Immunogenicity of a 30-valent M protein mRNA group A Streptococcus vaccine.

BACKGROUND: Group A Streptococcus (Strep A) causes both uncomplicated and severe invasive infections, as well as the post-infection complications acute rheumatic fever and rheumatic heart disease. Despite the high global burden of disease resulting from Strep A infections, there is not a licensed vaccine. A 30-valent M protein-based vaccine has previously been shown to be immunogenic in animal models and in a Phase I clinical trial (NCT02564237). Here, we assessed the immunogenicity of a 30-valent messenger (m)RNA vaccine designed to express the same M peptide targets as the 30-valent protein vaccine and compared it with the protein vaccine. METHODS: Female New Zealand white rabbits were immunized with one of four vaccine formulations (3 doses of each formulation at days 1, 28, and 56): soluble mRNA (100 µg/animal), C-terminal transmembrane mRNA (100 µg/animal), protein vaccine (400 µg/animal), or a non-translatable RNA control (100 µg/animal). Serum was collected one day prior to the first dose and on days 42 and 70. Rabbit serum samples were assayed for antibody levels against synthetic M peptides by ELISA. HL-60 opsonophagocytic killing (OPK) assays were performed to assess functional antibody levels. RESULTS: Serum IgG levels were similar for the mRNA and protein vaccines. The CtTM version of the mRNA vaccine elicited slightly higher antibody levels than the mRNA designed to express soluble proteins. OPK activity was similar for the mRNA and protein vaccines, regardless of M type. CONCLUSIONS: The total antibody responses and functional antibody levels elicited by the 30-valent mRNA Strep A vaccines were similar to those observed following immunization with the analogous protein vaccine. The mRNA vaccine platform provides potential advantages to protein-based vaccines including inherent adjuvant activity, increased production efficiency, lower cost, and the potential to rapidly change epitopes/peptides, all of which are important considerations related to multivalent Strep A vaccine development.

Amoxicillin vs. placebo to reduce symptoms in children with group A streptococcal pharyngitis: a randomized, multicenter, double-blind, non-inferiority trial.

The efficacy of antibiotic therapy for group A streptococcus (GAS) pharyngitis is debated. The role of antibiotics in preventing complications seems limited, with the main potential benefit being symptom duration reduction. Our study aimed to evaluate whether a placebo is non-inferior to amoxicillin in reducing fever duration. We randomized 88 children between 3 and 15 years of age presenting with acute symptoms of pharyngitis and a positive rapid antigen detection test for GAS to receive 6-day treatment with either placebo (n = 46) or amoxicillin (n = 42). The primary outcome was the difference in fever duration, with a non-inferiority threshold set at 12 h. The secondary outcomes included pain intensity and complications of streptococcal pharyngitis. The mean difference in fever duration between the amoxicillin and placebo groups was 2.0 h (95% CI, - 8.3 to 12.3) in the per-protocol analysis and 2.8 h (95% CI, - 6.5 to 12.2) in the intention-to-treat analysis. Treatment failure was observed in six participants in the placebo group and two in the amoxicillin group (relative risk, 2.15; 95% CI, 0.44-10.57). All patients were identified early and recovered well. There was no clinically relevant difference in pain intensity between groups over the 7 days following randomization, with the largest difference of 0.5 (95% CI, - 0.62-1.80) observed on day 3. CONCLUSION: Placebo appears to be non-inferior to amoxicillin in reducing fever duration. Pain intensity and risk of complications were similar between the two groups. These findings support the restrictive antibiotic treatment for streptococcal pharyngitis. WHAT IS KNOWN: • Group A streptococcus pharyngitis is a common reason for prescribing antibiotics in pediatric care. • In high-income countries, while antibiotic treatment has not been effective in preventing non-suppurative complications, the primary justification for their use remains the reduction of symptoms. WHAT IS NEW: • Our results suggest that antibiotics have a limited impact on the duration of fever and the intensity of pain in children with streptococcal pharyngitis. • Considering that suppurative complications can be promptly treated if they arise, we recommend a more judicious approach to antibiotic prescriptions. TRIAL REGISTRATION: The trial is registered at the US National Institutes of Health (ClinicalTrials.gov) # NCT03264911 on 15.08.2017.

Molecular characterization of Streptococcus pyogenes (StrepA) non-invasive isolates during the 2022-2023 UK upsurge.

