Amelieke J H Cremers1,2,3, Fredrick M Mobegi1,2,4, Christa van der Gaast-de Jongh1,2, Michelle van Weert1,2, Fred J van Opzeeland1,2, Minna Vehkala5, Mirjam J Knol6, Hester J Bootsma6, Niko Välimäki5, Nicholas J Croucher7, Jacques F Meis8, Stephen Bentley9, Sacha A F T van Hijum2,4,10, Jukka Corander5,9,11, Aldert L Zomer12, Gerben Ferwerda1,2, Marien I de Jonge1,2. 1. Section of Pediatric Infectious Diseases, Laboratory of Medical Immunology, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands. 2. Radboud Center for Infectious Diseases, Center for Molecular and Biomolecular Informatics, Radboudumc, Nijmegen, The Netherlands. 3. Department of Medical Microbiology, Center for Molecular and Biomolecular Informatics, Radboudumc, Nijmegen, The Netherlands. 4. Bacterial Genomics Group, Center for Molecular and Biomolecular Informatics, Radboudumc, Nijmegen, The Netherlands. 5. Department of Mathematics and Statistics, University of Helsinki, Finland. 6. Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands. 7. Medical Research Council Centre for Outbreak Analysis and Modelling, Department of Infectious Disease Epidemiology, Imperial College London, United Kingdom. 8. Department of Medical Microbiology and Infectious Diseases, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands. 9. Wellcome Trust Sanger Institute, Pathogen Genomics Group, Hinxton, Cambridge, United Kingdom. 10. NIZO, Ede, The Netherlands. 11. Department of Biostatistics, University of Oslo, Norway. 12. Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, The Netherlands.
Abstract
Background: Different clinical manifestations of invasive pneumococcal disease (IPD) have thus far mainly been explained by patient characteristics. Here we studied the contribution of pneumococcal genetic variation to IPD phenotype. Methods: The index cohort consisted of 349 patients admitted to 2 Dutch hospitals between 2000-2011 with pneumococcal bacteremia. We performed genome-wide association studies to identify pneumococcal lineages, genes, and allelic variants associated with 23 clinical IPD phenotypes. The identified associations were validated in a nationwide (n = 482) and a post-pneumococcal vaccination cohort (n = 121). The contribution of confirmed pneumococcal genotypes to the clinical IPD phenotype, relative to known clinical predictors, was tested by regression analysis. Results: Among IPD patients, the presence of pneumococcal gene slaA was a nationwide confirmed independent predictor of meningitis (odds ratio [OR], 10.5; P = .001), as was sequence cluster 9 (serotype 7F: OR, 3.68; P = .057). A set of 4 pneumococcal genes co-located on a prophage was a confirmed independent predictor of 30-day mortality (OR, 3.4; P = .003). We could detect the pneumococcal variants of concern in these patients' blood samples. Conclusions: In this study, knowledge of pneumococcal genotypic variants improved the clinical risk assessment for detrimental manifestations of IPD. This provides us with novel opportunities to target, anticipate, or avert the pathogenic effects related to particular pneumococcal variants, and indicates that information on pneumococcal genotype is important for the diagnostic and treatment strategy in IPD. Ongoing surveillance is warranted to monitor the clinical value of information on pneumococcal variants in dynamic microbial and susceptible host populations.
