Genome analysis following a national increase in Scarlet Fever in England 2014, and comparison with invasive Group A Streptococcus

Background. During a substantial elevation in scarlet fever (SF) notifications in 2013/2014 a national genomic sequence study was undertaken of Streptococcus pyogenes (Group A Streptococci, GAS) isolates from patients with SF, in comparison to GAS from patients with invasive disease (iGAS). This was undertaken to test the hypotheses that the increase in SF was due to either the introduction of one or more new/emerging strains in the population in England or the transmission of a known genetic element through the population of GAS by horizontal gene transfer (HGT) resulting in infections with an increased likelihood of causing SF. Methods. A total of 555 isolates were collected to provide geographical representation, with a request for approximately 5% SF isolates from each region from 1st April 2014 to 18th June 2014. Contemporaneous invasive GAS (iGAS) isolates for which genomic data was available were included in the analysis for comparison for the same period. Data was analysed in order to determine emm gene sequence type, phylogenetic lineage and genomic clade representation, the presence of known prophage elements and the presence of genes known to confer pathogenicity and resistance to antibiotics. Results. A total of 555 isolates were analysed, comprising 303 were from patients with SF and 252 from patients with iGAS. The increase in SF cases was not attributed to the introduction of a single or dominant clone but was associated with multiple lineages within the GAS population. Isolates from patients with SF were of multiple distinct emm sequence types and phylogenetic lineages. Prior to data normalisation, emm3 was the predominant type (accounting for 42.9% of SF isolates, 130/303 95%CI 37.5-48.5; 14.7% higher than the percentage of emm3 isolates found in the iGAS isolates). Post-normalisation, two emm types, 4 and 12, were found to be over-represented in patients with SF versus iGAS (Fisher’s Exact Test p=0.0008 and 0.001, respectively). A single gene, ssa, was over-represented in isolates from patients with SF. Two known prophage were found to be over represented in SF vs iGAS (315.1 and 315.2) of which one encodes the ssa gene (315.2). The HKU360.vir phage described in some isolates from Hong Kong, where an increase in SF was seen in 2011, was not detected in this study. The HKU360.ssa phage associated with some emm12 isolates from the 2011 Hong Kong SF study was present in 43/63 emm12 isolates but was not found to be over-represented in isolates from patients with SF. Discussion. There is no evidence that the increased number of SF cases is a strain-specific or known mobile element specific phenomenon, as the increase in SF cases was associated with multiple lineages of GAS. Alternative possibilities include an increased prevalence of an unknown genetic feature within the GAS population, contributions from human host or environmental factors such as changes in population immunity, concurrent circulation of other pathogens such as respiratory viruses, healthcare attendance and antimicrobial practice affecting carriage in the population.