Global spread of Streptococcus pyogenes A genomics-supported narrative review

In December 2022, rising numbers of group A Streptococcus (GAS) infections were reported in the United Kingdom, Europe, and the United States.1 Clinical syndromes caused by GAS range from pharyngitis and scarlet fever to necrotising fasciitis and toxic shock syndrome. The mortality rate among people with invasive GAS (iGAS) infections, in which GAS can be isolated from a normally sterile tissue (eg, blood), is 12%.2 GAS infections are seasonal, their number rising in winter and peaking in spring.1 During the 2020–2021 coronavirus disease 2019 (COVID-19)-related restrictions, GAS infection rates fell to very low levels in many countries.1 Outbreaks in the northern hemisphere in 2022 may reflect an early return to pre-pandemic seasonal patterns, or a post-pandemic change in the epidemiology of GAS infection. Corresponding data for southern hemisphere countries have not been reported. On 23 December 2022, the Victorian Department of Health issued an advisory notice regarding rising iGAS case numbers in Victoria and overseas.3 However, longitudinal public health data are limited. iGAS has been nationally notifiable since 1 July 2021,4 and notifications have been received in Victoria since February 2022. Only limited data on non-invasive GAS infection are available, as it is not notifiable. We examined the results of throat swabs and blood cultures processed by Monash Pathology during 1 January 2017 – 20 December 2022. Monash Pathology provides services to a catchment area of about 1.5 million people in Melbourne, including the Monash Health network with its more than 2000 hospital beds (adult and children) and outpatient services. We compared monthly GAS isolation rates during 2022 with the mean monthly rates for 2017–2019 (ie, three years preceding the COVID-19 period) and the mean monthly rates during 2020–2021 (ie, two years during which social distancing restrictions applied). We estimated 95% confidence intervals using the Clopper–Pearson exact method. All analyses were performed in Stata 17.0. The Monash Health Ethics Advisory Group approved our analysis as a minimum risk/quality assurance study (QA/94180/MonH-2023-352627(v1)). Rates of GAS isolation in Melbourne began to rise in November 2022, and were substantially higher than pre-pandemic levels in December 2022. During 1–20 December 2022, GAS was isolated from 20 of 92 throat swabs (22%) and six of 2597 blood cultures (0.2%); during the corresponding months of 2017–2019 it had been isolated from 13 of 193 swabs (6.7%; v 2022) and nine of 11 013 blood cultures (0.08%) (Box; Supporting Information, table 1). Most GAS-positive samples were collected in hospital emergency departments or wards (throat swabs: 252 of 296, 85%; blood cultures: 113 of 114, 99%). During 2017–2022, the median age of people with streptococcal throat infections was eight years (interquartile range [IQR], 5–21 years), of those with bacteraemia 48 years (IQR, 33–65 years). During 2022, the median age of people with positive swabs was eight years (IQR, 5–23 years), of those with positive blood cultures 52 years (IQR, 18–68 years) Four of the twenty bacteraemia cases in 2022 were in children under ten years of age (Supporting Information, figure 1). During the December 2022 surge, the median age of people with positive throat swabs was six years (IQR, 4.5–15 years; sixteen under 18 years, ten aged five years or younger); the median age of those with positive blood cultures was 43 years (IQR, 11–64 years; two under 18 years, none aged five years or less). The twenty blood culture isolates collected during 2022 were subjected to M-protein gene (emm) typing, a technique for defining the clonal structure of GAS populations.5 emm type diversity (ten emm types) indicated a non-clonal outbreak; the most frequent type was emm 1.0 (five isolates). There were four emm types in the six blood culture isolates of December 2022. The role of viral co-infection, reduced GAS exposure, and reduced accrual of natural immunity during 2020–2021 (including 263 days of stay-at-home orders) in this rise in GAS disease in Melbourne warrant further investigation. Respiratory viral infection case numbers fell to very low levels, then rose after restrictions were lifted.6 A spike in GAS infection numbers during 2017 (in our catchment area: lower than the December 2022 rise; Supporting Information, figure 2) coincided with high rates of influenza A infection.7 Overseas media attention during December 2022 may have contributed to increased case finding (ascertainment bias), but GAS test numbers during 2022 were similar to the pre-pandemic numbers (Supporting Information, table 2). More comprehensive data from Victoria and elsewhere should be examined. Our single laboratory analysis found that the numbers of GAS isolates from throat swabs markedly increased in December 2022, reaching triple the mean pre-pandemic December rate and double the mean pre-pandemic winter and spring peak rates (6.7% for June 2017–2019; 8.4% for November 2017–2019). This suggests a surge in GAS throat infections, primarily in children. A parallel spike in invasive disease affecting both children and older adults was also noted. Our findings, together with northern hemisphere reports, possibly reflect a worldwide increase in GAS disease. Clinicians should be alert to clinical syndromes of GAS/iGAS infection, and be familiar with recommendations for treating infected people and with chemoprophylaxis for their close contacts. We thank the Microbiological Diagnostic Unit Public Health Laboratory, Melbourne, for performing emm typing of blood culture isolates. Open access publishing facilitated by Monash University, as part of the Wiley – Monash University agreement via the Council of Australian University Librarians. No relevant disclosures. Supplementary results Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Group A β-hemolytic streptococcus (GAS) or Streptococcus pyogenes may be encountered in diverse clinical situations in children. A rising incidence of invasive group A streptococcus (IGAS) infections has been noted in children in the past three decades. The aim of this study was to summarize the clinical characteristics and antimicrobial resistance of IGAS in children, and to raise the level of diagnosis and treatment of this infection. The clinical data from 19 cases of IGAS younger than 14 years old seen from January 2004 to December 2011 treated in the authors' hospital were analyzed. IGAS infections are defined as the isolation of GAS from a normally sterile site in patients. The 19 cases were identified as IGAS infections, among whom 15 were male and 4 were female, and the ratio of them was 3.75. The age ranged from 1 day to 14 years, with a median age of 4 years. The course of disease was 4 h-10 days. The average length of stay was 12.2 days. In 13 cases the episodes of the infection occurred in winter and spring. In 18 cases the infection was community-acquired. Overall, 10 cases had neck or foot dorsum abscess, four cases had purulent peritonitis, and 3 cases were diagnosed as streptococcal toxic shock syndrome (STSS) complicated with empyema, pyopneumothorax occurred in 1 case and neonatal septicemia in another. Three cases had an underlying disease, including 2 cases wounded in a car accident and 1 case of congenital esophageal atresia and tracheoesophageal fistula. Before the isolation of GAS, 5 cases had stayed in ICUs, the length of ICU stay was 1-32 days, 4 cases had received intubation and mechanical ventilation, the ventilation time was 8 h-24 days, 2 cases had received major surgery; 5 cases had other pathogen coinfection, including 4 cases of abdominal pus at the same time and Escherichia coli was isolated, and 1 case had parainfluenza virus type I coinfection. Peripheral blood leucocyte increased in 18 cases, one case dropped off. The C-reactive protein (CRP) levels increased in all patients, including 16 cases who had 14-160 mg/L, 3 cases had levels higher than 160 mg/L. Twenty strains of GAS were isolated from 19 cases' sterile sites, of them 10 strains were isolated from abscess, 4 strains were isolated from blood and another 4 from ascites. Two strains were from the same patient at different times of pleural effusion. All 20 strains displayed a full susceptibility to cefazolin, levofloxacin and vancomycin, and the rates of resistance to both cefotaxime and penicillin were 10.0%. The rates of resistance to erythromycin and clindamycin were 55.0% and 70.0% respectively. Among the patients 3 cases were cured, 14 cases improved, and 2 cases died, of whom 1 case died of STSS secondary to multiple organ dysfunction, 1 case died of basic disease secondary to multiple organ dysfunction. Skin and soft tissues were the most common IGAS infection sites in children, and IGAS infection also can lead to serious STSS and even can be life threatening. Penicillin and cephalosporin are still sensitive for children IGAS infections.