At the end of 2022 into early 2023, the UK Health Security Agency reported unusually high levels of scarlet fever and invasive disease caused by Streptococcus pyogenes (StrepA or group A Streptococcus). During this time, we collected and genome-sequenced 341 non-invasive throat and skin S. pyogenes isolates identified during routine clinical diagnostic testing in Sheffield, a large UK city. We compared the data with that obtained from a similar collection of 165 isolates from 2016 to 2017. Numbers of throat-associated isolates collected peaked in early December 2022, reflecting the national scarlet fever upsurge, while skin infections peaked later in December. The most common emm-types in 2022-2023 were emm1 (28.7 %), emm12 (24.9 %) and emm22 (7.7 %) in throat and emm1 (22 %), emm12 (10 %), emm76 (18 %) and emm49 (7 %) in skin. While all emm1 isolates were the M1UK lineage, the comparison with 2016-2017 revealed diverse lineages in other emm-types, including emm12, and emergent lineages within other types including a new acapsular emm75 lineage, demonstrating that the upsurge was not completely driven by a single genotype. The analysis of the capsule locus predicted that only 51 % of throat isolates would produce capsule compared with 78% of skin isolates. Ninety per cent of throat isolates were also predicted to have high NADase and streptolysin O (SLO) expression, based on the promoter sequence, compared with only 56% of skin isolates. Our study has highlighted the value in analysis of non-invasive isolates to characterize tissue tropisms, as well as changing strain diversity and emerging genomic features which may have implications for spillover into invasive disease and future S. pyogenes upsurges.

Stratification of Group A Streptococcal Pharyngitis Children Using Unsupervised Learning.

Background and objectives Group A Streptococcus (GAS) is the most frequent cause of bacterial pharyngitis, and it is advised to selectively use rapid antigen detection testing (RADT). Currently, the decision to perform this test is based on pediatricians' observations, but the criteria are not well-defined. Therefore, we utilized unsupervised learning to categorize patients based on the clinical manifestations of GAS pharyngitis. Our goal was to pinpoint the clinical symptoms that should prompt further examination and treatment in patients diagnosed with pharyngitis. Methods We analyzed categorical data from 305 RADT-positive patients aged three to 15 years using the K-modes clustering method. Each explanatory variable's relationship with cluster variables was statistically examined. Finally, we tested the differences between clusters for continuous variables statistically. Results The K-modes method categorized the cases into two clusters. Cluster 1 included older children with lymph node tenderness, while Cluster 2 consisted of younger children with cough and rhinorrhea. Conclusion Differentiating streptococcal pharyngitis from common cold or upper respiratory tract infection based on clinical symptoms alone is challenging, particularly in young patients. Future research should focus on identifying indicators that can aid in suspecting streptococcal infection in young patients.

Case report: Abscesses in children caused by invasive group A Streptococcus.

Streptococcus is one of the common pathogens of suppurative infections. Invasive group A Streptococcus (iGAS) infections often develop from skin or soft tissue infections, and streptococcal toxic shock syndrome is considered the main cause of death in Chinese children with iGAS infectious disease. However, soft tissue infections caused by iGAS infections, especially the formation of abscesses, are relatively rare. A retrospective study was conducted, and pediatric in-patients who were diagnosed with an iGAS infection identified by cultures from normally sterile sites and treated in a tertiary hospital during 2016-2018 were included. A total of 14 patients were identified, which included 10 boys and four girls. The patients had an age range from 3 months to 10 years and were diagnosed with soft tissue infections and a formation of abscesses caused by iGAS infections. The most common sites of infections were the lower limbs. In five patients, the abscess was accompanied by fever, and the local soft tissue showed redness, swelling, tenderness, and an elevated skin temperature. Laboratory findings included an increased white blood cell (WBC) count in 12 patients, an increased C reactive protein (CRP) level in seven patients, and an increased erythrocyte sedimentation rate (ESR) in 10 patients. No patients had an elevated procalcitonin level. For all 14 patients, we performed puncture and drainage of abscesses, and cultured GAS from the drainage fluid. All children also received antibiotic treatment. During 2 months of follow-up, the patients' condition remained stable and no evidence of kidney or heart damage was observed. For pediatric patients with abscesses, early diagnosis, prompt treatment with incision and drainage, and immediate culture of the drainage fluid are important. Upon confirmation of an iGAS infection, ß-lactam antibiotics should be given to provide effective treatment, and in some patients with poor therapeutic outcomes, the use of vancomycin as an alternative can achieve the desired results.

