Group A Streptococcal Infections Research Articles

Invasive and non-invasive group A β-haemolytic streptococcal infections in patients attending public sector facilities in South Africa: 2003–2015

Background: The burden of disease caused by group A streptococcus (GAS) in Africa is largely unknown. The aim of this study was to determine the incidence of invasive (iGAS) and non-invasive GAS (non-iGAS) infections in patients attending the public health sector of South Africa.Methods: iGAS and non-iGAS infection was defined as GAS isolated in culture from sterile and non-sterile sites respectively. Using annual census data, we calculated incidence rates (IR) of iGAS and non-iGAS infection by reviewing cases from the National Health Laboratory Service (NHLS) database derived from the 9 provinces of South Africa between 2003 and 2015.Results: About 50% of the samples were collected in the Eastern Cape province which had data for all the years under observation; missing data from the other eight provinces precluded analysis of annual incidence. A multi-modal distribution of 5 256 GAS cases was observed in the Eastern Cape province. iGAS cases (n = 428) showed an annual mean IR of 0.48 (Range: 0.15–1.12) cases per 105 per year (py) with a marginal decrease from 2003 to 2015 (Rate Difference (RD), 0.23/105 py; 95% CI: 0.02–0.44/105 py). The mean annual IR for non-iGAS infection (n = 4828) was 5.48 (Range: 0.19–11.55) cases/105py; IR showed a decrease (RD, 11.36/105 py; 95% CI: 10.53–12.19/105 py). The Mann-Kendall test and the Theil-Sen estimator showed a decreasing trend in the incidence of non-iGAS infection (p = 0.002) over the study period.Conclusions: The incidence of non-iGAS infection in the Eastern Cape province of South Africa declined from 2003 to 2015. The trends from the Eastern Cape and incomplete data from other provinces indicate the need for a detailed prospective evaluation of GAS infection in South Africa to verify this trend and provide information for planning appropriate interventions.

Outbreak of invasive group A streptococcus: investigations using agar settle plates detect perineal shedding from a healthcare worker

Outbreaks of group A streptococcus (GAS) infections may occur in healthcare settings. Transmission to patients is sometimes linked to colonized healthcare workers (HCWs) and/or a contaminated environment. To describe the investigation and control of an outbreak of healthcare-associated GAS on an elderly care medical ward, over six months. Four patients developed septicaemia due to GAS infection without a clinically obvious site of infection. The outbreak team undertook an investigation involving a retrospective review of GAS cases, prospective case finding, HCW screening and environmental sampling using both swabs and settle plates. Immediate control measures included source isolation and additional cleaning of the ward environment with a chlorine disinfectant and hydrogen peroxide. Prospective patient screening identified one additional patient with throat GAS carriage. Settle plate positivity for GAS was strongly associated with the presence of one individual HCW on the ward, who was subsequently found to have GAS perineal carriage. Contamination of a fabric-upholstered chair in an office adjacent to the ward, used by the HCW, was also detected. In total, three asymptomatic HCWs had throat GAS carriage and one HCW had both perineal and throat carriage. All isolates were typed as emm 28. This is the first outbreak report demonstrating the use of settle plates in a GAS outbreak investigation on a medical ward, to identify the likely source of the outbreak. Based on this report we recommend that both throat and perineal sites should be sampled if HCW screening is undertaken during an outbreak of GAS. Fabric, soft furnishings should be excluded from clinical areas as well as any adjacent offices because pathogenic bacteria such as GAS may contaminate this environment.