A one-year active surveillance study was conducted to investigate the epidemiological and microbiological characteristics of invasive group A streptococci (GAS) infections in Turkey and to provide data for the establishment of national preventive strategies related to invasive GAS infections. A total of 46 clinical microbiology laboratories from 12 different regions of Turkey (Istanbul; Eastern and Western Marmara; Eastern and Western Blacksea; Aegean; Mediterranean; Western, Central, Northeastern, Middle-eastern and Southeastern Anatolia) participated in the study. Accordingly, GAS strains isolated from sterile body sites (blood, cerebrospinal, synovial, pleural, peritoneal, pericardial fluids) in the study centers between June 2010-June 2011, were sent to Maltepe University Hospital Clinical Microbiology Laboratory for microbiological confirmation and further analysis. The isolates were identified by conventional methods, and for serotyping, opacity factor (OF) and T protein types were investigated. For genotyping GAS lysate preparation, emm gene amplification and sequencing were performed by using the protocols recommended by Centers for Disease Control and Prevention. A total of 65 invasive GAS strains were isolated in 15 of the participant centers, during the study period. The rate of invasive GAS isolation exhibited regional variation, with the highest rates in the Eastern Blacksea (Trabzon, n= 19), followed by Istanbul (n= 17) and Western Anatolia (Ankara, Konya, n= 14). Of the patients with invasive GAS infection 33 were female, 32 were male, with the age range of 0-89 years. GAS strains were most commonly isolated from soft tissue specimens (n= 18), followed by abscess material (n= 10), sterile body fluids (n= 8) and blood (n= 7) samples. Serotyping revealed that 55% (36/65) of the strains were OF positive, and the majority of T protein was polygroup T (n= 20), followed by U (n= 14), B (n= 5), X (n= 3) and Y (n= 2). T protein was not detected in 22 isolates. The strains were found to have 17 different emm types;emm1 (n= 13), emm4 (n= 6), emm6 (n= 6), emm12 (n= 6), emm24 (n= 4), emm14 (n= 3) and emm28 (n= 3). Nine of the strains could not be typed by sequencing. The correlation between emm typing and serotyping was detected as 58%. It was observed that 26-valent vaccines included 70.5% of the invasive GAS strains included in this study. Our study provided initial data concerning the epidemiological properties of invasive GAS infections and characterization of GAS strains in Turkey. The incidence of invasive GAS infections is low in our country. Although immunization programme by 26-valent GAS vaccine is not currently an urgent public health issue for our country, the results of this study indicated that emm types 4 and 24 should better be included in such a vaccine to be used in Turkey. Additionally, since epidemiological features of GAS infections and the microbiological characteristics of the strains can vary by time, for the diagnosis of invasive streptococcal infections and to take the necessary preventive measures, epidemiological studies should be conducted repeatedly.

