Characterization of gram-negative bloodstream infections in hospitalised Australian children and their clinical outcomes.

BACKGROUND: Gram-negative bloodstream infections (GNBSI) more commonly occur in children with comorbidities and are increasingly associated with antimicrobial resistance. There are few large studies of GNBSI in children that relate the clinical presentation, pathogen characteristics and outcomes. METHODS: A 3-year prospective study of GNBSI in children aged <18 years was conducted in five Australian children's hospitals between 2019-2021. The clinical characteristics, disease severity and outcomes were recorded. Causative pathogens underwent antibiotic susceptibility testing and whole genome sequencing. RESULTS: There were 931 GNBSI episodes involving 818 children. Median age was 3 years (IQR 0.6-8.5). 576/931 episodes (62%) were community onset though 661/931 (71%) occurred in children with comorbidities and a central venous catheter (CVC) was present in 558/931 (60%). CVC (145/931) and urinary tract (149/931) were the most common sources (16% each). 100/931 (11%) children required Intensive Care Unit (ICU) admission and a further 11% (105/931) developed GNBSI in ICU. 659/927 (71%) isolates were Enterobacterales of which 22% (138/630) were third generation cephalosporin resistant (3GCR). Extended spectrum beta-lactamase genes (ESBL) were confirmed in 65/138 (47%) 3GCR-Enterobacterales. Most common ESBL genes were blaCTX-M-15 (34/94, 36%) and blaSHV-12 (10/94, 11%). There were 48 deaths overall and 30-day in-hospital mortality was 3% (32/931). Infections with 3GCR Enterobacterales were independently associated with higher mortality (adjusted OR 3.2, 95%CI 1.6-6.4). CONCLUSION: GNBSI in children are frequently healthcare-associated and affect children under 5 years. Infections with 3GCR Enterobacterales were associated with worse outcomes. These findings will inform optimal management guidelines and help prioritise future antimicrobial clinical trials.

Respiratory Syncytial Virus Reinfections in Children in Western Australia.

Respiratory syncytial virus (RSV) reinfection in children is poorly understood. We examined the incidence, characteristics, and outcomes of hospital-attended RSV reinfections in children <16 years in Western Australia between 2012 and 2022. Individuals with repeat RSV detections ≥56 days apart were identified using laboratory data. The incidence of reinfection in the first five years of life was estimated using the total birth population from 2012 to 2017. Clinical data on a subset of reinfection episodes were obtained from two metropolitan pediatric centers. A total of 466 children with hospital-attended reinfections were identified. The median interval between RSV detections was 460 days (interquartile range: 324, 812), with a reinfection rate of 95 per 100,000 individuals (95% confidence interval: 82, 109). Reinfection was most common in children who experienced their first RSV detection <6 months of age. Predisposing factors were identified in 56% of children; children with predisposing factors were older at first and second detections, were more likely to be admitted, and had a longer length of stay. This study highlights the significant burden of hospital-attended RSV reinfections in children with and without predisposing factors. Expanded surveillance with in-depth clinical data is required to further characterize the impact of RSV reinfection.

Safety of BCG vaccination and revaccination in healthcare workers.

BCG vaccination and revaccination are increasingly being considered for the protection of adolescents and adults against tuberculosis and, more broadly, for the off-target protective immunological effects against other infectious and noninfectious diseases. Within an international randomized controlled trial of BCG vaccination in healthcare workers (the BRACE trial), we evaluated the incidence of local and serious adverse events, as well as the impact of previous BCG vaccination on local injection site reactions (BCG revaccination). Prospectively collected data from 99% (5351/5393) of participants in Australia, Brazil, Spain, The Netherlands and the UK was available for analysis. Most BCG recipients experienced the expected self-limiting local injection site reactions (pain, tenderness, erythema, swelling). BCG injection site itch was an additional common initial local symptom reported in 49% of BCG recipients. Compared to BCG vaccination in BCG-naïve individuals, BCG revaccination was associated with increased frequency of mild injection site reactions, as well as earlier onset and shorter duration of erythema and swelling, which were generally self-limiting. Injection site abscess and regional lymphadenopathy were the most common adverse events and had a benign course. Self-resolution occurred within a month in 80% of abscess cases and 100% of lymphadenopathy cases. At a time when BCG is being increasingly considered for its off-target effects, our findings indicate that BCG vaccination and revaccination have an acceptable safety profile in adults.

Erratum: Factors influencing scar formation following Bacille Calmette-Guérin (BCG) vaccination.

[This corrects the article DOI: 10.1016/j.heliyon.2023.e15241.].

Factors influencing scar formation following Bacille Calmette-Guérin (BCG) vaccination.

The prevalence of scar formation following Bacille Calmette-Guérin (BCG) vaccination varies globally. The beneficial off-target effects of BCG are proposed to be stronger amongst children who develop a BCG scar. Within an international randomised trial ('BCG vaccination to reduce the impact of coronavirus disease 2019 (COVID-19) in healthcare workers'; BRACE Trial), this nested prospective cohort study assessed the prevalence of and factors influencing scar formation, as well as participant perception of BCG scarring 12 months following vaccination . Amongst 3071 BCG-recipients, 2341 (76%) developed a BCG scar. Scar prevalence was lowest in Spain and highest in UK. Absence of post-injection wheal (OR 0.4, 95%CI 0.2-0.9), BCG revaccination (OR 1.7, 95%CI 1.3-2.0), female sex (OR 2.0, 95%CI 1.7-2.4), older age (OR 0.4, 95%CI 0.4-0.5) and study country (Brazil OR 1.6, 95%CI 1.3-2.0) influenced BCG scar prevalence. Of the 2341 participants with a BCG scar, 1806 (77%) did not mind having the scar. Participants more likely to not mind were those in Brazil, males and those with a prior BCG vaccination history. The majority (96%) did not regret having the vaccine. Both vaccination-related (amenable to optimisation) and individual-related factors affected BCG scar prevalence 12 months following BCG vaccination of adults, with implications for maximising the effectiveness of BCG vaccination.

