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

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 5 years 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.
Highlights • The study used all epidemiological data from 1950 to 2016, and describe increased incidence levels for the current outbreak. • Using global emm12 scarlet fever isolate genome sequences, the multiclonal nature of the outbreak was confirmed. • Global surveillance of GAS toxin and drug resistance mobile genes in the scarlet fever outbreak is necessary. Our study provides a detailed report of scarlet fever epidemiology and genomic analysis for mainland China since the 2011 outbreak began. We also provide a comprehensive comparison of the genomic relationship of scarlet fever outbreak emm12 isolates from China, Hong Kong and the United Kingdom, countries experiencing an unparalleled re-emergence of scarlet fever. Our observations implicate an important role for GAS toxin and drug resistance related mobile genes in the outbreak and reveal different evolutionary patterns, and identify common themes relating to the acquisition of toxin carrying prophage elements. This work emphasizes the importance of comprehensive nationwide surveillance to track scarlet fever, GAS emm types, exotoxin-encoding prophage and antibiotic resistance genes in a global context.