Publications by authors named "Elisabeth A M Sanders"

200 Publications

Persistence of antibodies to SARS-CoV-2 in relation to symptoms in a nationwide prospective study.

Clin Infect Dis 2021 Feb 24. Epub 2021 Feb 24.

Centre for Immunology of Infectious Diseases and Vaccines , National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.

Background: Assessing the duration of immunity following infection with SARS-CoV-2 is a first priority to gauge the degree of protection following infection. Such knowledge is lacking especially in the general population. Here, we studied changes in Immunoglobulin (Ig) isotype seropositivity and IgG binding strength of SARS-CoV-2-specific serum antibodies up to 7 months following onset of symptoms in a nationwide sample.

Methods: Participants from a prospective representative serological study in the Netherlands were included based on IgG seroconversion to the Spike S1 protein of SARS-CoV-2 (N=353), with up to three consecutive serum samples per seroconverted participant (N=738). IgM, IgA and IgG antibody concentrations to S1, and increase in IgG avidity in relation to time since onset of disease symptoms, were determined.

Results: While SARS-CoV-2-specific IgM and IgA antibodies declined rapidly after the first month post onset of disease, specific IgG was still present in 92% (95% confidence interval, CI, 89-95) of the participants after 7 months. The estimated 2-fold decrease of IgG antibodies was 158 days (95% CI 136-189). Concentrations sustained better in persons reporting significant symptoms compared to asymptomatic persons or those with mild upper respiratory complaints only. Similarly, avidity of IgG antibodies for symptomatic persons showed a steeper increase over time compared with persons with mild or no symptoms (p=0.022).

Conclusion: SARS-CoV-2-specific IgG antibodies persist and show increasing avidity over time, indicative of underlying immune maturation. These data support development of immune memory against SARS-CoV-2 providing insight into protection of the general unvaccinated part of the population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/ciab172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7929058PMC
February 2021

Similar impact and replacement disease after pneumococcal conjugate vaccine introduction in hospitalised children with invasive pneumococcal disease in Europe and North America.

Vaccine 2021 Mar 18;39(11):1551-1555. Epub 2021 Feb 18.

Department of Infectious Disease Epidemiology, Faculty of Epidemiology & Population Health, London School of Hygiene & Tropical Medicine, London, UK.

High incidence of childhood invasive pneumococcal disease (IPD) in the US declined steeply after 7-valent pneumococcal conjugate vaccine (PCV7) introduction, outweighing reductions observed elsewhere. We re-analysed aggregate published data and compared pre- and post-PCV IPD-incidence in different countries to explore PCV impact on hospitalised and outpatient IPD separately. The proportion of hospitalised IPD cases was consistently high (>80%) in England&Wales, Finland, the Netherlands, and Quebec/Canada, but only 32% in the US before PCV introduction, increasing to 69% during the PCV era. In the US, a higher reduction in outpatient IPD incidence (94% in 2015 versus 1998-99) was observed compared to hospitalised IPD (79%); a 51% reduction in the non-PCV13-type IPD incidence among outpatient cases was estimated compared to a >2-fold increase for hospitalised cases. After stratification by hospitalization status, PCV programmes resulted in similar impact and serotype replacement in hospitalised IPD in US when compared to other countries.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.vaccine.2021.01.070DOI Listing
March 2021

Short term impact of the COVID-19 pandemic on incidence of vaccine preventable diseases and participation in routine infant vaccinations in the Netherlands in the period March-September 2020.

Vaccine 2021 02 6;39(7):1039-1043. Epub 2021 Jan 6.

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

We aimed to assess the impact of the COVID-19 pandemic on the incidence of vaccine-preventable diseases (VPDs) and participation in the routine infant vaccination programme in the Netherlands. The incidence of various VPDs initially decreased by 75-97% after the implementation of the Dutch COVID-19 response measures. The participation in the first measles-mumps-rubella vaccination among children scheduled for vaccination in March-September 2020 initially dropped by 6-14% compared with the previous year. After catch-up vaccination, a difference in MMR1 participation of -1% to -2% still remained. Thus, the pandemic has reduced the incidence of several VPDs and has had a limited impact on the routine infant vaccination programme.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.vaccine.2020.12.080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787078PMC
February 2021

The respiratory microbiota during and following mechanical ventilation for respiratory infections in children.

Eur Respir J 2020 Dec 10. Epub 2020 Dec 10.

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

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1183/13993003.02652-2020DOI Listing
December 2020

Influenza-like Illness Exacerbates Pneumococcal Carriage in Older Adults.

Clin Infect Dis 2020 Oct 30. Epub 2020 Oct 30.

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

Background: In older adults pneumococcal disease is strongly associated with respiratory viral infections, but the impact of viruses on Streptococcus pneumoniae carriage prevalence and load remains poorly understood. Here, we investigated the effects of influenza-like illness (ILI) on pneumococcal carriage in community-dwelling older adults.

Methods: We investigated the presence of pneumococcal DNA in saliva samples collected in the 2014/2015 influenza season from 232 individuals aged ≥60 years at ILI-onset, followed by sampling 2-3 weeks and 7-9 weeks after the first sample. We also sampled 194 age-matched controls twice 2-3 weeks apart. Pneumococcal DNA was detected with quantitative-PCRs targeting piaB and lytA genes in raw and in culture-enriched saliva. Bacterial and pneumococcal abundances were determined in raw saliva with 16S and piaB quantification.

Results: The prevalence of pneumococcus-positive samples was highest at onset of ILI (18% or 42/232) and lowest among controls (13% or 26/194, and 11% or 22/194, at the first and second sampling moment, respectively), though these differences were not significant. Pneumococcal carriage was associated with exposure to young children (OR:2.71, 95%CI 1.51-5.02, p<0.001), and among asymptomatic controls with presence of rhinovirus infection (OR:4.23; 95%CI 1.16-14.22, p<0.05). When compared with carriers among controls, pneumococcal absolute abundances were significantly higher at onset of ILI (p<0.01), and remained elevated beyond recovery from ILI (p<0.05). Finally, pneumococcal abundances were highest in carriage events newly-detected after ILI-onset (estimated geometric mean 1.21E -5, 95%CI 2.48E -7-2.41E -5, compared with pre-existing carriage).

