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Pyogenic β-hemolytic streptococci (including Group A, C and G ) are some of the most important Gram-positive bacterial pathogens in human medicine. Although effective therapy is available, invasive streptococcal infections are associated with a significant disease burden. In this retrospective study, the epidemiological characteristics of invasive Group A (iGAS) and Group C and G (iGCGS) streptococci, along with tonsillo-pharyngitis-causing pGAS and pGCGS infections, were assessed in Southern Hungary. A total of 1554 cases of streptococcal tonsillo-pharyngitis infections (26.5-44.1/100,000 persons, pGAS: 95.5%; n=1484) and 1104 cases of invasive streptococcal infections were detected (12.5-31.4/100,000 persons, iGAS: 77.9%; n=861). The average age of the affected patients in the various groups were the following: pGAS: 13.2±13.1 years, pGCGS: 21.0±15.0 years (p=0.039), iGAS: 49.1±12.8 years, iGCGS: 58.7±18.5 years (p>0.05). iGAS isolates originated from abscesses (47.1%), blood culture samples (24.1%), surgical samples (16.7%), biopsies (4.6%), pleural fluid (3.5%), pus (2.0%), synovial fluid (1.3%) and cerebrospinal fluid samples (0.7%). In contrast, iGCGS isolates mainly originated from blood culture samples (53.8%), abscesses (22.9%), surgical samples (12.3%), synovial fluid (5.1%), pleural fluid (3.7%), pus (1.8%) and cerebrospinal fluid samples (0.4%). All respective isolates were susceptible to benzyl-penicillin; overall resistance levels for erythromycin (10.5% for GAS, 21.4% for GCGS) and clindamycin (9.2% for GAS, 17.2% for GCGS) were significantly higher in GCGS isolates, while resistance levels for norfloxacin were higher in GAS isolates (13.5% for GAS, 6.9% for GCGS). The rates of resistance to macrolides and clindamycin are a cause for concern (especially among GCGS isolates); however, resistance levels are still relatively low, compared to Southern European countries.

The most common bacterial cause of pharyngitis is infection by Group A -hemolytic streptococcus (GABHS), commonly known as strep throat. 5-15% of adults and 15-35% of children in the United States with pharyngitis have a GABHS infection. The symptoms of GABHS overlap with non-GABHS and viral causes of acute pharyngitis, complicating the problem of diagnosis. A careful physical examination and patient history is the starting point for diagnosing GABHS. After a physical examination and patient history is completed, five types of diagnostic methods can be used to ascertain the presence of a GABHS infection: clinical scoring systems, rapid antigen detection tests, throat culture, nucleic acid amplification tests, and machine learning and artificial intelligence. Clinical guidelines developed by professional associations can help medical professionals choose among available techniques to diagnose strep throat. However, guidelines for diagnosing GABHS created by the American and European professional associations vary significantly, and there is substantial evidence that most physicians do not follow any published guidelines. Treatment for GABHS using analgesics, antipyretics, and antibiotics seeks to provide symptom relief, shorten the duration of illness, prevent nonsuppurative and suppurative complications, and decrease the risk of contagion, while minimizing the unnecessary use of antibiotics. There is broad agreement that antibiotics with narrow spectrums of activity are appropriate for treating strep throat. But whether and when patients should be treated with antibiotics for GABHS remains a controversial question. There is no clearly superior management strategy for strep throat, as significant controversy exists regarding the best methods to diagnose GABHS and under what conditions antibiotics should be prescribed.

