin Enders Aloys C M Kroes Ann C T M Vossen

J Clin Virol 2020 08 2;129:104482. Epub 2020 Jun 2.

Department of Medical Microbiology, Leiden University Medical Center, Leiden, the Netherlands.

Background: Diagnosis of congenital viral infection at birth is generally attempted by direct detection of the virus by PCR in various neonatal materials. How to reliably diagnose intrauterine infection with parvovirus B19 (B19 V) at birth is unknown.

Objectives: To evaluate the performance of B19 V DNA detection in cord blood (CB) or neonatal dried blood spots (DBS) in diagnosing fetal infection.

Study Design: Two cohorts of children diagnosed prenatally with an intrauterine B19 V infection were included in this study. CB samples of intrauterine B19 V infections that were sent to a reference laboratory for congenital infections in Stuttgart, Germany in the period 1995-2014 were tested in triplicate for B19 V DNA by quantitative PCR. DBS from children with intrauterine B19 V infection that underwent IUT at the LUMC, Leiden, the Netherlands in the period 2009-2014 were tested for B19 V DNA by quantitative B19 V PCR in triplicate.

Results: Fourteen of twenty (70 %) CB samples tested positive for B19 V DNA. The positivity rate was 40 % (4/10) in those with a prenatal diagnosis <20 weeks gestation. When intrauterine B19 V infection was diagnosed thereafter, 100 % (10/10) samples were B19 V DNA positive. Of the thirteen available DBS, twelve (92 %) tested positive. Viral load in CB and DBS corresponded inversely with time from fetal diagnosis to birth.

Conclusion: B19 V DNA can be detected in neonatal blood samples of children following intrauterine B19 V infection, although the possibility of false-negatives, even in severe infections, should be considered. B19 V viral load at birth correlates with timing of infection.
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http://dx.doi.org/10.1016/j.jcv.2020.104482DOI Listing
August 2020

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.

Authors:
Stijn F H Raven Christian J P A Hoebe Ann C T M Vossen Leo G Visser Jeannine L A Hautvast Anna H E Roukens Jim E van Steenbergen

Lancet Infect Dis 2020 01 16;20(1):92-101. Epub 2019 Oct 16.

Department of Infectious Diseases, Leiden University Medical Centre, Leiden, Netherlands; Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, Netherlands.

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.
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http://dx.doi.org/10.1016/S1473-3099(19)30417-7DOI Listing
January 2020

Generation and infusion of multi-antigen-specific T cells to prevent complications early after T-cell depleted allogeneic stem cell transplantation-a phase I/II study.

Authors:
Marthe C J Roex Peter van Balen Lothar Germeroth Lois Hageman Esther van Egmond Sabrina A J Veld Conny Hoogstraten Ellis van Liempt Jaap J Zwaginga Liesbeth C de Wreede Pauline Meij Ann C T M Vossen Sophia Danhof Hermann Einsele M Ron Schaafsma Hendrik Veelken Constantijn J M Halkes Inge Jedema J H Frederik Falkenburg

Leukemia 2020 03 17;34(3):831-844. Epub 2019 Oct 17.

Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands.

Prophylactic infusion of selected donor T cells can be an effective method to restore specific immunity after T-cell-depleted allogeneic stem cell transplantation (TCD-alloSCT). In this phase I/II study, we aimed to reduce the risk of viral complications and disease relapses by administrating donor-derived CD8 T cells directed against cytomegalovirus (CMV), Epstein-Barr virus (EBV) and adenovirus antigens, tumor-associated antigens (TAA) and minor histocompatibility antigens (MiHA). Twenty-seven of thirty-six screened HLA-A*02:01 patients and their CMV and/or EBV donors were included. Using MHC-I-Streptamers, 27 T-cell products were generated containing a median of 5.2 × 10 cells. Twenty-four products were administered without infusion-related complications at a median of 58 days post alloSCT. No patients developed graft-versus-host disease during follow-up. Five patients showed disease progression without coinciding expansion of TAA/MiHA-specific T cells. Eight patients experienced CMV- and/or EBV-reactivations. Four of these reactivations were clinically relevant requiring antiviral treatment, of which two progressed to viral disease. All resolved ultimately. In 2/4 patients with EBV-reactivations and 6/8 patients with CMV-reactivations, viral loads were followed by the expansion of donor-derived virus target-antigen-specific T cells. In conclusion, generation of multi-antigen-specific T-cell products was feasible, infusions were well tolerated and expansion of target-antigen-specific T cells coinciding viral reactivations was illustrated in the majority of patients.
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http://dx.doi.org/10.1038/s41375-019-0600-zDOI Listing
March 2020

Impact of congenital cytomegalovirus infection on transcriptomes from archived dried blood spots in relation to long-term clinical outcome.

