Publications by authors named "Louis Bont"

168 Publications

Placenta Pathology From Term Born Neonates With Normal or Adverse Outcome.

Pediatr Dev Pathol 2021 Jan 20:1093526620980608. Epub 2021 Jan 20.

Department of Obstetrics, University Medical Center Utrecht, Utrecht, the Netherlands.

Background: The incidence of umbilical cord or placental parenchyma abnormalities associated with mortality or morbidity of term infants is lacking.

Methods: Placentas of 55 antepartum stillbirths (APD), 21 intrapartum stillbirths (IPD), 12 neonatal deaths (ND), and 80 admissions to a level 3 neonatal intensive care unit (NS) were studied and compared with 439 placentas from neonates from normal term pregnancies and normal outcome after vaginal delivery (NPVD) and with 105 placentas after an elective caesarian sections (NPEC).

Results: NPVD and NPEC placentas showed no or one abnormality in 70% and placentas from stillbirth showed two or more abnormalities in 80% of cases. APD placentas more frequently had a low weight and less formation of terminal villi. Hypercoiling was more often present in all study groups. Severe chronic villitis was almost exclusively present in APD placentas. Chorioamnionitis was significantly more frequent in APD, IPD and NS placentas and funisitis was more often observed in IPD and NS placentas.

Conclusion: Multiple placental abnormalities are significantly more frequent in placentas from term neonates with severe perinatal morbidity and mortality. These placental abnormalities are thought to be associated with disturbed oxygen transfer or with inflammation.
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http://dx.doi.org/10.1177/1093526620980608DOI Listing
January 2021

Neutrophils in respiratory syncytial virus infection: From harmful effects to therapeutic opportunities.

Br J Pharmacol 2021 Feb 15;178(3):515-530. Epub 2020 Dec 15.

Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.

Respiratory syncytial virus (RSV) is an important infectious agent in infants and young children. In most cases, RSV infection only causes mild disease, but in some, it requires invasive ventilation. Although antiviral drugs are obvious candidates to treat viral illness, and some have shown antiviral effects in humans, antivirals such as GS-5806, ALX-0171 and ALS-8176 have not yet met their expectations. Since the inappropriate or dysregulated immune response against RSV leads to harmful immune pathology, a robust immune cascade is probably underway by the time patients reach the hospital. RSV infection is associated with a strong neutrophil influx into the airway. It not clear if these cells contribute to antiviral defence or to lung pathology. This article discusses the protective and harmful roles of neutrophils during RSV infection and provides an overview of mechanisms by which neutrophil function could be targeted to prevent tissue injury and preserve homeostasis.
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http://dx.doi.org/10.1111/bph.15318DOI Listing
February 2021

Global Molecular Epidemiology of Respiratory Syncytial Virus from the 2017-2018 INFORM-RSV Study.

J Clin Microbiol 2020 Dec 17;59(1). Epub 2020 Dec 17.

Microbial Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland, USA

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection among infants and young children, resulting in annual epidemics worldwide. INFORM-RSV is a multiyear clinical study designed to describe the global molecular epidemiology of RSV in children under 5 years of age by monitoring temporal and geographical evolution of current circulating RSV strains, F protein antigenic sites, and their relationships with clinical features of RSV disease. During the pilot season (2017-2018), 410 RSV G-F gene sequences were obtained from 476 RSV-positive nasal samples collected from 8 countries (United Kingdom, Spain, The Netherlands, Finland, Japan, Brazil, South Africa, and Australia). RSV B (all BA9 genotype) predominated over RSV A (all ON1 genotype) globally (69.0% versus 31.0%) and in all countries except South Africa. Geographic clustering patterns highlighted wide transmission and continued evolution with viral spread. Most RSV strains were from infants of <1 year of age (81.2%), males (56.3%), and patients hospitalized for >24 h (70.5%), with no differences in subtype distribution. Compared to 2013 reference sequences, variations at F protein antigenic sites were observed for both RSV A and B strains, with high-frequency polymorphisms at antigenic site Ø (I206M/Q209R) and site V (L172Q/S173L/K191R) in RSV B strains. The INFORM-RSV 2017-2018 pilot season establishes an important molecular baseline of RSV strain distribution and sequence variability with which to track the emergence of new strains and provide an early warning system of neutralization escape variants that may impact transmission or the effectiveness of vaccines and MAbs under development.
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http://dx.doi.org/10.1128/JCM.01828-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771447PMC
December 2020

Burden of respiratory syncytial virus infection in community-dwelling older adults in Europe (RESCEU): an international prospective cohort study.

Eur Respir J 2020 Oct 15. Epub 2020 Oct 15.

Department of Pediatric Infectious Diseases and Immunology, Wilhelmina Children's Hospital, University Medical Center Utrecht, the Netherlands.

Background: Respiratory syncytial virus (RSV) infection in older adults is recognized as an important health issue. We aimed to assess the community burden of RSV in Europe in older adults aged ≥60 years.

Methods: This international prospective observational cohort study is part of REspiratory Syncytial virus Consortium in EUrope (RESCEU). Participants were recruited before two independent RSV-seasons through general practitioner's offices. Participants reported weekly about symptoms of acute respiratory tract infection (ARTI) during one RSV-season. . ARTI patients were tested for RSV during home visits and completed a daily symptom diary. RSV-illness included PCR-confirmed ARTI and those showing seroconversion over the season. RSV-ARTI was based on PCR alone (ClinicalTrials.gov, NCT03621930).