Whole-genome sequencing in the investigation of recurrent invasive group A streptococcus outbreaks in a maternity unit

The clinical manifestations of group A streptococcus (GAS) (Streptococcus pyogenes) are diverse, ranging from asymptomatic colonization to devastating invasive disease. Maternity-related clusters of invasive GAS (iGAS) infection are complex to investigate and control, especially if recurrent. To investigate three episodes of emm 75 GAS/iGAS infection in maternity patients at one hospital site over a four-year period (two with monophyletic ancestry). The episodes are described, together with whole-genome sequence (WGS) isolate analyses. Single nucleotide polymorphism differences were compared with contemporaneous emm 75 genomes. Over the four-year study period, seven mothers had emm 75 GAS/iGAS and one mother had emm 3 iGAS (in year 4) (subsequently discounted as linked). Three (clinical/screening samples) of the seven babies of emm-75-positive mothers and three screened healthcare workers were positive for emm 75 GAS. WGS similarity suggested a shared ancestral lineage and a common source transmission, but directionality of transmission cannot be inferred. However, the findings indicate that persistence of a particular clone in a given setting may be long term. Occupational health procedures were enhanced, staff were screened, and antibiotic therapy was provided to GAS-positive staff and patients. The definitive source of infection could not be identified, although staff-patient transmission was the most likely route. The pattern of clonal GAS transmission over the four-year study period suggests that long-term persistence of GAS may have occurred.

Clinical features predicting group A streptococcal pharyngitis in a Japanese paediatric primary emergency medical centre.

ObjectivesTo identify clinical features that predict Group A streptococcal (GAS) pharyngitis in a Japanese paediatric primary emergency medical centre.MethodsThe prevalence of GAS pharyngitis according to age and body temperature (BT) was calculated among 3098 paediatric patients with pharyngitis. The numbers of GAS-positive and -negative patients for each clinical parameter, and each point increase in the McIsaac score were compared and likelihood ratios (LRs) were calculated.ResultsThe prevalence of GAS pharyngitis was extremely low in patients aged < 1 (1.2%) and 1 year (3.9%). The GAS-positive rate was significantly higher in patients with a BT < 38.0°C compared with ≥ 38.0°C (30.0% vs. 19.8%). A BT ≥ 38.0°C was not a predictive finding for GAS pharyngitis (positive LR: 0.82). Rash was the most useful individual predictor, and a McIsaac score of 4 or 5 increased the probability; however, the positive LRs were 1.74 and 1.30, respectively.ConclusionsThe prevalence of GAS pharyngitis is extremely low in patients aged < 1 and 1 year, and a BT ≥ 38.0°C is not a predictive symptom. Although a rash and McIsaac score of 4 or 5 are associated with an increased probability, they cannot be used to confirm GAS infection.

Pathogenic mechanisms of invasive group A Streptococcus infections by influenza virus-group A Streptococcus superinfection.

Group A Streptococcus (GAS) are pathogenic bacteria of the genus Streptococcus and cause severe invasive infections that comprise a wide range of diverse diseases, including acute respiratory distress syndrome, renal failure, toxic shock-like syndrome, sepsis, cellulitis and necrotizing fasciitis. The essential virulence, infected host and external environmental factors required for invasive GAS infections have not yet been determined. Superinfection with influenza virus and GAS induced invasive GAS infections was demonstrated by our team in a mouse model, after which clinical cases of invasive GAS infections secondary to influenza virus infection were reported by other investigators in Japan, USA, Canada, UK China, and other countries. However, the pathogenic mechanisms underlying influenza virus-GAS superinfection are not yet fully understood. The present review describes the current knowledge about invasive GAS infections by superinfection. Topics addressed include the bacteriological, virological and immunological mechanisms impacting invasion upon superinfection on top of underlying influenza virus infection by GAS and other bacteria (i.e., Streptococcus pneumoniae and Staphylococcus aureus). Future prospects are also discussed.

Group A Streptococcus Prevents Mast Cell Degranulation to Promote Extracellular Trap Formation.

