New strain of strep a is causing scarlet fever and invasive infections in England and Wales

In 2014, England experienced the biggest surge in scarlet fever cases since the 1960s. Numbers continued to increase, with 15,000 cases in 2014, 17,000 in 2015 and over 19,000 in 2016. Symptoms, which affect young children, include a high temperature, sore throat, and a pink-red rash that feels like sandpaper [1]. Scarlet fever is caused by toxins released by the bacterium Streptococcus pyogenes, also known as Strep A, and cases follow a seasonal pattern peaking between March and May. Scarlet fever is easily treated with antibiotics. Cases of invasive infections caused by the same bacterium also increased in 2016 compared to the previous five years.

In this new study, the authors provide an explanation for the association between increased incidence of scarlet fever and increased incidence of more serious invasive infections such as bloodstream infections. They uncovered a new strain of Streptococcus pyogenes with increased capacity to produce scarlet fever toxin.

"Given that this strain has an apparently enhanced ability to cause all types of Strep A infection, it is important to monitor the bacterium both here and globally," says joint first author, Dr Nicola Lynskey from Imperial College London, UK.

The researchers set out to identify the Strep A strains causing infections in London and more widely in England and Wales, as defined by the type of emm gene present. They found that the initial upsurge of scarlet fever in 2014 in London was associated with Strep A strain types emm3 and emm4. However, during the spring of 2015 and 2016, emm1 strains became dominant among throat infections.

In Spring 2014, only 5% (five of 96) of isolates of the bacterium collected in northwest London were emm1 strains, but by 2015, this had increased to 19% (28 of 147). In 2016, emm1 became the single most frequent strain at 33% (47 of 144 isolates).

Analysis confirmed that emm1 strains also became increasingly dominant among strains causing severe invasive infections more widely within England and Wales. By Spring 2016, 42% (267 of 637) of invasive strains collected in England and Wales were emm1 isolates, up from 31% (183 of 587) in Spring 2015.

To investigate the emm1 isolates further, researchers sequenced the genomes of all 135 non-invasive emm1 isolates of the bacterium, collected in northwest London between 2009 and 2016, and all 552 invasive emm1 isolates collected in England and Wales during the seasonal disease spikes between 2013 and 2016, and compared them with one another. They assessed how much toxin was produced by different emm1 strains.

The researchers found that the majority of emm1 strains from 2015 and 2016 were a distinct, breakaway emm1 clone which they refer to as M1UK. The clone had 27 unique mutations, and was associated with significantly increased production of the toxin streptococcal pyrogenic exotoxin A (SpeA). This toxin triggers scarlet fever and may contribute to Strep A pharyngitis and some invasive infections. Analysis confirmed that M1UK produces nine times more toxin than other emm1 strains (190 nanograms per millilitre (ng/mL) compared to 21 ng/mL). It was present in England as early as 2010 and by 2016, M1UK represented 84% of all emm1 genomes analysed in England and Wales.

"The new, more toxigenic strain that we have identified has become the dominant cause of more serious emm1 Strep A infections," says joint first author Dr Elita Jauneikaite from Imperial College London, UK.

The authors speculate that the recent increase in activity of the Streptococcus pyogenes bacterium, which coincided with upsurges of scarlet fever, might have provided the conditions required for it to adapt genetically and spread within the UK.

The researchers compared the M1UK strains with 2,800 emm1 genomes from around the world. The M1UK strains were found to be unique and distinct. However, genetic analysis of strains collected in Denmark and the US also revealed single isolates of M1UK. The authors cannot confirm whether the new strain will be suited to environments in other countries, where factors such as climate and management of streptococcal sore throat vary. However, as SpeA toxin was implicated in the global re-emergence of severe invasive infections in the 1980s, they indicate that wider surveillance will be important.

"The distinct bacterial clone we have discovered appears so far to be largely limited to the UK, but the fact that we have identified two examples of it elsewhere suggests it has the potential to spread internationally and may already be present in other countries. However, it's also possible that the lineage will not last. In the past, some lineages have appeared and then disappeared quickly. Only further research on recent strains will provide more insights." says senior author Professor Shiranee Sriskandan from Imperial College London, UK.

Writing in a linked Comment, Professor Mark Walker from the University of Queensland, Australia, says: "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 GAS disease activity as a public-health priority. We believe that the report by Lynskey and colleagues sends out an important warning for the global public health community -- recently emerging scarlet fever GAS strains have enhanced invasive potential which may have profound implications for the future global health burden."

This study was funded by the UK Medical Research Council, the UK National Institute for Health Research (NIHR), the Wellcome Trust, and the Rosetrees and Stoneygates Trusts. It was conducted by researchers from Imperial College London, the University of Sheffield, Public Health England and the Wellcome Sanger Institute.

[1] See NHS information: https://www.nhs.uk/conditions/scarlet-fever/