Invasive Group A Streptococcal Disease Research Articles

Reduction in Acute Post-Streptococcal Glomerulonephritis Incidence in Counties Manukau, New Zealand, after the COVID-19 Pandemic.

The COVID-19 pandemic has altered the epidemiology of many common childhood infections, including Group A streptococcal (GAS) disease. Acute post-streptococcal glomerulonephritis (APSGN) is a nonsuppurative complication of GAS pharyngitis and pyoderma. It remains the most common cause of pediatric acute glomerulonephritis globally. In Counties Manukau, New Zealand, APSGN rates have previously been shown to be the highest in the country, with marked ethnic and socioeconomic disparities. We performed a retrospective review of children aged 0-14 years who were discharged from Kidz First Hospital, Counties Manukau, between 2015 and 2023 and met the Strep A Vaccine Global Consortium consensus definition of APSGN. We describe a marked, sustained reduction in APSGN hospitalizations, temporally associated with the COVID-19 pandemic. This ongoing reduction in APSGN incidence is notable in light of contrasting reports of increasing incidence of rheumatic fever in New Zealand and invasive GAS disease internationally.

Complicated pneumonia caused by group A Streptococcus in children - 2022/2023 infectious season outbreak and update on clinical characteristics

BackgroundAn increased incidence of group A Streptococcus (GAS) infections has been observed in pediatric population post-COVID-19 pandemic. While the majority of reports refer to scarlet fever or invasive GAS disease, detailed data on pulmonary manifestations such as complicated community-acquired pneumonia (CAP) are scarce. The aim of this study was to assess the contribution of GAS to complicated CAP in children during the 2022/2023 infectious season. MethodsWe retrospectively analyzed the etiology and clinical presentation of complicated CAP patients hospitalized in our tertiary care center in Warsaw, Poland, between August 2022 and May 2023. ResultsAmong 91 patients with complicated CAP, GAS was the dominant cause constituting 24.2% (22/91; 95% CI 15.8–34.3%) of the study group. 68.2% of GAS pneumonia patients presented symptoms of scarlet fever, and 27.3% had preceding or concurrent viral infection. GAS complicated CAP was associated with longer hospitalization, higher incidence of chest tube insertion, but shorter duration of chest tube drainage than complicated CAP of other etiology. Children with GAS complicated CAP had higher procalcitonin concentration (28.1 vs. 1.5 ng/dL; p<0.0001) and a lower platelets level (254.5 vs. 422 × 103/μL; p = 0.0031) than those with non-GAS infection. ConclusionsGAS is currently the predominant pathogen of complicated CAP in children. Clinicians should be aware of the current epidemiological situation and a more severe course of GAS pneumonia in this age group, and should monitor patients presenting with symptoms of scarlet fever and preceding viral infection closely.

Preadmission course and management of severe pediatric group A streptococcal infections during the 2022-2023 outbreak: a single-center experience.

The massive increase of infections with Group A Streptococcus (GAS) in 2022-2023 coincided in Switzerland with a change of the recommendations for the management of GAS pharyngitis. Therefore, the objective of the present study was to investigate whether the clinical manifestations and management before hospitalization for GAS infection differed in 2022-2023 compared with 2013-2022. Retrospective study of GAS infections requiring hospitalization in patients below 16years. Preadmission illness (modified McIsaac score), oral antibiotic use, and outcome in 2022-2023 were compared with 2013-2022. Time series were compared with surveillance data for respiratory viruses. In 2022-2023, the median modified McIsaac score was lower (2 [IQR 2-3] vs. 3 [IQR 2-4], p = < 0.0001) and the duration of preadmission illness was longer (4days [3-7] vs. 3 [2-6], p = 0.004) than in 2013-2022. In both periods, withholding of preadmission oral antibiotics despite a modified McIsaac score ≥ 3 (12% vs. 18%, n.s.) or ≥ 4 (2.4% vs. 10.0%, p = 0.027) was rare. Respiratory disease, skeletal/muscle infection, and invasive GAS disease were significantly more frequent in 2022-2023, but there were no differences in clinical outcome. The time course of GAS cases in 2022-2023 coincided with the activity of influenza A/B. We found no evidence supporting the hypothesis that the 2022-2023 GAS outbreak was associated with a change in preadmission management possibly induced by the new recommendation for GAS pharyngitis. However, clinical manifestations before admission and comparative examination of time-series strongly suggest that viral co-circulation played an important role in this outbreak.

