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Background: The Global COVID Vaccine Safety (GCoVS) Project, established in 2021 under the multinational Global Vaccine Data Network™ (GVDN®), facilitates comprehensive assessment of vaccine safety. This study aimed to evaluate the risk of adverse events of special interest (AESI) following COVID-19 vaccination from 10 sites across eight countries. Methods: Using a common protocol, this observational cohort study compared observed with expected rates of 13 selected AESI across neurological, haematological, and cardiac outcomes. Expected rates were obtained by participating sites using pre-COVID-19 vaccination healthcare data stratified by age and sex. Observed rates were reported from the same healthcare datasets since COVID-19 vaccination program rollout. AESI occurring up to 42 days following vaccination with mRNA (BNT162b2 and mRNA-1273) and adenovirus-vector (ChAdOx1) vaccines were included in the primary analysis. Risks were assessed using observed versus expected (OE) ratios with 95 % confidence intervals. Prioritised potential safety signals were those with lower bound of the 95 % confidence interval (LBCI) greater than 1.5. Results: Participants included 99,068,901 vaccinated individuals. In total, 183,559,462 doses of BNT162b2, 36,178,442 doses of mRNA-1273, and 23,093,399 doses of ChAdOx1 were administered across participating sites in the study period. Risk periods following homologous vaccination schedules contributed 23,168,335 person-years of follow-up. OE ratios with LBCI > 1.5 were observed for Guillain-Barré syndrome (2.49, 95 % CI: 2.15, 2.87) and cerebral venous sinus thrombosis (3.23, 95 % CI: 2.51, 4.09) following the first dose of ChAdOx1 vaccine. Acute disseminated encephalomyelitis showed an OE ratio of 3.78 (95 % CI: 1.52, 7.78) following the first dose of mRNA-1273 vaccine. The OE ratios for myocarditis and pericarditis following BNT162b2, mRNA-1273, and ChAdOx1 were significantly increased with LBCIs > 1.5. Conclusion: This multi

Background: The Global COVID Vaccine Safety (GCoVS) project was established in 2021 under the multinational Global Vaccine Data Network (GVDN) consortium to facilitate the rapid assessment of the safety of newly introduced vaccines. This study analyzed data from GVDN member sites on the background incidence rates of conditions designated as adverse events of special interest (AESI) for COVID-19 vaccine safety monitoring. Methods: Eleven GVDN global sites obtained data from national or regional healthcare databases using standardized methods. Incident events of 13 pre-defined AESI were included for a pre-pandemic period (2015–19) and the first pandemic year (2020). Background incidence rates (IR) and 95% confidence intervals (CI) were calculated for inpatient and emergency department encounters, stratified by age and sex, and compared between pre-pandemic and pandemic periods using incidence rate ratios. Results: An estimated 197 million people contributed 1,189,652,926 person-years of follow-up time. Among inpatients in the pre-pandemic period (2015–19), generalized seizures were the most common neurological AESI (IR ranged from 22.15 [95% CI 19.01–25.65] to 278.82 [278.20–279.44] per 100,000 person-years); acute disseminated encephalomyelitis was the least common (<0.5 per 100,000 person-years at most sites). Pulmonary embolism was the most common thrombotic event (IR 45.34 [95% CI 44.85–45.84] to 93.77 [95% CI 93.46–94.08] per 100,000 person-years). The IR of myocarditis ranged from 1.60 [(95% CI 1.45–1.76) to 7.76 (95% CI 7.46–8.08) per 100,000 person-years. The IR of several AESI varied by site, healthcare setting, age and sex. The IR of some AESI were notably different in 2020 compared to 2015–19. Conclusion: Background incidence of AESIs exhibited some variability across study sites and between pre-pandemic and pandemic periods. These findings will contribute to global vaccine safety surveillance and research.

Influenza is a common cause of acute respiratory infection, and is a major cause of morbidity and mortality. This report summarises the epidemiology of hospitalisations with laboratory-confirmed influenza during the 2019 influenza season. The Influenza Complications Alert Network (FluCAN) is a sentinel hospital-based surveillance program that operates at sites in all jurisdictions in Australia. Cases were defined as patients hospitalised at any of the 17 sentinel hospitals with influenza confirmed by nucleic acid detection. Data were also collected on a frequency matched control group of influenza-negative patients admitted with acute respiratory infection. During the period 1 April to 31 October 2019 (the 2019 influenza season), there were 4,154 patients admitted with confirmed influenza to one of 17 FluCAN sentinel hospitals. Of these, 44% were elderly (>= 65 years), 21% were children (< 16 years), 7.7% were Aboriginal and Torres Strait Islander peoples, 1.7% were pregnant and 73% had chronic comorbidities. Most admissions were due to influenza A infection (85%). Estimated vaccine coverage was 75% in the elderly, 49% in non-elderly adults with medical comorbidities, and 27% in young children (< 5 years). The estimated vaccine effectiveness in the target adult population was 42% (95% confidence interval [95% CI]: 36%, 49%). There were a larger number of hospital admissions detected with confirmed influenza in this national observational surveillance system in 2019 than in 2018.Copyright © Commonwealth of Australia CC BY-NC-ND.