Background Group A Streptococcus (GAS) is a known cause of invasive infections in humans leading to significant morbidity and mortality. During the COVID-19 pandemic the incidence of respiratory infections had decreased, likely due to pandemic interventions. Previous studies found a correlation between the rates of viral respiratory infections and a predisposition to invasive GAS infections (iGAS). We hypothesize that the incidence of iGAS among adults may have been affected by the COVID-19 pandemic, but evidence is lacking. GASCO compares the rate of iGAS infections before, during and after the COVID-19 pandemic, and evaluates factors that may affect the incidence and outcomes. In this pilot study, we describe the incidence of total GAS infection (tGAS) and iGAS in relation to the COVID-19 pandemic. Study FlowFigure 1.*GAS= Group A Streptococcus infection. **Invasive GAS = Group A Streptococcus isolated from blood, sputum, body fluid, tissue, urine, or cervical culture. ***Non-invasive GAS = Group A Streptococcus isolated from throat or wound culture. Methods We retrospectively identified all patients hospitalized at Corewell Health in West Michigan from April 1st, 2018, through March 31st, 2024, with positive GAS culture obtained in the emergency department or hospital. Patients were classified based on the type of infection (invasive versus noninvasive) and time period in relation to COVID-19 (pre-COVID, COVID, and post-COVID) (figure 1). iGAS was defined as being isolated from blood, sputum, body fluid, tissue, urine or cervical culture. Cultures from throat or wound samples were classified as non-invasive. Number of Total and Invasive Group A Streptococcus Infections during Pre-COVID, COVID and Post-COVIDFigure 2.The number of total GAS infections was 2.7 times higher post-COVID than during and pre-COVID. Number of invasive GAS infections post-COVID was 2 times higher than pre-COVID and 3.2 times higher than during the COVID pandemic. Results Of 1278 patients who had positive GAS culture between 2018 and 2024, 350 (27%) had iGAS. Absolute number of tGAS and iGAS increased post-COVID compared with COVID and pre-COVID (figure 2), although percentage of tGAS representing iGAS was higher pre-COVID (94/269, 35%) than during COVID (61/272, 22%) or post-COVID (195/737, 26%), p=0.003 (Figure 3). Types of iGAS are shown in figure 4.Figure 3.Percentage of total Group A Streptococcus (GAS) infections representing invasive and non-invasive infections during pre-COVID, COVID, and post-COVID periods. Although the absolute number of total and invasive GAS infections was highest post-COVID, the proportion of total GAS infections classified as invasive was highest pre-COVID. Conclusion Our findings suggest that the incidence of tGAS and iGAS increased significantly after COVID-19. Some pediatric studies documented an increase in total GAS infections in Europe, possibly due to the pandemic interventions that led to a gap in immunity and increased susceptibility to infection, and expansion of strains with increased fitness. The full study will evaluate iGAS outcomes and address the factors impacting incidence and outcomes, aiming to provide better insight into the epidemiology of iGAS infections.Figure 4.Types of invasive Group A Streptococcus infection during pre-COVID, COVID, and post-COVID periods. Blood cultures were the most frequently positive throughout the whole study period. There was no significant difference in the types of positive cultures between periods. Disclosures All Authors: No reported disclosures