Group A Streptococcus Infection in Neonatal Population: A Systematic Review of The Literature.

(1) Background: The importance of group A streptococcus (GAS) infection severity has been recognized in children and adults. However, to our knowledge, there have been no systematic reviews or pooled assessments of the incidence and outcome of invasive GAS (iGAS) disease in neonates, a potentially high-risk population. Therefore, we performed a systematic review of available data regarding the risk factors, clinical presentation, and outcome of GAS infection in neonates. (2) Methods: An electronic search of the existing literature was carried out during the period July 2023-September 2023 in the PubMed and Scopus databases, considering studies referring to GAS infection in the neonatal population. (3) Results: Overall, 39 studies met all the inclusion criteria and were included in this review, evaluating data from 194 neonates. Unfortunately, there were a lot of missing data among the retrieved studies. Our systematic review highlighted the presence of differences with regards to clinical presentation, infection sites, and outcome of GAS invasive disease between neonates with early-onset (EOS) or late-onset sepsis (LOS). Common characteristics of EOS included respiratory distress, rapid deterioration, and high mortality rate irrespective of the infection site, while rash, gastrointestinal tract symptoms, and fever appeared to be the most frequent symptoms/clinical signs and manifestations of LOS disease. The management of severe invasive iGAS disease consists mainly of specific antimicrobial treatment as well as supportive care with fluids and electrolyte supplementation, minimizing or counteracting the effects of toxins. Furthermore, a mortality rate of approximately 14% was recorded for iGAS disease in the total of all studies' neonates. (4) Conclusions: Although iGAS is a rare entity of neonatal infections, the potential severity of the disease and the rapid deterioration requires the development of quick analysis methods for the detection of GAS allowing the prompt diagnosis and administration of the indicated antibiotic treatment. Furthermore, given the exceptional risk for both the pregnant woman and the neonate, it is very important to raise awareness and create easily accessible guidelines that could facilitate the prevention and management of maternal as well as the subsequent neonatal severe iGAS disease.

Invasive group A streptococcal disease in pregnant women and young children: a systematic review and meta-analysis

SummaryBackgroundThe incidence of invasive disease caused by group A streptococcus (GAS) has increased in multiple countries in the past 15 years. However, despite these reports, to the best of our knowledge, no systematic reviews and combined estimates of the incidence of invasive GAS have been done in key high-risk groups. To address this, we estimated the incidence of invasive GAS disease, including death and disability outcomes, among two high-risk groups—namely, pregnant women and children younger than 5 years.MethodsWe did a systematic review and meta-analyses on invasive GAS outcomes, including incidence, case fatality risks, and neurodevelopmental impairment risk, among pregnant women, neonates (younger than 28 days), infants (younger than 1 year), and children (younger than 5 years) worldwide and by income region. We searched several databases for articles published from Jan 1, 2000, to June 3, 2020, for publications that reported invasive GAS outcomes, and we sought unpublished data from an investigator group of collaborators. We included studies with data on invasive GAS cases, defined as laboratory isolation of Streptococcus pyogenes from any normally sterile site, or isolation of S pyogenes from a non-sterile site in a patient with necrotising fasciitis or streptococcal toxic shock syndrome. For inclusion in pooled incidence estimates, studies had to report a population denominator, and for inclusion in pooled estimates of case fatality risk, studies had to report aggregate data on the outcome of interest and the total number of cases included as a denominator. We excluded studies focusing on groups at very high risk (eg, only preterm infants). We assessed heterogeneity with I2.FindingsOf the 950 published articles and 29 unpublished datasets identified, 20 studies (seven unpublished; 3829 cases of invasive GAS) from 12 countries provided sufficient data to be included in pooled estimates of outcomes. We did not identify studies reporting invasive GAS incidence among pregnant women in low-income and middle-income countries (LMICs) nor any reporting neurodevelopmental impairment after invasive GAS in LMICs. In nine studies from high-income countries (HICs) that reported invasive GAS in pregnancy and the post-partum period, invasive GAS incidence was 0·12 per 1000 livebirths (95% CI 0·11 to 0·14; I2=100%). Invasive GAS incidence was 0·04 per 1000 livebirths (0·03 to 0·05; I2=100%; 11 studies) for neonates, 0·13 per 1000 livebirths (0·10 to 0·16; I2=100%; ten studies) for infants, and 0·09 per 1000 person-years (95% CI 0·07 to 0·10; I2=100%; nine studies) for children worldwide; 0·12 per 1000 livebirths (95% CI 0·00 to 0·24; I2=100%; three studies) in neonates, 0·33 per 1000 livebirths (−0·22 to 0·88; I2=100%; two studies) in infants, and 0·22 per 1000 person-years (0·13 to 0·31; I2=100%; two studies) in children in LMICs; and 0·02 per 1000 livebirths (0·00 to 0·03; I2=100%; eight studies) in neonates, 0·08 per 1000 livebirths (0·05 to 0·11; I2=100%; eight studies) in infants, and 0·05 per 1000 person-years (0·03 to 0·06; I2=100%; seven studies) in children for HICs. Case fatality risks were high, particularly among neonates in LMICs (61% [95% CI 33 to 89]; I2=54%; two studies).InterpretationWe found a substantial burden of invasive GAS among young children. In LMICs, little data were available for neonates and children and no data were available for pregnant women. Incidences of invasive GAS are likely to be underestimates, particularly in LMICs, due to low GAS surveillance. It is essential to improve available data to inform development of prevention and management strategies for invasive GAS.FundingWellcome Trust.