The resurgence of Group A Streptococcus (GAS) infections in the past two decades has been a rising major public health concern. Due to a large number of GAS infections occurring in the skin, mast cells (MCs), innate immune cells known to localize to the dermis, could play an important role in controlling infection. MCs can exert their antimicrobial activities either early during infection, by degranulation and release of antimicrobial proteases and the cathelicidin-derived antimicrobial peptide LL-37, or by forming antibacterial MC extracellular traps (MCETs) in later stages of infection. We demonstrate that MCs do not directly degranulate in response to GAS, reducing their ability to control bacterial growth in early stages of infection. However, MC granule components are highly cytotoxic to GAS due to the pore-forming activity of LL-37, while MC granule proteases do not significantly affect GAS viability. We therefore confirmed the importance of MCETs by demonstrating their capacity to reduce GAS survival. The data therefore suggests that LL-37 from MC granules become embedded in MCETs, and are the primary effector molecule by which MCs control GAS infection. Our work underscores the importance of a non-traditional immune effector cell, utilizing a non-conventional mechanism, in the defense against an important human pathogen.

Streptococcus pyogenes infection in paediatrics: from pharyngotonsillitis to invasive infections

Abstract Background Streptococcus pyogenes or Group A Streptococci (GAS) cause many infections in infancy. Changes in its epidemiology have been described in recent years, including an increase in invasive infections (iGAS). Methods A retrospective-descriptive study was conducted on children less than 15-years-old, with GAS infections, in particular iGAS, and their complications from February 2004 to April 2014. Results A total of 2192 positive cultures were obtained of which 92.7% were pharyngeal cultures. Twenty-nine patients were admitted to hospital: 4 with suppurative complications, 7 post-infective, 14 iGAS, and 4 probable iGAS cases. There were no differences in the frequency of GAS isolations/year. Non-invasive isolates were more frequent in winter and spring (P The incidence of iGAS was 2.1/100 000 children/year. There was no seasonality, and it was more frequent in younger children (P = .039). The most common diagnosis was pneumonia (6/14). Eight patients required intensive care. They were treated empirically with second or third-generation cephalosporin or with intravenous penicillin, and pneumonia required longer treatment times (P = .016). All GAS isolates were sensitive to penicillin, and 10.6% were resistant to erythromycin. The time spent in hospital was longer for iGAS than other cases (P = .028). No patients died. Conclusions Pharyngotonsillitis caused by GAS is common in childhood, and its incidence is increasing in children younger than 5 years. At the moment, post-infectious complications are rare. Invasive infections are the most severe forms of presentation, and are more common in younger children.

Post-Streptococcal Syndrome in a 5-Years Old Boy with Sever Vitamin D Deficiency Only Responding to Monoclonal Antibody: First Case Report

Despite the reduction in incidence of Group A Streptococcal (GAS) infections in the last few decades its global burden on mortality and morbidity remained significantly high and represent major concerns in many developing countries. These morbidities and mortalities can be serious in immunocompromised individuals. It has been shown for the last two decades that vitamin D plays an important role in the immune system modulation and its deficiency were associated with recurrent and sever infections. Only few literatures were written about the vitamin D deficiency and GAS infections and very scarce about its complications. One of the rarely reported complications of GAS infections is post-streptococcal systemic vasculitis. The association of this complications and the vitamin D deficiency was not reported before. We report for the first time a 5 years old boy presented with sever post-scarlet fever vasculitis with sever vitamin D deficiency, only responded to monoclonal antibody infusion. The presentation was complicated by more than one complications of GAS infection, hence difficult to diagnose initially and found to have sever vitamin D deficiency which we concluded is the causative factor for these complications. On correction of vitamin D level the deranged immunological and other factors causing the vasculitis were corrected subsequent to vitamin D correction. It is therefore recommended to check vitamin D concentration in cases of sever GAS especially in association with its complications such as the systemic vasculitis.

Selective autophagy mechanism against Group A Streptococcus infection

Autophagy acts as an intracellular host defense system against invading pathogenic microorganisms such as Group A Streptococcus (GAS). Autophagy is a membrane-mediated degradation system that is regulated by intracellular membrane trafficking regulators, including small GTPase Rab proteins. Here, we revealed Rab GTPase network that regulate autophagosome formation against GAS. A unique set of Rab GTPases coordinates autophagy to enable to form huge autophagosomes surrounding GAS by linking recycling endosomes and trans Golgi-network. We also found that NLRP4, one of intracellular pathogen recognition receptor, directs Rho signaling to facilitate autophagosome formation. In this article, we would like to show our findings on how host autophagy regulators coordinate autophagy during GAS infection.