Authors:
Roberta Rovito Hans-Jörg Warnatz Szymon M Kiełbasa Hailiang Mei Vyacheslav Amstislavskiy Ramon Arens Marie-Laure Yaspo Hans Lehrach Aloys C M Kroes Jelle J Goeman Ann C T M Vossen

PLoS One 2018 19;13(7):e0200652. Epub 2018 Jul 19.

Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands.

Congenital Cytomegalovirus infection (cCMV) is the leading infection in determining permanent long-term impairments (LTI), and its pathogenesis is largely unknown due to the complex interplay between viral, maternal, placental, and child factors. The cellular activity, considered to be the result of the response to exogenous and endogenous factors, is captured by the determination of gene expression profiles. In this study, we determined whole blood transcriptomes in relation to cCMV, CMV viral load and LTI development at 6 years of age by using RNA isolated from neonatal dried blood spots (DBS) stored at room temperature for 8 years. As DBS were assumed to mainly reflect the neonatal immune system, particular attention was given to the immune pathways using the global test. Additionally, differential expression of individual genes was performed using the voom/limma function packages. We demonstrated feasibility of RNA sequencing from archived neonatal DBS of children with cCMV, and non-infected controls, in relation to LTI and CMV viral load. Despite the lack of statistical power to detect individual genes differences, pathway analysis suggested the involvement of innate immune response with higher CMV viral loads, and of anti-inflammatory markers in infected children that did not develop LTI. Finally, the T cell exhaustion observed in infected neonates, in particular with higher viral load, did not correlate with LTI, therefore other mechanisms are likely to be involved in the long-term immune dysfunction. Despite these data demonstrate limitation in determining prognostic markers for LTI by means of transcriptome analysis, this exploratory study represents a first step in unraveling the pathogenesis of cCMV, and the aforementioned pathways certainly merit further evaluation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0200652PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6053152PMC
January 2019

Maternal and child human leukocyte antigens in congenital cytomegalovirus infection.

Authors:
Roberta Rovito Frans H J Claas Geert W Haasnoot Dave L Roelen Aloys C M Kroes Ann C T M Vossen

J Reprod Immunol 2018 04 31;126:39-45. Epub 2018 Jan 31.

Department of Medical Microbiology, Leiden University Medical Center, Leiden (LUMC), The Netherlands. Electronic address:

Congenital Cytomegalovirus infection (cCMV) is the most common cause of congenital infections worldwide causing permanent long-term impairment (LTI). cCMV immunopathogenesis remains largely unknown due to the complex interplay between viral, maternal, placental and child factors. The aim of this study was to determine the possible role of particular HLA antigens, of the number of HLA mismatches (mm) and non-inherited maternal antigens (NIMAs) in a large retrospective nation-wide cohort of children with cCMV and their mothers. HLA Class I (HLA-A, HLA-B and HLA-C) and HLA Class II (HLA-DR and HLA-DQ) were assessed in 96 mother-child pairs in relation to a control group of 5604 Dutch blood donors, but no significant differences were observed. Next, although these HLA antigens could not be assessed in relation to symptoms at birth, nor to LTI, due to the low number of cases, they could be evaluated in relation to CMV viral load. HLA-DRB1*04, and potentially HLA-B*51, was shown to have a protective role in the children as its frequency was increased in the low viral load group compared to the high viral load group, and this remained significant after correction. The number of HLA mm and of NIMAs were not associated to symptoms at birth nor to LTI or viral load. In conclusion, although none of the HLA alleles could be put forward as prognostic marker for long-term outcome, our findings give useful insights into cCMV pathogenesis, and identify potential HLAs that correlate with a better viral control.
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http://dx.doi.org/10.1016/j.jri.2018.01.002DOI Listing
April 2018

Healthcare costs attributable to congenital cytomegalovirus infection.

Authors:
Marjolein J Korndewal Marlies Weltevrede M Elske van den Akker-van Marle Anne Marie Oudesluys-Murphy Hester E de Melker Ann C T M Vossen

Arch Dis Child 2018 05 23;103(5):452-457. Epub 2018 Jan 23.

Department of Medical Microbiology, Leiden University Medical Center (LUMC), Leiden, The Netherlands.

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.
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http://dx.doi.org/10.1136/archdischild-2017-312805DOI Listing
May 2018

Congenital Cytomegalovirus Infection: Maternal-Child HLA-C, HLA-E, and HLA-G Affect Clinical Outcome.

Authors:
Roberta Rovito Frans H J Claas Geert W Haasnoot Dave L Roelen Aloys C M Kroes Michael Eikmans Ann C T M Vossen

Front Immunol 2017 5;8:1904. Epub 2018 Jan 5.

