Scarlet fever changes its spots
Authors: Stephan Brouwer, Jake A Lacey, Yuanhai You, Mark R Davies, Mark J Walker
Journal: The Lancet Infectious Diseases (2019)

Historically, the human pathogen Streptococcus pyogenes (group A streptococcus) was a major cause of death as a result of sepsis and fatal epidemics of scarlet fever.1Katz AR Morens DM Severe streptococcal infections in historical perspective.Clin Infect Dis. 1992; 14: 298-307Crossref PubMed Scopus (108) Google Scholar Despite a decline in the incidence and severity of these toxin-mediated diseases over the past century in high-income countries, group A streptococcus is still among the top ten infectious causes of human mortality, with more than 500 000 deaths annually.2Carapetis JR Steer AC Mulholland EK Weber M The global burden of group A streptococcal diseases.Lancet Infect Dis. 2005; 5: 685-694Summary Full Text Full Text PDF PubMed Scopus (1964) Google Scholar In addition to the persistently high disease burden in low-resource nations, an unprecedented global resurgence of scarlet fever and severe invasive group A streptococcal infections has been seen in the past few decades. However, there is continuing scientific uncertainty surrounding specific factors that might have led to the re-emergence of these diseases. Group A streptococcus is classified into more than 200 emm types.3Davies MR McIntyre L Mutreja A et al.Atlas of group A streptococcal vaccine candidates compiled using high-throughput genomics.Nat Genet. 2019; 51: 1035-1043Crossref PubMed Scopus (85) Google Scholar Since the mid-1980s, a hypervirulent serotype emm1 group A streptococcus clone has been frequently isolated from severe forms of invasive group A streptococcal disease.4Aziz RK Kotb M Rise and persistence of global M1T1 clone of Streptococcus pyogenes.Emerg Infect Dis. 2008; 14: 1511-1517Crossref PubMed Scopus (147) Google Scholar The ongoing outbreak of scarlet fever in the UK, first reported in 2014, is polyclonal in nature and not caused by a single epidemic strain of group A streptococcus.5Turner CE Pyzio M Song B et al.Scarlet fever upsurge in England and molecular-genetic analysis in North-West London, 2014.Emerg Infect Dis. 2016; 22: 1075-1078Crossref PubMed Scopus (35) Google Scholar, 6Lamagni T Guy R Chand M et al.Resurgence of scarlet fever in England, 2014-16: a population-based surveillance study.Lancet Infect Dis. 2018; 18: 180-187Summary Full Text Full Text PDF PubMed Scopus (84) Google Scholar This scarlet fever outbreak is associated with multiple distinct emm types, with emm3, emm12, emm1, and emm4 being the most prevalent. In The Lancet Infectious Diseases, Nicola Lynskey and colleagues7Lynskey NN Jauneikaite E Li HK et al.Emergence of dominant toxigenic M1T1 Streptococcus pyogenes clone during increased scarlet fever activity in England: a population-based molecular epidemiological study.Lancet Infect Dis. 2019; (published online Sept 10.)http://dx.doi.org/10.1016/S1473-3099(19)30446-3Summary Full Text Full Text PDF PubMed Scopus (52) Google Scholar report on the rapid emergence of a new dominant group A streptococcus emm1 lineage in the UK (M1UK) during the 2014–16 scarlet fever seasonal surges, accounting for a synchronous rise in the incidence of invasive infections. Comparative genomic and phylogenetic analysis of upper respiratory tract (isolates from 2009–16) and invasive (2013–16) emm1 group A streptococcus isolates from the UK showed that the M1UK lineage—which appears to have evolved in the UK as early as 2010—is genotypically distinct from other pandemic emm1 isolates and is characterised by 27 lineage-defining mutations in regulatory and metabolic genes. These conserved and lineage-specific mutations are associated with significantly increased expression of streptococcal pyrogenic exotoxin A (SpeA)—a phage-encoded superantigen that is crucial for the establishment of nasopharyngeal infection8Kasper KJ Zeppa JJ Wakabayashi AT et al.Bacterial superantigens promote acute nasopharyngeal infection by Streptococcus pyogenes in a human MHC Class II-dependent manner.PLoS Pathog. 