Health-Economic Value of Vaccination Against Group A Streptococcus in the United States.

Vaccines are needed to reduce the burden of group A Streptococcus (GAS). We assessed the potential health-economic value of GAS vaccines achievable through prevention of invasive disease and acute upper respiratory infections in the United States. We estimated annual incidence of invasive GAS disease and associated costs incurred from hospitalization and management of long-term sequelae, as well as productivity losses resulting from acute illness, long-term disability, and mortality. We also estimated healthcare and productivity costs associated with GAS pharyngitis, sinusitis, and acute otitis media. We estimated costs averted by prevention of invasive disease and acute upper respiratory infections for vaccines with differing efficacy profiles; our base case considered vaccines meeting the World Health Organization Preferred Product Profile (WHO-PPP) with a 6-year average duration of protection. Costs of invasive GAS disease and acute upper respiratory infections totaled $6.08 (95% confidence interval [CI], $5.33-$6.86) billion annually. Direct effects of vaccines meeting WHO-PPP characteristics and administered at ages 12 and 18 months would avert $609 (95% CI, $558-$663) million in costs annually, primarily by preventing noninvasive disease; with an additional dose at age 5 years, averted costs would total $869 (95% CI, $798-$945) million annually. Adult vaccination at age 65 years would avert $326 (95% CI, $271-$387) million in annual costs associated with invasive GAS disease. Indirect effects of vaccination programs reducing incidence of GAS diseases across all ages by 20% would avert roughly $1 billion in costs each year. The economic burden of GAS is substantial. Our findings should inform prioritization of GAS vaccine development and evaluation.

Invasive Group a Streptococcal Disease in Pregnant Women and Young Children Worldwide: Systematic Review and Meta-Analyses