Department of Medical Microbiology, Leiden University Medical Center, Leiden, Netherlands.

Congenital CMV infection (cCMV) is the most common congenital infection causing permanent long-term impairments (LTI). cCMV immunopathogenesis is largely unknown due to the complex interplay between viral, maternal, placental, and child factors. In this study, a large retrospective nationwide cohort of children with cCMV and their mothers was used. HLA-C, HLA-E, and HLA-G were assessed in 96 mother-child pairs in relation to symptoms at birth and LTI at 6 years of age. The mothers were additionally typed for killer cell immunoglobulin-like receptors. The maternal HLA-G 14 bp deletion/deletion polymorphism was associated with a worse outcome, as the immunomodulation effect of higher protein levels may induce less CMV control, with a direct impact on placenta and fetus. The absence of maternal HLA-C belonging to the C2 group was associated with symptoms at birth, as activating signals on decidual NK may override inhibitory signals, contributing to a placental pro-inflammatory environment. Here, the increased HLA-E*0101 and HLA-C mismatches, which were associated with symptoms at birth, may enhance maternal allo-reactivity to fetal Ags, and cause suboptimal viral clearance. Finally, HLA-C non-inherited maternal antigens (NIMAs) were associated with LTI. The tolerance induced in the fetus toward NIMAs may indirectly induce a suboptimal CMV antiviral response throughout childhood. In light of our findings, the potential role of maternal-child HLA in controlling CMV infection and cCMV-related disease, and the clinical value as predictor for long-term outcome certainly deserve further evaluation.
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http://dx.doi.org/10.3389/fimmu.2017.01904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5760553PMC
January 2018

Congenital Cytomegalovirus: A European Expert Consensus Statement on Diagnosis and Management.

Authors:
Suzanne E Luck Jantien W Wieringa Daniel Blázquez-Gamero Philipp Henneke Katharina Schuster Karina Butler Maria Grazia Capretti Maria José Cilleruelo Nigel Curtis Francesca Garofoli Paul Heath Elias Iosifidis Nigel Klein Giuseppina Lombardi Hermione Lyall Tea Nieminen Dasja Pajkrt Vassiliki Papaevangelou Klara Posfay-Barbe Laura Puhakka Emmanuel Roilides Pablo Rojo Jesús Saavedra-Lozano Teshri Shah Mike Sharland Harri Saxen Ann C T M Vossen

Pediatr Infect Dis J 2017 12;36(12):1205-1213

From the *Paediatric Infectious Diseases Research Group, St George's University, London, United Kingdom; †Centre for Virology, University College Medical School, London; ‡Kingston Hospital NHS Foundation Trust, London, United Kingdom; §The Hague Medical Center (HMC), Department of Pediatrics and Sophia Children's hospital, Erasmus Medical Center Rotterdam Department of Pediatric Infectious Diseases; ¶Pediatric Infectious Diseases Unit, Hospital Universitario 12 de Octubre, Universidad Complutense, Instituto de Investigación Hospital 12 de Octubre, Madrid, Spain; ∥Center for Chronic Immunodeficiency and Center for Pediatrics and Adolescent Medicine, Medical Center and Faculty of Medicine, University of Freiburg, Germany; **Our Lady's Children's Hospital Crumlin, UCD School of Medicine and Health Sciences, Dublin, Ireland; ††Department of Obstetrical, Gynaecological and Paediatric Sciences, Operative Unit of Neonatology, Polyclinic St. Orsola-Malpighi, University of Bologna, Bologna, Italy; ‡‡Pediatric Infectious Diseases, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain; §§Department of Paediatrics, The University of Melbourne & Murdoch Children's Research Institute, Royal Children's Hospital Melbourne, Parkville, Australia; ¶¶NICU and Neonatal Unit, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy; ∥∥Infectious Diseases Unit, 3rd Department of Pediatrics, Faculty of Medicine, Aristotle University School of Health Sciences, Thessaloniki, Greece; ***Great Ormond Street Children's Hospital, London, and the Institute of Child Health, UCL, London, United Kingdom; †††NICU and Neonatal Unit, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy; ‡‡‡Imperial College NHS Healthcare, London, United Kingdom; §§Pediatric Infectious Diseases, Children's Hospital, University of Helsinki and Helsinki University Hospital, Finland; ¶¶¶Department of Pediatric Infectious Diseases, Emma Children's Hospital, Academic Medical Center, Amsterdam, The Netherlands; ∥∥∥National and Kapodistrian University of Athens, Greece; ****Children's Hospital of Geneva, University Hospitals of Geneva, Switzerland; ††††Pediatric Infectious Diseases Unit, Gregorio Marañón Hospital, Madrid, Spain; and ‡‡‡‡Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands.