Results: We recruited 1040 participants (527 in season 2017-2018, 513 in season 2018-2019) with a median age of 75 years (range 60-100). 1023 (99%) lived independently at home at baseline. RSV-illness incidence was 4.2% (22/527) and 7.2% (37/513) in the respective seasons. RSV-illness did not affect frailty or cardiopulmonary status during the course of the study. No patients were hospitalized or died from RSV-illness. In the 36 patients with PCR confirmed RSV-ARTI, symptom duration averaged 19 days, while a doctor's visit took place in 11/36 (31%) of cases. RSV-ARTI could not clinically be differentiated from all other ARTI based on symptoms.

Conclusion: This European study showed that RSV is prevalent in community-dwelling older adults and rarely causes severe disease. This suggests that watchful waiting, using a continuity of care approach to identify those who do need more intensive care is often justified when RSV is suspected in family practice.
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http://dx.doi.org/10.1183/13993003.02688-2020DOI Listing
October 2020

Defining asthma in children: how well do parents, doctors and spirometry agree?

ERJ Open Res 2020 Oct 5;6(4). Epub 2020 Oct 5.

Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht, The Netherlands.

Background: Because diagnosing asthma in school-aged children is challenging, a variety of proxies for asthma are used in clinical practice and research settings as indicators of this disease. We aimed to provide insight into the agreement between various asthma indicators based on parental report, medical diagnosis and spirometry.

Methods: Children from the WHISTLER birth cohort performed spirometry and were followed up with parental ISAAC (International Study of Asthma and Allergies in Childhood) questionnaires about asthma at 5 and 8 years of age. Medical data were extracted from primary care records. We compared 15 asthma indicators based on parental report, medical diagnosis and spirometry using positive agreement, κ statistics and latent class cluster analysis.

Results: At 5 years of age, 1007 children completed a study visit, while 803 children visited at 8 years of age. Depending on the indicator, the responder and child's age, the asthma prevalence ranged from 0.2% to 26.6%. Cluster analysis revealed classes related to the presence of recent symptoms and a decreased lung function. Agreement between parents and doctors was generally low with κ coefficients ranging from 0.07 (recent wheeze) to 0.52 (recent asthma medication). Additionally, parental report showed to be sensitive to recall bias over time.

Conclusions: Dependent on the asthma indicator, the responder and the age of the child, substantial differences in agreement were observed between commonly used indicators associated with asthmatic disease in school-aged children. Most agreement between parents and doctors was seen for objective and recent indicators such as the recent use of asthma medication. We advocate caution when literature with different asthma indicators is compared.
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http://dx.doi.org/10.1183/23120541.00348-2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533381PMC
October 2020

Live-attenuated Respiratory Syncytial Virus Vaccines: Time for the Next Step.

Am J Respir Crit Care Med 2021 Mar;203(5):538-539

Departments of Pediatrics University Medical Center Utrecht Utrecht, the Netherlands.

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http://dx.doi.org/10.1164/rccm.202009-3431EDDOI Listing
March 2021

Comparison of Illumina versus Nanopore 16S rRNA Gene Sequencing of the Human Nasal Microbiota.

Genes (Basel) 2020 09 21;11(9). Epub 2020 Sep 21.

Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center (Erasmus MC), 3015 CN Rotterdam, The Netherlands.

Illumina and nanopore sequencing technologies are powerful tools that can be used to determine the bacterial composition of complex microbial communities. In this study, we compared nasal microbiota results at genus level using both Illumina and nanopore 16S rRNA gene sequencing. We also monitored the progression of nanopore sequencing in the accurate identification of species, using pure, single species cultures, and evaluated the performance of the nanopore EPI2ME 16S data analysis pipeline. Fifty-nine nasal swabs were sequenced using Illumina MiSeq and Oxford Nanopore 16S rRNA gene sequencing technologies. In addition, five pure cultures of relevant bacterial species were sequenced with the nanopore sequencing technology. The Illumina MiSeq sequence data were processed using bioinformatics modules present in the Mothur software package. Albacore and Guppy base calling, a workflow in nanopore EPI2ME (Oxford Nanopore Technologies-ONT, Oxford, UK) and an in-house developed bioinformatics script were used to analyze the nanopore data. At genus level, similar bacterial diversity profiles were found, and five main and established genera were identified by both platforms. However, probably due to mismatching of the nanopore sequence primers, the nanopore sequencing platform identified in much lower abundance compared to Illumina sequencing. Further, when using default settings in the EPI2ME workflow, almost all sequence reads that seem to belong to the bacterial genus and a considerable part to the genus were only identified at family level. Nanopore sequencing of single species cultures demonstrated at least 88% accurate identification of the species at genus and species level for 4/5 strains tested, including improvements in accurate sequence read identification when the basecaller Guppy and Albacore, and when flowcell versions R9.4 (Oxford Nanopore Technologies-ONT, Oxford, UK) and R9.2 (Oxford Nanopore Technologies-ONT, Oxford, UK) were compared. In conclusion, the current study shows that the nanopore sequencing platform is comparable with the Illumina platform in detection bacterial genera of the nasal microbiota, but the nanopore platform does have problems in detecting bacteria within the genus . Although advances are being made, thorough validation of the nanopore platform is still recommendable.
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http://dx.doi.org/10.3390/genes11091105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565314PMC
September 2020

Transcriptome of airway neutrophils reveals an interferon response in life-threatening respiratory syncytial virus infection.

Clin Immunol 2020 Nov 11;220:108593. Epub 2020 Sep 11.

Center for Translational Immunology, University Medical Centre Utrecht, Utrecht, Lundlaan 6, 3584 EA Utrecht, the Netherlands; Department of cardiology, University Medical Centre Utrecht, Utrecht, Lundlaan 6, 3584 EA Utrecht, the Netherlands. Electronic address:

Background: Neutrophils are the most abundant cell type infiltrating the airways during severe respiratory syncytial virus (RSV) infection. Their exact role in disease pathophysiology remains enigmatic. Therefore, we determined genome-wide RNA expression profiles of local and systemic neutrophils in RSV bronchiolitis to provide further insight into local neutrophil biology.