Conclusions: ILI exacerbates pneumococcal colonization of the airways in older adults, and this effect persists beyond recovery from ILI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/ciaa1551DOI Listing
October 2020

Different Long-Term Duration of Seroprotection against in Adolescents and Middle-Aged Adults after a Single Meningococcal ACWY Conjugate Vaccination in The Netherlands.

Vaccines (Basel) 2020 Oct 25;8(4). Epub 2020 Oct 25.

Centre for Infectious Disease Control (Cib), National Institute of Public Health and the Environment (RIVM), 3720 BA Bilthoven, The Netherlands.

is often asymptomatically carried in the nasopharynx but may cause invasive meningococcal disease, leading to morbidity and mortality. Meningococcal conjugate vaccinations induce functional protective antibodies against capsular antigens, but seroprotection wanes over time. We measured functional antibody titers five years after administration of a single dose of the meningococcal ACWY-polysaccharide-specific tetanus toxoid-conjugated (MenACWY-TT) vaccine in adolescents and middle-aged adults in the Netherlands, using the serum bactericidal antibody with baby rabbit complement (rSBA) assay. Protection was defined as rSBA titer ≥8. The meningococcal ACWY-specific serum IgG concentrations were measured with a multiplex immunoassay. Duration of protection was estimated by a bi-exponential decay model. Sufficient protection for MenC, MenW, and MenY was achieved in 94-96% of the adolescents five years postvaccination, but, in middle-aged adults, only in 32% for MenC, 65% for MenW and 71% for MenY. Median duration of protection for MenCWY was 4, 14, and 21 years, respectively, in middle-aged adults, while, in adolescents, it was 32, 98, and 33 years. Our findings suggest that adolescents, primed in early childhood with MenC conjugate vaccination, remain sufficiently protected after a single dose of MenACWY-TT vaccine. Middle-aged adults without priming vaccination show fast waning of antibodies, particularly MenC, for which protection is lost after four years.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/vaccines8040624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7712102PMC
October 2020

Severity of Respiratory Infections With Seasonal Coronavirus Is Associated With Viral and Bacterial Coinfections.

Pediatr Infect Dis J 2021 01;40(1):e36-e39

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

The clinical presentation of human coronavirus (HCoV) infections in children varies strongly. We show that children with an HCoV-associated lower respiratory tract infection more frequently had respiratory syncytial virus codetected and higher abundance of Haemophilus influenzae/haemolyticus than asymptomatic HCoV carriers as well as children with a non-HCoV-associated lower respiratory tract infection. Viral and bacterial cooccurrence may drive symptomatology of HCoV-associated infections including coronavirus disease 2019.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/INF.0000000000002940DOI Listing
January 2021

Association of Routine Infant Vaccinations With Antibody Levels Among Preterm Infants.

JAMA 2020 09;324(11):1068-1077

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

Importance: The standard schedule of national immunization programs for infants may not be sufficient to protect extremely and very preterm infants.

Objective: To evaluate the immunogenicity of routine vaccinations administered to preterm infants.

Design, Setting, And Participants: A multicenter, prospective, observational cohort study of preterm infants stratified according to gestational age recruited from 8 hospitals across the Netherlands between October 2015 and October 2017, with follow-up until 12 months of age (October 2018). In total, 296 premature infants were enrolled and compared with a control group of 66 healthy term infants from a 2011 study, immunized according to the same schedule with the same vaccines.

Exposures: Three primary doses of the diphtheria-tetanus toxoids-acellular pertussis-inactivated poliomyelitis-Haemophilus influenza type b-hepatitis B combination vaccine were given at 2, 3, and 4 months after birth followed by a booster at 11 months and a 10-valent pneumococcal conjugate vaccine at 2, 4, and 11 months after birth.

Main Outcomes And Measures: Primary end points were (1) proportion of preterm infants who achieved IgG antibody against vaccine antigens at concentrations above the internationally defined threshold for protection after the primary series and booster dose and (2) serum IgG geometric mean concentrations after the primary series and booster vaccination. Proportions and geometric mean concentrations were compared in preterm infants and the control group of term infants.

Results: Of 296 preterm infants (56.1% male; mean gestational age, 30 weeks), complete samples before vaccination, 1 month after the primary series, and 1 month after the booster were obtained from 220 preterm infants (74.3%). After the primary series, the proportion of preterm infants across all gestational age groups who achieved protective IgG antibody levels against pertussis toxin, diphtheria, tetanus and 6 of 10 pneumococcal serotypes varied between 83.0% and 100%, Haemophilus influenzae type b between 34.7% and 46.2% (40.6% among all preterm infants overall), and pneumococcal serotypes 4, 6B, 18C, and 23F between 45.8% and 75.1%. After the booster dose, protective antibody levels were achieved in more than 95% of all preterm groups, except for Haemophilus influenzae type b (88.1%). In general, geometric mean concentrations of all vaccine-induced antibodies were significantly lower in all preterm infants vs term infants, except for pertussis toxin and pneumococcal serotypes 4 and 19F after the primary series and booster vaccination.

Conclusions And Relevance: Among preterm infants, administration of routine vaccinations during the first year of life was associated with protective antibody levels against most antigens in the majority of infants after the primary series and booster, except for Haemophilus influenzae type b. However, antibody concentrations were generally lower among preterm infants compared with historical controls.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jama.2020.12316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492917PMC
September 2020

Upper airways colonisation of Streptococcus pneumoniae in adults aged 60 years and older: A systematic review of prevalence and individual participant data meta-analysis of risk factors.

J Infect 2020 Oct 17;81(4):540-548. Epub 2020 Jun 17.

Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom. Electronic address:

Background: Colonisation with Streptococcus pneumoniae can lead to invasive pneumococcal disease and pneumonia. Pneumococcal acquisition and prevalence of colonisation are high in children. In older adults, a population susceptible to pneumococcal disease, colonisation prevalence is reported to be lower, but studies are heterogeneous.

Methods: This is a systematic review and meta-analysis of prevalence of, and risk factors for, pneumococcal colonisation in adults ≥ 60 years of age (PROSPERO #42016036891). We identified peer-reviewed studies reporting the prevalence of S. pneumoniae colonisation using MEDLINE and EMBASE (until April 2016), excluding studies of acute disease. Participant-level data on risk factors were sought from each study.

Findings: Of 2202 studies screened, 29 were analysable: 18 provided participant-level data (representing 6290 participants). Prevalence of detected pneumococcal colonisation was 0-39% by conventional culture methods and 3-23% by molecular methods. In a multivariate analysis, colonisation was higher in persons from nursing facilities compared with the community (odds ratio (OR) 2•30, 95% CI 1•26-4•21 and OR 7•72, 95% CI 1•15-51•85, respectively), in those who were currently smoking (OR 1•69, 95% CI 1•12-2•53) or those who had regular contact with children (OR 1•93, 95%CI 1•27-2•93). Persons living in urban areas had significantly lower carriage prevalence (OR 0•43, 95%CI 0•27-0•70).

Interpretation: Overall prevalence of pneumococcal colonisation in older adults was higher than expected but varied by risk factors. Future studies should further explore risk factors for colonisation, to highlight targets for focussed intervention such as pneumococcal vaccination of high-risk groups.

Funding: No funding was required.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jinf.2020.06.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532703PMC
October 2020

Development of the gut microbiota in early life: The impact of cystic fibrosis and antibiotic treatment.

J Cyst Fibros 2020 07 30;19(4):553-561. Epub 2020 May 30.

Department of Pediatric infectious diseases and immunology, Wilhelmina Children's Hospital, University Medical Center Utrecht, the Netherlands; The Queen's Medical Research Institute, University of Edinburgh, United Kingdom. Electronic address:

Objectives: Patients with Cystic Fibrosis (CF) suffer from pancreatic insufficiency, lipid malabsorption and gastrointestinal complaints, next to progressive pulmonary disease. Altered mucosal homoeostasis due to malfunctioning chloride channels results in an adapted microbial composition of the gastrointestinal and the respiratory tract. Additionally, antibiotic treatment has the potential to distort resident microbial communities dramatically. This study aims to investigate early life development of the gut microbial community composition of children with CF compared to healthy infants and to study the independent effects of antibiotics taking into account other clinical and lifestyle factors.

Study Design: Faecal samples from 20 infants with CF and 45 healthy infants were collected regularly during the first 18 months of life and microbial composition was determined using 16S rRNA based sequencing.

Results: We observed significant differences in the overall microbiota composition between infants with CF and healthy infants (p<0.001). Akkermansia and Anaerostipes were significantly more abundant in control infants, whereas Streptococci and E. coli were significantly more abundant in infants with CF, also after correction for several clinical factors (p<0.05). Antibiotic use in infants with CF was associated with a lower alpha diversity, a reduced abundance of Bifidobacterium and Bacteroides, and a higher abundance of Enterococcus.

Conclusion: Microbial development of the gut is different in infants with CF compared to healthy infants from the first months of life on, and further deviates over time, in part as a result of antibiotic treatment. The resulting dysbiosis may have significant functional consequences for the microbial ecosystem in CF patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jcf.2020.04.007DOI Listing
July 2020

Infant antibody levels following 10-valent pneumococcal-protein D conjugate and DTaP-Hib vaccinations in the first year of life after maternal Tdap vaccination: An open-label, parallel, randomised controlled trial.

Vaccine 2020 06 21;38(29):4632-4639. Epub 2020 May 21.

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

Background: Maternal antibody levels after Tdap vaccination during pregnancy may affect infant primary antibody responses to pertussis, Tetanus toxoid (TT), Diphtheria toxoid (DT) vaccinations and pneumococcal vaccines with diphtheria toxin mutants like CRM197 as carrier protein.

Methods: Mothers were recruited in an open label randomised parallel controlled trial in 2014-2016 through midwifes. They received Tdap [Boostrix] at 30-32 weeks of pregnancy (n = 58) or within 48 h after delivery (n = 60). Infants received DTaP-IPV-Hib-HepB [Infanrix Hexa] and 10-valent protein D conjugated pneumococcal conjugate vaccine (PHiD-CV10 [Synflorix]) at age 3, 5 and 11 months. We now report on infant specific IgG levels towards DT, TT, Haemophilus influenzae type b polyribosylribitol phosphate (Hib PRP) and PHiD-CV10 before and after primary- and booster vaccination as secondary study endpoints; pertussis antibodies were the primary endpoint of the study. This trial is registered in clinicaltrialsregister.eu (EudraCT 2012-004006-9) and trialregister.nl (NTR number NTR4314).

Findings: Post primary vaccinations, antibody levels to DT, but not TT, were significantly lower after Tdap vaccination during pregnancy compared to controls (GMC ratio 0.4, 95% CI 0.3-0.6 and 0.9, 95% CI 0.6-1.2, respectively). Antibodies to serotype 19F were significantly lower in the maternal Tdap group, whereas there were no differences in antibody levels to Hib PRP and the other 9 pneumococcal serotypes. Post booster vaccinations, no significant differences were observed, except for DT.

Interpretation: Maternal Tdap vaccination results in significant interference with infants responses not only to DT but also to conjugated pneumococcal vaccines containing DT mutants as carrier proteins. These interactions after maternal Tdap vaccination need to be taken into account when designing infants' national immunization schedules and choice of vaccines.

Funding: The Dutch Ministry of Health, Welfare and Sport.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.vaccine.2020.04.001DOI Listing
June 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.
View Article and Find Full Text PDF

Download full-text PDF

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

Inactivated influenza vaccine does not reduce all cause respiratory illness in children with pre-existing medical conditions.

