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Swiss Pediatric Sepsis Study - a national prospective cohort study to assess epidemiology, novel immunodeficiencies and the impact of genetic variation on susceptibility to sepsis in children

English title Swiss Pediatric Sepsis Study - a national prospective cohort study to assess epidemiology, novel immunodeficiencies and the impact of genetic variation on susceptibility to sepsis in children
Applicant Aebi Christoph
Number 153158
Funding scheme Project funding (special)
Research institution Abteilung für Humangenetik Universitätsklinik für Kinderheilkunde Inselspital
Institution of higher education University of Berne - BE
Main discipline Paediatrics
Start/End 01.07.2014 - 30.06.2017
Approved amount 350'000.00
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All Disciplines (4)

Discipline
Paediatrics
Clinical Immunology and Immunopathology
Medical Microbiology
Genetics

Keywords (6)

child; sepsis; genomics; immunodeficiency; epidemiology; bacteremia

Lay Summary (German)

Lead
Titel des Forschungsprojektes:Swiss Pediatric Sepsis Study - eine nationale Kohortenstudie zur Epidemiologie und zu den genetischen und immunologischen Ursachen der Sepsis bei Kindern Lead:Schwere bakterielle Infektionen (sogenannte Sepsis) bei Kindern sind relativ häufig und verursachen zum Teil schwerste Folgen. Die Swiss Pediatric Sepsis Study soll die Epidemiologie der Sepsis in der Schweiz erfassen und die genetischen Ursachen der Sepsis bei Kindern erforschen.
Lay summary

Inhalt und Ziele des Forschungsprojektes:

Schwere bakterielle Infektionen stellen weiterhin eine der Hauptursachen der Kindersterblichkeit dar. Etwa die Hälfte aller Sepsisfälle in Industrieländern treten bei vorher gesunden Kindern auf. Aus Zwillingsstudien ist bekannt, dass eine starke genetische Prädisposition zu Infektionen besteht. Die Fortschritte der Technologie der letzten Jahre machen es nun möglich, mittels Genom-weiter Studien die Anfälligkeit und den Verlauf von schweren Infektionen grundlegend neu zu untersuchen.

Die Swiss Pediatric Sepsis Study wurde 2011 lanciert und wird durch die Pädiatrische Infektiologiegruppe Schweiz in Zusammenarbeit mit allen A-Kinderspitälern durchgeführt. Diese Studie untersucht Kinder, welche mit einer schweren bakteriellen Infektion hospitalisiert werden. Zum einen monitorisiert die Studie schwere Infektionen bei Kindern in der Schweiz, und liefert dadurch wichtige Informationen zu Risikofaktoren, Schweregrad, ursächlichen Keimen und Resistenzen. Zum anderen werden im Rahmen der Studie modernste Untersuchungen des menschlichen Genoms bei Kindern mit schweren Infektionen durchgeführt. Speziell handelt es sich um Genom-weite Assoziationsstudien und um Exomsequenzierung. Diese Analysen werden in Zusammenarbeit mit führenden nationalen und internationalen Experten durchgeführt. Diese Analysen sollen neue, bisher unbekannte Immundefekte entdecken, welche Kinder äusserst anfällig für Sepsis machen.

 

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojektes:

Dieses nationale Forschungsprojekt verbindet Forschungsaktivitäten von allen grossen Kinderkliniken der Schweiz, und untersucht zentrale Fragen zu schweren Infektionen bei Kindern. Diese Studie soll helfen, in  Zukunft Kinder mit einem hohen Risiko für Sepsis frühzeitig zu erkennen, und neuartige Ansätze für Therapie und Prävention von schweren Infektionen bei Kindern liefern.

Direct link to Lay Summary Last update: 31.03.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Epidemiology of blood culture-proven bacterial sepsis in children in Switzerland: a population-based cohort study
Agyeman Philipp K. A. Luregn J. Schlapbach Eric Giannoni Martin Stocker Klara M. Posfay-Barbe (2017), Epidemiology of blood culture-proven bacterial sepsis in children in Switzerland: a population-based cohort study, in The Lancet Child & Adolescent Health., 0(0), 1-10.
Exome Sequencing Reveals Primary Immunodeficiencies in Children with Community-Acquired Pseudomonas aeruginosa Sepsis
Asgari S. McLaren P. J. Peake J. Wong M. Wong R. Bartha I. Francis J. R. Abarca K. Gelderman (2016), Exome Sequencing Reveals Primary Immunodeficiencies in Children with Community-Acquired Pseudomonas aeruginosa Sepsis, in Front Immunol, 7(357), 1-11.
Incidence and Outcome of Group B Streptococcal Sepsis in Infants in Switzerland
Giannoni E. Berger C. Stocker M. Agyeman P. Posfay-Barbe K. M. Heininger U. Konetzny G. Niede (2016), Incidence and Outcome of Group B Streptococcal Sepsis in Infants in Switzerland, in Pediatr Infect Dis J, 35(2), 222-224.

