Genomic features of Streptococcus pneumoniae associated with recurrent invasive pneumococcal disease

Invasive pneumococcal disease (IPD) is a major cause of morbidity and mortality worldwide, particularly in children and the elderly. Recurrent IPD (rIPD) is more challenging to manage and differentiate between re-infection with a new strain of Streptococcus pneumoniae, and relapse associated with host immunodeficiency ​or unrecognised antimicrobial resistance (AMR). This study examined genomic features of S. pneumoniae associated with rIPD. A set of 140 S. pneumoniae isolates from 67 patients with rIPD was investigated. All isolates were subjected to Quellung serotyping and whole-genome sequencing to determine episodes of rIPD relapse and reinfection and to identify AMR genes. In the first and second episodes, 33 (49%) of cases of rIPD were associated with different serotypes of S. pneumoniae and were classified as reinfections. In 34 cases, both presentations were caused by S. pneumoniae of the same serotype. Genomic comparison of pneumococci associated with these rIPD episodes indicated that a further 7% (5/67) were reinfections and the rest (29 cases of rIPD; 43%) were cases of relapse caused by genomically closely related strains. rIPD cases with over 6000 mutations between core genome in S. pneumoniae were classified as reinfection, while endogenous relapse cases were characterised by fewer than 34 mutations between the core genomes of S. pneumoniae. rIPD recurrence within a year was more likely to be a relapse than a reinfection. Relapse cases were more likely to have AMR markers present in the initial episode, with no significant evidence of AMR acquisition between episodes. These findings suggest a role for S. pneumoniae genome sequence analysis in differentiating endogenous relapse from exogenous reinfection in rIPD to inform clinical management and public health follow-up.