Methods: We performed a single-center analysis, in 16 infants, admitted to the pediatric intensive care unit with severe RSV bronchiolitis. Neutrophils were isolated from blood and tracheobronchial aspirates (sputum). After low input RNA sequencing, differential expression of genes was determined followed by gene set analysis.

Results: Paired transcriptomic analysis of airway versus blood neutrophils showed an inflammatory phenotype, characterized by NF-kB signaling and upregulated expression of IL-6 and interferon pathways. We observed distinct expression of neutrophil activation genes (TNFSF13B, FCER1G).

Discussion: Our data indicate that airway neutrophils regulate their function at the transcriptional level in response to viral infection. It also suggests that local interferon drives the neutrophil response of severe RSV bronchiolitis.
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http://dx.doi.org/10.1016/j.clim.2020.108593DOI Listing
November 2020

Bovine IgG Prevents Experimental Infection With RSV and Facilitates Human T Cell Responses to RSV.

Front Immunol 2020 6;11:1701. Epub 2020 Aug 6.

Center for Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands.

Respiratory syncytial virus (RSV) infections represent a major burden of disease in infants and are the second most prevalent cause of death worldwide. Human milk immunoglobulins provide protection against RSV. However, many infants depend on processed bovine milk-based nutrition, which lacks intact immunoglobulins. We investigated the potential of bovine antibodies to neutralize human RSV and facilitate-cell immune activation. We show cow's milk IgG (bIgG) and Intravenous Immunoglobulin (IVIG) have a similar RSV neutralization capacity, even though bIgG has a lower pre-F to post-F binding ratio compared to human IVIG, with the majority of bIgG binding to pre-F. RSV is better neutralized with human IVIG. Consequently, we enriched RSV specific T cells by culturing human PBMC with a mixture of RSV peptides, and used these T cells to study the effect of bIgG and IVIG on the activation of pre-F-pecific T cells. bIgG facilitated T cell activation in a similar manner as IVIG. Moreover, bIgG was able to mediate T cell activation and internalization of pathogens, which are prerequisites for inducing an adaptive viral response. Using mouse experiments, we showed that bIgG is able to bind the murine activating IgG Fc Receptors (FcγR), but not the inhibiting FcγRII. Intranasal administration of the monoclonal antibody palivizumab, but also of bIgG and IVIG prevented RSV infection in mice. The concentration of bIgG needed to prevent infection was ~5-fold higher compared to IVIG. In conclusion, the data presented here indicate that functionally active bIgG facilitates adaptive antiviral T cell responses and prevents RSV infection and .
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http://dx.doi.org/10.3389/fimmu.2020.01701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423966PMC
August 2020

Respiratory Syncytial Virus Consortium in Europe (RESCEU) Birth Cohort Study: Defining the Burden of Infant Respiratory Syncytial Virus Disease in Europe.

J Infect Dis 2020 10;222(Suppl 7):S606-S612

Department of Paediatric Immunology and Infectious Diseases, Wilhelmina Children's Hospital/University Medical Center Utrecht, Utrecht, The Netherlands.

Background: Respiratory syncytial virus (RSV) causes significant morbidity and mortality in infants worldwide. Although prematurity and cardiopulmonary disease are risk factors for severe disease, the majority of infants hospitalized with RSV are previously healthy. Various vaccines and therapeutics are under development and expected to be available in the near future. To inform the use of these new vaccines and therapeutics, it is necessary to determine the burden of RSV disease in Europe. We will prospectively follow-up a birth cohort to obtain incidence data on RSV acute respiratory tract infection (ARTI).

Methods: Multicenter prospective study of a birth cohort consisting of 10 000 healthy infants, recruited during 3 consecutive years. RSV associated hospitalization in the first year of life will be determined by questionnaires and hospital chart reviews. A nested cohort of 1000 infants will be actively followed. In case of ARTI, a respiratory sample will be collected for RSV molecular diagnosis.

Results: The primary outcome is the incidence rate of RSV-associated hospitalization in the first year of life. In the active cohort the primary outcome is RSV associated ARTI and MA-ARTI.

Conclusions: We will provide key information to fill the gaps in knowledge about the burden of RSV disease in healthy infants.

Clinical Trials Registration: NCT03627572.
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http://dx.doi.org/10.1093/infdis/jiaa310DOI Listing
October 2020

Presumed Risk Factors and Biomarkers for Severe Respiratory Syncytial Virus Disease and Related Sequelae: Protocol for an Observational Multicenter, Case-Control Study From the Respiratory Syncytial Virus Consortium in Europe (RESCEU).

J Infect Dis 2020 10;222(Suppl 7):S658-S665

Department of Paediatrics, Oxford Vaccine Group, Oxford, United Kingdom.

Respiratory syncytial virus (RSV) is the leading viral pathogen associated with acute lower respiratory tract infection and hospitalization in children < 5 years of age worldwide. While there are known clinical risk factors for severe RSV infection, the majority of those hospitalized are previously healthy infants. There is consequently an unmet need to identify biomarkers that predict host response, disease severity, and sequelae. The primary objective is to identify biomarkers of severe RSV acute respiratory tract infection (ARTI) in infants. Secondary objectives include establishing biomarkers associated with respiratory sequelae following RSV infection and characterizing the viral load, RSV whole-genome sequencing, host immune response, and transcriptomic, proteomic, metabolomic and epigenetic signatures associated with RSV disease severity. Six hundred thirty infants will be recruited across 3 European countries: the Netherlands, Spain, and the United Kingdom. Participants will be recruited into 2 groups: (1) infants with confirmed RSV ARTI (includes upper and lower respiratory tract infections), 500 without and 50 with comorbidities; and (2) 80 healthy controls. At baseline, participants will have nasopharyngeal, blood, buccal, stool, and urine samples collected, plus complete a questionnaire and 14-day symptom diary. At convalescence (7 weeks ± 1 week post-ARTI), specimen collection will be repeated. Laboratory measures will be correlated with symptom severity scores to identify corresponding biomarkers of disease severity.

