The Comeback of Scarlet Fever

Streptococcus pyogenes (group A Streptococcus, GAS) is arguably the most virulent of all clinically important streptococci with a propensity to cause severe invasive diseases, toxic shock syndrome, and immunopathological damages such as acute rheumatic fever. Since the 1980s, severe GAS infections such as necrotizing fasciitis and toxic shock syndrome have been increasingly recognized (Stevens and Bryant, 2016). Scarlet fever, a toxin-mediated disease, occurred in epidemics in the nineteenth century but was relatively uncommon in the second half of the twentieth century in most developed countries. However, there has been a re-emergence of scarlet fever in the past decade in some countries such as the United Kingdom (since 2014), Hong Kong (since 2011), and mainland China (Lamagni et al., 2017, Tse et al., 2012, You et al., 2018). Historically, epidemics of scarlet fever often occurred every five to six years, possibly due to the accumulation of type-specific herd immunity among the susceptible population in the community, but also affected by various environmental and meteorological factors (Wong and Yuen, 2012). The appearance of GAS epidemics has sometimes been attributed to the introduction of hitherto uncommon emm types or acquisition of new mobile genetic elements which may carry virulence determinants, although these have not been consistently demonstrated in all outbreaks.

Different emm types predominate in different parts of the world. For example, the increase in scarlet fever incidence in England since 2014 was caused by multiple lineages of GAS, especially emm3, emm4, and emm12 types, while the acapsular emm89 has emerged as an important cause of invasive GAS diseases (Chalker et al., 2017). In the UK outbreak of scarlet fever in 2014, no single lineage of GAS or virulence gene predominated in all the strains (Chalker et al., 2017). In contrast, the 2011 epidemics of scarlet fever in Hong Kong and mainland China were predominantly caused by emm12 strains (Tse et al., 2012, You et al., 2018). Similarly, the commonest strains found in scarlet fever cases also belonged to emm12 type in northern Taiwan in 2010–2011 (Wu et al., 2014). However, even in scarlet fever epidemics where a particular emm type predominated, genomic studies showed that the strains often belonged to multiple phylogenetic lineages rather than a single clone (Tse et al., 2012, You et al., 2018). The emm12 type is not new to the Far East region. In China, emm12 was already the commonest emm type found in S. pyogenes isolates between 2005 and 2008. (Liang et al., 2012) The 2011 scarlet fever outbreak in Hong Kong was notable in that most of the outbreak emm12 strains were associated with new genomic insertions containing tetracycline and macrolide resistance genes, and the presence of novel prophages ΦHKU.ssa and ΦHKU.vir, which carried genes for superantigens and DNase (ssa, speC, spd1) (Tse et al., 2012). The ΦHKU.vir and ΦHKU.ssa prophages were also present in half of the contemporary Chinese scarlet fever-associated emm12 strains (You et al., 2018). In addition to the possible roles of these virulence factors in pathogenesis, the presence of macrolide resistance may impart survival advantages to these strains in areas where antibiotic consumption is high, especially where macrolides are commonly prescribed for respiratory tract infections in the primary care setting. Although the 2014 UK scarlet fever outbreak was caused by multiple emm types and lineages (but especially emm3, 4, and 12), a ΦHKU.ssa-like prophage was found in 68.3% of the emm12 isolates but not in other emm types (except for one [3.5%] emm28 isolate) (Chalker et al., 2017).

The problem of clindamycin resistance has been a clinically pertinent issue for many years. Historically, clindamycin plus penicillin is the recommended treatment of severe GAS infections by reducing toxin and superantigen production (Wong and Yuen, 2012). However, the use of clindamycin is potentially detrimental in the presence of clindamycin resistance because it can paradoxically increase the production of exotoxins. In the recent scarlet fever outbreaks in Hong Kong and mainland China, clindamycin resistance was present in 85.6% and 97% of the isolates respectively (Luk et al., 2012, You et al., 2013). This high prevalence of macrolide and clindamycin resistance may necessitate the use of alternative adjunctive therapy such as linezolid in the treatment of severe GAS infections (Wong and Yuen, 2012).

The use of whole genome sequencing has enhanced our understanding of the molecular epidemiology of S. pyogenes infections. It allows for detailed analysis of the emm types of strains, phylogenetic analysis, antibiotic resistance genes characterization, and discovery of novel genetic elements. The approach has been used in the study of invasive GAS infections and scarlet fever outbreaks in different countries (Chalker et al., 2017, Tse et al., 2012, You et al., 2018). The wider availability of whole genome sequencing will allow a better understanding of the epidemiology and pathogenesis of infections due to S. pyogenes.

Disclosure

The authors declared no conflicts of interest.