Investigation of Scarlet Fever Outbreak in a Kindergarten.

BackgroundScarlet fever is caused by a group A streptococcal (GAS) infection. On April 3, 2017, an outbreak among children in a kindergarten was reported to the local health department. An epidemiologic investigation was conducted to identify the possible transmission route of this outbreak and to recommend appropriate control measures.Materials and MethodsA retrospective cohort study was conducted using questionnaires including age, sex, the classroom attended at a kindergarten, and date and type of symptoms developed. A case-patient is defined as a child having sore throat, fever, skin rash, or strawberry tongue with or without laboratory confirmation of GAS infection between March 28 and April 28, 2017.ResultsThe index case-patients developed symptoms on March 28, 2017, and this outbreak persisted over a period of 16 days. The outbreak affected 21 out of 158 children (13.3%) in the kindergarten, with the mean age of 4.2 (range 3–5) years; 12 (57.1%) of them were boys. The common symptoms reported were fever (71.4%), sore throat (71.4%), reddened tonsil (57.1%), and skin rash (52.4%). The epidemiologic analysis showed that children attending one of the classrooms in the kindergarten were 14.12 times affected than the other classrooms (relative risk, 14.12; 95% confidence interval, 4.99–33.93; P <0.01). All case-patients were recommended to stay away from the kindergarten and its social activities for >24 hours after starting appropriate antibiotic treatment, and all the children in the kindergarten were instructed to keep strict personal hygiene practices.ConclusionOur results suggest that the outbreak likely affected from the index case-patients who attended to one of the classrooms in the kindergarten. This highlights the importance of immediate notification of outbreak to prevent large number of patients.

Cellular interactions of covR/S mutant group A Streptococci

Group A Streptococci (GAS) are responsible for a wide array of non-invasive and invasive diseases and varying immune sequelae with high rates of mortality and morbidity. GAS strains with a mutation in their covR/S regulatory system are hypervirulent with an increased capacity for causing invasive disease. covR/S mutants augment their virulence through the up-regulation of important virulence factors and target host immune surveillance primarily by inhibiting neutrophils. An in-depth understanding of the immunopathogenesis of covR/S mutants will facilitate the development of vaccine strategies and design. Ultimately, by targeting separate virulence mechanisms, multi-component vaccines may provide improved protective efficacy against hypervirulent GAS infections.

Prospective Surveillance of Pediatric Invasive Group A Streptococcus Infection.

Invasive group A Streptococcus (GAS) disease has an incidence in high-income countries of 3 to 5 per 100000 per annum and a case-fatality ratio of 10% to 15%. Although these rates are comparable to those of invasive meningococcal disease in Australia before vaccine introduction, invasive GAS disease currently requires reporting in only 2 jurisdictions. Data were collected prospectively through active surveillance at the Royal Children's Hospital, Melbourne (October 2014 to September 2016). Isolation of GAS from a sterile site was required for inclusion. Comprehensive demographic and clinical data were collected, and emm typing was performed on all isolates. Disease was considered severe if the patient required inotropic support or mechanical ventilation. We recruited 28 patients. The median age of the patients was 3.5 years (range, 4 days to 11 years). Ten (36%) patients had severe disease. Fifteen (54%) children had presented to a medical practitioner for review in the 48 hours before their eventual admission, including 7 of the 10 patients with severe GAS infection. Complications 6 months after discharge persisted in 21% of the patients. emm1 was the most common emm type (29%). We found considerable short- and longer-term morbidity associated with pediatric invasive GAS disease in our study. Disease manifestations were frequently severe, and more than one-third of the patients required cardiorespiratory support. More than one-half of the patients attended a medical practitioner for assessment but were discharged in the 48-hour period before admission, which suggests that there might have been a window for earlier diagnosis. Our methodology was easy to implement as a surveillance system.

