Scarlet Fever Epidemic in China Caused by Streptococcus pyogenes Serotype M12: Epidemiologic and Molecular Analysis

Abstract

From 2011, Hong Kong and mainland China have witnessed a sharp increase in reported cases, with subsequent reports of epidemic scarlet fever in North Asia and the United Kingdom. Here we examine epidemiological data and investigate the genomic context of the predominantly serotype M12 Streptococcus pyogenes scarlet fever isolates from mainland China. Incident case data was obtained from the Chinese Nationwide Notifiable Infectious Diseases Reporting Information System. The relative risk of scarlet fever in recent outbreak years 2011-2016 was calculated using the median age-standardised incidence rate, compared to years 2003-2010 prior this outbreak. Whole genome sequencing was performed on 32 emm12 scarlet fever isolates and 13 emm12 non-scarlet fever isolates collected from different geographic regions of China, and compared with 203 published emm12 S. pyogenes genomes predominantly from scarlet fever outbreaks in Hong Kong (n=134) and the United Kingdom (n=63). We found during the outbreak period (2011-2016), the median age-standardised incidence in China was 4.14/100,000 (95% confidence interval (CI) 4.11-4.18), 2.62-fold higher (95% CI 2.57-2.66) than that of 1.58/100,000 (95% CI 1.56-1.61) during the baseline period prior to the outbreak (2003-2010). Highest incidence was reported for children 5years of age (80.5/100,000). Streptococcal toxin encoding prophage φHKU.vir and φHKU.ssa in addition to the macrolide and tetracycline resistant ICE-emm12 and ICE-HKU397 elements were found amongst mainland China multi-clonal emm12 isolates suggesting a role in selection and expansion of scarlet fever lineages in China. Global dissemination of toxin encoded prophage has played a role in the expansion of scarlet fever emm12 clones. These findings emphasize the role of comprehensive surveillance approaches for monitoring of epidemic human disease.

Keywords: Epidemiological data; Genomic evolution; Group A Streptococcus; Mainland China; Scarlet fever.

Fig. 1

Scarlet fever incidence in China over the period 1950–2016.

Fig. 2

Monthly reported scarlet fever cases and incidence across the last fourteen years in China (2003–2010 and 2011–2016).

Fig. 3

Reported scarlet fever incidence according to geographic region in China (2011–2016).

Fig. 4

Age, gender and incidence of reported scarlet fever cases in China for 2016.

Fig. 5

Midpoint-rooted maximum-likelihood phylogenetic tree of 248 GAS emm12 isolates based on 2637 polymorphisms after mapping to the Hong Kong scarlet fever reference genome HKU163 and removal of confounding genomic regions (see methods). Phylogenetic location of the HKU16 genome is represented by the cross. Previously defined phylogenetic clades of the Hong Kong emm12 lineage, termed Clades I-IV, are shown on major branches (Davies et al., 2015). Asterisks represent major nodes with > 95% bootstrap support. Terminal nodes are coloured by country of origin and clinical scarlet fever association. Relative distribution of selected virulence genes, prophage elements, antimicrobial resistance genes and integrative conjugative elements (ICE) that have previously been linked to the emergence of scarlet fever clones in Hong Kong(Davies et al., 2015) are displayed.