Group a Streptococcal Carriage among Residents of an Urban Homeless Shelter

The IL-8 Protease SpyCEP/ScpC of Group A Streptococcus Promotes Resistance to Neutrophil Killing

To discuss skin and soft tissue infections (SSTIs) caused by group A Streptococcus (GAS) by focusing on their pathogenesis, clinical manifestations, and management strategies. GAS is responsible for a wide range of infections from mild disease to severe fatal invasive infections with high mortality rates. Invasive GAS (iGAS) infections affect both young and old individuals and account for 1.8 million cases worldwide, with a mortality rate of up to 20%. In addition, conditions resulting by immune responses triggered by GAS also contribute to GAS-associated morbidity, and should not be overlooked. GAS has the ability to produce a wide set of virulence factors which contribute to its pathogenicity and its ability to colonize different body site and subsequently cause invasive infections. Management of SSTIs caused by GAS is challenging due to the risk of rapid progression and the risk of developing complications. During the COVID-19 pandemic, a relevant increase in iGAS infections has been registered. A constantly updated knowledge of the clinical presentation of iGAS infections is thus necessary to reduce their high mortality rates. Proper recognition and treatment of iGAS infections remain crucial.

Objective Streptococcus pyogenes also called Group A streptococci (GAS) is an important pathogen known since past years and infects millions of people around the world every year and can cause death. Although it often causes pharyngitis and skin infections, it can also spread to the bloodstream and cause invasive GAS (iGAS) infections. In this review, studies on the epidemiology of GAS and iGAS and vaccine studies were reviewed. Methods A comprehensive search of databases was conducted up to April 1, 2023 to related studies, in English using the following terms: S. pyogenes, GAS, invasive S. pyogenes infections, iGAS, S. pyogenes vaccine. The data extraction was conducted by two investigators using the same methodology. Results There has been an increase in iGAS infections in various countries in the last year and they have been followed closely. Although the reason for the increase in iGAS cases cannot be determined exactly, it is thought that the recent removal of coronavirus disease 2019 restrictions and the increase in the number of individuals susceptible to GAS and to viral respiratory pathogens is thought to have caused this situation. Another important issue with GAS is the vaccine studies. Vaccines are based on two different targets: M protein-based and non-M protein-based. Phase-I clinical trials have been initiated for some vaccines. Conclusion The increase in recent iGAS infections will draw attention to this agent and accelerate vaccine studies.