Investigating group A Streptococcus antibiotic tolerance in necrotizing fasciitis.

Group A Streptococcus (GAS) necrotizing fasciitis (NF) is a difficult-to-treat bacterial infection associated with high morbidity and mortality despite extensive surgery and targeted antibiotic treatment. Difficult-to-treat infections are often characterized by the presence of bacteria surviving prolonged antibiotic exposure without displaying genetic resistance, referred to as persisters. In the present study, we investigated the presence of GAS persisters in tissue freshly debrided from patients as well as in an in vivo mouse model of NF and examined the phenomenon of antibiotic tolerance. Time-lapse imaging of GAS plated directly upon isolation from NF debrided tissue and an antibiotic challenge-based persisters assay were used to assess the presence of persisters. We show for the first time that GAS recovered directly from freshly debrided NF tissue is characterized by heterogeneous and overall delayed colony appearance time, suggesting the presence of persisters. Acidic pH or nutrient stress exposure, mimicking the NF-like environment in vitro, led to a similar phenotypic heterogeneity and resulted in enhanced survival upon antibiotic challenge, confirming the presence of GAS persisters. GAS persisters might contribute to NF treatment failure, despite extensive surgery and adequate antibiotic treatment.IMPORTANCEDifficult-to-treat and recurrent infections are a global problem burdening society and the health care system alike. Unraveling the mechanisms by which bacteria can survive antibiotic treatment without developing genetic resistance is of utmost importance to lay the foundation for new, effective therapeutic approaches. For the first time, we describe the phenomenon of antibiotic tolerance in group A Streptococcus (GAS) isolated from necrotizing fasciitis (NF) patients. Dormant, non-replicating cells (persisters) are tolerant to antibiotics and their occurrence in vivo is reported in an increasing number of bacterial species. Tailored treatment options, including the use of persisters-targeting drugs, need to be developed to specifically target dormant bacteria causing difficult-to-treat and recurrent infections.

[Clinical diagnosis of group A streptococcal pharyngitis and progress in the application of scoring systems]. / A族链球菌咽炎的临床诊断及评分制的应用进展.

Pharyngitis can be caused by various pathogens, including viruses and bacteria. Group A streptococcus (GAS) is the most common bacterial cause of pharyngitis. However, distinguishing GAS pharyngitis from other types of upper respiratory tract infections is challenging in clinical settings. This often leads to empirical treatments and, consequently, the overuse of antimicrobial drugs. With the advancement of antimicrobial drug management and healthcare payment reform initiatives in China, reducing unnecessary testing and prescriptions of antimicrobial drugs is imperative. To promote standardized diagnosis and treatment of GAS pharyngitis, this article reviews various international guidelines on the clinical diagnosis and differential diagnosis of GAS pharyngitis, particularly focusing on clinical scoring systems guiding laboratory testing and antimicrobial treatment decisions for GAS pharyngitis and their application recommendations, providing a reference for domestic researchers and clinical practitioners.

Nationwide upsurge in invasive disease in the context of longitudinal surveillance of carriage and invasive Streptococcus pyogenes 2009-2023, the Netherlands: a molecular epidemiological study.

Since 2022, many countries have reported an upsurge in invasive group A streptococcal (iGAS) infections. We explored whether changes in Streptococcus pyogenes carriage rates or emergence of strains with potentially altered virulence, such as emm1 variants M1UK and M1DK, contributed to the 2022/2023 surge in the Netherlands. We determined emm (sub)type distribution for 2,698 invasive and 351 S. pyogenes carriage isolates collected between January 2009 and March 2023. Genetic evolution of emm1 was analyzed by whole-genome sequencing of 497 emm1 isolates. The nationwide iGAS upsurge coincided with a sharp increase of emm1.0 from 18% (18/100) of invasive isolates in Q1 2022 to 58% (388/670) in Q1 2023 (Fisher's exact test, P < 0.0001). M1UK became dominant among invasive emm1 isolates in 2016 and further expanded from 72% in Q1 2022 to 96% in Q1 2023. Phylogenetic comparison revealed evolution and clonal expansion of four new M1UK clades in 2022/2023. DNase Spd1 and superantigen SpeC were acquired in 9% (46/497) of emm1 isolates. S. pyogenes carriage rates and emm1 proportions in carriage isolates remained stable during this surge, and the expansion of M1UK in iGAS was not reflected in carriage isolates. During the 2022/2023 iGAS surge in the Netherlands, expansion of four new M1UK clades was observed among invasive isolates, but not carriage isolates, suggesting increased virulence and fitness of M1UK compared to contemporary M1 strains. The emergence of more virulent clades has important implications for public health strategies such as antibiotic prophylaxis for close contacts of iGAS patients.IMPORTANCEThis study describes the molecular epidemiology of invasive group A streptococcal (iGAS) infections in the Netherlands based on >3,000 Streptococcus pyogenes isolates from both asymptomatic carriers and iGAS patients collected before, during, and after the COVID-19 pandemic period (2009-2023) and is the first to assess whether changes in carriage rates or carried emm types contributed to the alarming post-COVID-19 upsurge in iGAS infections. We show that the 2022/2023 iGAS surge coincided with a sharp increase of emm1, particularly the toxicogenic M1UK variant, in invasive isolates, but not in carriage isolates. These findings suggest that increased virulence and fitness of M1UK likely contributes to an increased dissemination between hosts. The emergence of a more virulent and fit lineage has important implications for iGAS control interventions such as antibiotic prophylaxis for close contacts of iGAS patients and calls for a reappraisal of iGAS control interventions and guidelines.