Background: The incidence of invasive disease caused by group A Streptococcus (GAS) has recently increased in multiple countries. To inform interventions such as GAS vaccines currently in development, we estimated the incidence of invasive GAS (iGAS) disease, including death and disability outcomes, among two high risk groups—pregnant women and children under 5 years of age. Methods: We searched a range of databases and sought unpublished data to identify inputs (1 st January 2000 and 30 th June 2020) to calculate pooled incidence of iGAS disease, case fatality risks (CFRs), and neurodevelopmental impairment among pregnant women, neonates, infants, and children (under 5 years of age). Findings: We identified 950 published articles and 29 unpublished datasets for consideration. Of these 20 studies were eligible for meta-analyses; no studies among pregnant women or on neurodevelopmental impairment in low- and middle-income countries (LMICs) were available. In high income countries (HICs), iGAS incidence among pregnant women was 0·12/1000 live births (95%CI 0·11-0·14). Worldwide iGAS incidence estimates included: neonates, 0·04/1000 live births (0·03-0·05); infants, 0·13/1000 live births (0·10-0·16); and, children aged 0-5 years, 0·09/1000 person-years (95%CI 0·07-0·10). Incidences among children were higher in LMICs, particularly in neonates (0·12/1000 live births; 95%CI 0·00-0·24) compared to HICs (0·02/1000 live births; 0·00-0.03). CFRs among young children were high, particularly among neonates in LMICs (61%; 95%CI 33-89%). Interpretation: We found a high disease incidence and risk of death among young children with iGAS, particularly in LMICs. Notably, for LMICs, limited data are available for neonates and children, and no data are available for pregnant women. Incidences are likely underestimated, particularly in LMICs, due to limited GAS surveillance. Improving available data is essential to inform GAS vaccine development and evaluation. Funding: ACSe is funded by The Wellcome Trust. ACSt is funded by a Viertel Senior Medical Research Fellowship. Declaration of Interest: We declare no competing interests

Increasing incidence of invasive group A streptococcal disease in Western Australia, particularly among Indigenous people.

To quantify the burden of invasive group A Streptococcus (GAS) disease in Western Australia during 2000-2018. Population-based data linkage study: Hospital Morbidity Data Collection (HMDC; all WA public and private hospital records), PathWest pathology data (government-owned pathology services provider), and death registrations. People with invasive GAS disease, defined by an isolate from a normally sterile site (PathWest) or a hospital-based principal ICD-10-AM diagnosis code (HMDC). Incidence of invasive GAS disease; median length of hospital stay; all-cause mortality. We identified 2237 cases of GAS disease during 2000-2018; 1283 were in male patients (57%). 1950 cases had been confirmed by GAS isolates from normally sterile tissues (87%; including 1089 from blood [56% of cases] and 750 from tissue [38%]). The age-standardised incidence increased from 2.0 (95% CI, 1.4-2.7) cases per 100000 population in 2000 to 9.1 (95% CI, 7.9-10.2) cases per 100000 in 2017 (by year, adjusted for age group and sex: incidence rate ratio [IRR], 1.09; 95% CI, 1.08-1.10). Incidence was consistently higher among Indigenous than non-Indigenous Australians (year-adjusted IRR, 13.1; 95% CI, 11.3-15.1). All-cause 30-day mortality was 5% (116 deaths), and 90-day mortality 7% (156 deaths); 30-day mortality, adjusted for age group and sex, was not statistically significantly different for cases involving Indigenous or non-Indigenous patients (adjusted odds ratio, 0.8; 95% CI, 0.6-1.1). The incidence of invasive GAS disease in WA increased between 2000 and 2018, particularly among Indigenous Australians. Mandatory notification of invasive GAS disease would therefore be appropriate. The social determinants of differences in incidence should be addressed, and other relevant host, pathogen, and health system factors investigated.

Challenges in Surveillance for Streptococcal Toxic Shock Syndrome: Active Bacterial Core Surveillance, United States, 2014-2017.

Routine surveillance for streptococcal toxic shock syndrome (STSS), a severe manifestation of invasive group A Streptococcus (GAS) infections, likely underestimates its true incidence. The objective of our study was to evaluate routine identification of STSS in a national surveillance system for invasive GAS infections. Active Bacterial Core surveillance (ABCs) conducts active population-based surveillance for invasive GAS disease in selected US counties in 10 states. We categorized invasive GAS cases with a diagnosis of STSS made by a physician as STSS-physician and cases that met the Council of State and Territorial Epidemiologists (CSTE) clinical criteria for STSS based on data in the medical record as STSS-CSTE. We evaluated agreement between the 2 methods for identifying STSS and compared the estimated national incidence of STSS when applying proportions of STSS-CSTE and STSS-physician among invasive GAS cases from this study with national invasive GAS estimates for 2017. During 2014-2017, of 7572 invasive GAS cases in ABCs, we identified 1094 (14.4%) as STSS-CSTE and 203 (2.7%) as STSS-physician, a 5.3-fold difference. Of 1094 STSS-CSTE cases, we identified only 132 (12.1%) as STSS-physician cases. Agreement between the 2 methods for identifying STSS was low (κ = 0.17; 95% CI, 0.14-0.19). Using ABCs data, we estimated 591 cases of STSS-physician and 3618 cases of STSS-CSTE occurred nationally in 2017. We found a large difference in estimates of incidence of STSS when applying different surveillance methods and definitions. These results should help with better use of currently available surveillance data to estimate the incidence of STSS and to evaluate disease prevention efforts, in addition to guiding future surveillance efforts for STSS.