Clinical Trials Registration: NCT03756766.
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http://dx.doi.org/10.1093/infdis/jiaa239DOI Listing
October 2020

Assessing the strength of evidence for a causal effect of respiratory syncytial virus lower respiratory tract infections on subsequent wheezing illness: a systematic review and meta-analysis.

Lancet Respir Med 2020 08;8(8):795-806

Department of Psychology, Rowan University, Glassboro, NJ, USA. Electronic address:

Background: Although a positive association has been established, it is unclear whether lower respiratory tract infections (LRTIs) with respiratory syncytial virus (RSV) cause chronic wheezing illnesses. If RSV-LRTI were causal, we would expect RSV-LRTI prevention to reduce the incidence of chronic wheezing illnesses in addition to reducing acute disease. We aimed to evaluate the strength of evidence for a causal effect of RSV-LRTI on subsequent chronic wheezing illness to inform public health expectations for RSV vaccines.

Methods: We did a systematic review and meta-analysis of observational studies evaluating the association between RSV-LRTI and subsequent wheezing illness (exposure studies) and studies evaluating the association between RSV immunoprophylaxis and subsequent wheezing illness (immunoprophylaxis studies). Exposure studies were included if the exposure group members had an LRTI with laboratory-confirmed RSV and if the exposure ascertainment period began before 2 years of age and ended before 5 years of age. We required a wash-out period of more than 30 days between the index RSV-LRTI and the outcome measurement to allow for resolution of the acute illness. Comparisons between RSV-LRTI and non-RSV-LRTI were not included. Immunoprophylaxis studies were included if they measured the association with subsequent wheezing illness relative to a control group, either in a randomised controlled trial (RCT) or an observational design. For the immunoprophylaxis drugs in question, we required evidence of efficacy in targeting RSV-LRTI from at least one RCT to ensure biological plausibility. All variations of wheezing illness were combined into a single outcome that refers broadly to asthma or any other respiratory illness with wheezing symptoms. Ovid MEDLINE and Embase databases were searched from inception up to Aug 28, 2018. We evaluated whether data from exposure studies could provide evidence against the most viable non-causal theory that RSV-LRTI is a marker of respiratory illness susceptibility rather than a causal factor. Additionally, we tested whether RSV immunoprophylaxis reduces the odds of subsequent wheezing illnesses. We used a random-effects modelling framework and, to accommodate studies providing multiple correlated estimates, robust variance estimation meta-regressions. Meta-regression coefficients (b) quantify differences between exposure and comparator groups on the log odds ratio (log OR) scale.

Findings: From 14 235 records we identified 57 eligible articles that described 42 studies and provided 153 effect estimates. 35 studies estimated the direct effect of RSV-LRTI on wheezing illnesses (exposure studies) and eight evaluated the effect of RSV immunoprophylaxis (immunoprophylaxis studies). Exposure studies that adjusted for genetic influences yielded a smaller mean adjusted OR estimate (aOR 2·45, 95% CI 1·23-4·88) compared with those that did not (4·17, 2·36-7·37), a significant difference (b 0·53, 95% CI 0·04-1·02). Infants who were not protected with RSV immunoprophylaxis tended to have higher odds of subsequent wheezing illness, as we would expect if RSV-LRTI were causal, but the effect was not significant (OR 1·21, 95% CI 0·73-1·99). There was generally a high threat of confounding bias in the observational studies. Additionally, in both the observational studies and immunoprophylaxis RCTs, there was high risk of bias due to missing outcome data.

Interpretation: Our findings, limited to exposure and immunoprophylaxis studies, do not support basing policy decisions on an assumption that prevention of RSV-LRTI will reduce recurrent chronic wheezing illnesses.

Funding: Bill & Melinda Gates Foundation.
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http://dx.doi.org/10.1016/S2213-2600(20)30109-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464591PMC
August 2020

TIPICO X: report of the 10th interactive infectious disease workshop on infectious diseases and vaccines.

Hum Vaccin Immunother 2020 Aug 5:1-14. Epub 2020 Aug 5.

Translational Paediatrics and Infectious Diseases, Department of Paediatrics, Hospital Clínico Universitario De Santiago De Compostela , Santiago De Compostela, Spain.

TIPICO is an expert meeting and workshop that aims to provide the most recent evidence in the field of infectious diseases and vaccination. The 10th Interactive Infectious Disease TIPICO workshop took place in Santiago de Compostela, Spain, on November 21-22, 2019. Cutting-edge advances in vaccination against respiratory syncytial virus, , rotavirus, human papillomavirus, , influenza virus, and Typhi were discussed. Furthermore, heterologous vaccine effects were updated, including the use of Bacillus Calmette-Guérin (BCG) vaccine as potential treatment for type 1 diabetes. Finally, the workshop also included presentations and discussion on emergent virus and zoonoses, vaccine resilience, building and sustaining confidence in vaccination, approaches to vaccine decision-making, pros and cons of compulsory vaccination, the latest advances in decoding infectious diseases by RNA gene signatures, and the application of big data approaches.
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http://dx.doi.org/10.1080/21645515.2020.1788301DOI Listing
August 2020

Simultaneous Viral Whole-Genome Sequencing and Differential Expression Profiling in Respiratory Syncytial Virus Infection of Infants.