Vaccine 2020 04 16;38(17):3397-3403. Epub 2019 Dec 16.

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands. Electronic address:

Background: The effectiveness of inactivated influenza vaccine (IIV) immunization in preventing all cause respiratory illness (RI) in children with pre-existing medical conditions has not been fully established and varies from season to season. This study aims to quantify the overall impact of IIV immunization on primary care attended RI episodes in children with pre-existing medical conditions, using robust observational data spanning twelve influenza seasons.

Methods: Electronic records of IIV eligible children aged 6 months to 18 years were extracted from primary care databases over the years 2004-2015. IIV eligibility criteria according to Dutch guidelines included (chronic) respiratory and cardiovascular disease and diabetes mellitus. For each year, information on IIV immunization status, primary care attended RI episodes (including influenza, acute respiratory tract infections and asthma exacerbations) and potential confounders were collected. Generalized estimating equations were used to model the association between IIV status and occurrence of at least one RI episode during the influenza epidemic period with "current year immunized" as reference group. Robustness of findings were assessed by performing various sensitivity analyzes in which (i) seasons with a mismatch between the dominant circulating influenza virus and vaccine strain were excluded, (ii) influenza periods were further restricted to weeks with at least 30% influenza virus positive specimens in sentinel surveillance (instead of 5%), (iii) propensity scores were used to adjust for confounding.

Results: In total, 11,797 children (follow-up duration: 38,701 child-years) were eligible for IIV for ≥ one season with 29% immunized at least once. The adjusted odds for primary care attended RI episodes during the influenza epidemic period did not differ between current season immunized versus not immunized children (adjusted OR:1.01; 95%CI:0.90-1.13). The various sensitivity analysis showed comparable results.

Conclusions: IIV immunization in children with pre-existing medical conditions does not reduce all cause RI episodes encountered in primary care during the influenza season.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.vaccine.2019.11.086DOI Listing
April 2020

Author Correction: Impact of delivery mode-associated gut microbiota dynamics on health in the first year of life.

Nat Commun 2019 Nov 25;10(1):5352. Epub 2019 Nov 25.

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

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-13373-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6877559PMC
November 2019

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00431-019-03526-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645511PMC
February 2020

Rectal swabs are a reliable proxy for faecal samples in infant gut microbiota research based on 16S-rRNA sequencing.

Sci Rep 2019 11 5;9(1):16072. Epub 2019 Nov 5.

Department of Paediatric Immunology and Infectious Diseases, Wilhelmina Children's Hospital of University Medical Centre Utrecht, 3508 AB, Utrecht, The Netherlands.

Rectal swabs are potentially a valuable method for monitoring the gut microbiome in research and clinical settings, where it is important to adhere to strict timing, or where acute sampling is needed. It is currently unknown whether rectal swabs give comparable results to faecal samples regarding microbiota community composition in neonates and infants. To study how well the two sampling methods correlate in infants, we compared the 16S-rRNA-based sequencing results of 131 paired rectal swabs and faecal samples collected from 116 infants at two timepoints in early life. The paired samples were highly comparable regarding both diversity and overall community composition, and strongly correlated on taxonomical level. We observed no significant nor relevant contribution of sampling method to the variation in overall gut microbiota community composition in a multivariable model. Our study provides evidence supporting the use of rectal swabs as a reliable proxy for faecal samples in infant gut microbiota research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-52549-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831562PMC
November 2019

Impact of delivery mode-associated gut microbiota dynamics on health in the first year of life.

Nat Commun 2019 11 1;10(1):4997. Epub 2019 Nov 1.

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

The early-life microbiome appears to be affected by mode of delivery, but this effect may depend on intrapartum antibiotic exposure. Here, we assess the effect of delivery mode on gut microbiota, independent of intrapartum antibiotics, by postponing routine antibiotic administration to mothers until after cord clamping in 74 vaginally delivered and 46 caesarean section born infants. The microbiota differs between caesarean section born and vaginally delivered infants over the first year of life, showing enrichment of Bifidobacterium spp., and reduction of Enterococcus and Klebsiella spp. in vaginally delivered infants. The microbiota composition at one week of life is associated with the number of respiratory infections over the first year. The taxa driving this association are more abundant in caesarean section born children, providing a possible link between mode of delivery and susceptibility to infectious outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-13014-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825150PMC
November 2019

Pertussis hospitalizations among term and preterm infants: clinical course and vaccine effectiveness.

BMC Infect Dis 2019 Oct 29;19(1):919. Epub 2019 Oct 29.

Centre for Infectious Disease Control, National Institute for Public Health and the Environment, PObox 1, 3720BA, Bilthoven, The Netherlands.

Background: Pertussis causes severe disease in young unvaccinated infants, with preterms potentially at highest risk. We studied pertussis in hospitalized infants as related to gestational age (GA) and vaccination history.

Methods: Medical record data of 0-2y old patients hospitalized for pertussis during 2005-2014 were linked to vaccination data. Multivariable logistic regression was used to study the association between GA and vaccination history on the clinical disease course. We compared vaccine effectiveness (VE) against hospitalization for pertussis between term and preterm infants (i.e., <37w GA) using the screening method as developed by Farrington.

Results: Of 1187 records, medical data from 676 were retrieved. Of these, 12% concerned preterms, whereas they are 8% of Dutch birth cohorts. Median age at admission was 3 m for preterms and 2 m for terms (p < 0.001). Preterms more often had received pertussis vaccination (62% vs 44%; p = 0.01) and more often had coinfections (37% vs 21%; p = 0.01). Preterms tended more often to have complications, to require artificial respiration or to need admittance to the intensive care unit (ICU). Preterms had longer ICU stays (15d vs 9d; p = 0.004). Vaccinated preterms and terms had a lower median length of hospital stay and lower crude risks of apneas and the need for artificial respiration, additional oxygen, and ICU admittance than those not vaccinated. After adjustment for presence of coinfections and age at admittance, these differences were not significant, except the lower need of oxygen treatment in vaccinated terms. Effectiveness of the first vaccination against pertussis hospitalizations was 95% (95% CI 93-96%) and 73% (95% CI 20-91%) in terms and preterms, respectively. Effectiveness of the second dose of the primary vaccination series was comparable in both groups (86 and 99%, respectively).