453. High Burden of Invasive and Severe Group A Streptococcus Disease Among Native Americans on the White Mountain Apache Tribal Lands

BackgroundNative Americans are overrepresented in outbreaks of Group A Streptococcus (GAS) in the United States (US). In 2016, several invasive cases of GAS were detected at the Whiteriver Indian Health Service (IHS) Hospital in Arizona that primarily serves the White Mountain Apache (WMA) Tribe. The objective of this study was to determine the burden of invasive and severe GAS disease among Native Americans on the WMA Tribal lands.MethodsProspective population and laboratory-based surveillance for invasive and severe GASinfections was conducted for two years from March 2017 through February 2019. A case was defined as a Native American individual living on or around WMA Tribal lands with GAS isolated from a normally sterile body site (invasive) or from a non-sterile site (e.g., wound, throat, ear) requiring hospitalization (severe). Incidence rates were calculated using the IHS User Population as the denominators. Age-standardized incidence rates were calculated using US Census data from 2015 as the reference group.Results157 cases were identified (Year 1: 85; Year 2: 72), including 42 (27%) invasive and 115 (73%) severe cases. Most cases were adults (88.5%; median age: 40.5 years) and had ≥1 underlying medical condition (99.4%), including alcoholism (57.1%), hypertension (37.2%), and diabetes (34.0%). 47.8% of cases had a trigger in the past two weeks, including penetrating trauma (31.8%) and blunt force trauma (14.0%). For 72.9% of cases, a co-infection was detected (most commonly Staphylocccus aureus: 96.8%). 4.5% of cases required amputation and 1.9% died within 30 days of initial culture. The incidence of invasive and severe GAS was 460.9 per 100,000 persons (95% confidence interval: 394.3, 538.8), with no significant difference by year. The incidence was highest among adults ≥65 and lowest among children 5–17 years of age. Age-standardized incidence rates of invasive and severe GAS and invasive only GAS are presented in the Figure.ConclusionThe WMA community has experienced disproportionately high rates of invasive and severe GAS for over two years. Studies to determine the reservoirs for transmission are urgently needed, as are interventions to reduce the morbidity and mortality associated with these infections. Disclosures All authors: No reported disclosures.

Invasive group A streptococcal disease: Management and chemoprophylaxis.

Reporting of severe invasive group A streptococcal disease (IGAS) has increased in Canada over the past decade, highlighting the importance of optimal chemoprophylaxis and management strategies. Canadian guidelines have had variable uptake across Canada. This practice point updates relevant aspects of these guidelines, with a focus on chemoprophylaxis of contacts of IGAS cases and clinical management of IGAS. The importance of penicillin in treating group A streptococcal disease is reaffirmed, and the role of clindamycin is discussed. In situations in which chemoprophylaxis may be considered, preferred agents are summarized.

A Cluster of Pediatric Invasive Group A Streptococcus Disease in Melbourne, Australia, Coinciding with a High-Burden Influenza Season

Background Invasive group A streptococcal disease (IGAS) carries significant morbidity and mortality in children. Fluctuations in disease incidence are well documented. However, the modulating factors that contribute to these changes remain unclear. Prospective monitoring of IGAS cases in Victoria, Australia, showed an increased number of cases in 2017, coinciding with a peak of influenza illness. Methods Children identified to have IGAS are prospectively monitored in Melbourne through a disease surveillance network. Data on their presentation, investigations, and clinical course are collected. An increased number of cases identified between June 1, 2017, and October 31, 2017, have been retrospectively analyzed. Results We identified 22 cases of pediatric IGAS during the study period. Increased case detection occurred during a period of increased influenza disease. Of 11 children in our cohort who underwent respiratory viral testing, 4 were confirmed to have concurrent respiratory tract illnesses, and 2 were confirmed to have influenza.