J Infect Dis 2020 10;222(Suppl 7):S666-S671

Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, United Kingdom.

Targeted metagenomics using strand-specific libraries with target enrichment is a sensitive, generalized approach to pathogen sequencing and transcriptome profiling. Using this method, we recovered 13 (76%) complete human respiratory syncytial virus (RSV) genomes from 17 clinical respiratory samples, reconstructed the phylogeny of the infecting viruses, and detected differential gene expression between 2 RSV subgroups, specifically, a lower expression of the P gene and a higher expression of the M2 gene in RSV-A than in RSV-B. This methodology can help to relate viral genetics to clinical phenotype and facilitate ongoing population-level RSV surveillance and vaccine development. Clinical Trials Registration. NCT03627572 and NCT03756766.
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http://dx.doi.org/10.1093/infdis/jiaa448DOI Listing
October 2020

How viral sequence analysis may guide development of RSV monoclonal antibodies.

Clin Infect Dis 2020 Jul 8. Epub 2020 Jul 8.

Department of Paediatrics, University Medical Center Utrecht, Utrecht, Netherlands.

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http://dx.doi.org/10.1093/cid/ciaa944DOI Listing
July 2020

Global molecular diversity of RSV - the "INFORM RSV" study.

BMC Infect Dis 2020 Jun 26;20(1):450. Epub 2020 Jun 26.

Department of Paediatric Immunology and Infectious Diseases, Wilhelmina Children's Hospital, University Medical Centre Utrecht, Utrecht University, Utrecht, the Netherlands.

Background: Respiratory syncytial virus (RSV) is a global cause of severe respiratory morbidity and mortality in infants. While preventive and therapeutic interventions are being developed, including antivirals, vaccines and monoclonal antibodies, little is known about the global molecular epidemiology of RSV. INFORM is a prospective, multicenter, global clinical study performed by ReSViNET to investigate the worldwide molecular diversity of RSV isolates collected from children less than 5 years of age.

Methods: The INFORM study is performed in 17 countries spanning all inhabited continents and will provide insight into the molecular epidemiology of circulating RSV strains worldwide. Sequencing of > 4000 RSV-positive respiratory samples is planned to detect temporal and geographical molecular patterns on a molecular level over five consecutive years. Additionally, RSV will be cultured from a subset of samples to study the functional implications of specific mutations in the viral genome including viral fitness and susceptibility to different monoclonal antibodies.

Discussion: The sequencing and functional results will be used to investigate susceptibility and resistance to novel RSV preventive or therapeutic interventions. Finally, a repository of globally collected RSV strains and a database of RSV sequences will be created.
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http://dx.doi.org/10.1186/s12879-020-05175-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316634PMC
June 2020

Respiratory Syncytial Virus-related Death in Children With Down Syndrome: The RSV GOLD Study.

Pediatr Infect Dis J 2020 08;39(8):665-670

From the Division of Infectious Diseases, Department of Pediatrics, University Medical Centre Utrecht, Utrecht, The Netherlands.

Background: Respiratory syncytial virus (RSV) is a major cause of mortality in children younger than 5 years worldwide. Systematic reviews have shown that Down syndrome (DS) is an independent risk factor for severe RSV infection. We aimed to describe demographic and clinical characteristics of children with DS who died with RSV infection.

Methods: We performed a retrospective case series in which data were shared by individual researchers, research networks and physicians worldwide as part of the RSV Global Online Database study. We included children with DS who died when younger than 5 years of age with laboratory-confirmed RSV infection.

Results: We included 53 children with DS and RSV-related mortality from 20 countries in 5 continents. Five (9.4%) children were from low-income or lower-middle-income countries. Median age at time of death was 6.0 months [interquartile range (IQR): 3.00-12.0]. Thirteen (24.5%) children were born term and had no other risk factors for severe RSV disease. In total, 36 (67.9%) children had congenital heart disease, 8 (15.1%) had chronic lung disease and 1 (1.9%) had congenital immunodeficiency. Duration of hospitalization was significantly longer for children with DS compared with children without DS [median length of stay, 13 days (IQR: 6.8-21.0) vs. 8 days (IQR: 3.0-18.5), P=0.005].

Conclusions: One-fourth of children with DS and RSV-confirmed death did not have risk factors for severe RSV disease, indicating that DS is an important risk factor for RSV-related mortality. Age distribution at time of death demonstrates that maternal vaccination would not be sufficient to protect children with DS against RSV-related mortality.
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http://dx.doi.org/10.1097/INF.0000000000002666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360096PMC
August 2020

Low Sensitivity of BinaxNOW RSV in Infants.

J Infect Dis 2020 10;222(Suppl 7):S640-S647

Department of Paediatric Immunology and Infectious Diseases, Wilhelmina Children's Hospital/University Medical Center Utrecht, Utrecht, Netherlands.

Background: Respiratory syncytial virus (RSV) is a major cause of hospitalization in infants. Early detection of RSV can optimize clinical management and minimize use of antibiotics. BinaxNOW RSV (BN) is a rapid antigen detection test that is widely used. We aimed to validate the sensitivity of BN in hospitalized and nonhospitalized infants against the gold standard of molecular diagnosis.

Methods: We evaluated the performance of BN in infants with acute respiratory tract infections with different degrees of disease severity. Diagnostic accuracy of BN test results were compared with molecular diagnosis as reference standard.

Results: One hundred sixty-two respiratory samples from 148 children from October 2017 to February 2019 were studied. Sixty-six (40.7%) samples tested positive for RSV (30 hospitalizations, 31 medically attended episodes not requiring hospitalization, and 5 nonmedically attended episodes). Five of these samples tested positive with BN, leading to an overall sensitivity of BN of 7.6% (95% confidence interval [CI], 3.3%-16.5%) and a specificity of 100% (95% CI, 96.2%-100%). Sensitivity was low in all subgroups.