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http://dx.doi.org/10.1097/INF.0000000000001763DOI Listing
December 2017

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

Authors:
Marjolein J Korndewal Anne Marie Oudesluys-Murphy Aloys C M Kroes Marianne A B van der Sande Hester E de Melker Ann C T M Vossen

Dev Med Child Neurol 2017 12 9;59(12):1261-1268. Epub 2017 Oct 9.

Department of Medical Microbiology, Leiden University Medical Center, Leiden, the Netherlands.

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.
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http://dx.doi.org/10.1111/dmcn.13556DOI Listing
December 2017

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

Authors:
Michiel van Boven Jan van de Kassteele Marjolein J Korndewal Christiaan H van Dorp Mirjam Kretzschmar Fiona van der Klis Hester E de Melker Ann C Vossen Debbie van Baarle

PLoS Comput Biol 2017 Sep 26;13(9):e1005719. Epub 2017 Sep 26.

Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, the Netherlands.

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.
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http://dx.doi.org/10.1371/journal.pcbi.1005719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5630159PMC
September 2017

Neonatal screening parameters in infants with congenital Cytomegalovirus infection.

Authors:
Roberta Rovito Marjolein J Korndewal Peter C J I Schielen Aloys C M Kroes Ann C T M Vossen

Clin Chim Acta 2017 Oct 25;473:191-197. Epub 2017 Aug 25.

Department of Medical Microbiology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. Electronic address:

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.
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http://dx.doi.org/10.1016/j.cca.2017.08.029DOI Listing
October 2017

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

Authors:
Marjolein J Korndewal Anne Marie Oudesluys-Murphy Aloys C M Kroes Ann C T M Vossen Hester E de Melker

Pediatr Infect Dis J 2017 Dec;36(12):1141-1147

From the *Centre for Infectious Diseases, Epidemiology and Surveillance, National Institute for Public Health and the Environment, Bilthoven, the Netherlands, †Department of Medical Microbiology, Leiden University Medical Center, Leiden, the Netherlands, and ‡Willem-Alexander Children's Hospital, Leiden University Medical Center, Leiden, the Netherlands.

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.
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http://dx.doi.org/10.1097/INF.0000000000001663DOI Listing
December 2017

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.

Authors:
Roberta Rovito Marjolein J Korndewal Menno C van Zelm Dimitrios Ziagkos Els Wessels Mirjam van der Burg Aloys C M Kroes Anton W Langerak Ann C T M Vossen

J Immunol 2017 01 30;198(1):102-109. Epub 2016 Nov 30.

Department of Medical Microbiology, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.

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.
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http://dx.doi.org/10.4049/jimmunol.1601182DOI Listing
January 2017

Immune status of health care workers to measles virus: evaluation of protective titers in four measles IgG EIAs.

Authors:
J Wendelien Dorigo-Zetsma Maurine A Leverstein-van Hall Joyce Vreeswijk Jutte J C de Vries Ann C T M Vossen Hinke I Ten Hulscher Jeroen Kerkhof Gaby P Smits Wilhelmina L M Ruijs Marion P G Koopmans Robert S van Binnendijk

J Clin Virol 2015 Aug 24;69:214-8. Epub 2015 Jun 24.

Center for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), 3720 BA Bilthoven, The Netherlands. Electronic address:

Background: Following the recognition of a measles case in a hospital in The Netherlands, health care workers (HCW) from the premises were screened by a commercial enzyme immunoassay (EIA) for measles IgG to identify persons at risk for measles. At least 10% of the HCW were tested measles IgG-negative. As this was considered an unusually high proportion, we hypothesized suboptimal sensitivity of EIAs, especially in medical personnel that had vaccine-induced immunity rather than antibodies resulting from natural infection.

Objectives: To determine (vaccine-induced) measles immunity in HCW, using different EIAs compared to the plaque reduction neutralization (PRN) test, the best surrogate marker for vaccine efficacy and immune protection.

Study Design: Sera from HCW were tested for measles IgG antibodies in three commercial EIAs, in a bead-based multiplex immunoassay (MIA) and in the PRN test, and evaluated against age and vaccination history of the HCW.

Results: Of the 154 HCW, born between 1960 and 1995, 153 (99.4%) had protective levels of measles antibodies (PRN> 120mIU/ml). The three EIAs failed to detect any measles IgG antibodies in approximately 10% of the HCW, while this percentage was approximately 3% for the MIA. Negative IgG results rose to 19% for individuals born between 1975 and 1985, pointing to an age group largely representing vaccinated persons from the first measles vaccination period in The Netherlands.