Group A Streptococcus (GAS) is a widely distributed bacterium that is Gram-positive and serves as the primary cause of acute rheumatic fever (ARF) episodes. Rheumatic heart disease (RHD) is a sequela resulting from repeated ARF attacks which are also caused by repeated GAS infections. ARF/RHD morbidity and mortality rates are incredibly high in low- and middle-income countries. This is closely related to poor levels of sanitation which causes the enhanced incidence of GAS infections. Management of carditis in RHD cases is quite challenging, particularly in developing countries, considering that medical treatment is only palliative, while definitive treatment often requires more invasive procedures with high costs. Preventive action through vaccination against GAS infection is one of the most effective steps as a solution in reducing RHD morbidity and mortality due to curative treatments are expensive. Various developments of M-protein-based GAS vaccines have been carried out over the last few decades and have recently begun to enter the clinical stage. Nevertheless, this vaccination generates cross-reactive antibodies that might trigger ARF assaults as a result of the resemblance between the M-protein structure and proteins found in many human tissues. Consequently, the development of a vaccine utilizing L-Rhamnose derived from the poly-rhamnose backbone of Group A Carbohydrate (GAC) commenced. The L-Rhamnose-based vaccine was chosen due to the absence of the Rhamnose biosynthesis pathway in mammalian cells including humans thus this molecule is not found in any body tissue. Recent pre-clinical studies reveal that L-Rhamnose-based vaccines provide a protective effect by increasing IgG antibody titers without causing cross-reactive antibodies in test animal tissue. These findings demonstrate that the L-Rhamnose-based vaccine possesses strong immunogenicity, which effectively protects against GAS infection while maintaining a significantly higher degree of safety.

Currently, it remains unclear why some children develop invasive group A Streptococcus (iGAS) and how to manage this condition. Therefore, to explore available works in the literature, we performed a scoping review aiming to analyze the current literature on clinical presentation of different illnesses outcomes of iGAS, with a specific focus on predictors of invasive infection, including an assessment of the prodromal stages of the disease and the possible presence of previous non-invasive GAS infections in children that later developed iGAS. Methods: We conducted a systematic search on PubMed and SCOPUS of all pediatric studies reporting iGAS cases, following the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) checklist. For those studies in which multivariable analysis investigating iGAS risk factors was performed, a second review was performed and reported in detail. Results: A total of 209 studies were included. Five studies investigated risk factors for iGAS, the most relevant being varicella infection, chronic underlying illness, presence of the speC gene in GAS strains, acetaminophen and ibuprofen use, children nonwhite, living in low-income households, exposure to varicella at home, persistent high fever, having more than one other child in the home, and new use of NSAIDs. Although we observed a progressive increase in the number of papers published on this topic, no trials investigating the benefits of clindamycin or intravenous immunoglobulins were found and low-to-middle-income countries were found to be poorly represented in the current literature. Conclusions: Our scoping review highlights important gaps regarding several aspects of iGAS in children, including prodromic presentation and optimal treatment strategies. There is also little representation of low–middle-income countries. The current literature does not allow the performance of systematic reviews or meta-analyses, but this work should inform healthcare professionals, policy makers, and funding agencies on which studies to prioritize on this topic.

Group B Streptococcus (Streptococcus agalactiae or GBS) is the leading infectious cause of neonatal mortality, causing roughly 150,000 infant deaths and stillbirths annually across the globe. Approximately 20% of pregnant women are asymptomatically colonized by GBS, which is a major risk factor for severe fetal and neonatal infections as well as preterm birth, low birth weight, and neurodevelopmental abnormalities. Current clinical interventions for GBS infection are limited to antibiotics, and no vaccine is available. We previously described VAX-A1 as a highly effective conjugate vaccine against group A Streptococcus that is formulated with three antigens, SpyAD, streptolysin O, and C5a peptidase (ScpA). ScpA is a surface-expressed, well-characterized GAS virulence factor that shares nearly identical sequences with the lesser studied GBS homolog ScpB. Here, we show that GBS C5a peptidase ScpB cleaves human complement factor C5a and contributes to disease severity in the murine models of pneumonia and sepsis. Furthermore, antibodies elicited by GAS C5a peptidase bind to GBS in an ScpB-dependent manner, and VAX-A1 immunization protects mice against lethal GBS heterologous challenge. These findings support the contribution of ScpB to GBS virulence and underscore the importance of choosing vaccine antigens; a universal GAS vaccine such as VAX-A1 whose formulation includes GAS C5a peptidase may have additional benefits through some measure of cross-protection against GBS infections.

