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The contribution of genetic variation of Streptococcus pneumoniae to the clinical manifestation of invasive pneumococcal disease

By Amelieke JH Cremers, Fredrick M Mobegi, Christa van der Gaast –de Jongh, Michelle van Weert, Fred J van Opzeeland, Minna Vehkala, Mirjam J. Knol, Hester J Bootsma, Niko Välimäki, Jacques F. Meis, Stephen Bentley, Sacha A.F.T. van Hijum, Jukka Corander, Aldert L Zomer, Gerben Ferwerda, Marien I. de Jonge

Posted 30 Jul 2017
bioRxiv DOI: 10.1101/169722 (published DOI: 10.1093/cid/ciy417)

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 two Dutch hospitals between 2000-2011 with pneumococcal bacteraemia. 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. Findings: The presence of pneumococcal gene slaA was a nationwide confirmed independent predictor of meningitis (OR=10.5, p=0.001), as was sequence cluster 9 (OR=3.68, p=0.057). A set of 4 pneumococcal genes co-located on a prophage was a confirmed independent predictor of 30-day mortality (OR=3.4, p=0.003). We could detect the pneumococcal variants of concern in these patients' blood samples by molecular amplification. In the post-vaccination cohort where the distribution of both patient characteristics and pneumococcal serotypes had changed, the relative importance of the prophage was no longer supported. Interpretation: Knowledge of pneumococcal genotypic variants improved our clinical risk assessment for detrimental manifestations of IPD. This provides us with novel opportunities to target, anticipate or avert the pathogenic effects that are related to particular pneumococcal variants. Therefore, future diagnostics should facilitate prompt appreciation of pathogen diversity in clinical sepsis management. Ongoing surveillance is warranted to monitor the clinical value of information on pathogen variants in dynamic microbial and susceptible host populations.

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