Introduction: Influenza is a common cause of acute respiratory infection, and is a major cause of morbidity and mortality. Coronavirus disease 2019 (COVID-19) is an acute respiratory infection that emerged as a pandemic worldwide before the start of the 2020 Australian influenza season. This report summarises the epidemiology of hospitalisations with laboratory-confirmed influenza and COVID-19 during the 2020 influenza season in a sentinel surveillance system. Method(s): The Influenza Complications Alert Network (FluCAN) is a sentinel hospital-based surveillance program that operates at sites in all jurisdictions in Australia. Influenza and COVID-19 cases were defined as patients hospitalised at sentinel hospitals and confirmed by nucleic acid detection. Result(s): There were 448 patients with COVID-19 admitted between 16 March and 31 December 2020, and only 20 patients with influenza admitted between 1 April and 30 November 2020, to one of 22 FluCAN hospitals. Of the COVID-19 cases, 173 (39%) were > 65 years of age, 36 (8%) were children (< 16 years), 6 (1%) were Aboriginal and Torres Strait Islander peoples, 4 (1%) were pregnant and 289 (65%) had chronic comorbidities. COVID-19 hospital admissions peaked between weeks 13 and 15 (first wave) nationally, and again between weeks 31 and 35 (Victoria), with most admissions represented by those above 40 years of age. Discussion(s): There was an unusually low number of hospital admissions with laboratory-confirmed influenza in this season, compared to recent seasons. This is likely to be due to effective public health interventions and international border closures as a result of a rise in COVID-19 respiratory infections and associated hospitalisations.Copyright © Commonwealth of Australia CC BY-NC-ND.

Introduction: Influenza is a common cause of acute respiratory infection, and is a major cause of morbidity and mortality. Coronavirus disease 2019 (COVID-19) is an acute respiratory infection that emerged as a pandemic worldwide before the start of the 2020 Australian influenza season. This report summarises the epidemiology of hospitalisations with laboratory-confirmed influenza and COVID-19 during the 2020 influenza season in a sentinel surveillance system. Methods: The Influenza Complications Alert Network (FluCAN) is a sentinel hospital-based surveillance program that operates at sites in all jurisdictions in Australia. Influenza and COVID-19 cases were defined as patients hospitalised at sentinel hospitals and confirmed by nucleic acid detection. Results: There were 448 patients with COVID-19 admitted between 16 March and 31 December 2020, and only 20 patients with influenza admitted between 1 April and 30 November 2020, to one of 22 FluCAN hospitals. Of the COVID-19 cases, 173 (39%) were > 65 years of age, 36 (8%) were children (< 16 years), 6 (1%) were Aboriginal and Torres Strait Islander peoples, 4 (1%) were pregnant and 289 (65%) had chronic comorbidities. COVID-19 hospital admissions peaked between weeks 13 and 15 (first wave) nationally, and again between weeks 31 and 35 (Victoria), with most admissions represented by those above 40 years of age. Discussion: There was an unusually low number of hospital admissions with laboratory-confirmed influenza in this season, compared to recent seasons. This is likely to be due to effective public health interventions and international border closures as a result of a rise in COVID-19 respiratory infections and associated hospitalisations.

Febrile seizures are one of the commonest presentations in young children, with a 2-5% incidence in Western countries. Though they are generally benign, with rare long-term sequelae, there is much to be learned about their pathophysiology and risk factors. Febrile seizures are propagated by a variety of genetic and environmental factors, including viruses and vaccines. These factors must be taken into consideration by a clinician aiming to assess, diagnose and treat a child presenting with fevers and seizures, as well as to explain the sequelae of the febrile seizures to the concerned parents of the child. Our article provides an overview of this common childhood condition, outlining both the underlying mechanisms and the appropriate clinical approach to a child presenting with febrile seizures.

BACKGROUND: Febrile seizures are the commonest type of seizure in occurring in the first few years of life, mostly affecting children aged six months to five years old. While largely benign, the incidence of each febrile seizure increases the risk of recurrence, afebrile seizures and epilepsy. Viruses are the most frequent cause of febrile illnesses in which a febrile seizure occurs. Febrile seizure presentation patterns appear to follow a seasonal trend. AIMS: To identify patterns of febrile seizure incidence across different seasons with specific viral activity, and to establish a framework for analysing virus circulation data with common illnesses within a shared region and population. SETTING: Our study was a study of febrile seizure presentations in Victoria, Australia and respiratory virus detection. PARTICIPANTS: We obtained independent datasets of emergency department febrile seizure presentations at Monash Health and all respiratory multiplex PCR tests performed at Monash Health from January 2010-December 2019 to observe common trends in virus circulation and febrile seizure incidence. STUDY DESIGN: Trends were studied temporally through mixed effects Poisson regression analysis of the monthly incidence of febrile seizures and the rate of positive PCR tests. Peak viral seasons (95th centile incidence) were compared to median viral circulation (50th centile incidence) to calculate peak season risk ratios. RESULTS: We found a 1.75-2.06 annual risk ratio of febrile seizure incidence in June-September. Temporal analysis of our data showed this peak in febrile seizures was attributable to circulating viruses in this season, and virus modelling showed correlation with increased rates of positive Influenza A (1.48 peak season risk ratio), Influenza B (1.31 peak season risk ratio), Human metapneumovirus (1.19 peak season risk ratio) and Respiratory Syncytial Virus (1.53 peak season risk ratio) on PCR testing. CONCLUSION: Our ecological study statistically demonstra

BACKGROUND: Traditional monitoring for adverse events following immunization (AEFI) relies on various established reporting systems, where there is inevitable lag between an AEFI occurring and its potential reporting and subsequent processing of reports. AEFI safety signal detection strives to detect AEFI as early as possible, ideally close to real time. Monitoring social media data holds promise as a resource for this. OBJECTIVE: The primary aim of this study is to investigate the utility of monitoring social media for gaining early insights into vaccine safety issues, by extracting vaccine adverse event mentions (VAEMs) from Twitter, using natural language processing techniques. The secondary aims are to document the natural language processing techniques used and identify the most effective of them for identifying tweets that contain VAEM, with a view to define an approach that might be applicable to other similar social media surveillance tasks. METHODS: A VAEM-Mine method was developed that combines topic modeling with classification techniques to extract maximal VAEM posts from a vaccine-related Twitter stream, with high degree of confidence. The approach does not require a targeted search for specific vaccine reaction-indicative words, but instead, identifies VAEM posts according to their language structure. RESULTS: The VAEM-Mine method isolated 8992 VAEMs from 811,010 vaccine-related Twitter posts and achieved an F1 score of 0.91 in the classification phase. CONCLUSIONS: Social media can assist with the detection of vaccine safety signals as a valuable complementary source for monitoring mentions of vaccine adverse events. A social media-based VAEM data stream can be assessed for changes to detect possible emerging vaccine safety signals, helping to address the well-recognized limitations of passive reporting systems, including lack of timeliness and underreporting.