It is currently unclear what the role of Group A streptococcus (GAS) virulence factors (VFs) is in contributing to the invasive potential of GAS. This work investigated the evidence for the association of GAS VFs with invasive disease. We employed a broad search strategy for studies reporting the presence of GAS VFs in invasive and non-invasive GAS disease. Data were independently extracted by two reviewers, quality assessed, and meta-analyzed using Stata®. A total of 32 studies reported on 45 putative virulence factors [invasive (n = 3,236); non-invasive (n = 5,218)], characterized by polymerase chain reaction (PCR) (n = 30) and whole-genome sequencing (WGS) (n = 2). The risk of bias was rated as low and moderate, in 23 and 9 studies, respectively. Meta-,analyses of high-quality studies (n = 23) revealed a significant association of speM [OR, 1.64 (95%CI, 1.06; 2.52)] with invasive infection. Meta-analysis of WGS studies demonstrated a significant association of hasA [OR, 1.91 (95%CI, 1.36; 2.67)] and speG [OR, 2.83 (95%CI, 1.63; 4.92)] with invasive GAS (iGAS). Meta-analysis of PCR studies indicated a significant association of speA [OR, 1.59 (95%CI, 1.10; 2.30)] and speK [OR, 2.95 (95%CI, 1.81; 4.80)] with invasive infection. A significant inverse association was observed between prtf1 [OR, 0.42 (95%CI, 0.20; 0.87)] and invasive infection. This systematic review and genomic meta-analysis provides evidence of a statistically significant association with invasive infection for the hasA gene, while smeZ, ssa, pnga3, sda1, sic, and NaDase show statistically significantly inverse associations with invasive infection. SpeA, speK, and speG are associated with GAS virulence; however, it is unclear if they are markers of invasive infection. This work could possibly aid in developing preventative strategies.

To describe demographic and clinical features of invasive group A streptococcal (GAS) infections in children with varicella in Southern California in early 1994. From hospitals of Los Angeles and Orange Counties, children with invasive GAS infections after varicella between January 1 and April 8, 1994, were identified by hospital infection control nurses. Medical records of patients were reviewed, and any available GAS isolate was further tested. Twenty-four cases were identified; 54% were male, 50% were Hispanic and the median age was 3 years (range, 0.5 to 8). Four cases died before hospitalization. The other 20 were hospitalized for a median of 10 days (range, 4 to 50): 14 presented with cellulitis (1 with concomitant epiglottitis), 2 with myositis/necrotizing fasciitis, 2 with pneumonia and 2 with bacteremia without apparent source. Five had evidence of multiorgan involvement including two patients fulfilling criteria of streptococcal toxic shock-like syndrome. Of 19 patients with blood cultures, 10 (53%) had GAS bacteremia. Onset of GAS infection was suggested, as a median, on Day 4 of varicella, with fever, vomiting and localized swelling being commonly reported. The mean maximum temperature on the day of admission was 39.4 degrees C (102.9 degrees F). Four GAS isolates were M1T1 and one was M3T3. Five isolates produced streptococcal pyrogenic exotoxins A and B. Invasive GAS disease, including streptococcal toxic shock-like syndrome, is a serious complication of varicella. Physicians should be alert for the complication of GAS when fever and localized swelling or signs of cellulitis develop 3 days or more after the onset of varicella. Widespread use of varicella vaccine may decrease invasive GAS infections in this setting.

Group A streptococcus (GAS) causes variety of diseases ranging from common pharyngitis to life-threatening severe invasive diseases, including necrotizing fasciitis and streptococcal toxic shock-like syndrome. The characteristic of invasive GAS infections has been thought to attribute to genetic changes in bacteria, however, no clear evidence has shown due to lack of an intriguingly study using serotype-matched isolates from clinical severe invasive GAS infections. In addition, rare outbreaks of invasive infections and their distinctive pathology in which infectious foci without neutrophil infiltration hypothesized us invasive GAS could evade host defense, especially neutrophil functions. Herein we report that a panel of serotype-matched GAS, which were clinically isolated from severe invasive but not from non-invaive infections, could abrogate functions of human polymorphnuclear neutrophils (PMN) in at least two independent ways; due to inducing necrosis to PMN by enhanced production of a pore-forming toxin streptolysin O (SLO) and due to impairment of PMN migration via digesting interleukin-8, a PMN attracting chemokine, by increased production of a serine protease ScpC. Expression of genes was upregulated by a loss of repressive function with the mutation of csrS gene in the all emm49 severe invasive GAS isolates. The csrS mutants from clinical severe invasive GAS isolates exhibited high mortality and disseminated infection with paucity of neutrophils, a characteristic pathology seen in human invasive GAS infection, in a mouse model. However, GAS which lack either SLO or ScpC exhibit much less mortality than the csrS-mutated parent invasive GAS isolate to the infected mice. These results suggest that the abilities of GAS to abrogate PMN functions can determine the onset and severity of invasive GAS infection.