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.

Case of Fatal Hemorrhagic Pneumonia Secondary to Invasive Group A Streptococcus

SESSION TITLE: Critical Care 4 SESSION TYPE: Affiliate Case Report Poster PRESENTED ON: Tuesday, October 31, 2017 at 01:30 PM - 02:30 PM INTRODUCTION: Group A Streptococcus (GAS) often manifests as pharyngeal, soft tissue or skin infections. The epidemiology of GAS causing fulminant hemorrhagic pneumonia is poorly described in literature. To our knowledge, only three cases of rapidly fatal hemorrhagic pneumonia due to GAS have been reported from Europe1 but none in the USA. CASE PRESENTATION: 26 Y/O Hispanic male emigrated from Mexico 10 years ago, without any past medical history, presented with hemoptysis, of one day duration. He provided a history of “flu-like” symptoms for the past 1 week. Upon examination he was found to be tachycardic, hypothermic and hypoxic wth cold clammy extremities and severe respiratory distress. He was intubated, sedated and ventilated in volume assist control mode with a low tidal volume protocol . Frank red blood was suctioned from the endotracheal tube. Chest Xray (Pic 1) post intubation showed dense consolidation in the right lower lung zone. CT Angiogram of thorax (Pic 2) revealed near complete consolidation of the right lung with air bronchograms and predominant consolidation in the left lower lobe without an active bleeding bronchial vessel. He was started on broad spectrum antibiotics, Oseltamivir and IV corticosteroids. Patient was deemed not a candidate for ECMO due to active bleeding. He developed hemodynamic instability and cardiac arrest with in 24 hours after presentation to the hospital. Rapid influenza antibody test returned positive for Influenza A. Sputum cultures and blood cultures obtained on admission were positive for Group-A Alpha Hemolytic Streptococcus. Workup for vasculitis including Anti-basement membrane antibody was negative. DISCUSSION: GAS is a virulent bacterial pathogen. It causes a spectrum of disease severity ranging from mild non-invasive infections (strep throat, impetigo) to less common fatal infections (necrotizing fasciitis, toxic shock syndrome). Older age, toxic shock syndrome, and pneumonia are predictors of death in persons with invasive GAS disease. Invasive infection with pneumonia is associated with exceptionally high mortality rate and currently there is no vaccine available for GAS. CONCLUSIONS: Through our case report we aim to highlight that, influenza infection can potentiate extremely fatal hemorrhagic pneumonia by invasive group A Streptococcus even in previously healthy individuals. Reference #1: Santagati, Maria, et al. Rapidly fatal hemorrhagic pneumonia and group A Streptococcus serotype M1. Emerging infectious diseases. 2014 Jan;20(1):98. DISCLOSURE: The following authors have nothing to disclose: Syed Iqbal, Jagadish Akella No Product/Research Disclosure Information

Enhanced nasopharyngeal infection and shedding associated with an epidemic lineage of emm3 group A Streptococcus

ABSTRACTBackground: A group A Streptococcus (GAS) lineage of genotype emm3, sequence type 15 (ST15) was associated with a 6 month upsurge in invasive GAS disease in the UK. The epidemic lineage (Lineage C) had lost 2 typical emm3 prophages, Φ315.1 and Φ315.2 associated with the superantigen ssa, but gained a different prophage (ΦUK-M3.1) associated with a different superantigen, speC and a DNAse spd1. Methods and Results: The presence of speC and spd1 in Lineage C ST15 strains enhanced both in vitro mitogenic and DNase activities over non-Lineage C ST15 strains. Invasive disease models in Galleria mellonella and SPEC-sensitive transgenic mice, revealed no difference in overall invasiveness of Lineage C ST15 strains compared with non-Lineage C ST15 strains, consistent with clinical and epidemiological analysis. Lineage C strains did however markedly prolong murine nasal infection with enhanced nasal and airborne shedding compared with non-Lineage C strains. Deletion of speC or spd1 in 2 Lineage C strains identified a possible role for spd1 in airborne shedding from the murine nasopharynx. Conclusions: Nasopharyngeal infection and shedding of Lineage C strains was enhanced compared with non-Lineage C strains and this was, in part, mediated by the gain of the DNase spd1 through prophage acquisition.