Conclusion: The results show limitations in the usefulness of current EIA assays for determining protective measles antibodies in persons with a vaccination history.
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http://dx.doi.org/10.1016/j.jcv.2015.06.095DOI Listing
August 2015

Valganciclovir for Congenital Cytomegalovirus.

Authors:
Fleurtje A Schornagel Anne M Oudesluys-Murphy Ann C Vossen

N Engl J Med 2015 06;372(25):2462

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http://dx.doi.org/10.1056/NEJMc1504937DOI Listing
June 2015

Mumps serum antibody levels before and after an outbreak to assess infection and immunity in vaccinated students.

Authors:
Sigrid Gouma Tessa M Schurink-Van't Klooster Hester E de Melker Jeroen Kerkhof Gaby P Smits Susan J M Hahné Cécile A C M van Els Greet J Boland Ann C T M Vossen Pulak R Goswami Marion P G Koopmans Rob S van Binnendijk

Open Forum Infect Dis 2014 Dec 13;1(3):ofu101. Epub 2014 Nov 13.

Centre for Infectious Disease Control , National Institute for Public Health and the Environment , Bilthoven , The Netherlands.

Background: Since 2009, various mumps outbreaks have occurred in the Netherlands, affecting mostly young adults vaccinated against mumps. In this retrospective study, we estimated attack rates for symptomatic and asymptomatic mumps virus infection based on mumps-specific immunoglobulin (Ig)G concentrations in paired blood samples obtained before and after the mumps outbreaks, collected in 2 university cities. We aimed to identify a serological correlate of immune protection and risk factors for mumps virus infection.

Methods: Mumps-specific IgG levels were measured by Luminex technology in paired pre- and post-outbreak samples from students from Leiden (n = 135) and Utrecht (n = 619). Persons with a 4-fold increase in mumps IgG concentrations or mumps IgG concentrations >1500 RU/mL were assumed to have had a mumps virus infection.

Results: Attack rates for symptomatic and asymptomatic mumps virus infection were 2.0% and 3.8%, respectively. Pre-outbreak mumps-specific IgG concentrations were lower among cases than among noncases (P = .005) despite vaccination history, but no serological cutoff for immune protection could be established. Mumps among housemates was significantly associated with serological evidence for mumps virus infection (odds ratio, 7.25 [95% confidence interval, 3.20-16.40]; P < .001).

Conclusions: Symptomatic and asymptomatic mumps virus infections in vaccinated persons can be identified by retrospective assessment of mumps-specific IgG antibodies in blood samples.
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http://dx.doi.org/10.1093/ofid/ofu101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4324217PMC
December 2014

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

Authors:
Jairo Gooskens Vishnu van der Ploeg Ram N Sukhai Ann C T M Vossen Eric C J Claas Aloys C M Kroes

BMC Pediatr 2014 Dec 10;14:297. Epub 2014 Dec 10.

Department of Medical Microbiology, Leiden University Medical Center, Leiden, 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.
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http://dx.doi.org/10.1186/s12887-014-0297-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4276012PMC
December 2014

Complete suppression of the gut microbiome prevents acute graft-versus-host disease following allogeneic bone marrow transplantation.

Authors:
Jaak M Vossen Harry F L Guiot Arjan C Lankester Ann C T M Vossen Robbert G M Bredius Ron Wolterbeek Hanny D J Bakker Peter J Heidt

PLoS One 2014 2;9(9):e105706. Epub 2014 Sep 2.

Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands; Biomedical Primate Research Centre, Rijswijk, The Netherlands.

The hypothesis that elimination of facultative and strict anaerobic microorganisms from the gastro-intestinal tract by antimicrobial drugs in the period of time around allogeneic bone marrow transplantation (BMT) prevents acute graft-versus-host disease (GVHD), was examined in a cohort of 112 children grafted between 1989 and 2002 for hematological malignancies. All patients received T-cell replete marrow from human leukocyte antigens (HLA) matched sibling donors under identical transplantation conditions. To eliminate microorganisms from the gastro-intestinal tract, total gastro-intestinal decontamination (GID) was applied by high doses of non-absorbable antimicrobial drugs while the graft recipient was maintained in strict protective isolation. About half of the children (51%) proved to be successfully decontaminated, and about half (49%) unsuccessfully. One recipient got acute GVHD in the first group and 8 in the second group (p = 0.013). The degree of success of total GID was decisive for the occurrence of acute GVHD, irrespective of the presence of other risk factors such as higher age of recipient and/or donor, female donor for male recipient and carriership or reactivation of herpesviruses. Our results demonstrate that successful total GID of the graft recipient prevents moderate to severe acute GVHD. We suppose that substantial translocation of gastro-intestinal microorganisms or parts of these, functioning as microbial-associated molecular patterns (MAMP's), triggering macrophages/dendritic cells via pattern recognizing receptors (PRR's) is prohibited. As a consequence the initiation and progression of an inflammatory process leading to acute GVHD is inhibited.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0105706PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4152127PMC
May 2015

[Viral infections in pregnancy bearing a risk for the child].