2014; 10: e1004155-e1004156Crossref PubMed Scopus (63) Google Scholar and has played an important role in the epidemic spread of emm1 strains since the 1980s.4Aziz RK Kotb M Rise and persistence of global M1T1 clone of Streptococcus pyogenes.Emerg Infect Dis. 2008; 14: 1511-1517Crossref PubMed Scopus (147) Google Scholar Lynskey and colleagues' findings, therefore, provide a plausible explanation for the increased capacity of M1UK to cause toxin-mediated scarlet fever and invasive infections in the UK. Given that intermediate members of the M1UK lineage were also identified in countries outside the UK, there is major concern as to whether similar pathogenic changes might occur elsewhere. Public Health England reported an alarming rise in scarlet fever notifications across the UK in 2018, with a doubling in numbers of reported cases compared with the start of the outbreak in 2014. Mainland China and Hong Kong also have an ongoing outbreak of scarlet fever, with about 500 000 reported cases since 2011.9You Y Davies MR Protani M McIntyre L Walker MJ Zhang J Scarlet fever epidemic in China caused by Streptococcus pyogenes Serotype M12: epidemiologic and molecular analysis.EBioMedicine. 2018; 28: 128-135Summary Full Text Full Text PDF PubMed Scopus (48) Google Scholar Similar to the UK, case numbers have been increasing in east Asia in the past 2 years; however, the driving force responsible for the enhanced pathogenicity of group A streptococcus in this region is yet to be understood. In contrast to the UK, acquisition of novel prophages harbouring new combinations of toxin genes (encoding the superantigens streptococcal superantigen A and streptococcal pyrogenic exotoxin C, and the DNase Spd1) and antimicrobial resistance genes were closely associated with the emergence and expansion of scarlet fever-associated emm12 and emm1 lineages in mainland China and Hong Kong.9You Y Davies MR Protani M McIntyre L Walker MJ Zhang J Scarlet fever epidemic in China caused by Streptococcus pyogenes Serotype M12: epidemiologic and molecular analysis.EBioMedicine. 2018; 28: 128-135Summary Full Text Full Text PDF PubMed Scopus (48) Google Scholar, 10Ben Zakour NL Davies MR You Y et al.Transfer of scarlet fever-associated elements into the group A Streptococcus M1T1 clone.Sci Rep. 2015; 515877Crossref PubMed Scopus (44) Google Scholar Comparative population analyses of scarlet fever emm1 genomes from east Asia and the UK support the conclusions made by Lynskey and colleagues that these lineages have different evolutionary histories (appendix). None of the scarlet fever genomes from east Asia carry the M1UK defining polymorphisms, including rofA mutations. Variable carriage of scarlet fever associated virulence genes (ssa, speA, and speC) and the DNase spd1 is also evident within the global scarlet fever emm1 population, providing further support that scarlet fever emm1 lineages from different geographical regions are evolving independently and are associated with different virulence characteristics. These data show that multiple mechanisms related to toxin carriage and expression characteristics probably play a key role in global disease outcomes. The continuing increase in scarlet fever and invasive disease notifications in the UK exemplifies the essential need to install global surveillance systems and address the increased group A streptococcus disease activity as a public health priority. The report by Lynskey and colleagues sends out an important warning for the global public health community: recently emerging scarlet fever group A streptococcus strains have enhanced invasive potential, which might have profound implications for the future global health burden. We declare no competing interests. Download .pdf (.32 MB) Help with pdf files Supplementary appendix Emergence of dominant toxigenic M1T1 Streptococcus pyogenes clone during increased scarlet fever activity in England: a population-based molecular epidemiological studyA dominant new emm1 S pyogenes lineage characterised by increased SpeA production has emerged during increased S pyogenes activity in England. The expanded reservoir of M1UK and recognised invasive potential of emm1 S pyogenes provide plausible explanation for the increased incidence of invasive disease, and rationale for global surveillance. Full-Text PDF Open Access