An Outbreak of Group A Streptococcus Invasive Infections among Pediatric Patients in Columbus, Ohio

BackgroundA cluster of invasive disease caused by group A Streptococcus (GAS) was detected among children admitted to Nationwide Children’s Hospital (NCH) in Columbus, Ohio. Clinical characteristics and molecular epidemiology of this cluster were studied to find out whether the observed cases were caused by closely related GAS strains.MethodsPatient electronic medical records were reviewed for demographic, epidemiologic and clinical data. Cases were defined as patients with GAS isolated from a normally sterile site, or from a non-sterile site in combination with clinical signs of severe streptococcal illness. Susceptibility testing (E-test), analysis of the GAS emm types, multilocus sequence typing (MLST) and pulse field gel electrophoresis (PFGE) from isolates were performed.ResultsThirteen children were admitted to NCH with invasive GAS disease between February 19 and March 23, 2017, from seven different Ohio counties (total population of approximately 1.8 million). The spectrum of illness was broad, including STSS (3 patients), GAS sepsis (3), orbital cellulitis with epidural abscess (3), bacteremia and subdural empyema (2), peritonsillar abscess (1), and septic arthritis (1). One patient with STSS died. Only two patients had chronic illnesses. One patient was diagnosed with acute myeloid leukemia on admission. Median age was eight years (range 0.1–16 years). Of six patients with STSS and sepsis only one received clindamycin and four were given IVIG. Hypocalcemia (67%) was common. Isolates from 12 patients were available for emm gene analysis and belonged to nine different emm types: 1, 2, 3, 6, 12, 22, 89, 118, 227. Two emm 1 and one emm 227 isolates had the same PFGE pattern. All isolates were susceptible to macrolides.ConclusionIn a population of 1.8 million, 13 pediatric patients with invasive GAS disease during a five-week period represented an apparent outbreak with polyclonal GAS isolates. There was no reported epidemiologic association among the patients and the outbreak was not preventable. A proposed 30-valent M-protein vaccine would have provided protection against 93% of outbreak isolates.Disclosures A. Leber, BioFIre Diagnostics: Research Contractor and Scientific Advisor, Research support, Speaker honorarium and Travel expenses

A group A Streptococcus ADP-ribosyltransferase toxin stimulates a protective interleukin 1β-dependent macrophage immune response.

ABSTRACTThe M1T1 clone of group A Streptococcus (GAS) is associated with severe invasive infections, including necrotizing fasciitis and septicemia. During invasive M1T1 GAS disease, mutations in the covRS regulatory system led to upregulation of an ADP-ribosyltransferase, SpyA. Surprisingly, a GAS ΔspyA mutant was resistant to killing by macrophages and caused higher mortality with impaired bacterial clearance in a mouse intravenous challenge model. GAS expression of SpyA triggered macrophage cell death in association with caspase-1-dependent interleukin 1β (IL-1β) production, and differences between wild-type (WT) and ΔspyA GAS macrophage survival levels were lost in cells lacking caspase-1, NOD-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein (ASC), or pro-IL-1β. Similar in vitro findings were identified in macrophage studies performed with pseudomonal exotoxin A, another ADP-ribosylating toxin. Thus, SpyA triggers caspase-1-dependent inflammatory cell death in macrophages, revealing a toxin-triggered IL-1β-dependent innate immune response pathway critical in defense against invasive bacterial infection.