The COVID-19 pandemic has caused widespread illness with varying clinical manifestations. One less-commonly-reported presentation of COVID-19 infection is chilblain-like lesions. We conducted an ecological analysis of chilblain presentations in comparison with confirmed and suspected COVID-19 infections in a primary care setting to establish that a relationship exists between the two. Our study collated data from three Primary Health Networks across Victoria, Australia, from 2017-2021, to understand patterns of chilblain presentations prior to and throughout the pandemic. Using a zero-inflated negative binomial regression analysis, we estimated the relationship between local minimum temperature, COVID-19 infections and the frequency of chilblain presentations. We found a 5.72 risk ratio of chilblain incidence in relation to COVID-19 infections and a 3.23 risk ratio associated with suspected COVID-19 infections. COVID-19 infections were also more strongly associated with chilblain presentations in 0-16-year-olds throughout the pandemic in Victoria. Our study statistically suggests that chilblains are significantly associated with COVID-19 infections in a primary care setting. This has major implications for clinicians aiming to diagnose COVID-19 infections or determine the cause of a presentation of chilblains. Additionally, we demonstrate the utility of large-scale primary care data in identifying an uncommon manifestation of COVID-19 infections, which will be significantly beneficial to treating physicians.

Introduction: The World Health Organization (WHO) recommends all newborn infants receive the first dose of the hepatitis B vaccine within 24 h of birth irrespective of maternal hepatitis B carrier status. However, the physiological immaturity of the immune system in preterm infants may influence the immune responses to the vaccine particularly in the first few days and weeks of life, and adverse events may occur following vaccination that are not observed in infants born at term. Objectives: To review existing published guidelines surrounding timing of the first dose of the hepatitis B vaccine in preterm infants born to hepatitis B surface antigen negative (HBsAg-negative) mothers. Methods: A search was performed for relevant papers and guidelines published between January 2002 and July 2022 on the Ovid MEDLINE and Embase databases and through targeted searches. Two authors independently reviewed the search results to identify relevant sources, which were then analysed and described through narrative synthesis. Results: Twenty-seven relevant papers and guidelines regarding 15 countries and regions were included. Of these, 13.3% of guidelines, which represented 16.8% of the overall population of 4.1 billion people covered by the identified guidelines, recommended a nationwide birth dose of the hepatitis B vaccine to all preterm infants. In 40.0% of guidelines (77.9% of the overall population), the birth dose was only recommended for infants with a birth weight of more than 2000-2200 g. Another 33.3% of countries and regions (covering 4.4% of the population) recommended no universal birth dose for all infants, including preterm infants, whilst 13.3% (1.0% of the population) had guidelines that varied between jurisdictions and hospitals within their country/region. Conclusions: Existing guidelines surrounding the timing of the first dose of the hepatitis B vaccine in preterm infants vary substantially between countries and regions. Further research comparing the immuno

Surveillance of Adverse Events Following Vaccination in the Community (SAEFVIC), Victoria's vaccine safety service for reporting adverse events following immunisation (AEFI), has provided integrated spontaneous surveillance and clinical services for individuals affected by AEFI since 2007. We describe SAEFVIC's response to the COVID-19 vaccine program, and reflect on lessons learned for vaccine safety. The massive scale of the Australian COVID-19 vaccine program required rapid adaptations across all aspects of SAEFVIC's vaccine safety services. Collection of AEFI reports was streamlined and expanded, incorporating both spontaneous and active surveillance data. Dramatically increased report volumes were managed with additional staffing, and innovations to automate, filter, and triage reports for priority follow up. There were two major adverse events of special interest (AESI): thrombosis with thrombocytopaenia syndrome and myocarditis, with multiple other AESI also investigated. Rapid escalation mechanisms to respond to AESI were established, along with AESI-specific databases for enhanced monitoring. Vaccine education and training resources were developed and public-facing vaccine safety reports updated weekly. Frequent communication with local and national government and regulatory bodies, and consultation with specialist groups was essential. The COVID-19 vaccine program has highlighted the importance of vaccine safety in supporting public confidence in vaccines and informing evidence-based immunisation policy. Supporting the COVID-19 vaccine program has required flexibility in adapting to policy changes and evolving vaccine safety signals, careful triage and prioritisation, informatics innovation, and enhanced engagement with the public regarding vaccine safety. Long-term investment to continue strengthening vaccine safety systems, building on lessons learned, will be essential for the ongoing success of Australian vaccination programs.

Objective To present Australia-wide data on paediatric COVID-19 and multisystem inflammatory syndromes to inform health service provision and vaccination prioritisation. Design Prospective, multicentre cohort study. Setting Eight tertiary paediatric hospitals across six Australian states and territories in an established research surveillance network - Paediatric Active Enhanced Disease (PAEDS). Participants All children aged <19 years with SARS-CoV-2 infection including COVID-19, Paediatric Inflammatory Multisystem Syndrome Temporally Associated with SARS-CoV-2 (PIMS-TS) and Kawasaki-like disease TS infection (KD-TS) treated at a PAEDS site from 24 March 2020 to 31 December 2020. Intervention Laboratory-confirmed SARS-CoV-2 infection. Main outcome Incidence of severe disease among children with COVID-19, PIMS-TS and KD-TS. We also compared KD epidemiology before and during the COVID-19 pandemic. Results Among 386 children with SARS-CoV-2 infection, 381 (98.7%) had COVID-19 (median 6.3 years (IQR 2.1-12.8),53.3% male) and 5 (1.3%) had multisystem inflammatory syndromes (PIMS-TS, n=4; KD-TS, n=1) (median 7.9 years (IQR 7.8-9.8)). Most children with COVID-19 (n=278; 73%) were Australian-born from jurisdictions with highest community transmission. Comorbidities were present in 72 (18.9%); cardiac and respiratory comorbidities were most common (n=32/72;44%). 37 (9.7%) children with COVID-19 were hospitalised, and two (0.5%) required intensive care. Postinfective inflammatory syndromes (PIMS-TS/KD-TS) were uncommon (n=5; 1.3%), all were hospitalised and three (3/5; 60%) required intensive care management. All children recovered and there were no deaths. KD incidence remained stable during the pandemic compared with prepandemic. Conclusions Most children with COVID-19 had mild disease. Severe disease was less frequent than reported in high prevalence settings. Preventative strategies, such as vaccination, including children and adolescents, could reduce both the acute and