The Emergence and Impact of the M1UK Lineage on Invasive Group A Streptococcus Disease in Aotearoa New Zealand.

M1UK is associated with current surges in invasive infection globally, partly due to increased production of superantigen streptococcal pyrogenic exotoxin A. We show that M1UK is now the dominant invasive emm1 lineage in Aotearoa New Zealand and is genomically related to community infections, suggesting that measures that effectively prevent group A Streptococcus pharyngitis in children could reduce invasive disease.

Bacterial Tracheitis: A New Presentation of a Well-Known Disease.

Bacterial tracheitis (BT) is an uncommon life-threatening condition that results in acute upper airway obstruction. Classical signs include a toxic appearance, stridor, tachypnoea, and fever, often leading to rapid clinical deterioration. Recent studies have shown a shift in BT epidemiology and presentation, where stridor and respiratory distress are now predominant. A poor response to corticosteroids or nebulized epinephrine is also commonly described, along with a need for mechanical ventilation. We present the case of a five-year-old boy admitted to the emergency department with cough, stridor, and dyspnea that had significantly worsened over the previous hours. He presented reasonable general condition, marked retractions, poor air entry, stridor, and wheezing. Investigation revealed a slight elevation of C-reactive protein and leukocytosis with neutrophilia. Anteroposterior x-ray showed narrowing of subglottic airways (steeple sign). There was no response to oral/nebulized corticoids, nebulized adrenaline, or bag-valve-mask oxygenation. Antibiotic therapy with ceftriaxone was initiated. Due to deteriorating clinical conditions with severe respiratory acidosis, orotracheal intubation was required. Later Streptococcus pyogenes was isolated in the bronchial secretions and a targeted antibiotic regimen was administered. Progressive clinical and analytical improvement was observed with no complications. Although uncommon, BT remains a severe infectious condition affecting otherwise healthy children. Our case underscores the severity of the disease and the imperative for invasive interventions to achieve favorable outcomes. It also supports recent findings indicating a shift in predominant symptoms and prognosis. Clinicians must be vigilant and knowledgeable, recognizing that worsening stridor and respiratory distress unresponsive to conservative treatment are key indicators for diagnosing BT.

Local Genomic Surveillance of Invasive Streptococcus pyogenes in Eastern North Carolina (ENC) in 2022-2023.

The recent increase in Group A Streptococcus (GAS) incidences in several countries across Europe and some areas of the Unites States (U.S.) has raised concerns. To understand GAS diversity and prevalence, we conducted a local genomic surveillance in Eastern North Carolina (ENC) in 2022-2023 with 95 isolates and compared its results to those of the existing national genomic surveillance in the U.S. in 2015-2021 with 13,064 isolates. We observed their epidemiological changes before and during the COVID-19 pandemic and detected a unique sub-lineage in ENC among the most common invasive GAS strain, ST28/emm1. We further discovered a multiple-copy insertion sequence, ISLgar5, in ST399/emm77 and its single-copy variants in some other GAS strains. We discovered ISLgar5 was linked to a Tn5801-like tetM-carrying integrative and conjugative element, and its copy number was associated with an ermT-carrying pRW35-like plasmid. The dynamic insertions of ISLgar5 may play a vital role in genome fitness and adaptation, driving GAS evolution relevant to antimicrobial resistance and potentially GAS virulence.