Authors:
Ann C T M Vossen

Ned Tijdschr Geneeskd 2014 ;158:A7418

Leids Universitair Medisch Centrum, afd. Medische Microbiologie, Leiden.

Specific viral infections during pregnancy can be transmitted to the fetus or newborn. Infections transmitted to the fetus during pregnancy are called prenatal or congenital infections, whereas infections passed from mother to child during delivery or in the first weeks after birth are called perinatal or neonatal infections. Vertical transmission risk depends on the virus, maternal immunity against this virus and gestational age. Interpretation of microbiological diagnostics for possible intrauterine infection requires specific knowledge on sensitivity and specificity of different assays in relation to the presumed moment of infection. Some of the prenatal and perinatal infections can be prevented by vaccination and by 1st trimester screening in pregnancy, followed by preventive measures. Infections with CMV and parvovirus B19 can have serious consequences for the fetus and newborn. There are no effective preventive or intervention options at this time.
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April 2015

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

Authors:
Jacqueline J Janse Gary W K Wong James Potts Ludmila M Ogorodova Olga S Fedorova P A Mahesh Alexandros Sakellariou Nikolaos G Papadopoulos André C Knulst Serge A Versteeg Aloys C M Kroes Ann C T M Vossen Maiza Campos Ponce Ischa Kummeling Peter Burney Ronald van Ree Maria Yazdanbakhsh

Pediatr Allergy Immunol 2014 May 10;25(3):250-6. Epub 2013 Dec 10.

Department of Parasitology, Leiden University Medical Center, Leiden, the Netherlands.

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.
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http://dx.doi.org/10.1111/pai.12175DOI Listing
May 2014

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

Authors:
Jutte J C de Vries Erik W van Zwet Friedo W Dekker Aloys C M Kroes Paul H Verkerk Ann C T M Vossen

Rev Med Virol 2013 Jul 5;23(4):241-9. Epub 2013 Apr 5.

Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands.

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.
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http://dx.doi.org/10.1002/rmv.1744DOI Listing
July 2013

How to use... neonatal TORCH testing.

Authors:
Eveline P de Jong Ann C T M Vossen Frans J Walther Enrico Lopriore

Arch Dis Child Educ Pract Ed 2013 Jun 7;98(3):93-8. Epub 2013 Mar 7.

Department of Paediatrics, Juliana Children’s Hospital, HAGA Hospital, The Hague, The Netherlands.

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.
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http://dx.doi.org/10.1136/archdischild-2012-303327DOI Listing
June 2013

Cytomegalovirus DNA detection in dried blood spots and perilymphatic fluids from pediatric and adult cochlear implant recipients with prelingual deafness.

Authors:
Jutte J C de Vries Annemarie Vesseur Liselotte J C Rotteveel Anna M H Korver Lisette G Rusman Els Wessels Aloys C M Kroes Emmanuel A Mylanus Anne M Oudesluys-Murphy Johan H M Frijns Ann C T M Vossen

J Clin Virol 2013 Feb 9;56(2):113-7. Epub 2012 Nov 9.

Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands.

Background: Congenital cytomegalovirus (CMV) infection is the leading cause of non-genetic congenital hearing loss. The contribution of congenital CMV to prelingual deafness and the pathophysiology is largely unknown.

Objective: (1) To analyze the prevalence of congenital CMV among cochlear implant (CI) recipients with prelingual deafness. (2) To genotype CMV present in dried blood spots (DBS) and in the inner ear years after birth.

Study Design: Children and adults with prelingual deafness who received a CI in 2010-2011 were included prospectively. Perilymphatic fluids were collected during CI surgery and, in the pediatric cases, DBS were retrieved for CMV DNA detection. Furthermore, a cohort of children with prelingual deafness who received a CI between 2003 and 2008 were included retrospectively. CMV detection in DBS and perilymph was followed by gB and gH genotyping.

Results: Seventysix pediatric CI recipients were included. Seventy DBS were tested for CMV DNA, resulting in a prevalence of congenital CMV of 14% (10/70). Perilymphatic fluid was available from 29 pediatric CI recipients. One perilymph fluid, of a 21-month old girl with congenital CMV, asymptomatic at birth, was CMV DNA positive. The CMV strain in the perilymph was genotypically identical to the strain present in her DBS (gB1/gH2). Perilymph samples from 21 adult CI recipients were CMV DNA negative.

