Genomic Characteristics Behind the Spread of Bacteremic Group A Streptococcus Type emm89 in Finland, 2004–2014

The Journal of Infectious Diseases MAJOR ARTICLE Genomic Characteristics Behind the Spread of Bacteremic Group A Streptococcus Type emm89 in Finland, 2004–2014 Francesca Latronico,1,3 Waleed Nasser,4 Kai Puhakainen,1,2 Jukka Ollgren,1 Hanne-Leena Hyyryläinen,1 Stephen B. Beres,4 Outi Lyytikäinen,1 Jari Jalava,1 James M. Musser,4 and Jaana Vuopio1,2 1 Department of Infectious Diseases, National Institute for Health and Welfare, Helsinki, and 2Department of Medical Microbiology and Immunology, University of Turku, Finland; 3European Programme for Public Health Microbiology Training, European Centre for Disease Prevention and Control, Stockholm, Sweden; and 4Center for Molecular and Translational Human Infectious Diseases Research, Department of Pathology and Genomic Medicine, Houston Methodist Research Institute, Texas Group A Streptococcus (GAS) is a gram-positive human-adapted pathogen with the ability to cause diseases with a wide clinical range, from mild infections such as pharyngitis to severe infections such as bacteremia and necrotizing fasciitis. When the isolation of GAS from a normally sterile body site is associated with disease, it is referred as an invasive GAS (iGAS) infection. Worldwide, GAS infections are responsible for >600 million cases of mild infections and for 663 000 new cases of iGAS per year, with incidence rates ranging from 2.45 to 46.00 cases per 100 000 population and case-fatality rates (CFRs) of up to 25% [1, 2]. The emm gene, which encodes M protein, one of the most important GAS virulence factors, is a target for genotyping. Received 6 July 2016; accepted 27 September 2016; published online 5 October 2016. Presented in part: European Conference of Clinical Microbiology and Infectious Diseases, Amsterdam, Netherlands, April 2016. Abstract 2158. Correspondence: J. Vuopio, Department of Medical Microbiology and Immunology, University of Turku, Kiinamyllynkatu 13, 20250 Turku, Finland (). The Journal of Infectious Diseases® 2016;214:1987–95 © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/ 4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, contact . DOI: 10.1093/infdis/jiw468 To date, >240 emm types have been reported, and genetic diversity can exist among strains of the same emm type [3, 4]. Dynamic changes and fluctuations in emm type frequency in iGAS infection occur over time and space [4], including emergence and replacement of new clones or subtypes [5–7]. Some emm types, such as emm1, have been linked to more severe disease manifestations and higher CFRs [4, 8–10]. Our recent study on iGAS infection in Finland showed that although the overall incidence of iGAS infections remained relatively stable during last few years, the incidence of cases caused by emm89 strains increased [11]. Similar findings have been reported from other countries in Europe [4, 6, 12–15], North America [7, 9, 16], and elsewhere [17–19]. The emergence of emm89 GAS strains has led investigators to perform bacterial genomic studies to understand reasons behind it. Thus far, the study of the largest sample of 1125 emm89 isolates, covering 2003–2013 from 3 countries, including Finland, revealed that emm89 strains underwent recombinational replacement events previously reported for the successful intercontinental epidemic emm1 clone [5, 7]. The goal of this study was to analyze, in detail, temporal, spatial, genomic, and clinical aspects of emm89 bacteremic infections in Finland during 2004–2014. We linked the epidemiological information with whole-genome sequencing (WGS) data for emm89 Group A Streptococcus in Finland • JID 2016:214 (15 December) • 1987 Background. Many countries worldwide have reported increasing numbers of emm89 group A Streptococcus (GAS) infections during last decade. Pathogen genetic factors linked to this increase need assessment. Methods. We investigated epidemiological characteristics of emm89 GAS bacteremic infections, including 7-day and 30-day case-fatality rates, in Finland during 2004–2014 and linked them to whole-genome sequencing data obtained from corresponding strains. The Fisher exact test and exact logistic regression were used to compare differences between bacteremic infections due to emm89 GAS belonging to different genetic clades and subclades. Results. Out of 1928 cases of GAS bacteremic infection, 278 were caused by emm89 GAS. We identified 2 genetically distinct clades, arbitrarily designated clade 2 and clade 3. Both clades were present during 2004–2008, but clade 3 increased rapidly from 2009 onward. Six subclades (designated subclades A–F) were identified within clade 3, based on phylogenetic core genome analysis. The case-fatality rate differed significantly between subclades (P < .05), with subclade D having the highest 30-day estimated case-fatality rate (19% vs 3%–14%). Conclusions. A new emm89 clone, clade 3, emerged in 2009 and spread rapidly in Finland. Patients infected with certain subclades of clade 3 were significantly more likely to die. A specific polymerase chain reaction assay was developed to follow the spread of subclade D in 2015. Keywords. Streptococcus pyogenes; bacteremia; whole genome sequencing; surveillance; molecular epidemiology; bacterial genome; emm type. the corresponding 272 strains. We found that progeny of a new genetic clone (designated clade 3) emerged in 2009, spread rapidly in Finland, and caused a significantly increased number of iGAS infections throughout the country. Patients infected with certain subclades of this new clone were significantly more likely to die from the infection. A specific polymerase chain reaction (PCR) assay was developed to permit rapid identification of a distinct subclade for epidemiologic purposes. MATERIALS AND METHODS Surveillance of Bacteremic Infections Due to GAS Case Definition and Outcome A case of bacteremic GAS disease was defined as isolation of Streptococcus pyogenes (GAS) from a blood culture in Finland during 2004–2014 and as an emm89 GAS bacteremic infection when emm89 was specifically detected. All bacteremic GAS cases reported to the NIDR (n = 1977) and all available corresponding isolates (n = 1928) submitted to NRL from January 2004 to December 2014 were included in this study. Data about deaths of bacteremic GAS cases with appropriate personal identity codes (n = 1915) within 7-day and 30-day follow-up periods after GAS blood isolation were obtained from the National Population Register and used to assess 7-day and 30-day CFRs, respectively. In case of suspected epidemiological link among emm89 bacteremic GAS cases, medical records were reviewed b (...truncated)