A surge in the incidence of invasive Group A Streptococcus hand infections: a single Hand Unit experience.

We highlight an increase in the number of invasive Group A streptococcal soft tissue infections and present the impact of those on the hand surgery service, based on a single Hand Unit experience at the Pulvertaft Hand Centre.

An efficient in vivo-inducible CRISPR interference system for group A Streptococcus genetic analysis and pathogenesis studies.

While genome-wide transposon mutagenesis screens have identified numerous essential genes in the significant human pathogen Streptococcus pyogenes (group A Streptococcus or GAS), many of their functions remain elusive. This knowledge gap is attributed in part to the limited molecular toolbox for controlling GAS gene expression and the bacterium's poor genetic transformability. CRISPR interference (CRISPRi), using catalytically inactive GAS Cas9 (dCas9), is a powerful approach to specifically repress gene expression in both bacteria and eukaryotes, but ironically, it has never been harnessed for controlled gene expression in GAS. In this study, we present a highly transformable and fully virulent serotype M1T1 GAS strain and introduce a doxycycline-inducible CRISPRi system for efficient repression of bacterial gene expression. We demonstrate highly efficient, oligo-based single guide RNA cloning directly to GAS, enabling the construction of a gene knockdown strain in just 2 days, in contrast to the several weeks typically required. The system is shown to be titratable and functional both in vitro and in vivo using a murine model of GAS infection. Furthermore, we provide direct in vivo evidence that the expression of the conserved cell division gene ftsZ is essential for GAS virulence, highlighting its promise as a target for emerging FtsZ inhibitors. Finally, we introduce SpyBrowse (https://veeninglab.com/SpyBrowse), a comprehensive and user-friendly online resource for visually inspecting and exploring GAS genetic features. The tools and methodologies described in this work are poised to facilitate fundamental research in GAS, contribute to vaccine development, and aid in the discovery of antibiotic targets. IMPORTANCE: While group A Streptococcus (GAS) remains a predominant cause of bacterial infections worldwide, there are limited genetic tools available to study its basic cell biology. Here, we bridge this gap by creating a highly transformable, fully virulent M1T1 GAS strain. In addition, we established a tight and titratable doxycycline-inducible system and developed CRISPR interference (CRISPRi) for controlled gene expression in GAS. We show that CRISPRi is functional in vivo in a mouse infection model. Additionally, we present SpyBrowse, an intuitive and accessible genome browser (https://veeninglab.com/SpyBrowse). Overall, this work overcomes significant technical challenges of working with GAS and, together with SpyBrowse, represents a valuable resource for researchers in the GAS field.

Divergent effects of emm types 1 and 12 on invasive group A streptococcal infections-results of a retrospective cohort study, Germany 2023.

As a potential side effect of the severe acute respiratory syndrome coronavirus type 2 pandemic, invasive group A Streptococcus (iGAS) infections in Europe have increased dramatically in both children and adults in the end of 2022. This epidemiological and molecular study describes the distributions of streptococcal genes encoding the M antigen (emm types) and superantigens in patients with invasive and non-invasive GAS infections. From December 2022 to December 2023, a total of 163 GAS isolates were collected from sterile and non-sterile sites of patients at five hospitals in Germany including two tertiary care centers. Genes encoding M protein and superantigens were determined following the guidelines of CDC Streptococcus laboratory. Patients' characteristics were reviewed retrospectively. Correlations of clinical factors, emm types, and superantigens with rates of invasive infections were analyzed. Of the 163 included GAS cases, 112 (69%) were considered as invasive. In total, 33 different emm types were observed, of which emm1.0 (n = 49; 30%), emm89.0 (n = 15; 9%), and emm12.0 (n = 14; 9%) were most prevalent. In total, 70% of emm1.0 isolates belonged to M1UK lineage. No difference in invasive infections was observed for the M1UK lineage compared with other emm1.0 isolates. However, the emm1.0 type, presence of speA1-3, speG, or speJ, as well as adulthood were significantly associated with invasive infections. In contrast, emm12.0 isolates were significantly less associated with invasive infections. Multivariable analysis confirmed a significant influence of speJ and adulthood on iGAS infections. This study underlines the importance of continuous monitoring of genomic trends and identification of emerging GAS variants. This may aid in delineating pathogenicity factors of Streptococcus pyogenes that propel invasive infections.

Tracking trends in the Top End: clindamycin and erythromycin resistance in Group A Streptococcus in the Northern Territory, 2012-2023.