Objectives: The Pre-school Osteoarticular Infection (POI) study aimed to describe the burden of disease, epidemiology, microbiology and treatment of acute osteoarticular infections (OAI) and the role of Kingella kingae in these infections. Method(s): Information about children 3-60 months of age who were hospitalized with an OAI to 11 different hospitals across Australia and New Zealand between January 2012 and December 2016 was collected retrospectively. Result(s): A total of 907 cases (73%) were included. Blood cultures grew a likely pathogen in only 18% (140/781). The peak age of presentation was 12 to 24 months (466/907, 51%) and Kingella kingae was the most frequently detected microorganism in this age group (60/466, 13%). In the majority of cases, no microorganism was detected (517/907, 57%). Addition of PCR to culture increased detection rates of K. kingae. However, PCR was performed infrequently (63/907, 7%). Conclusion(s): This large multi-national study highlights the need for more widespread use of molecular diagnostic techniques for accurate microbiological diagnosis of OAI in pre-school aged children. The data from this study supports the hypothesis that a substantial proportion of pre-school aged children with OAI and no organism identified may in fact have undiagnosed K. kingae infection. Improved detection of Kingella cases is likely to reduce the average length of antimicrobial treatment.Copyright © 2021

Background: Children with comorbidities are at greater risk of severe influenza outcomes compared with healthy children. In Australia, influenza vaccination was funded for those with comorbidities from 2010 and all children aged <5 years from 2018. Influenza vaccine coverage remains inadequate in children with and without comorbidities. Method(s): Children <=16 years admitted with acute respiratory illness and tested for influenza at sentinel hospitals were evaluated (2010-2019). Multivariable regression was used to identify predictors of severe outcomes. Vaccine effectiveness was estimated using the modified incidence density test-negative design. Result(s): Overall, 6057 influenza-confirmed hospitalized cases and 3974 test-negative controls were included. Influenza A was the predominant type (68.7%). Comorbidities were present in 40.8% of cases. Children with comorbidities were at increased odds of ICU admission, respiratory support, longer hospitalizations, and mortality. Specific comorbidities including neurological and cardiac conditions increasingly predisposed children to severe outcomes. Influenza vaccine coverage in influenza negative children with and without comorbidities was low (33.5% and 17.9%, respectively). Coverage improved following introduction of universal influenza vaccine programs for children <5 years. Similar vaccine effectiveness was demonstrated in children with (55% [95% confidence interval (CI): 45; 63%]) and without comorbidities (57% [(95%CI: 44; 67%]). Conclusion(s): Comorbidities were present in 40.8% of influenza-confirmed admissions and were associated with more severe outcomes. Children with comorbidities were more likely experience severe influenza with ICU admission, mechanical ventilation, and in-hospital morality. Despite demonstrated vaccine effectiveness in those with and without comorbidities, vaccine coverage was suboptimal. Interventions to increase vaccination are expected to reduce severe influenza outcomes.Copyright © 2

Aim: This study aimed to determine the feasibility and parental acceptability of screening for congenital cytomegalovirus (cCMV) through saliva polymerase chain reaction in infants who did not pass their newborn hearing screening. Additionally, the utility (i.e. time to diagnosis and treatment) of this enhanced clinical pathway was evaluated. Method(s): The study was conducted through the Victorian Infant Hearing Screening Programme (VIHSP) across four maternity hospitals in Melbourne, Australia, during June 2019-March 2020. Parents were approached by VIHSP staff about obtaining a test for cytomegalovirus (CMV) at the time of their baby's second positive ('refer') result on the VIHSP screen. Participating parents collected a saliva swab for CMV polymerase chain reaction from their infants. Feasibility was determined by the proportion of 'referred' infants whose parents completed the salivary CMV screening test <=21 days of life. Acceptability was measured through parent survey. Result(s): Of 126 eligible families, 96 (76.0%) had salivary screening swabs taken <=21 days of life. Most families (>92.0%) indicated that screening was acceptable, straightforward and thought testing their baby for cCMV was a good idea. One infant screened positive on day 30, was diagnosed with cCMV via confirmatory testing by day 31 and commenced valganciclovir on day 32. Conclusion(s): Obtaining a saliva sample to screen for cCMV in infants who do not pass their newborn hearing screen is feasible and appears acceptable to parents. This targeted cCMV screening method could be an option where mothers are rapidly discharged from hospital, especially in the context of the COVID-19 pandemic.Copyright © 2021 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).