Collaboration

Group / person Country
Types of collaboration
Pediatric Respiratory Research Groups, University Children’s Hospital Basel and Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
ANRESIS, Dr. A. Kronenberg, University of Bern, Switzerland Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Claudia Kuehni, Institute of Social and Preventive Medic Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
PD Dr. Bendicht Wagner, President IG Pädiatrische und Neonatologische Intensivmedizin Schweiz Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. Luregn Schlapbach, Paediatric Critical Care Research Group, Mater Children's Hospital, Brisbane Australia (Oceania)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
EUCLIDS, Prof. Michael Levin, Imperial College London, UK Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Fellay Lab, EPFL Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Pediatric Infectious Diseases Group Switzerland Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
A/Prof. Roland Ammann, Pediatric Oncology, University of Bern, SPOG Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
ESPNIC Talk given at a conference WHOLE EXOME SEQUENCING FOR THE IDENTIFICATION OF PRIMARY IMMUNODEFICIENCIES IN A NATIONAL COHORT OF CHILDREN WITH BACTERIAL SEPSIS 08.06.2017 Lisbon, Portugal Aebi Christoph; Berger Christoph; Fellay Jacques;
European Society of Neonatal and Pediatric Intensive Care ESPNIC Talk given at a conference Association of the number of organ dysfunctions with case fatality rate in children with sepsis – The Swiss Pediatric Sepsis Study 05.06.2017 Lisbon, Portugal Berger Christoph; Aebi Christoph;
SGP Jahreskongress Talk given at a conference Whole exome sequencing for the identification of primary immunodeficiencies in a national cohort of children with bacterial sepsis 01.06.2017 St. Gallen, Switzerland Berger Christoph; Aebi Christoph; Fellay Jacques;
SGP Talk given at a conference Frequency of organ dysfunction and impact on mortality in children with blood culture-proven sepsis – results from The Swiss Pediatric Sepsis Study 29.05.2017 St. Gallen, Switzerland Berger Christoph; Aebi Christoph;
ESPID Talk given at a conference Whole exome sequencing for the identification of primary immunodeficiencies in a national cohort of children with bacterial sepsis 25.05.2017 Madrid, Spain Berger Christoph; Aebi Christoph;
Journées Francophones de Recherche en Néonatologie (JFRN 2016) Talk given at a conference Epidémiologie des septicémies néonatales en Suisse: résultats de la "Swiss Pediatric Sepsis Study 15.12.2016 Paris, France Aebi Christoph; Berger Christoph;
ESPNIC Talk given at a conference SEVERE SEPSIS WITH BACTEREMIA IN CHILDREN IN SWITZERLAND - RESULTS FROM THE SWISS PEDIATRIC SEPSIS STUDY 24.10.2016 Geneva, Switzerland Berger Christoph; Aebi Christoph;
ANZICS/ACCN ASM Talk given at a conference 'Exome Sequencing Reveals Primary Immunodeficiencies in Children with Community-Acquired Pseudomonas aeruginosa Sepsis' 30.10.2015 Auckland, New Zealand Berger Christoph; Aebi Christoph; Fellay Jacques;


Communication with the public

Communication Title Media Place Year
Media relations: radio, television Schwere Infektionen bei Kindern auch in der Schweiz verbreitet  SNF press release, press release der beteiligten Spitaeler, Radio, diverse Printmedien Western Switzerland German-speaking Switzerland 2017

Awards

Title Year
Sandra Asner, CHUV: International Sepsis Forum and European Society of Clinical Microbiology and Infectious Diseases Award 2017 for her work on Invasive Pneumococcal Disease 2017
A/Prof Luregn Schlapbach, Unversity of Bern and University of Queensland, Australia: Australian and New Zealand Intensive Care Society Best Paediatric Paper Award 2015 for his work on Exome Sequencing to Identify Primary Immunodeficiencies in Children with Pseudomonas Sepsis 2015