Increasing incidence of invasive group A streptococcus disease in New Zealand, 2002–2012: A national population-based study

To analyse the incidence, demographics and molecular epidemiology of invasive group A streptococcal (GAS) disease in New Zealand between 2002 and 2012. Using laboratory-based surveillance data, invasive GAS isolates were identified from the Institute of Environmental Science and Research, New Zealand. Hospitalization and mortality data were obtained from the New Zealand Ministry of Health. Molecular typing was performed by sequence analysis of the emm gene. The incidence of invasive GAS infections increased from 3.9 per 100,000 population in 2002 to 7.9 per 100,000 population (P<0.001) in 2012. The incidence was highest in the over 75-year age group, and in Pacific peoples. There was temporal variation in emm types associated with invasive GAS disease, with emm1 being the overall predominant emm type. The diversity of emm types varied significantly according to ethnicity. Overall, 59% of GAS isolates were theoretically covered by an experimental M-protein vaccine. Our study provides valuable data on the epidemiology of invasive GAS disease in New Zealand, and represents one of the few studies to assess such longitudinal data across an entire nation. The increase in invasive GAS disease is concerning, and reasons for this should be explored further.

Severe group A streptococcal infections in a paediatric intensive care unit.

To describe the clinical presentation, management and outcomes for children with invasive group A streptococcal (GAS) infection in a paediatric intensive care unit (PICU). We reviewed the clinical and laboratory records of patients admitted to a PICU in Melbourne with invasive GAS infection from April 2010 to April 2013. Outcomes recorded included survival, organ failure, need for extracorporeal support, renal replacement therapy and prolonged neuromuscular weakness. Twelve cases of invasive GAS infection were identified. The most common clinical presentations were pneumonia (n=5), bacteraemia with no septic focus (n=4) and septic arthritis (n=3). Necrotising fasciitis occurred in one patient and another patient presented with ischaemic lower limbs requiring amputation. Of the eight isolates with available emm typing results, the most common emm type was emm1 (n=4) followed by emm4, 12 and 22. Nine patients had multi-organ failure. Ten patients required mechanical ventilation for a median duration of 8 days. Nine patients required inotropic and/or vasopressor support and four patients extracorporeal membrane oxygenation support. Eleven patients survived. A prolonged period of neuromuscular weakness following the initial severe illness was common (n=5), but most children returned to normal or near normal neurological function. Invasive GAS disease in children may cause severe multi-organ failure with resultant prolonged intensive care stay and significant morbidity. However, a high rate of survival and return to normal functioning may be achieved with multi-system intensive care support and multi-disciplinary rehabilitation.

Dual-site phosphorylation of the control of virulence regulator impacts group a streptococcal global gene expression and pathogenesis.

Phosphorylation relays are a major mechanism by which bacteria alter transcription in response to environmental signals, but understanding of the functional consequences of bacterial response regulator phosphorylation is limited. We sought to characterize how phosphorylation of the control of virulence regulator (CovR) protein from the major human pathogen group A Streptococcus (GAS) influences GAS global gene expression and pathogenesis. CovR mainly serves to repress GAS virulence factor-encoding genes and has been shown to homodimerize following phosphorylation on aspartate-53 (D53) in vitro. We discovered that CovR is phosphorylated in vivo and that such phosphorylation is partially heat-stable, suggesting additional phosphorylation at non-aspartate residues. Using mass spectroscopy along with targeted mutagenesis, we identified threonine-65 (T65) as an additional CovR phosphorylation site under control of the serine/threonine kinase (Stk). Phosphorylation on T65, as mimicked by the recombinant CovR T65E variant, abolished in vitro CovR D53 phosphorylation. Similarly, isoallelic GAS strains that were either unable to be phosphorylated at D53 (CovR-D53A) or had functional constitutive phosphorylation at T65 (CovR-T65E) had essentially an identical gene repression profile to each other and to a CovR-inactivated strain. However, the CovR-D53A and CovR-T65E isoallelic strains retained the ability to positively influence gene expression that was abolished in the CovR-inactivated strain. Consistent with these observations, the CovR-D53A and CovR-T65E strains were hypervirulent compared to the CovR-inactivated strain in a mouse model of invasive GAS disease. Surprisingly, an isoalleic strain unable to be phosphorylated at CovR T65 (CovR-T65A) was hypervirulent compared to the wild-type strain, as auto-regulation of covR gene expression resulted in lower covR gene transcript and CovR protein levels in the CovR-T65A strain. Taken together, these data establish that CovR is phosphorylated in vivo and elucidate how the complex interplay between CovR D53 activating phosphorylation, T65 inhibiting phosphorylation, and auto-regulation impacts streptococcal host-pathogen interaction.