Conclusions: Our study stresses the important contribution of congenital CMV among pediatric CI recipients. Furthermore, our genotyping data support the hypothesis that CMV-related hearing loss is associated with ongoing viral replication in the inner ear up to years after birth.
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http://dx.doi.org/10.1016/j.jcv.2012.10.008DOI Listing
February 2013

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

Authors:
Martha T van der Beek Clementien L Vermont Robbert G M Bredius Erik W A Marijt Caroline S van der Blij-de Brouwer Aloys C M Kroes Eric C J Claas Ann C T M Vossen

Clin Infect Dis 2013 Feb 16;56(3):335-43. Epub 2012 Oct 16.

Department of Medical Microbiology, Leiden University Medical Center, The Netherlands.

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.
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http://dx.doi.org/10.1093/cid/cis879DOI Listing
February 2013

Rapid susceptibility testing for herpes simplex virus type 1 using real-time PCR.

Authors:
Martha T van der Beek Eric C J Claas Caroline S van der Blij-de Brouwer Florence Morfin Lisette G Rusman Aloys C M Kroes Ann C T M Vossen

J Clin Virol 2013 Jan 29;56(1):19-24. Epub 2012 Sep 29.

Department of Medical Microbiology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.

Background: Susceptibility testing of herpes simplex virus type 1 (HSV-1) is traditionally performed by a plaque reduction assay (PRA), but this is labor intensive, time consuming and has a manual read out.

Objectives: The goal of this study was to develop an internally controlled real time PCR-based phenotypical susceptibility test for HSV-1 that is suitable for use in a clinical diagnostic setting.

Study Design: A DNA reduction assay (DRA) was developed and validated on a test panel of 26 well-characterized isolates of varying susceptibility to aciclovir or foscarnet, including low-level resistant isolates. The DRA consisted of pre-culture of a clinical sample for 48 h and subsequent culture in the presence of antivirals for 24 h. Viral DNA concentration in the culture lysates was measured by an internally controlled quantitative real-time HSV-1 PCR and corrected for cell count and lysis by beta-globin PCR. DRA results were compared to results from PRA and sequence analysis.

Results: DRA results were in accordance with PRA results for both aciclovir and foscarnet susceptibility and appeared to have good discriminative value for low-level resistance due to UL30 gene mutations. Although the direct application of DRA in clinical samples appeared not possible, short pre-culture of 48 h was sufficient and ensured results within a clinically relevant time frame of 5 days.

Conclusions: DRA is an accurate, rapid and easy to perform phenotypical susceptibility test for HSV-1.
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http://dx.doi.org/10.1016/j.jcv.2012.09.004DOI Listing
January 2013

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

Authors:
Sijia Chen Anton J M de Craen Yotam Raz Evelyna Derhovanessian Ann C T M Vossen Rudi G J Westendorp Graham Pawelec Andrea B Maier

Immun Ageing 2012 Aug 28;9(1):18. Epub 2012 Aug 28.

Department of Gerontology and Geriatrics, Leiden University Medical Center, Albinusdreef 2, Leiden, 2333 ZA, The Netherlands.

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.
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http://dx.doi.org/10.1186/1742-4933-9-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3478991PMC
August 2012

Pleconaril revisited: clinical course of chronic enteroviral meningoencephalitis after treatment correlates with in vitro susceptibility.

Authors:
Joanne G Wildenbeest Peterhans J van den Broek Kimberley S M Benschop Gerrit Koen Peter C Wierenga Ann C T M Vossen Taco W Kuijpers Katja C Wolthers

Antivir Ther 2012 24;17(3):459-66. Epub 2011 Oct 24.

Department of Pediatric Hematology, Immunology and Infectious Diseases, Emma Children's Hospital, Academic Medical Center, Amsterdam, The Netherlands.

Background: Human enteroviruses (HEVs) can cause severe infections, especially in patients with a deficient humoral immune response, such as X-linked agammaglobulinemia. In this patient group, chronic enteroviral meningitis (CEMA) is feared because of extensive morbidity and high fatality rate. Treatment options consist of intravenous immunoglobulin (IVIG), with various outcomes. Pleconaril is an antiviral agent with in vitro activity against HEVs that has been used in the treatment of HEV infections.

Methods: The efficacy of pleconaril and IVIG against HEV isolated from the patients was assessed in vitro in two patients with CEMA.