Background: Different clinical manifestations of invasive pneumococcal disease (IPD) have thus far mainly been explained by patient characteristics. Here we studied the contribution of pneumococcal genetic variation to IPD phenotype. Methods: The index cohort consisted of 349 patients admitted to 2 Dutch hospitals between 2000-2011 with pneumococcal bacteremia. We performed genome-wide association studies to identify pneumococcal lineages, genes, and allelic variants associated with 23 clinical IPD phenotypes. The identified associations were validated in a nationwide (n = 482) and a post-pneumococcal vaccination cohort (n = 121). The contribution of confirmed pneumococcal genotypes to the clinical IPD phenotype, relative to known clinical predictors, was tested by regression analysis. Results: Among IPD patients, the presence of pneumococcal gene slaA was a nationwide confirmed independent predictor of meningitis (odds ratio [OR], 10.5; P = .001), as was sequence cluster 9 (serotype 7F: OR, 3.68; P = .057). A set of 4 pneumococcal genes co-located on a prophage was a confirmed independent predictor of 30-day mortality (OR, 3.4; P = .003). We could detect the pneumococcal variants of concern in these patients' blood samples. Conclusions: In this study, knowledge of pneumococcal genotypic variants improved the clinical risk assessment for detrimental manifestations of IPD. This provides us with novel opportunities to target, anticipate, or avert the pathogenic effects related to particular pneumococcal variants, and indicates that information on pneumococcal genotype is important for the diagnostic and treatment strategy in IPD. Ongoing surveillance is warranted to monitor the clinical value of information on pneumococcal variants in dynamic microbial and susceptible host populations.
Authors: Marien I de Jonge; Amelieke J H Cremers; Daan W Arends; Wynand Alkema; Indri Hapsari Putri; Christa E van der Gaast-de Jongh; Marc Eleveld; Jeroen D Langereis; Quirijn de Mast; Jacques F Meis Journal: Microbiol Spectr Date: 2022-06-09
Authors: John A Lees; Bart Ferwerda; Philip H C Kremer; Nicole E Wheeler; Mercedes Valls Serón; Nicholas J Croucher; Rebecca A Gladstone; Hester J Bootsma; Nynke Y Rots; Alienke J Wijmega-Monsuur; Elisabeth A M Sanders; Krzysztof Trzciński; Anne L Wyllie; Aeilko H Zwinderman; Leonard H van den Berg; Wouter van Rheenen; Jan H Veldink; Zitta B Harboe; Lene F Lundbo; Lisette C P G M de Groot; Natasja M van Schoor; Nathalie van der Velde; Lars H Ängquist; Thorkild I A Sørensen; Ellen A Nohr; Alexander J Mentzer; Tara C Mills; Julian C Knight; Mignon du Plessis; Susan Nzenze; Jeffrey N Weiser; Julian Parkhill; Shabir Madhi; Thomas Benfield; Anne von Gottberg; Arie van der Ende; Matthijs C Brouwer; Jeffrey C Barrett; Stephen D Bentley; Diederik van de Beek Journal: Nat Commun Date: 2019-05-15 Impact factor: 14.919
Authors: Rebecca A Gladstone; Stephanie W Lo; John A Lees; Nicholas J Croucher; Andries J van Tonder; Jukka Corander; Andrew J Page; Pekka Marttinen; Leon J Bentley; Theresa J Ochoa; Pak Leung Ho; Mignon du Plessis; Jennifer E Cornick; Brenda Kwambana-Adams; Rachel Benisty; Susan A Nzenze; Shabir A Madhi; Paulina A Hawkins; Dean B Everett; Martin Antonio; Ron Dagan; Keith P Klugman; Anne von Gottberg; Lesley McGee; Robert F Breiman; Stephen D Bentley Journal: EBioMedicine Date: 2019-04-16 Impact factor: 8.143
Authors: Amber C A Hendriks; Frans A G Reubsaet; A M D Mirjam Kooistra-Smid; John W A Rossen; Bas E Dutilh; Aldert L Zomer; Maaike J C van den Beld Journal: BMC Genomics Date: 2020-02-10 Impact factor: 3.969
Authors: D W Arends; W R Miellet; J D Langereis; T H A Ederveen; C E van der Gaast-de Jongh; M van Scherpenzeel; M J Knol; N M van Sorge; D J Lefeber; K Trzciński; E A M Sanders; H C Dorfmueller; H J Bootsma; M I de Jonge Journal: Infect Immun Date: 2021-07-12 Impact factor: 3.441