Invasive group A streptococcal infections as a consequence of coexisting or previous viral infection in the post-COVID-19 pandemic period.

RARE CASE OF SEVERE NECROTIZING PNEUMONIA DUE TO STREPTOCOCCUS PYOGENES RESULTING IN REFRACTORY HYPOXEMIA

An apparent worldwide resurgence of invasive group A Streptococcus (GAS) infections remains unexplained. However, we recently demonstrated in mice that when an otherwise nonlethal intranasal GAS infection is preceded by a nonlethal influenza A virus (IAV) infection, induction of lethal invasive GAS infections is often the result. In the present study, we established several isogenic mutants from a GAS isolate and evaluated several virulence factors as candidates responsible for the induction of invasive GAS infections. Disruption of the synthesis of the capsule, Mga, streptolysin O, streptolysin S, or streptococcal pyrogenic exotoxin B of GAS significantly reduced mortality among mice superinfected with IAV and a mutant. In addition, the number of GAS organisms adhering to IAV-infected alveolar epithelial cells was markedly reduced with the capsule-depleted mutant, although this was not the case with the other mutants. Wild-type GAS was found to bind directly to IAV particles, whereas the nonencapsulated mutant showed much less ability to bind. These results suggest that the capsule plays a key role in the invasion of host tissues by GAS following superinfection with IAV and GAS.

Background Group A streptococcal (GAS) disease is a major problem worldwide and can cause both noninvasive and invasive disease, including necrotizing fasciitis, with significant morbidity and mortality. Overall, the number of invasive GAS infections has been increasing in the United States over the past decade, primarily in adults. We aim to characterize the genomic features of circulating GAS strains causing invasive disease.Table.Patient demographics and genomic characteristics Methods We performed whole-genome sequencing (WGS) on clinically obtained GAS blood isolates at Henry Ford Health, a comprehensive, integrated, health care organization in Southeast Michigan from Jan 2017-Dec 2023. Sequencing libraries were created using the QIAseq FX DNA Library Kit (Qiagen,USA) according to manufacturer’s instructions and sequenced on NextSeq 2000 (Illumina Sandiego, USA). Fastq files were used to determine the distribution of traits, virulence factors, and resistance genes using the 1928 Platform. Results We sequenced unique isolates from 64 patients, of whom 38 (59%) were males with median age 57 years [Table]. Most isolates were from 2022 (25%) and 2023 (53%). Fifteen M protein (emm) serotypes and 19 sequence type (ST) were obtained from 64 characterized isolates. The most frequent emm lineages were emm1 (n=16) and emm12 (n=12), where most patients had skin and soft tissue infection. The predominant emm1 lineage belonged to ST28. None of the emm1 and emm12 isolates carried aminoglycoside, macrolides/lincosamides/streptogramines (MLS), or tetracycline resistance genes. All the emm11 and emm49 isolates exhibited erm(A) and tetracycline resistance genes. Streptococcal superantigen (SAgs) genes were frequently detected; streptococcal pyrogenic exotoxin (SPE)-G was the most detected SAgs (97%), followed by streptococcal mitogenic exotoxin (SME)-Z (75%). SPE-H and SPE-I were each found in 48% of the isolates. Conclusion In our cohort of patients with invasive GAS, several SAgs were detected. SPE-A, SPE-G, SME-Z and SPE-J were most frequently found in emm1 lineages. However, there was no correlation between various clinical syndromes and the virulence genes identified. Continued genomic surveillance can help characterize features associated with emerging invasive strains to inform management and infection prevention strategies. Disclosures All Authors: No reported disclosures