Results: Echovirus 11 was found in the cerebrospinal fluid (CSF) of case 1. Treatment with high-dose IVIG and pleconaril did not provide any clinical improvement and HEV PCR in CSF remained positive. Case 2 (echovirus 13 positive in CSF) was also treated with IVIG and pleconaril. The patient recovered completely and HEV PCR in CSF became negative. Recent IVIG batches contained low titres of neutralizing antibodies against the patient strains. Echovirus 11 (case 1) was resistant to pleconaril in vitro, whereas echovirus 13 (case 2) was susceptible, in accordance with virological response after treatment and subsequent clinical results.

Conclusions: This is the first report that evaluates efficacy of antiviral treatment in CEMA patients in relation to in vitro susceptibility of clinical virus isolates. Since pleconaril is no longer available for compassionate use we strongly propagate that new drugs should be developed against these potential life threatening HEV infections.
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http://dx.doi.org/10.3851/IMP1936DOI Listing
August 2012

Failure of pre-emptive treatment of cytomegalovirus infections and antiviral resistance in stem cell transplant recipients.

Authors:
Martha T van der Beek Erik W A F Marijt Ann C T M Vossen Caroline S van der Blij-de Brouwer Ron Wolterbeek Constantijn J M Halkes Eric C J Claas Aloys C M Kroes

Antivir Ther 2012 ;17(1):45-51

Department of Medical Microbiology, Leiden University Medical Center, Leiden, the Netherlands.

Background: Treatment of cytomegalovirus (CMV) infections after stem cell transplantation (SCT) does not always lead to a rapid viral response. The causes of treatment failure may be either viral resistance or immunological failure to control viral replication. This study investigated the response to pre-emptive treatment in CMV infections in order to define risk factors for treatment failure, including the role of antiviral resistance.

Methods: Adult recipients of allogeneic T-cell depleted SCT were studied retrospectively (n=92). CMV infections were treated with (val)ganciclovir according to a CMV DNA-load-based pre-emptive strategy. Treatment failure was defined as a CMV DNA load of 1,000 copies/ml or more after at least 2 weeks of treatment. Resistance was analysed by nucleotide sequence analysis of the UL97 and UL54 genes in the first CMV DNA-positive sample and in samples during treatment failure.

Results: Treatment failure occurred in 26 of the 47 pre-emptively treated patients (55%) and in 39 of 86 (45%) treatment episodes. The risk of treatment failure was increased during first treatment episodes (P=0.01) and during the use of immunosuppressive medication (P=0.02). Antiviral resistance was found in only 1 patient (4%) with treatment failure.

Conclusions: A slow response to pre-emptive antiviral treatment occurred frequently in CMV infections in SCT recipients. Antiviral resistance was observed but played a minor role in treatment failure.
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http://dx.doi.org/10.3851/IMP1899DOI Listing
February 2013

Real-time PCR versus viral culture on urine as a gold standard in the diagnosis of congenital cytomegalovirus infection.

Authors:
Jutte J C de Vries Annemiek A van der Eijk Katja C Wolthers Lisette G Rusman Suzan D Pas Richard Molenkamp Eric C Claas Aloys C M Kroes Ann C T M Vossen

J Clin Virol 2012 Feb 15;53(2):167-70. Epub 2011 Dec 15.

Department of Medical Microbiology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands.

Background: Cytomegalovirus (CMV) infection is the most common cause of congenital infection. Whereas CMV PCR has replaced viral culture and antigen detection in immunocompromised patients because of higher sensitivity, viral culture of neonatal urine is still referred to as the gold standard in the diagnosis of congenital CMV infection.

Objective: To compare real-time CMV PCR with shell vial culture on urine in the diagnosis of congenital CMV, in a multicenter design.

Study Design: A series of neonatal urines (n=340), received for congenital CMV diagnostics and routinely assessed with shell vial CMV culture, was retrospectively tested by real-time CMV PCR.

Results: The proportion of newborns found to be congenitally infected by real-time CMV PCR was 8.2% (28/340, 95%CI 5.6-11.8%), and 7.4% (25/340, 95%CI 4.9-10.8%) by rapid culture. When considering rapid culture as reference, real-time PCR was highly sensitive (100%), whereas sensitivity of rapid culture was 89.3% when considering real-time PCR as reference.

Conclusions: Our results, supported by analytical and clinical data on CMV DNA detection in neonatal urine, suggest enhanced sensitivity of recent PCR techniques when compared to viral culture. There is considerable rationale to favor real-time CMV PCR as a gold standard in the diagnosis of congenital CMV infection. A large-scale study combining both laboratory and clinical data is required to determine the exact time frame for sampling of neonatal urine when using real-time PCR.
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http://dx.doi.org/10.1016/j.jcv.2011.11.006DOI Listing
February 2012