Conclusions: Infants hospitalized for pertussis suffer from severe disease. Preterms were overrepresented, with higher need for intensive treatment and less VE of first vaccination. These findings stress the need for alternative prevention, in particular prenatal vaccination of mothers, to reduce pertussis in both groups.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12879-019-4563-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820906PMC
October 2019

The Clinical Picture and Severity of Invasive Meningococcal Disease Serogroup W Compared With Other Serogroups in the Netherlands, 2015-2018.

Clin Infect Dis 2020 05;70(10):2036-2044

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

Background: An increase in invasive meningococcal disease (IMD) serogroup W (IMD-W) cases caused by sequence type-11 clonal complex (cc11) was observed from October 2015 in the Netherlands. We compared the clinical picture and disease outcome of IMD-W cases with other serogroups, adjusting for host characteristics.

Methods: We included IMD cases reported from January 2015 to June 2018 in the Netherlands and assessed clinical manifestation and symptoms at disease onset and calculated case fatality rates (CFRs). We used logistic regression to compare clinical manifestations and mortality of IMD-W with IMD caused by meningococci serogroup B, Y, or C, adjusting for age, gender, and comorbidities.

Results: A total of 565 IMD cases were reported, of which 204 were IMD-W, 270 IMD-B, 63 IMD-Y, and 26 IMD-C. Most IMD-W isolates belonged to cc11 (93%; 175/188). Compared with other serogroups, IMD-W patients were diagnosed more often with septicemia (46%) or pneumonia (12%) and less often with meningitis (17%, P < .001). IMD-W cases presented more often with respiratory symptoms (45%, P < .001); 16% of IMD-W patients presented with diarrhea without IMD-specific symptoms (P = .061). The CFR for IMD-W was 16% (32/199, P < .001). The differences between IMD-W and other serogroups remained after adjusting for age, gender, and comorbidities.

Conclusions: The atypical presentation and severe outcome among IMD-W cases could not be explained by age, gender, and comorbidities. Almost all our IMD-W cases were caused by cc11. More research is needed to identify the bacterial factors involved in clinical presentation and severity of IMD-W cc11.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/ciz578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201410PMC
May 2020

Twelve years of pneumococcal conjugate vaccination in the Netherlands: Impact on incidence and clinical outcomes of invasive pneumococcal disease.

Vaccine 2019 10 6;37(43):6558-6565. Epub 2019 Sep 6.

Centre for Infectious Disease Control Netherlands (CIb), National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands. Electronic address:

Introduction: In 2006, the Netherlands introduced the 7-valent pneumococcal conjugate vaccine (PCV7) in their national immunisation programme. In 2011, PCV7 was replaced by the 10-valent vaccine (PCV10). We report on the impact of PCV on invasive pneumococcal disease (IPD) incidence, clinical syndromes and patient outcomes.

Methods: Pneumococcal isolates of hospitalised IPD patients between June 2004 and May 2018 were obtained from nine sentinel laboratories, covering 25% of the Dutch population. All isolates were serotyped. IPD incidence and clinical outcome were determined before and after introduction of PCV7 and after the switch to PCV10, stratified by age and serotype.

Results: Compared to before PCV7 introduction, significant declines in IPD incidence were observed in 2016-2018 in children <5 years (69%), 18-49 year olds (31%) and ≥65 year olds (19%). Compared to before PCV10 introduction, the IPD incidence in 2016-2018 declined in children <5 years (RR:0.68, 95%CI:0.42-1.11), 5-17 year olds (RR:0.58, 95%CI:0.29-1.14) and 18-49 year olds (RR:0.72, 95%CI:0.57-0.90), but not in 50-64 year olds (RR:0.94, 95%CI:0.81-1.10) and ≥65 year olds (RR:1.04, 95%CI:0.0.93-1.15). While the case fatality rate (CFR) decreased from 16.2% pre-PCV to 13.4% post-PCV10 (RR:0.83, 95%CI:0.70-0.99), the switch to PCV10 had no further impact on CFR (RR:1.14, 95%CI:0.96-1.36).

Conclusion: Twelve years of PCV in the Netherlands has resulted in a sustained reduction of IPD incidence in children and younger adults. The switch from PCV7 to PCV10 did not have additional impact on the IPD incidence in older adults and CFR due to emerging non-vaccine serotypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.vaccine.2019.08.025DOI Listing
October 2019

Timeliness of immunisations in preterm infants in the Netherlands.

Vaccine 2019 09 20;37(39):5862-5867. Epub 2019 Aug 20.

Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, the Netherlands; Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht University, the Netherlands.

Background: In the Netherlands, preterm infants receive the immunisations at the same chronological age as recommended for term infants without correction for gestational age (GA). The aim of this paper was to describe the timeliness of the routine Dutch national immunisation schedule in preterm infants in their first year of life and to evaluate possible determinants of delay.

Methods: Preterm infants were prospectively recruited between October 2015 and October 2017 and stratified according to GA (<28, 28-32 and 32-36 weeks). Data from the baseline parental questionnaire, monthly parental questionnaires and medical records were used to determine the immunisation age and proportion of infants timely receiving the first immunisations (between 42 and 63 days). Results were compared between the GA and birth weight (BW) groups. Determinants associated with timeliness of immunisation were studied by multivariate logistic regression analysis.