Group A Streptococcus encounters with host macrophages.

Group A Streptococcus (GAS) is a leading human bacterial pathogen with diverse clinical manifestations. Macrophages constitute a critical first line of host defense against GAS infection, using numerous surface and intracellular receptors such as Toll-like receptors and inflammasomes for pathogen recognition and activation of inflammatory signaling pathways. Depending on the intensity of the GAS infection, activation of these signaling cascades may provide a beneficial early alarm for effective immune clearance, or conversely, may cause hyperinflammation and tissue injury during severe invasive infection. Although traditionally considered an extracellular pathogen, GAS can invade and replicate within macrophages using specific molecular mechanisms to resist phagolysosomal and xenophagic killing. Unraveling GAS-macrophage encounters may reveal new treatment options for this leading agent of infection-associated mortality. [Formula: see text].

Group A streptococcal M-like proteins: From pathogenesis to vaccine potential.

M and M-like surface proteins from group A Streptococcus (GAS) act as virulence factors and have been used in multiple vaccine candidates. While the M protein has been extensively studied, the two genetically and functionally related M-like proteins, Mrp and Enn, although present in most streptococcal strains have been relatively less characterised. We compile the current state of knowledge for these two proteins, from discovery to recent studies on function and immunogenicity, using the M protein for comparison as a prototype of this family of proteins. We focus on the known interactions between M-like proteins and host ligand proteins, and analyse the genetic data supporting these interactions. We discuss known and possible functions of M-like proteins during GAS infections, and highlight knowledge gaps where further investigation is warranted.

Orbital Inflammatory Syndrome Post Group A Streptococcal Infection — Case Series and Review of Literature

ABSTRACTObjective: To report new cases of orbital inflammatory syndrome (OIS) post group A streptococcal (GAS) infection and review the literature.Methods: A retrospective case series of patients with OIS post GAS infection seen in our clinic (from January 2015 to December 2016) and review of additional patients from the literature.Results: A total of nine patients with OIS post GAS infection were included in the study (four patients seen in our clinic and five from previous literature); seven females and two males, three children (under the age of 16), and six adults. Eight patients (89%) presented with a single rectus muscle (5 medial, 3 lateral) myositis, and one (11%) presented with posterior scleritis and diffuse OIS.Conclusions: Although there are very few reports on OIS post GAS infection, it may be more common than previously thought and should be considered in the differential diagnosis of patients with orbital inflammation.

Binding host proteins to the M protein contributes to the mortality associated with influenza-Streptococcus pyogenes superinfections.

The mortality associated with influenza A virus (IAV) is often due to the development of secondary bacterial infections known as superinfections. The group A streptococcus (GAS) is a relatively uncommon cause of IAV superinfections, but the mortality of these infections is high. We used a murine model to determine whether the surface-localized GAS M protein contributes to the outcome of IAV-GAS superinfections. A comparison between wild-type GAS and an M protein mutant strain (emm3) showed that the M3 protein was essential to virulence. To determine whether the binding, or recruitment, of host proteins to the bacterial surface contributed to virulence, GAS was suspended with BALF collected from mice that had recovered from a sub-lethal infection with IAV. Following intranasal inoculation of naïve mice, the mortality associated with the wild-type strain, but not the emm3 mutant strain, was greater compared to mice inoculated with GAS suspended with either BALF from uninfected mice or PBS. Further analyses showed that both albumin and fibrinogen (Fg) were more abundant in the respiratory tract 8 days after IAV infection, that M3 bound both proteins to the bacterial surface, and that suspension of GAS with either protein increased GAS virulence in the absence of antecedent IAV infection. Overall, the results showed that M3 is essential to the virulence of GAS in an IAV superinfection and suggested that increased abundance of albumin and Fg in the respiratory tract following IAV infection enhanced host susceptibility to secondary GAS infection.