OBJECTIVE: This study explored whether all-cause healthcare attendance rate post-vaccination could detect the two historical influenza safety episodes occurring in 2010 and 2015 using a large de-identified general practitioner (GP) consultations dataset. METHOD(S): A retrospective observational cohort study was conducted using GP consultation data routinely collected from 2008 to 2017 in Victoria, Australia. Post-vaccination GP consultation rates were monitored, over a 22-week surveillance period each year that aligned with each year's influenza vaccination season, using the Observed minus Expected (O-E) and the Log-Likelihood Ratio (LLR) CUSUM charts. Days 1-7 post-vaccination were considered as the risk period. The LLR CUSUM was designed to detect both a 50% and two-fold rise in the odds of the baseline post-vaccination GP consultation rates. RESULT(S): Over the 10-year study period, more than 1.5 million seasonal influenza vaccines doses were administered to 295,091 persons. Overall, 1.29% had a GP consultation within one week of vaccination, but 98.53% of the consultations occurred in days 1-3 post-vaccination. The LLR CUSUM chart detected significant increases in the weekly rates of post-vaccination GP consultation in 2010 in children aged under ten years and in 2015 in adults aged 19-64 years. These increases were aligned by week, but one week earlier and by age category, with the historical adverse events following immunisation (AEFI) signals occurring in 2010 and 2015. However, in the absence of historical AEFI signals, increased rates of post-vaccination GP consultations were identified in three of the eight influenza vaccination years. CONCLUSION(S): The crude post-vaccination healthcare attendance rate has the potential to offer a sensitive proxy to monitor vaccine safety signal. Implications for public health: Vaccine safety monitoring using syndromic indicator has the potential to augment the existing surveillance systems as part of an integrated vaccin

AIM: This study aimed to determine the feasibility and parental acceptability of screening for congenital cytomegalovirus (cCMV) through saliva polymerase chain reaction in infants who did not pass their newborn hearing screening. Additionally, the utility (i.e. time to diagnosis and treatment) of this enhanced clinical pathway was evaluated. METHODS: The study was conducted through the Victorian Infant Hearing Screening Programme (VIHSP) across four maternity hospitals in Melbourne, Australia, during June 2019-March 2020. Parents were approached by VIHSP staff about obtaining a test for cytomegalovirus (CMV) at the time of their baby's second positive ('refer') result on the VIHSP screen. Participating parents collected a saliva swab for CMV polymerase chain reaction from their infants. Feasibility was determined by the proportion of 'referred' infants whose parents completed the salivary CMV screening test ≤21 days of life. Acceptability was measured through parent survey. RESULTS: Of 126 eligible families, 96 (76.0%) had salivary screening swabs taken ≤21 days of life. Most families (>92.0%) indicated that screening was acceptable, straightforward and thought testing their baby for cCMV was a good idea. One infant screened positive on day 30, was diagnosed with cCMV via confirmatory testing by day 31 and commenced valganciclovir on day 32. CONCLUSIONS: Obtaining a saliva sample to screen for cCMV in infants who do not pass their newborn hearing screen is feasible and appears acceptable to parents. This targeted cCMV screening method could be an option where mothers are rapidly discharged from hospital, especially in the context of the COVID-19 pandemic.

Our healthcare system faces a burgeoning aging population, rising complexity, and escalating costs. Around 10% of healthcare is harmful, and evidence is slow to implement. Innovation to deliver quality and sustainable health systems is vital, and the methods are challenging. The aim of this study is to describe the process and present a perspective on a coproduced Learning Health System framework. The development of the Framework was led by publicly funded, collaborative, Academic Health Research Translation Centres, with a mandate to integrate research into healthcare to deliver impact. The focus of the framework is "learning together for better health," with coproduction involving leadership by an expert panel, a systematic review, qualitative research, a stakeholder workshop, and iterative online feedback. The coproduced framework incorporates evidence from stakeholders, from research, from data (practice to data and data to new knowledge), and from implementation, to take new knowledge to practice. This continuous learning approach aims to deliver evidence-based healthcare improvement and is currently being implemented and evaluated.

OBJECTIVE: To present Australia-wide data on paediatric COVID-19 and multisystem inflammatory syndromes to inform health service provision and vaccination prioritisation. DESIGN: Prospective, multicentre cohort study. SETTING: Eight tertiary paediatric hospitals across six Australian states and territories in an established research surveillance network-Paediatric Active Enhanced Disease (PAEDS). PARTICIPANTS: All children aged <19 years with SARS-CoV-2 infection including COVID-19, Paediatric Inflammatory Multisystem Syndrome Temporally Associated with SARS-CoV-2 (PIMS-TS) and Kawasaki-like disease TS infection (KD-TS) treated at a PAEDS site from 24 March 2020 to 31 December 2020. INTERVENTION: Laboratory-confirmed SARS-CoV-2 infection. MAIN OUTCOME: Incidence of severe disease among children with COVID-19, PIMS-TS and KD-TS. We also compared KD epidemiology before and during the COVID-19 pandemic. RESULTS: Among 386 children with SARS-CoV-2 infection, 381 (98.7%) had COVID-19 (median 6.3 years (IQR 2.1-12.8),53.3% male) and 5 (1.3%) had multisystem inflammatory syndromes (PIMS-TS, n=4; KD-TS, n=1) (median 7.9 years (IQR 7.8-9.8)). Most children with COVID-19 (n=278; 73%) were Australian-born from jurisdictions with highest community transmission. Comorbidities were present in 72 (18.9%); cardiac and respiratory comorbidities were most common (n=32/72;44%). 37 (9.7%) children with COVID-19 were hospitalised, and two (0.5%) required intensive care. Postinfective inflammatory syndromes (PIMS-TS/KD-TS) were uncommon (n=5; 1.3%), all were hospitalised and three (3/5; 60%) required intensive care management. All children recovered and there were no deaths. KD incidence remained stable during the pandemic compared with prepandemic. CONCLUSIONS: Most children with COVID-19 had mild disease. Severe disease was less frequent than reported in high prevalence settings. Preventative strategies, such as vaccination, including children and adolescents, could reduce both the acu

BACKGROUND: Children with SARS-CoV-2 infection generally present with milder symptoms or are asymptomatic in comparison with adults, however severe disease occurs in a subset of children. To date, the immune correlates of severe COVID-19 in young children have been poorly characterised. METHODS: We report the kinetics of immune responses in relation to clinical and virological features in an infant with acute severe COVID-19 using high-dimensional flow cytometry and multiplex cytokine analysis. RESULTS: Systemic cellular and cytokine profiling show an initial increase in neutrophils and monocytes with depletion of lymphoid cell populations (particularly CD8 + T and NK cells) and elevated inflammatory cytokines. Expansion of memory CD4 + T (but not CD8 + T) cells occurred over time, with a predominant Th2 bias. Marked activation of T cell populations observed during the acute infection gradually resolved as the child recovered. Substantial in vitro activation of T-cell populations and robust cytokine production, in response to inactivated SARS-CoV-2 stimulation, was observed 3 months after infection indicating durable, long-lived cellular immune memory. CONCLUSIONS: These findings provide important insights into the immune response of a young infant with severe COVID-19 and will help to inform future research into therapeutic targets for high-risk groups.