Results: Timely start of immunisation occurs in 60.5% of preterm infants in the Netherlands. The proportion of infants receiving the first immunisation on time was lowest for the group with GA <28 weeks (37%). The mean age of the first immunisation across all GA groups was 62.7 days (range 33-118) and differed significantly between GA group <28 weeks and the other two GA groups of 28-32 and 32-36 weeks (p < 0.001). Similar results were seen when stratified by BW. Multivariate analysis showed that low socioeconomic status (SES) and prolonged hospitalisation beyond 37 weeks each negatively influenced timeliness of the first immunisation.

Conclusion: These findings indicate that start of immunisations was often delayed in prematures and differs for different GA groups, being lowest (37%) in infants <28 weeks GA. Lower SES and prolonged hospital stay beyond 37 weeks GA are important determinants of timeliness. Efforts to improve timeliness should focus most on counselling parents in lower SES.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.vaccine.2019.08.006DOI Listing
September 2019

Interaction between the nasal microbiota and S. pneumoniae in the context of live-attenuated influenza vaccine.

Nat Commun 2019 07 5;10(1):2981. Epub 2019 Jul 5.

Department of Paediatric Immunology and Infectious Diseases, Wilhelmina Children's Hospital/University Medical Center Utrecht, Lundlaan 6, Utrecht, 3584 EA, The Netherlands.

Streptococcus pneumoniae is the main bacterial pathogen involved in pneumonia. Pneumococcal acquisition and colonization density is probably affected by viral co-infections, the local microbiome composition and mucosal immunity. Here, we report the interactions between live-attenuated influenza vaccine (LAIV), successive pneumococcal challenge, and the healthy adult nasal microbiota and mucosal immunity using an experimental human challenge model. Nasal microbiota profiles at baseline are associated with consecutive pneumococcal carriage outcome (non-carrier, low-dense and high-dense pneumococcal carriage), independent of LAIV co-administration. Corynebacterium/Dolosigranulum-dominated profiles are associated with low-density colonization. Lowest rates of natural viral co-infection at baseline and post-LAIV influenza replication are detected in the low-density carriers. Also, we detected the fewest microbiota perturbations and mucosal cytokine responses in the low-density carriers compared to non-carriers or high-density carriers. These results indicate that the complete respiratory ecosystem affects pneumococcal behaviour following challenge, with low-density carriage representing the most stable ecological state.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-10814-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611866PMC
July 2019

Joint sequencing of human and pathogen genomes reveals the genetics of pneumococcal meningitis.

Nat Commun 2019 05 15;10(1):2176. Epub 2019 May 15.

Amsterdam UMC, University of Amsterdam, Department of Neurology, Amsterdam Neuroscience, Meibergdreef 9, Amsterdam, 1105 AZ, The Netherlands.

Streptococcus pneumoniae is a common nasopharyngeal colonizer, but can also cause life-threatening invasive diseases such as empyema, bacteremia and meningitis. Genetic variation of host and pathogen is known to play a role in invasive pneumococcal disease, though to what extent is unknown. In a genome-wide association study of human and pathogen we show that human variation explains almost half of variation in susceptibility to pneumococcal meningitis and one-third of variation in severity, identifying variants in CCDC33 associated with susceptibility. Pneumococcal genetic variation explains a large amount of invasive potential (70%), but has no effect on severity. Serotype alone is insufficient to explain invasiveness, suggesting other pneumococcal factors are involved in progression to invasive disease. We identify pneumococcal genes involved in invasiveness including pspC and zmpD, and perform a human-bacteria interaction analysis. These genes are potential candidates for the development of more broadly-acting pneumococcal vaccines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-09976-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520353PMC
May 2019

Disease burden of neonatal invasive Group B Streptococcus infection in the Netherlands.

PLoS One 2019 9;14(5):e0216749. Epub 2019 May 9.

Department of Neurology, Amsterdam Neuroscience, Amsterdam University Medical Centre, Amsterdam, The Netherlands.

Background: Group B Streptococcus (GBS) is the leading cause of neonatal sepsis and meningitis worldwide. We aimed to estimate the current burden of neonatal invasive GBS disease in the Netherlands, as a first step in providing an evidence base for policy makers on the potential benefits of a future maternal GBS vaccine.

Methods: Surveillance of neonatal invasive GBS occurs at the National Reference Laboratory for Bacterial Meningitis, where culture isolates from cerebrospinal fluid and blood are sent by diagnostic laboratories. From the number of cultures we estimated the incidence of neonatal (age 0-90 days) GBS meningitis and sepsis. We constructed a disease progression model informed by literature and expert consultation to estimate the disease burden of neonatal invasive GBS infection. As many neonates with a probable GBS sepsis are never confirmed by blood culture, we further estimated the disease burden of unconfirmed cases of probable GBS sepsis in sensitivity analyses.

Results: An estimated 97 cases and 6.5 deaths occurred in the Netherlands in 2017 due to culture positive neonatal invasive GBS infection. This incidence comprised 15 cases of meningitis and 42 cases of sepsis per 100.000 births, with an estimated mortality of 3.8 per 100.000 live births. A disease burden of 780 disability-adjusted life years (DALY) (95% CI 650-910) or 460 DALY per 100.000 live births was attributed to neonatal invasive GBS infection. In the sensitivity analysis including probable neonatal GBS sepsis the disease burden increased to 71 cases and 550 DALY (95% CI 460-650) per 100.000 live births.

Conclusion: In conclusion, neonatal invasive GBS infection currently causes a substantial disease burden in the Netherlands. However, important evidence gaps are yet to be filled. Furthermore, cases of GBS sepsis lacking a positive blood culture may contribute considerably to this burden potentially preventable by a future GBS vaccine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0216749PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6508726PMC
February 2020

Disease burden of varicella versus other vaccine-preventable diseases before introduction of vaccination into the national immunisation programme in the Netherlands.