Background: Invasive group A streptococcus infection (iGAS) is a serious, sometimes life-threatening condition, with high case fatality rates and high morbidity whose incidence is greatly increased in the last years. Despite the increasing importance and frequency of this condition, at the best of our knowledge, no previous reviews have been published focusing on the risk factors for the development of this condition and its early clinical features. This paper reports the study protocol for a scoping review that aims to analyze the early signs and clinical features of invasive group A streptococcus disease in children, to recognize the prodromal stage of the disease. Methods: Comprehensive research combining the terms pediatric and invasive group A streptococcus infection has been performed on PubMed and SCOPUS to identify potential eligible studies. The search strategy for PubMed will be available in this paper. Two reviewers will screen first the abstract and subsequently the full text to identify eligible articles according to the predefined inclusion criteria. Divergences between the reviewers will be resolved by discussion (with a third author if necessary). Two review authors will extract data independently, everyone on a different Excel spreadsheet. Each researcher will be blinded to the decision of the other researcher. When the process will be completed, in case of discordance, any disagreement will be identified and resolved through discussion (with a third author if necessary). Dissemination: The findings of this review will be published in a peer-reviewed journal.

Background. Invasive group A Streptococcus (GAS) infections are associated with significant morbidity and mortality rates. We report the epidemiology and trends of invasive GAS over 8 years of surveillance. Methods. From January 2005 through December 2012, we collected data from the Centers for Disease Control and Prevention's Active Bacterial Core surveillance, a population-based network of 10 geographically diverse US sites (2012 population, 32.8 million). We defined invasive GAS as isolation of GAS from a normally sterile site or from a wound in a patient with necrotizing fasciitis (NF) or streptococcal toxic shock syndrome (STSS). Available isolates were emm typed. We calculated rates and made age- and race-adjusted national projections using census data. Results. We identified 9557 cases (3.8 cases per 100 000 persons per year) with 1116 deaths (case-fatality rate, 11.7%). The case-fatality rates for septic shock, STSS, and NF were 45%, 38%, and 29%, respectively. The annual incidence was highest among persons aged ≥65 years (9.4/100 000) or <1 year (5.3) and among blacks (4.7/100 000). National rates remained steady over 8 years of surveillance. Factors independently associated with death included increasing age, residence in a nursing home, recent surgery, septic shock, NF, meningitis, isolated bacteremia, pneumonia, emm type 1 or 3, and underlying chronic illness or immunosuppression. An estimated 10 649–13 434 cases of invasive GAS infections occur in the United States annually, resulting in 1136–1607 deaths. In a 30-valent M-protein vaccine, emm types accounted for 91% of isolates. Conclusions. The burden of invasive GAS infection in the United States remains substantial. Vaccines under development could have a considerable public health impact.

Background The pathophysiological understanding of the inflammatory response in necrotizing soft‐tissue infection (NSTI) and its impact on clinical progression and outcomes are not resolved. Hyperbaric oxygen (HBO2) treatment serves as an adjunctive treatment; however, its immunomodulatory effects in the treatment of NSTI remains unknown. Accordingly, we evaluated fluctuations in inflammatory markers during courses of HBO2 treatment and assessed the overall inflammatory response during the first 3 days after admission. Methods In 242 patients with NSTI, we measured plasma TNF‐α, IL‐1β, IL‐6, IL‐10, and granulocyte colony‐stimulating factor (G‐CSF) upon admission and daily for three days, and before/after HBO2 in the 209 patients recieving HBO2. We assessed the severity of disease by Simplified Acute Physiology Score (SAPS) II, SOFA score, and blood lactate. Results In paired analyses, HBO2 treatment was associated with a decrease in IL‐6 in patients with Group A‐Streptococcus NSTI (first HBO2 treatment, median difference −29.5 pg/ml; second HBO2 treatment, median difference −7.6 pg/ml), and overall a decrease in G‐CSF (first HBO2 treatment, median difference −22.5 pg/ml; 2− HBO2 treatment, median difference −20.4 pg/ml). Patients presenting with shock had significantly higher baseline cytokines values compared to non‐shock patients (TNF‐α: 51.9 vs. 23.6, IL‐1β: 1.39 vs 0.61, IL‐6: 542.9 vs. 57.5, IL‐10: 21.7 vs. 3.3 and G‐CSF: 246.3 vs. 11.8 pg/ml; all p < 0.001). Longitudinal analyses demonstrated higher concentrations in septic shock patients and those receiving renal‐replacement therapy. All cytokines were significantly correlated to SAPS II, SOFA score, and blood lactate. In adjusted analysis, high baseline G‐CSF was associated with 30‐day mortality (OR 2.83, 95% CI: 1.01–8.00, p = 0.047). Conclusion In patients with NSTI, HBO2 treatment may induce immunomodulatory effects by decreasing plasma G‐CSF and IL‐6. High levels of inflammatory markers were associated with disease severity, whereas high baseline G‐CSF was associated with increased 30‐day mortality. In necrotizing soft‐tissue infections, the inflammatory response at admission is immense with a rapid decline during the first 3 days. Hyperbaric oxygen treatment may induce immunomodulatory effects by decreasing IL‐6 and G‐CSF potentially limiting the risk of collateral damage.

