Post-pandemic upsurge in Group A Streptococcus infections at an Italian tertiary university hospital

Abstract

Streptococcus pyogenes (Group A Streptococcus; GAS) is a pathogen of global significance. In the pre-antibiotic era, GAS was a major cause of childhood morbidity and mortality, but its spread rapidly declined until the mid-2010s. The continuing increase in GAS infections, associated with the expansion of the M1_UK lineage, was observed first in the United Kingdom (UK) and, later, globally. Here, we endeavor to assess the various determinants underlying the post-pandemic GAS upsurge, with a focus on microbial genomic features. We performed an epidemiological analysis of all laboratory-confirmed GAS infections identified between June 2018 and June 2024 at a tertiary University Hospital located in Northern Italy, dividing them into three levels of severity: mild, moderate, and invasive GAS infections. A subset of 34 representative GAS isolates identified in the post-pandemic period were subjected to short- and long-read whole genome sequencing (WGS). Of the 531 GAS cases analyzed during this period, the majority (415, 78.2%) occurred in the last two years. This increase in GAS cases correlated with a significant shift in infection severity: among the 118 GAS cases identified in the June 2018-May 2022 period, only one resulted in an invasive infection (1/118, 0.8%). In contrast, among the 531 GAS cases identified in the June 2022-May 2024 period, 32 caused invasive infections (32/531, 7.9%). WGS of 34 isolates (including 15 invasive isolates) identified 11 different emm types, the most frequent being emm1 (9 isolates) followed by emm12 (7 isolates), then emm89 and emm28 (4 isolates each). Among the emm1 isolates, the M1_UK sublineage was the most represented (8 out of 9 isolates), with the remaining "singleton" belonging to the M1_13SNP sublineage.

Importance: Streptococcus pyogenes (GAS) is a narrow-spectrum pathogen, circulating only in humans. Following the loosening of various public health measures implemented to face the challenge of the COVID-19 pandemic, a significant rise in GAS cases has been observed. Our study revealed a significant rise in GAS cases, particularly invasive infections, over the last two years. Genomic analysis identified multiple sequence types, including isolates belonging to an emerging lineage named M1_UK. These findings underscore the importance of ongoing surveillance and genomic monitoring of GAS infections, especially considering their rising incidence and severity. Public health strategies should consider not only microbe-associated aspects but also host-associated and external factors to effectively address this resurgence and prevent future outbreaks.

Keywords: Streptococcus pyogenes; antimicrobial resistance; emm typing; genomic epidemiology; invasive infections; phylogenetics.

Fig 1

Age distribution of GAS cases according to infection severity and sex. (A) Violin plots describing the age distribution of GAS cases, split according to their severity (as defined in the Methods section). Welch’s one-way ANOVA was used to compare the mean age among the three severity groups, and the Games–Howell post hoc test was used to compare the possible combinations of group differences. Results considered significant (P value ≤  0.05) are reported. In the boxes within violin plots, bold dotted lines indicate median age, while upper and lower boundaries indicate 75th percentile (third quartile) and 25th percentile (first quartile), respectively. (B) Violin plots describing the age distribution of GAS cases, split according to sex. Welch’s t-test was used to compare the mean age between the two groups (females and males). Results considered significant (P value ≤  0.05) are reported. In the boxes within violin plots, bold dotted lines indicate median age, while upper and lower boundaries indicate 75th percentile (third quartile) and 25th percentile (first quartile), respectively.

Fig 2

Distribution of laboratory-confirmed GAS infections. (A) Epidemiological distribution of GAS cases from June 2018 to June 2024. The severity of GAS infections (as defined in the Results section) is color-coded as follows: mild: green; moderate: yellow; iGAS: pink. The period during which COVID-19-associated restrictions were in place (from March 2020 to March 2022) is shaded in light blue. (B) Balloon plots showing the cumulative distribution of GAS cases by month of isolation split into two periods: June 2018–May 2022 and June 2022–May 2024. The severity of the cases is color-coded as follows: mild: green; moderate: yellow; iGAS: pink. The size of each balloon is proportional to the number of GAS cases in the corresponding month as per the legend. A clear seasonality was not observed either before or after the pandemic. (C) Bubble chart displaying the distribution of GAS cases, split according to severity, from May 2023 to January 2024. The chart highlights age (proportional to the size of the bubble) and sex of patients (female: dark pink; male: blue). Isolates subjected to WGS are represented by solid bubbles.

Fig 3

Annotation- and alignment-free phylogenetic analysis based on K-mers performed on 35 GAS isolates, 34 were subjected to WGS in this study and the reference M1 GAS isolate SF370 (accession number GCA_000006785.2). Starting from the left, metadata report the sequence type (ST) and the associated emm type (color-coded according to the legend), the severity of GAS infections (as defined in the Results section, color-coded as follows: mild: green; moderate: yellow; iGAS: pink), the presence of the hasABC operon (color-coded as follows: empty square: absent; light blue square: present; dark blue square: presence of the hasABC operon flanked by an IS1239), and the number of prophages and integrative and conjugative elements (ICEs)/integrative and mobilizable elements (IMEs) proportional to the size of the gray circles.