Euro Surveill 2019 May;24(18)

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

IntroductionEstimating burden of disease (BoD) is an essential first step in the decision-making process on introducing new vaccines into national immunisation programmes (NIPs). For varicella, a common vaccine-preventable disease, BoD in the Netherlands was unknown.AimTo assess national varicella BoD and compare it to BoD of other vaccine-preventable diseases before their introduction in the NIP.MethodsIn this health estimates reporting study, BoD was expressed in disability-adjusted life years (DALYs) using methodology from the Burden of Communicable Diseases in Europe (BCoDE)-project. As no parameters/disease model for varicella (including herpes zoster) were available in the BCoDE toolkit, incidence, disease progression model and parameters were derived from seroprevalence, healthcare registries and published data. For most other diseases, BoD was estimated with existing BCoDE-parameters, adapted to the Netherlands if needed.ResultsIn 2017, the estimated BoD of varicella in the Netherlands was 1,800 (95% uncertainty interval (UI): 1,800-1,900) DALYs. Herpes zoster mainly contributed to this BoD (1,600 DALYs; 91%), which was generally lower than the BoD of most current NIP diseases in the year before their introduction into the NIP. However, BoD for varicella was higher than for rotavirus gastroenteritis (1,100; 95%UI: 440-2,200 DALYs) and meningococcal B disease (620; 95%UI: 490-770 DALYs), two other potential NIP candidates.ConclusionsWhen considering the introduction of a new vaccine in the NIP, BoD is usually estimated in isolation. The current approach assesses BoD in relation to other vaccine-preventable diseases' BoD, which may help national advisory committees on immunisation and policymakers to set vaccination priorities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2807/1560-7917.ES.2019.24.18.1800363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6505181PMC
May 2019

[Revised prevention strategies for persons with (functional) hypo- or asplenie].

Ned Tijdschr Geneeskd 2019 04 4;163. Epub 2019 Apr 4.

Isala, afd. Infectieziekten, Zwolle.

The Dutch guideline for the preventions of infections in persons with (functional) hypo- or asplenie has been revised, recommending adjustments for the use of vaccinations and antibiotics. The spleen has an important function in the defence against infections. Around 1,000 splenectomies are performed in the Netherlands every year. Three different groups of patients are distinguished: (a) persons with a partially or completely removed spleen after surgery or embolization; (b) persons with congenital asplenia; and (c) a heterogeneous group of patients, who may have functional hyposplenie or asplenia due to an underlying condition or specific treatments. Patients with asplenia have an increased risk of severe infections by encapsulated bacteria, including in particular Streptococcus pneumoniae, but also Haemophilus influenzae type b and Neisseria meningitides may lead to an increased risk S.pneumoniae causes up to 90% of the infections, which makes it the most important infectious agent in patients with asplenia. A number of preventive measures are recommended to prevent infections in patients with hypo- or asplenie, including the use of vaccinations and antibiotics and patient counselling.
View Article and Find Full Text PDF

Download full-text PDF

Source
April 2019

Maternal pertussis vaccination and its effects on the immune response of infants aged up to 12 months in the Netherlands: an open-label, parallel, randomised controlled trial.

Lancet Infect Dis 2019 04 27;19(4):392-401. Epub 2019 Mar 27.

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

Background: Maternal tetanus, diphtheria, and acellular pertussis (Tdap) vaccination offers protection for neonates against clinical pertussis until primary vaccinations, but maternal antibodies also interfere with infants' immune responses to primary vaccinations. We investigated the effect of maternal Tdap vaccination on the pertussis antibody responses of infants starting primary vaccinations at age 3 months.

Methods: In an open-label, parallel, randomised, controlled trial, pregnant women aged 18-40 years with a low risk of pregnancy complications were recruited through independent midwives at 36 midwife clinics in the Netherlands and received Tdap vaccination either at 30-32 weeks of pregnancy (maternal Tdap group) or within 48 h after delivery (control group). All term-born infants were vaccinated with the diphtheria, tetanus, and pertussis-inactivated poliomyelitis-Haemophilus influenzae type B-hepatitis B six-in-one vaccine and a ten-valent pneumococcal vaccine at 3 months, 5 months, and 11 months. Randomisation was done using a number generator in a 1:1 ratio and with sealed envelopes. Participants and clinical trial staff were not masked, but laboratory technicians were unaware of study group assignments. The primary endpoint was serum IgG pertussis toxin antibody concentrations at age 3 months. Cord blood and infant blood samples were collected at age 2 months, 3 months, 6 months, 11 months, and 12 months. Analysis was done by modified intention to treat with all randomly assigned participants in case a laboratory result was available. This trial is registered with ClinicaltTrialsRegister.eu (EudraCT 2012-004006-9) and trialregister.nl (NTR number NTR4314). The trial is now closed to new participants.

Findings: Between Jan 16, 2014, and March 4, 2016, 118 pregnant women were enrolled into our study, with 58 in the maternal Tdap group and 60 in the control group. The geometric mean concentration (GMC) of pertussis toxin antibodies were higher in infants in the maternal Tdap group than in the control group infants at age 3 months (GMC ratio 16·6, 95% CI 10·9-25·2) and also significantly higher compared with control infants at age 2 months. After primary vaccinations, antibody concentrations for pertussis toxin, filamentous haemagglutinin, and pertactin were significantly lower at all timepoints in infants of the maternal Tdap group than in infants in the control group. No safety issues after maternal Tdap vaccination were encountered.

Interpretation: In view of the high pertussis toxin antibody concentrations at age 3 months, maternal vaccination supports a delay of the first pertussis vaccination in infants until at least age 3 months. Maternal antibody interference affects antibody concentrations after primary and booster vaccinations. The clinical consequences of this interference remain to be established.

Funding: The Dutch Ministry of Health, Welfare, and Sport.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1473-3099(18)30717-5DOI Listing
April 2019

Bacterial and viral respiratory tract microbiota and host characteristics in children with lower respiratory tract infections: a matched case-control study.

Lancet Respir Med 2019 05 15;7(5):417-426. Epub 2019 Mar 15.

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

Background: Lower respiratory tract infections (LRTIs) are a leading cause of childhood morbidity and mortality. Potentially pathogenic organisms are present in the respiratory tract in both symptomatic and asymptomatic children, but their presence does not necessarily indicate disease. We aimed to assess the concordance between upper and lower respiratory tract microbiota during LRTIs and the use of nasopharyngeal microbiota to discriminate LRTIs from health.