Abstract: This retrospective study reviewed the macrolide resistance rates of Group A Streptococcus (GAS) isolates in the Northern Territory from 2012 to 2023. Clindamycin and erythromycin resistance rates peaked in 2021, at 6.0% and 12.2% respectively, and then returned to near baseline at 1-2% in 2023. Increased resistance rates were identified in the Top End of Australia from mid-2020, followed 15 months later by high rates in central Australia in 2022. Factors associated with resistant isolates were living in a rural region and of age 18 years and older. Possible explanations include a transient clonal introduction of a resistant GAS strain to the Northern Territory from 2020 to 2022. Ongoing surveillance is required to monitor regional trends and identify temporal variations in resistant isolates.

Necrotizing Fasciitis Due to Group A Streptococcus: A Case of a Deteriorating Biphasic-like Clinical Course Over Five Days with a Devastating Outcome.

Necrotizing fasciitis (NF) is a life-threatening disease with high mortality and rapidly progressive clinical manifestations1. Early detection and surgical management coupled with antibiotic treatment are crucial for the survival, and the patient survival is heavily dependent on clinical decisions2,3. However, it is not widely known that NF does not always follow a typical clinical course, and there have been no case reports of NF following an atypical clinical course. Although the course of the disease depends on the individual patient, it remains a challenge for physicians to determine the precise timing when patients are most likely to survive multiple surgical interventions. We encountered a challenging case presenting with an atypical clinical course. We herein report a 31-year-old man who followed a deteriorating biphasic-like clinical course and presented with extensive NF and streptococcal toxic shock syndrome due to Group A Streptococcus. This case serves to inform physicians of the existence of NF with an atypical and deteriorating biphasic-like clinical course, emphasizing the need for a careful evaluation of the patient condition.

Rising clindamycin resistance in group A Streptococcus in an Irish healthcare institution.

Group A streptococcus (GAS) can cause serious invasive disease in humans with a high mortality rate. An increase in GAS infections was reported in Ireland in 2022, and this increase has been sustained in 2023 and is paralleled by similar trends in Europe. Rising antimicrobial resistance is a global problem and presents significant challenges to clinicians treating GAS infection. There was a reported increase in clindamycin resistance in GAS isolates in Ireland in 2022. We examined antimicrobial susceptibility patterns of GAS isolates in our institution in 2022. Although all GAS isolates included in our study were susceptible to penicillin, we noted a high clindamycin resistance rate of 28 % in our invasive GAS isolates. We also noted high tetracycline and erythromycin resistance, 43 and 30 %, respectively. Our results could have implications for empiric antimicrobial prescribing guidelines for skin and soft tissue infections, which often include clindamycin as it inhibits the production of many virulence factors associated with GAS. In addition, macrolides are often the first line recommended antibiotic for patients with anaphylaxis to penicillin. This study emphasises the importance of continuous surveillance and antimicrobial susceptibility testing of invasive and non-invasive isolates in order to monitor trends in increasing antimicrobial resistance.

Invasive group A Streptococcus infection (Streptococcus pyogenes): Current situation in Spain.

Group A ß-hemolytic Streptococcus (S. pyogenes), also known as GAS, is a Gram-positive bacterium. It can be easily identified in the microbiology laboratory by its ability to hemolyse blood in culture media. This bacterium is highly virulent due to its production of enzymes and toxins, and its ability to cause immunologically mediated diseases such as rheumatic fever and post-streptococcal glomerulonephritis. GAS is the primary cause of bacterial pharyngotonsillitis, although it is typically a benign and non-invasive disease. However, it also has the potential to cause severe skin and soft tissue infections, necrotising fasciitis, bacteraemia and endocarditis, pneumonia and empyema, and streptococcal toxic shock syndrome, without any age or predisposition limits. The term invasive GAS disease (iGAS) is used to refer to this group of conditions. In more developed countries, iGAS disease has declined thanks to improved hygiene and the availability of antibiotics. For example, rheumatic fever has practically disappeared in countries such as Spain. However, recent data suggests a potential increase in some iGAS diseases, although the accuracy of this data is not consistent. Because of this, the COVID and Emerging Pathogens Committee of the Illustrious Official College of Physicians of Madrid (ICOMEM) has posed several questions about invasive GAS infection, especially its current situation in Spain. The committee has enlisted the help of several experts in the field to answer these questions. The following lines contain the answers that we have collaboratively produced, aiming to assist not only the members of ICOMEM but also anyone interested in this topic.