Linoleic and palmitoleic acid block streptokinase-mediated plasminogen activation and reduce severity of invasive group A streptococcal infection

In contrast to mild infections of Group A Streptococcus (GAS) invasive infections of GAS still pose a serious health hazard: GAS disseminates from sterile sites into the blood stream or deep tissues and causes sepsis or necrotizing fasciitis. In this case antibiotics do not provide an effective cure as the bacteria are capable to hide from them very quickly. Therefore, new remedies are urgently needed. Starting from a myxobacterial natural products screening campaign, we identified two fatty acids isolated from myxobacteria, linoleic and palmitoleic acid, specifically blocking streptokinase-mediated activation of plasminogen and thereby preventing streptococci from hijacking the host’s plasminogen/plasmin system. This activity is not inherited by other fatty acids such as oleic acid and is not attributable to the killing of streptococci. Moreover, both fatty acids are superior in their inhibitory properties compared to two clinically used drugs (tranexamic or ε-amino caproic acid) as they show 500–1000 fold lower IC50 values. Using a humanized plasminogen mouse model mimicking the clinical situation of a local GAS infection that becomes systemic, we demonstrate that these fatty acids ameliorate invasive GAS infection significantly. Consequently, linoleic and palmitoleic acid are possible new options to combat GAS invasive diseases.

Binding of NAD+-Glycohydrolase to Streptolysin O Stabilizes Both Toxins and Promotes Virulence of Group A Streptococcus.

ABSTRACTThe globally dominant, invasive M1T1 strain of group A Streptococcus (GAS) harbors polymorphisms in the promoter region of an operon that contains the genes encoding streptolysin O (SLO) and NAD+-glycohydrolase (NADase), resulting in high-level expression of these toxins. While both toxins have been shown experimentally to contribute to pathogenesis, many GAS isolates lack detectable NADase activity. DNA sequencing of such strains has revealed that reduced or absent enzymatic activity can be associated with a variety of point mutations in nga, the gene encoding NADase; a commonly observed polymorphism associated with near-complete abrogation of activity is a substitution of aspartic acid for glycine at position 330 (G330D). However, nga has not been observed to contain early termination codons or mutations that would result in a truncated protein, even when the gene product contains missense mutations that abrogate enzymatic activity. It has been suggested that NADase that lacks NAD-glycohydrolase activity retains an as-yet-unidentified inherent cytotoxicity to mammalian cells and thus is still a potent virulence factor. We now show that expression of NADase, either enzymatically active or inactive, augments SLO-mediated toxicity for keratinocytes. In culture supernatants, SLO and NADase are mutually interdependent for protein stability. We demonstrate that the two proteins interact in solution and that both the translocation domain and catalytic domain of NADase are required for maximal binding between the two toxins. We conclude that binding of NADase to SLO stabilizes both toxins, thereby enhancing GAS virulence.

Varicella complicated by cellulitis and deep vein thrombosis

We report a 16-month-old girl with varicella complicated by cellulitis, invasive Group A Streptococcus (GAS) infection and deep vein thrombosis. She presented with varicella lesions, fever and a painful firm...

Mucosal vaccination with pili from Group A Streptococcus expressed on Lactococcus lactis generates protective immune responses

The human pathogen Group A Streptococcus (GAS) produces pili that are involved in adhesion and colonisation of the host. These surface-exposed pili are immunogenic and therefore represent an attractive target for vaccine development. The pilus is encoded in the genomic region known as the fibronectin-collagen-T-antigen (FCT)-region, of which at least nine different types have been identified. In this study we investigate expressing two of the most common FCT-types (FCT-3 and FCT-4) in the food-grade bacteria Lactococcus lactis for use as a mucosal vaccine. We show that mucosally delivered L. lactis expressing GAS pili generates specific antibody responses in rabbits. Rabbit anti-pilus antibodies were shown to have both a neutralising effect on bacterial adhesion, and immunised rabbit antiserum was able to facilitate immune-mediated killing of bacteria via opsonophagocytosis. Furthermore, intranasal immunisation of mice improved clearance rates of GAS after nasopharyngeal challenge. These results demonstrate the potential for a novel, pilus-based vaccine to protect against GAS infections.