Associated projects

Number Title Start Funding scheme
121135 National Collaborative Center (NCC) 01.01.2008 Research Infrastructure
144280 The prospective Basel-Bern infant lung development birth cohort (BILD): early impact of genetic and environmental factors on lung growth and respiratory morbidity 01.10.2012 Project funding (special)
201060 Derivation of pediatric sepsis phenotypes using machine learning applied to clinical, functional and genomic data from the swiss pediatric sepsis study 01.04.2021 Project funding
133703 Host genomics of extreme phenotypes caused by common viral diseases: genome sequencing in children with severe respiratory infections 01.04.2011 SNSF Professorships

Abstract

Background: Sepsis remains one of the leading causes of infant and childhood mortality worldwide. Yet, large population-based cohorts of pediatric sepsis are rare, and there is a lack of epidemiologic data on culture-proven sepsis in children. Up to 50% of lethal infections occur in apparently healthy children. Immunodeficiencies causing increased susceptibility to sepsis have recently been discovered and severe sepsis in children without clinical risk factors may represent the first manifestation of a previously unrecognized primary immunodeficiency. The major improvements in genomic technology now allow for integrative studies of the human genome without the limitations inherent to previous candidate gene analyses. Genome-wide association studies (GWAS) can identify common genetic variants that associate with sepsis. Massive parallel sequencing allows for scanning of the entire human genome for rare variants that are directly responsible for extreme phenotypes, such as fulminant sepsis in children without established risk factors.Aims: 1. Prospective national survey of the epidemiology of bacteremia and septic shock in children, to assess morbidity, mortality, risk factors and pathogen distribution including resistance patterns; with special consideration of community-acquired and nocosomial sepsis.2. Identification of common human genetic variants that associate with increased susceptibility to sepsis in children using chip-based GWAS. 3. Investigation of rare genetic variations that are directly responsible for unusual susceptibility to bacterial sepsis using exome sequencing in children presenting with sepsis in the absence of comorbidities.4. Build-up of a pediatric sepsis biobank; this biobank is available for future research projects.5. Participation in international sepsis collaborations. The study has become a partner of EUCLIDS.Inclusion criteria: Newborns and children < 17 years with sepsis and positive blood-cultures. Study design: Prospective national multicenter observational cohort study. Coordinated by the Pediatric Infectious Diseases Group Switzerland (PIGS), all Swiss university hospitals and pediatric A-level hospitals are participating. DNA, RNA, serum and blood culture isolates are obtained. Clinical parameters are recorded in an online database. Data monitoring and quality controls are performed by the involved local CTUs under guidance of Swiss PedNet. The study has been approved by the cantonal Ethical Boards. The study was launched on September 1st 2011 and has included over 500 children with culture-positive sepsis during the first two years with 80% of parents giving informed consent for the study. Planned study duration: 4 years. Planned sample size: 800 patients with biobanking, >1000 patients with epidemiological data. Genomic analyses: GWAS will be performed in all patients using genome-wide genotyping arrays and association analysis. Exome and transcriptome sequencing will be performed in a selected subset of children presenting with sepsis in the absence of comorbidities. Genomic data from sepsis patients will be compared to populational controls form a prospective SNF birth cohort, the CoLaus cohort, and the 1000 Genomes project. Access to replication cohorts has been granted through the EUCLIDS consortium.Significance: Sepsis accounts for a high burden of childhood morbidity and mortality. From a public health perspective, this project provides surveillance of pediatric bacteremia in Switzerland, thereby generating representative information on whether current empiric treatment and prevention strategies are effective, and on the impact of sepsis in children in Switzerland. In addition, this study monitors risk factors and incidence of healthcare-acquired bloodstream infections in children and will thereby contribute to initiatives aiming to reduce nosocomial infections. This study for the first time combines a GWAS approach to investigate common genetic variations and massive parallel sequencing to investigate rare mutations in pediatric sepsis. This study aims to discover causative rare genetic variants and to unravel the impact of novel immunodeficiencies on bacterial sepsis in children. Ultimately, the goal is to improve recognition and treatment of children at very high risk of sepsis resulting in reduced sepsis mortality. The study design is ideally suited to promote further functional studies on host genomics and host-pathogen interaction, and genomic data can be integrated in future international sepsis genomics databases. Of note, this study has become a partner of EUCLIDS, the largest international consortium on severe childhood infections. Finally, this nationwide cohort study is enhancing the research network between pediatric hospitals and will thereby contribute to improved research for children in Switzerland.
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