Children have lower hospitalisation and mortality rates for coronavirus disease-2019 (COVID-19) than adults; however, younger children (<4 years of age) 1 may develop more severe disease than older children. To date, the immune correlates of severe COVID-19 in young children have been poorly characterized. We report the kinetics of immune responses in relation to clinical and virological features in an infant with acute severe COVID-19. Systemic cellular and cytokine profiling showed initial increase in neutrophils and monocytes with depletion of lymphoid cell populations (particularly CD8+ T and NK cells) and elevated inflammatory cytokines. Expansion of memory CD4+T (but not CD8+T) cells occurred over time, with predominant Th2 bias. Marked activation of T cell populations observed during the acute infection gradually resolved as the child recovered. Significant in vitro activation of T-cell populations and robust cytokine production, in response to inactivated SARS-CoV-2 stimulation, was observed 3 months after infection indicating durable, long-lived cellular immune memory.

OBJECTIVE: This study explored whether all-cause healthcare attendance rate post-vaccination could detect the two historical influenza safety episodes occurring in 2010 and 2015 using a large de-identified general practitioner (GP) consultations dataset. METHODS: A retrospective observational cohort study was conducted using GP consultation data routinely collected from 2008 to 2017 in Victoria, Australia. Post-vaccination GP consultation rates were monitored, over a 22-week surveillance period each year that aligned with each year's influenza vaccination season, using the Observed minus Expected (O-E) and the Log-Likelihood Ratio (LLR) CUSUM charts. Days 1-7 post-vaccination were considered as the risk period. The LLR CUSUM was designed to detect both a 50% and two-fold rise in the odds of the baseline post-vaccination GP consultation rates. RESULTS: Over the 10-year study period, more than 1.5 million seasonal influenza vaccines doses were administered to 295,091 persons. Overall, 1.29% had a GP consultation within one week of vaccination, but 98.53% of the consultations occurred in days 1-3 post-vaccination. The LLR CUSUM chart detected significant increases in the weekly rates of post-vaccination GP consultation in 2010 in children aged under ten years and in 2015 in adults aged 19-64 years. These increases were aligned by week, but one week earlier and by age category, with the historical adverse events following immunisation (AEFI) signals occurring in 2010 and 2015. However, in the absence of historical AEFI signals, increased rates of post-vaccination GP consultations were identified in three of the eight influenza vaccination years. CONCLUSION: The crude post-vaccination healthcare attendance rate has the potential to offer a sensitive proxy to monitor vaccine safety signal. Implications for public health: Vaccine safety monitoring using syndromic indicator has the potential to augment the existing surveillance systems as part of an integrated vaccine safet

BACKGROUND: Children with comorbidities are at greater risk of severe influenza outcomes compared with healthy children. In Australia, influenza vaccination was funded for those with comorbidities from 2010 and all children aged <5 years from 2018. Influenza vaccine coverage remains inadequate in children with and without comorbidities. METHODS: Children ≤16 years admitted with acute respiratory illness and tested for influenza at sentinel hospitals were evaluated (2010-2019). Multivariable regression was used to identify predictors of severe outcomes. Vaccine effectiveness was estimated using the modified incidence density test-negative design. RESULTS: Overall, 6057 influenza-confirmed hospitalized cases and 3974 test-negative controls were included. Influenza A was the predominant type (68.7%). Comorbidities were present in 40.8% of cases. Children with comorbidities were at increased odds of ICU admission, respiratory support, longer hospitalizations, and mortality. Specific comorbidities including neurological and cardiac conditions increasingly predisposed children to severe outcomes. Influenza vaccine coverage in influenza negative children with and without comorbidities was low (33.5% and 17.9%, respectively). Coverage improved following introduction of universal influenza vaccine programs for children <5 years. Similar vaccine effectiveness was demonstrated in children with (55% [95% confidence interval (CI): 45; 63%]) and without comorbidities (57% [(95%CI: 44; 67%]). CONCLUSIONS: Comorbidities were present in 40.8% of influenza-confirmed admissions and were associated with more severe outcomes. Children with comorbidities were more likely experience severe influenza with ICU admission, mechanical ventilation, and in-hospital morality. Despite demonstrated vaccine effectiveness in those with and without comorbidities, vaccine coverage was suboptimal. Interventions to increase vaccination are expected to reduce severe influenza outcomes.

An amendment to this paper has been published and can be accessed via the original article.

Purpose Febrile seizures (FSs) occur in 3-5% of children under 6 years of age, with peak incidence in the second year of life. This coincides with the timing of the first dose of measles-containing vaccine in the United States, which has been shown to have a two-fold increased risk of FS in the two weeks following vaccination. Whole-cell pertussis and some influenza vaccines in combination with pneumococcal vaccines have also been associated with an increased rate of FSs when fever peaks after vaccination. Concerns about potential adverse neurocognitive outcomes following a vaccine proximate febrile seizure (VP-FS) can affect public and immunisation provider confidence in vaccine safety and impact on receipt of further vaccines. In this study, we compared the developmental and behavioural outcomes of children who have experienced an initial VP-FS to children who have had a non-vaccine proximate FS (NVP-FS) and to healthy controls who have not had a seizure. Methods This first ever prospective case-control study was conducted across four tertiary paediatric hospitals. Children who had their first FS before 30 months of age between May 2013 and April 2016 were recruited. They were either recruited as a VP-FS case, defined as a FS occurring on day 0-2 following receipt of an inactivated vaccine, day 5-14 following a live-attenuated vaccine or day 0-14 following a combination of inactivated and live-attenuated vaccines or an NVP-FS participant, defined as a FS outside of this period. Similar aged children with no history of seizures were recruited as controls. The Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) was administered to all FS participants 12-24 months following their initial FS and controls of similar age to VP-FS cases at the time of their assessment. Pre-academic skills of children were assessed using Woodcock-Johnson Tests of Achievement, Third Edition. Parents rated their child's behaviour and executive functioning using Behav