Outer membrane vesicles (OMVs) from Gram-negative bacteria are gaining increasing attention as vaccine platform for their built-in adjuvanticity and for their potential use as carriers of heterologous antigens. These 2 properties offer the opportunity to make highly effective, easy to produce multi-valent vaccines. OMVs can be loaded with foreign antigens by targeting protein expression either to the outer membrane or to the periplasm of the OMV-producing strain. Periplasmic expression is simple and relatively efficient but leads to the accumulation of recombinant antigens in the lumen of OMVs and the ability of OMVs carrying internalized antigens to induce antigen-specific antibody responses has been only marginally investigated and is considered to be sub-optimal. We have systematically analyzed in qualitative and quantitative terms antibody responses induced by OMVs carrying different heterologous antigens in their lumen. Group A Streptococcus (GAS) Slo, SpyCEP, Spy0269 and Group B Streptococcus (GBS) SAM_1372 were fused to the OmpA leader sequence for secretion and expressed in Escherichia coli. OMVs from the recombinant strains were purified and tested for immunogenicity and protective activity. All proteins were incorporated into the OMVs lumen in their native conformation. Upon mice immunization, OMVs induced high functional antibody titers against the recombinant proteins. Furthermore, immunization with Slo-OMVs and SpyCEP-OMVs protected mice against GAS lethal challenge. The efficiency of antigen delivery to the vesicular lumen via periplasmic expression, and the surprisingly high immunogenicity and protective activity of OMVs carrying internalized recombinant antigens further strengthens the potential of OMVs as vaccine platform.

To face the COVID-19 outbreak, a wide range of non-pharmaceutical interventions (NPIs) aimed at limiting the spread of the virus in communities, such as mask-wearing, hand hygiene, social distancing, travel restrictions, and school closures, were introduced in most countries. Thereafter, a significant reduction of new asymptomatic and symptomatic COVID-19 cases occurred, although there were differences between countries according to the type and duration of the NPIs. In addition, the COVID-19 pandemic has been accompanied by significant variations in the global incidence of diseases due to the most common non-SARS-CoV-2 respiratory viruses and some bacteria. In this narrative review, the epidemiology of the most common non-SARS-CoV-2 respiratory infections during the COVID-19 pandemic is detailed. Moreover, factors that could have had a role in modifying the traditional circulation of respiratory pathogens are discussed. A literature analysis shows that NPIs were the most important cause of the general reduction in the incidence of influenza and respiratory syncytial virus infection in the first year of the pandemic, although the different sensitivity of each virus to NPIs, the type and duration of measures used, as well as the interference among viruses may have played a role in modulating viral circulation. Reasons for the increase in the incidences of Streptococcus pneumoniae and group A Streptococcus infections seem strictly linked to immunity debt and the role played by NPIs in reducing viral infections and limiting bacterial superimposed infections. These results highlight the importance of NPIs during pandemics, the need to monitor the circulation of infectious agents that cause diseases similar to those caused by pandemic agents, and the need to make efforts to improve coverage with available vaccines.