Conclusions: We found a low sensitivity of BN for point-of-care detection of RSV infection. BinaxNOW RSV should be used and interpreted with caution.
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http://dx.doi.org/10.1093/infdis/jiaa050DOI Listing
October 2020

Infant respiratory syncytial virus prophylaxis and nasopharyngeal microbiota until 6 years of life: a subanalysis of the MAKI randomised controlled trial.

Lancet Respir Med 2020 10 20;8(10):1022-1031. Epub 2020 Mar 20.

Department of Paediatric Immunology and Infectious Diseases, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, Netherlands; Medical Research Council-University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK. Electronic address:

Background: Respiratory syncytial virus (RSV) infection during infancy is suggested to cause long-term wheeze. In turn, wheeze has been associated with bacterial dysbiosis of the respiratory tract. We investigated the effects of RSV prophylaxis with palivizumab in otherwise healthy preterm infants on respiratory microbiota composition at 1 year and 6 years of age.

Methods: In a multicentre, single-blind, randomised, placebo-controlled trial (the MAKI trial), infants born between 32-35 weeks of gestation, in one university and in 15 regional hospitals in the the Netherlands, were randomly assigned (1:1) to receive palivizumab or placebo during the RSV season of their first year of life. Intramuscular injections of palivizumab 15 mg/kg or placebo were given during one RSV season: either from Oct 1, or from discharge from the neonatal unit until March 10 (minimun of 2 and maximum of 5 injections were given). Children were 6 months old or younger at the start of the RSV season; exclusion criteria included congenital heart disease, bronchopulmonary dysplasia, Down's syndrome, or other serious congenital disorders, use of mechanical ventilation at birth, treatment with surfactant, or physician-diagnosed wheeze before the start of the RSV season. Children were followed up for clinical symptoms until 6 years of age. For this subanalysis, we obtained nasopharyngeal swabs from children aged 1 year and 6 years and analysed them using 16S-rRNA sequencing. At 6 years we also measured reversible airway obstruction. The primary outcome was the effect of palivizumab during infancy on the respiratory microbiota composition at age 1 year and 6 years (intention-to-treat analysis). The trial is registered in the ISRCTN registry, number ISRCTN73641710.

Findings: From April 1, 2008, to Dec 31, 2010, 429 infants were enrolled in the MAKI trial (n=214 to the palivizumab group; n=215 to the placebo group). At 1 year, we collected swabs and sequenced DNA from 170 (40%) of 429 children, of which 145 (85%) samples had high-quality DNA. The overall microbiota composition was significantly different (R 1·3%; p=0·0185) between the palivizumab group and the placebo group at 1 year of life; children in the palivizumab group had a significantly lower abundance of the Staphylococcus-dominated cluster (odds ratio 0·28 [95% CI 0·11-0·68]; p=0·00394), an increased abundance of biomarker species, such as Klebsiella, and a more diverse set of oral taxa, including Streptococcus spp, compared with children in the placebo group. At 6 years, we collected swabs and sequenced DNA from 349 (88%) of 395 children who completed follow-up, of which 342 (98%) samples had high-quality DNA. The overall microbiota composition was not significantly different between groups at 6 years (R 0·6%; p=0·0575); however, children in the palivizumab group had a significantly increased abundance of Haemophilus spp and lower abundance of Moraxella and Neisseriaceae spp compared with children in the placebo group. Absence of PCR-confirmed RSV infection at 1 year was significantly associated with a higher abundance of Haemophilus spp at age 6 years and a significantly lower abundance of Moraxella and Neisseriaceae than children with RSV infection at 1 year. Reversible airway obstruction at 6 years was also positively associated with Haemophilus abundance and negatively associated with the abundance of health-associated taxa, such as Moraxella, Corynebacterium, Dolosigranulum, and Staphylococcus, even after correction for RSV immunoprophylaxis (all: p<0·05). Additionally, reversible airway instruction was associated with significantly higher Streptococcus pneumoniae abundance.

Interpretation: Palivizumab in infancy in otherwise healthy preterm infants is associated with persistent effects on the abundance of specific, potentially pathogenic, microbial taxa in the respiratory tract. Several of the palivizumab-associated biomarker species were associated with reversible airway obstruction at age 6 years. These results warrant further studies to establish the long-term ecological effects and health consequences of palivizumab in infancy.

Funding: MedImmune.
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http://dx.doi.org/10.1016/S2213-2600(19)30470-9DOI Listing
October 2020

Life-threatening bronchiolitis in children: eight decades of critical care.

Lancet Respir Med 2020 02 18;8(2):142-144. Epub 2019 Nov 18.

Paediatric Intensive Care Unit, Emma Children's Hospital, Amsterdam University Medical Centers, Academic Medical Center, 1100 DD Amsterdam, The Netherlands.

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http://dx.doi.org/10.1016/S2213-2600(19)30445-XDOI Listing
February 2020

Does respiratory syncytial virus lower respiratory illness in early life cause recurrent wheeze of early childhood and asthma? Critical review of the evidence and guidance for future studies from a World Health Organization-sponsored meeting.

Vaccine 2020 03 20;38(11):2435-2448. Epub 2020 Jan 20.

Department of Immunizations, Vaccines and Biologicals, World Health Organization, 20 Avenue Appia, Geneva, Switzerland.

Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection (LRTI) and hospitalization in infants and children globally. Many observational studies have found an association between RSV LRTI in early life and subsequent respiratory morbidity, including recurrent wheeze of early childhood (RWEC) and asthma. Conversely, two randomized placebo-controlled trials of efficacious anti-RSV monoclonal antibodies (mAbs) in heterogenous infant populations found no difference in physician-diagnosed RWEC or asthma by treatment group. If a causal association exists and RSV vaccines and mAbs can prevent a substantial fraction of RWEC/asthma, the full public health value of these interventions would markedly increase. The primary alternative interpretation of the observational data is that RSV LRTI in early life is a marker of an underlying predisposition for the development of RWEC and asthma. If this is the case, RSV vaccines and mAbs would not necessarily be expected to impact these outcomes. To evaluate whether the available evidence supports a causal association between RSV LRTI and RWEC/asthma and to provide guidance for future studies, the World Health Organization convened a meeting of subject matter experts on February 12-13, 2019 in Geneva, Switzerland. After discussing relevant background information and reviewing the current epidemiologic evidence, the group determined that: (i) the evidence is inconclusive in establishing a causal association between RSV LRTI and RWEC/asthma, (ii) the evidence does not establish that RSV mAbs (and, by extension, future vaccines) will have a substantial effect on these outcomes and (iii) regardless of the association with long-term childhood respiratory morbidity, severe acute RSV disease in young children poses a substantial public health burden and should continue to be the primary consideration for policy-setting bodies deliberating on RSV vaccine and mAb recommendations. Nonetheless, the group recognized the public health importance of resolving this question and suggested good practice guidelines for future studies.
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http://dx.doi.org/10.1016/j.vaccine.2020.01.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049900PMC
March 2020

Clinical Development of Respiratory Syncytial Virus Antivirals-What We Can Learn From Oseltamivir.

Clin Infect Dis 2020 Dec;71(11):2796-2798

Division of Infectious Diseases, Department of Pediatrics, University Medical Center Utrecht, Utrecht, The Netherlands.

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http://dx.doi.org/10.1093/cid/ciz1169DOI Listing
December 2020

Rubella seroprevalence in pregnant women living with and without HIV in Soweto, South Africa.

Int J Infect Dis 2020 Feb 19;91:255-260. Epub 2019 Dec 19.

Medical Research Council: Respiratory and Meningeal Pathogens Research Unit, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; Department of Science and Technology/National Research Foundation: Vaccine Preventable Diseases Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa. Electronic address:

Objectives: Rubella infection during pregnancy may cause foetal death or congenital rubella syndrome. In South Africa, the national public immunization programme does not include rubella vaccination. The aim of this study was to evaluate rubella sero-epidemiology in pregnant South African women living with and without HIV.

Methods: Serum samples obtained from women living with HIV (n=552) and without HIV (n=552) were tested for rubella immunoglobulin G antibodies using an ELISA. The proportions of women with seronegative titres (<8IU/ml) and seropositive titres (≥11IU/ml), and geometric mean titres (GMT) were compared by age group and HIV status.

Results: The overall proportion of rubella seropositivity was 97.8%. The proportion of seropositive women increased with age group (18-25 years: 97.0%; 26-32 years: 97.7%; 33-40 years: 99.3%; p=0.047 after adjusting for HIV status). Similar proportions of women living with and without HIV were seropositive.

Conclusions: Rubella immunity was high among South African pregnant women living with and without HIV in the absence of rubella vaccination in the public immunization programme. However, a lower percentage of younger women had seropositive titres, indicating the need for routine rubella vaccination after an increase in vaccine coverage rates.
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http://dx.doi.org/10.1016/j.ijid.2019.12.018DOI Listing
February 2020

Signal inhibitory receptor on leukocytes (SIRL)-1 and leukocyte- associated immunoglobulin-like receptor (LAIR)-1 regulate neutrophil function in infants.

Clin Immunol 2020 02 13;211:108324. Epub 2019 Dec 13.

Department of Paediatrics, Wilhelmina Children's Hospital, University Medical Centre Utrecht, Utrecht, Lundlaan 6, 3584, EA, Utrecht, the Netherlands; Center of Translational Immunology, University Medical Centre Utrecht, Utrecht, Lundlaan 6, 3584, EA, Utrecht, the Netherlands. Electronic address:

During severe respiratory syncytial virus (RSV) bronchiolitis there is a massive influx of activated neutrophils to the lungs. An exaggerated immune response contributes to lung damage and disease severity during RSV infection. We have previously shown that normal adult neutrophil function can be modulated by agonists of SIRL-1. Here we aimed to measure the potential of two immune checkpoints: SIRL-1 and LAIR-1, to regulate the function of fresh blood and sputum neutrophils from infants with and without severe RSV bronchiolitis. We show a modest inhibition of the oxidative burst through SIRL-1 and LAIR-1, in control and RSV-infected infants. In addition, SIRL-1 and LAIR-1 inhibited neutrophil extracellular traps (NET) formation by sputum neutrophils of RSV patients. Altogether our data show that inhibitory receptors LAIR-1 and SIRL-1 can be used to regulate neutrophil function.
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http://dx.doi.org/10.1016/j.clim.2019.108324DOI Listing
February 2020

Correction to: Cost-effectiveness of rule-based immunoprophylaxis against respiratory syncytial virus infections in preterm infants.

Eur J Pediatr 2020 Feb;179(2):355

Division of Pediatric Immunology and Infectious Diseases, University Medical Center Utrecht, P.O. Box 85090, 3508 AB, Utrecht, the Netherlands.

The name of the co-author Wendy J. Ungar was inadvertently omitted on the original published article. Her name and affiliation have now been added to the author list.
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http://dx.doi.org/10.1007/s00431-019-03526-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645511PMC
February 2020

Update of a clinical prediction model for serious bacterial infections in preschool children by adding a host-protein-based assay: a diagnostic study.

BMJ Paediatr Open 2019 20;3(1):e000416. Epub 2019 Sep 20.