Methods: First, we did a prospective study of children aged between 4 weeks and 5 years who were admitted to the paediatric intensive care unit (PICU) at Wilhelmina Children's Hospital (Utrecht, Netherlands) for a WHO-defined LRTI requiring mechanical ventilation. We obtained paired nasopharyngeal swabs and deep endotracheal aspirates from these participants (the so-called PICU cohort) between Sept 10, 2013, and Sept 4, 2016. We also did a matched case-control study (1:2) with the same inclusion criteria in children with LRTIs at three Dutch teaching hospitals and in age-matched, sex-matched, and time-matched healthy children recruited from the community. Nasopharyngeal samples were obtained at admission for cases and during home visits for controls. Data for child characteristics were obtained by questionnaires and from pharmacy printouts and medical charts. We used quantitative PCR and 16S rRNA-based sequencing to establish viral and bacterial microbiota profiles, respectively. We did sparse random forest classifier analyses on the bacterial data, viral data, metadata, and the combination of all three datasets to distinguish cases from controls.

Findings: 29 patients were enrolled in the PICU cohort. Intra-individual concordance in terms of viral microbiota profiles (96% agreement [95% CI 93-99]) and bacterial microbiota profiles (58 taxa with a median Pearson's r 0·93 [IQR 0·62-0·99]; p<0·05 for all 58 taxa) was high between nasopharyngeal and endotracheal aspirate samples, supporting the use of nasopharyngeal samples as proxy for lung microbiota during LRTIs. 154 cases and 307 matched controls were prospectively recruited to our case-control cohort. Individually, bacterial microbiota (area under the curve 0·77), viral microbiota (0·70), and child characteristics (0·80) poorly distinguished health from disease. However, a classification model based on combined bacterial and viral microbiota plus child characteristics distinguished children with LRTIs from their matched controls with a high degree of accuracy (area under the curve 0·92).

Interpretation: Our data suggest that the nasopharyngeal microbiota can serve as a valid proxy for lower respiratory tract microbiota in childhood LRTIs, that clinical LRTIs in children result from the interplay between microbiota and host characteristics, rather than a single microorganism, and that microbiota-based diagnostics could improve future diagnostic and treatment protocols.

Funding: Spaarne Gasthuis, University Medical Center Utrecht, and the Netherlands Organization for Scientific Research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2213-2600(18)30449-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7172745PMC
May 2019

Loss of Microbial Topography between Oral and Nasopharyngeal Microbiota and Development of Respiratory Infections Early in Life.

Am J Respir Crit Care Med 2019 09;200(6):760-770

Department of Paediatric Immunology and Infectious Diseases, Wilhelmina Children's Hospital, and.

The respiratory microbiota is increasingly being appreciated as an important mediator in the susceptibility to childhood respiratory tract infections (RTIs). Pathogens are presumed to originate from the nasopharyngeal ecosystem. To investigate the association between early life respiratory microbiota and development of childhood RTIs. In a prospective birth cohort (Microbiome Utrecht Infant Study: MUIS), we characterized the oral microbiota longitudinally from birth until 6 months of age of 112 infants (nine regular samples/subject) and compared them with nasopharyngeal microbiota using 16S-rRNA-based sequencing. We also characterized oral and nasopharynx samples during RTI episodes in the first half year of life. Oral microbiota were driven mostly by feeding type, followed by age, mode of delivery, and season of sampling. In contrast to our previously published associations between nasopharyngeal microbiota development and susceptibility to RTIs, oral microbiota development was not directly associated with susceptibility to RTI development. However, we did observe an influx of oral taxa, such as , , , , and , in the nasopharyngeal microbiota before and during RTIs, which was accompanied by reduced presence and abundance of , , and spp. Moreover, this phenomenon was accompanied by reduced niche differentiation indicating loss of ecological topography preceding confirmed RTIs. This loss of ecological topography was further augmented by start of daycare, and linked to consecutive development of symptomatic infections. Together, our results link the loss of topography to subsequent development of RTI episodes. This may lead to new insights for prevention of RTIs and antibiotic use in childhood.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1164/rccm.201810-1993OCDOI Listing
September 2019

Impact of Repeated Influenza Immunization on Respiratory Illness in Children With Preexisting Medical Conditions.

Ann Fam Med 2019 01;17(1):7-13

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

Purpose: Annual influenza immunization in medical risk groups is recommended in many countries. Recent evidence suggests that repeated inactivated influenza vaccine (IIV) immunization throughout childhood may impair long-term immunity against influenza. We assessed whether prior immunization altered the effect of IIV in children with preexisting medical conditions on primary care-diagnosed respiratory illness (RI) episodes during the influenza season.

Methods: Electronic records of IIV-immunized children who met the criteria for annual IIV immunization according to Dutch guidelines were extracted from a primary care database from 2004 to 2015. For each year, we collected information on IIV immunization status, primary care-attended RI episodes (including influenza-like illness, acute RI, and asthma exacerbation), and potential confounders. Generalized estimating equations were used to model the association between prior IIV and occurrence of at least one RI episode during the influenza season, with "current year immunized but without IIV history" as reference group.

Results: A total of 4,183 children (follow-up duration: 11,493 child-years) were IIV immunized at least once. Adjusted estimates showed lower odds for RI in current year-immunized children with prior IIV compared with those without (odds ratio [OR] = 0.61; 95% CI, 0.47-0.78 for "current year immunized and one IIV in previous 2 years"; OR = 0.85; 95% CI, 0.68-1.07 for "current year immunized and ≥2 IIVs in previous 3 years, including prior year").

Conclusion: Repeated IIV immunization in children with preexisting medical conditions has no negative impact on, and may even increase, long-term protection against RI episodes diagnosed during the influenza season in primary care.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1370/afm.2340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6342594PMC
January 2019