Background: Invasive group A streptococcal disease is a severe infection with a high case fatality rate, estimated to cause more than 150,000 deaths per year worldwide. The clinical presentation of this infection is variable, and early diagnosis can be challenging. There are few data on its short-and longer-term outcomes, especially in children. The aim of this study was to assess the clinical presentation, management and short-and longer-term outcomes of invasive group A streptococcal disease in children in Australia. Method(s): We undertook a prospective surveillance study of children with laboratory-confirmed invasive group A streptococcus disease admitted to 7 sentinel tertiary and quaternary pediatric hospitals in Australia between July 2016 and June 2018. We collected demographic and clinical data and contacted patients 6 months after discharge to assess longer-term outcomes. Result(s): We enrolled 181 children, 7 days to 16 years of age. The principal site of invasive infection was blood (126 children, 69.6%), and the most frequent clinical presentation was pneumonia in 46 children (25.4%). Twenty-six children developed streptococcal toxic shock syndrome (14.4%), and 74 had severe disease (40.9%), including 71 admitted to the intensive care unit. Five children died (2.8%). At discharge and 6 months, 29.3% and 15.2% of the children had persisting health problems, respectively. Conclusion(s): Invasive group A streptococcal infection in Australian children is frequently severe and has a high long-term morbidity burden, highlighting the need for strengthened clinical care pathways, epidemiologic surveillance and prevention strategies.Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

BACKGROUND: The Bacillus Calmette-Guerin (BCG) vaccine has an important role mitigating tuberculosis (TB) disease in high risk children. In Victoria, immunisation services at the Royal Children's Hospital (RCH) and Monash Health (MH) have been funded as the major providers of BCG vaccine since 2013. METHOD(S): In this article, we performed retrospective analysis of patients who attended RCH and MH for BCG between 1st November 2013- 30th November 2015. This was compared with local birth data in order to portray the distribution of BCG vaccine across various cohorts. OUTCOME(S): A total of 3,975 patients received BCG vaccine (1,775 at Monash, 2,200 from RCH). Detailed data is only available on 830 RCH patients. The median age of the study population was 6.9 months (IQR 3.9-11.3). The majority of children (98.9%, 2,575/2,604) received BCG vaccine prior to overseas travel. Of these, 96.0% (2,474/2,575) were travelling to countries in Asia. Only 13/2,604 (0.5%) were given BCG vaccine prior to travel to a country with low incidence of TB. Most infants were of Asian descent (93.3% mothers [2,425/2,604], 90.4% [2,346/2,604] fathers). A much smaller proportion was African (1.4% mothers [35/2,604], 1.5% [39/2,604] fathers). This contrasts with 2012 Victorian birth data, which showed that 82.2% (7,508/ 9,134) babies born to mothers from high TB prevalence countries were of Asian descent, whereas 8.9% (816/ 9,134) were of African descent. These results highlight scope to improve awareness and equity of BCG vaccine service, particularly to infants of African background.Copyright This work is copyright. You may download, display, print and reproduce the whole or part of this work in unaltered form for your own personal use or, if you are part of an organisation, for internal use within your organisation, but only if you or your organisation do not use the reproduction for any commercial purpose and retain this copyright notice and all disclaimer notices as part of that r

OBJECTIVES: Invasive group A Streptococcus (iGAS) disease is serious and sometimes life-threatening. The Paediatric Active Enhanced Disease Surveillance (PAEDS) Network collects voluntary notifications from seven major Australian paediatric hospitals on patients with certain conditions, including iGAS disease. Our aims were to: 1) Describe the epidemiological distribution of paediatric iGAS disease in Australia and correlate this with influenza notifications, 2) Identify GAS strains commonly associated with invasive disease in children. METHOD(S): IGAS and influenza notification data were obtained (from the PAEDS Network and the Australian Institute of Health and Welfare, respectively, for the period 1 July 2016 to 30 June 2018). Included iGAS patients had GAS isolated from a normally sterile body site. Data were described according to selected clinical and demographic characteristics, including by age group and Australian State, with proportions and minimum incidence rates estimated. RESULT(S): A total of 181 patients were identified, with most (115, 63.5%) <5years old. The mean annual minimum incidence rate was 1.6 (95% confidence interval: 1.1-2.3) per 100,000 children across the study period. An epidemiological correlation with the seasonal burden of influenza was noted. Contact prophylaxis was not consistently offered. Of 96 patients with emm-typing results available, 72.9% showed emm-1, -4 or-12. CONCLUSION(S): Robust surveillance systems and cohesive patient management guidelines are needed. Making iGAS disease nationally notifiable would help facilitate this. Influenza vaccination may contribute to reducing seasonal increases in iGAS incidence. The burden of disease emphasises the need for ongoing progress in GAS vaccine development.