General Paediatrics, Erasmus MC Sophia Childrens Hospital, Rotterdam, The Netherlands.

Objective: To determine whether updating a diagnostic prediction model by adding a combination assay (tumour necrosis factor-related apoptosis-inducing ligand, interferon γ induced protein-10 and C reactive protein (CRP)) can accurately identify children with pneumonia or other serious bacterial infections (SBIs).

Design: Observational double-blind diagnostic study.

Setting: Two hospitals in Israel and four hospitals in the Netherlands.

Patients: 591 children, aged 1-60 months, presenting with lower respiratory tract infections or fever without source. 96 of them had SBIs. The original Feverkidstool, a polytomous logistic regression model including clinical variables and CRP, was recalibrated and thereafter updated by using the assay.

Main Outcome Measures: Pneumonia, other SBIs or no SBI.

Results: The recalibrated original Feverkidstool discriminated well between SBIs and viral infections, with a c-statistic for pneumonia of 0.84 (95% CI 0.77 to 0.92) and 0.82 (95% CI 0.77 to 0.86) for other SBIs. The discriminatory ability increased when CRP was replaced by the combination assay; c-statistic for pneumonia increased to 0.89 (95% CI 0.82 to 0.96) and for other SBIs to 0.91 (95% CI 0.87 to 0.94). This updated Feverkidstool improved diagnosis of SBIs mainly in children with low-moderate risk estimates of SBIs.

Conclusion: We improved the diagnostic accuracy of the Feverkidstool by replacing CRP with a combination assay to predict pneumonia or other SBIs in febrile children. The updated Feverkidstool has the largest potential to rule out bacterial infections and thus to decrease unnecessary antibiotic prescription in children with low-to-moderate predicted risk of SBIs.
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http://dx.doi.org/10.1136/bmjpo-2018-000416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6782126PMC
September 2019

External validation and update of a prognostic model to predict mortality in hospitalized adults with RSV: A retrospective Dutch cohort study.

J Med Virol 2019 12 28;91(12):2117-2124. Epub 2019 Aug 28.

Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands.

Respiratory syncytial virus (RSV) causes significant mortality in hospitalized adults. Prediction of poor outcomes improves targeted management and clinical outcomes. We externally validated and updated existing models to predict poor outcome in hospitalized RSV-infected adults. In this single center, retrospective, observational cohort study, we included hospitalized adults with respiratory tract infections (RTIs) and a positive polymerase chain reaction for RSV (A/B) on respiratory tract samples (2005-2018). We validated existing prediction models and updated the best discriminating model by revision, recalibration, and incremental value testing. We included 192 RSV-infected patients (median age 60.7 years, 57% male, 65% immunocompromised, and 43% with lower RTI). Sixteen patients (8%) died within 30 days. During hospitalization, 16 (8%) died, 30 (16%) were admitted to intensive care unit, 21 (11%) needed invasive mechanical ventilation, and 5 (3%) noninvasive positive pressure ventilation. Existing models performed moderately at external validation, with C-statistics 0.6 to 0.7 and moderate calibration. Updating to a model including lower RTI, chronic pulmonary disease, temperature, confusion and urea, increased the C-statistic to 0.76 (95% confidence interval, 0.61-0.91) to predict in-hospital mortality. In conclusion, existing models to predict poor prognosis among hospitalized RSV-infected adults perform moderately at external validation. A prognostic model may help to identify and treat RSV-infected adults at high-risk of death.
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http://dx.doi.org/10.1002/jmv.25568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851775PMC
December 2019

Association Between Respiratory Syncytial Virus-Associated Acute Lower Respiratory Infection in Early Life and Recurrent Wheeze and Asthma in Later Childhood.

J Infect Dis 2020 10;222(Suppl 7):S628-S633

Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics.

Background: Recurrent wheeze and asthma in childhood are commons causes of chronic respiratory morbidity globally. We aimed to explore the association between respiratory syncytial virus (RSV) infection in early life and subsequent respiratory sequelae up to age 12 years.

Methods: We estimated the strength of association by 3 control groups and 3 follow-up age groups, with data from studies published between January 1995 and May 2018. We also estimated associations by diagnostic criteria, age at infection, and high-risk population.

Results: Overall, we included 41 studies. A statistically significant association was observed between early life RSV infection and subsequent childhood recurrent wheeze, in comparison to those who were healthy or those without respiratory symptoms: OR 3.05 (95% confidence interval [CI], 2.50-3.71) for 0 to <36 months follow-up age; OR 2.60 (95% CI, 1.67-4.04) for 36-72 months; and OR 2.14 (95% CI, 1.33-3.45) for 73-144 months. For the subsequent development of asthma, a statistically significant association was observed only in relation to those aged 73-144 months at follow-up: OR 2.95 (95% CI, 1.96-4.46).

Conclusions: Further studies using standardized definitions and from diverse settings are needed to elucidate the role of confounders and provide more robust estimates.
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http://dx.doi.org/10.1093/infdis/jiz311DOI Listing
October 2020

Sustained Cellular and Humoral Immune Responses From an Adenoviral Vector-based Respiratory Syncytial Virus Vaccine.

Clin Infect Dis 2020 05;70(10):2082-2083

Department of Pediatrics, University Medical Center Utrecht, The Netherlands.

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http://dx.doi.org/10.1093/cid/ciz659DOI Listing
May 2020

Comment on Transient Tachypnea of the Newborn Is Associated With an Increased Risk of Hospitalization Due to Respiratory Syncytial Virus Bronchiolitis.

Pediatr Infect Dis J 2019 09;38(9):e234-e235

Department of Pediatric Infectious Diseases and Immunology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.

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http://dx.doi.org/10.1097/INF.0000000000002385DOI Listing
September 2019