ObjectiveTo compare the developmental and behavioral outcomes of children experiencing an initial vaccine-proximate (VP) febrile seizure (FS) to those having a non-VP-FS (NVP-FS) and controls who have not had a seizure.MethodsIn this prospective multicenter cohort study, children with their first FS before 30 months of age between May 2013 and April 2016 were recruited from 4 Australian pediatric hospitals and classified as having VP-FS or NVP-FS. Similar-aged children with no seizure history were recruited as controls. The Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) was administered to participants with FS 12 to 24 months after their initial FS and to controls 12 to 42 months of age at the time of assessment. The primary outcome was the Bayley-III cognitive score. Children's preacademic skills were assessed with the Woodcock-Johnson Tests of Achievement, Third Edition, and their behavior and executive functioning were obtained from parent questionnaires.ResultsThere was no significant difference in cognitive function between children with VP-FS (n = 62), those with NVP-FS (n = 70), and controls (n = 90) (F2,219 = 2.645, p = 0.07). There were no differences between the groups for all other measures and no increased risk of borderline/significant impairment or behavior in the clinical range in children with VP-FS compared to those with NVP-FS or controls.ConclusionVP-FS was not associated with an increased risk of developmental or behavioral problems in young children compared to children with NVP-FS or controls. Parents and providers should be reassured by the absence of adverse effects of VP-FS on the development of children.Copyright © American Academy of Neurology.

Objective: Febrile seizures may follow vaccination. Common variants in the sodium channel gene, SCN1A, are associated with febrile seizures, and rare pathogenic variants in SCN1A cause the severe developmental and epileptic encephalopathy Dravet syndrome. Following vaccination, febrile seizures may raise the specter of poor outcome and inappropriately implicate vaccination as the cause. We aimed to determine the prevalence of SCN1A variants in children having their first febrile seizure either proximal to vaccination or unrelated to vaccination compared to controls. Method(s): We performed SCN1A sequencing, blind to clinical category, in a prospective cohort of children presenting with their first febrile seizure as vaccine proximate (n = 69) or as non-vaccine proximate (n = 75), and children with no history of seizures (n = 90) recruited in Australian pediatric hospitals. Result(s): We detected 2 pathogenic variants in vaccine-proximate cases (p.R568X and p.W932R), both of whom developed Dravet syndrome, and 1 in a non-vaccine-proximate case (p.V947L) who had febrile seizures plus from 9 months. All had generalized tonic-clonic seizures lasting >15 minutes. We also found enrichment of a reported risk allele, rs6432860-T, in children with febrile seizures compared to controls (odds ratio = 1.91, 95% confidence interval = 1.31-2.81). Interpretation(s): Pathogenic SCN1A variants may be identified in infants with vaccine-proximate febrile seizures. As early diagnosis of Dravet syndrome is essential for optimal management and outcome, SCN1A sequencing in infants with prolonged febrile seizures, proximate to vaccination, should become routine. ANN NEUROL 2020;87:281-288.Copyright © 2019 American Neurological Association

Bacille Calmete-Guerin vaccine is widely administered to reduce the risk of severe tuberculosis disease in children. Recent global vaccine supply issues have led to the use of alternative products, which may vary in side effect profile. We report on the safety of the Polish (Moreau strain) "Bacille Calmete-Guerin-10" vaccine in an Australian cohort. Using active surveillance, we identified an adverse event rate of 54.6 per 10,000 doses (95% confidence interval: 38.5-75.2), which was comparable to that reported with the Danish Sanofi-Pasteur and Connaught strains.Copyright © 2020 Lippincott Williams and Wilkins. All rights reserved.

Background: SAEFVIC is the Victorian surveillance system for adverse events following immunisation (AEFI). It enhances passive surveillance by also providing clinical support and education to vaccinees and immunisation providers. This report summarises surveillance, clinical and vaccine pharmacovigilance activities of SAEFVIC in 2018. Methods: A retrospective observational cohort study of AEFI reports received by SAEFVIC in 2018, compared with previous years since 2008. Data were categorised by vaccinee demographics of age, sex, pregnancy and Indigenous status, vaccines administered and AEFI reactions reported. Age cohorts were defined as infant (0-12 months); young child (1-4 years); school-aged (5-17 years); adult (18-64 years); and older person (65+ years). Proportional reporting ratios were calculated for signal investigation of serious adverse neurological events with all vaccines and with influenza vaccines. Clinical support services and educational activities are described. Results: SAEFVIC received 1730 AEFI reports (26.8 per 100,000 population), with 9.3% considered serious. Nineteen percent (n = 329) attended clinical review. Annual AEFI reporting trends increased for infants, children and older persons, but were stable for school-aged and adult cohorts. Females comprised 55% of all reports and over 80% of reports among adults. There were 17 reports of AEFI in pregnant women and 12 (0.7%) in persons identifying as Indigenous Australians. A possible signal regarding serious adverse neurological events (SANE) was detected, but was not supported by signal validation testing. A clinical investigation is ongoing. Two deaths were reported coincident to immunisation with no evidence of causal association. Conclusion: SAEFVIC continues to provide robust AEFI surveillance supporting vaccine safety monitoring in Victoria and Australia, with new signal detection and validation methodologies strengthening capabilities.

BACKGROUND: Invasive group A streptococcal disease is a severe infection with a high case fatality rate, estimated to cause more than 150,000 deaths per year worldwide. The clinical presentation of this infection is variable, and early diagnosis can be challenging. There are few data on its short- and longer-term outcomes, especially in children. The aim of this study was to assess the clinical presentation, management and short- and longer-term outcomes of invasive group A streptococcal disease in children in Australia. METHODS: We undertook a prospective surveillance study of children with laboratory-confirmed invasive group A streptococcus disease admitted to 7 sentinel tertiary and quaternary pediatric hospitals in Australia between July 2016 and June 2018. We collected demographic and clinical data and contacted patients 6 months after discharge to assess longer-term outcomes. RESULTS: We enrolled 181 children, 7 days to 16 years of age. The principal site of invasive infection was blood (126 children, 69.6%), and the most frequent clinical presentation was pneumonia in 46 children (25.4%). Twenty-six children developed streptococcal toxic shock syndrome (14.4%), and 74 had severe disease (40.9%), including 71 admitted to the intensive care unit. Five children died (2.8%). At discharge and 6 months, 29.3% and 15.2% of the children had persisting health problems, respectively. CONCLUSIONS: Invasive group A streptococcal infection in Australian children is frequently severe and has a high long-term morbidity burden, highlighting the need for strengthened clinical care pathways, epidemiologic surveillance and prevention strategies.