Australian hospital paediatricians and nurses' perspectives and practices for influenza vaccine delivery in children with medical comorbidities.

INTRODUCTION: Influenza vaccination of children with medical comorbidities is critical due their increased risks for severe influenza disease. In Australia, hospitals are an avenue for influenza vaccine delivery to children with comorbidities but are not always effectively utilised. Qualitative enquiry sought to ascertainment the barriers and enablers for influenza vaccination recommendation, delivery, and recording of these children at Australian hospitals. METHODS: Semi-structured interviews and discussion group sessions were conducted with paediatricians and nurses at four tertiary paediatric specialist hospitals and two general community hospitals in three Australian states. Transcripts from interviews and group sessions were inductively analysed for themes. The Capability, Opportunity, Motivation, and Behaviour (COM-B) model was used to explore the elements of each theme and identify potential interventions to increase influenza vaccination recommendation and delivery behaviours by providers. RESULTS: Fifteen discussion sessions with 28 paediatricians and 26 nurses, and nine in-depth interviews (five paediatricians and four nurses) were conducted. Two central thematic domains were identified: 1. The interaction between hospital staff and parents/patients for influenza vaccine recommendation, and 2. Vaccination delivery and recording in the hospital environment. Six themes across these domains emerged detailing the importance of dedicated immunisation services, hospital leadership, paediatricians' vaccine recommendation role, the impact of comorbidities, vaccination recording, and cocooning vaccinations. Supportive hospital leadership, engaged providers, and dedicated immunisation services were identified as essential for influenza vaccination of children with comorbidities in Australian hospital. CONCLUSION: Recommendation of influenza vaccination for Australian children with comorbidities is impacted by the beliefs of paediatricians and the perceived impact of influenza disease on children's comorbidities. Dedicated immunisation services and supportive hospital leadership were drivers for influenza vaccine delivery at hospitals. Future interventions targeting hospital-based influenza vaccine delivery for children with comorbidities should take a rounded approach targeting providers' attitudes, the hospital environment and leadership support.

The safety of co-administration of Bacille Calmette-Guérin (BCG) and influenza vaccines.

BACKGROUND: With the emergence of novel vaccines and new applications for older vaccines, co-administration is increasingly likely. The immunomodulatory effects of BCG could theoretically alter the reactogenicity of co-administered vaccines. Using active surveillance in a randomised controlled trial, we aimed to determine whether co-administration of BCG vaccination changes the safety profile of influenza vaccination. METHODS: Participants who received influenza vaccine alone (Influenza group) were compared with those who also received BCG-Denmark vaccine in the contralateral arm (Influenza+BCG group). Data on the influenza vaccination site were collected using serial questionnaires and active follow-up for 3 months post vaccination. RESULTS: Of 1351 participants in the Influenza+BCG group and 1418 participants in the Influenza group, 2615 (94%) provided influenza vaccine safety data. There was no significant difference in the proportion of participants with any local adverse reaction between the Influenza+BCG group and the Influenza group (918/1293 [71.0%] versus (906/1322 [68.5%], p = 0.17). The proportion of participants reporting any pain, erythema and tenderness at the influenza vaccination site were similar in both groups. Swelling was less frequent (81/1293 [6.3%] versus 119/1322 (9.0%), p = 0.01) and the maximal diameter of erythema was smaller (mean 1.8 cm [SD 2.0] versus 3.0 cm [SD 2.5], p<0.001) in the Influenza+BCG group. Sixteen participants reported serious adverse events: 9 participants in the Influenza+BCG group and 7 in the Influenza group. CONCLUSIONS: Adverse events following influenza vaccination are not increased when BCG is co-administered.

Status epilepticus following vaccination in children aged ≤24 months: A five-year retrospective observational study.

BACKGROUND: Status epilepticus is associated with significant morbidity and mortality. While vaccine-proximate status epilepticus (VP-SE) has rarely been associated with cases of Dravet syndrome, it is not known whether VP-SE differs clinically from non-vaccine proximate status epilepticus (NVP-SE). METHODS: Medical records of children aged ≤24 months, presenting to one of five Australian tertiary pediatric hospitals with their first episode of status epilepticus from 2013 to 2017 were identified using ICD-coded discharge diagnoses. Vaccination history was obtained from the Australian Immunisation Register. Hospitalization details, subsequent epilepsy diagnosis, and vaccination uptake were compared between VP-SE and NVP-SE cases. RESULTS: Of 245 first status epilepticus hospitalization with immunization records, 35 (14%) were VP-SE and 21 (60%) followed measles-containing vaccines. Vaccine-proximate status epilepticus cases had a median age of 12.5 months [IQR 7.1-14.73], 23 (66%) were in males, 15 (43%) were febrile status epilepticus and 17 (49%) had an infection confirmed. There were no significant differences in hospitalization duration (P = 0.50) or intensive care unit admission (P = 0.42) between children with VP-SE compared to children with NVP-SE. Children with no history of seizures at their first VP-SE had longer hospitalizations, were more likely to require intensive care unit admission, but were less likely to have a subsequent diagnosis of epilepsy than children with previous seizures at their first VP-SE. CONCLUSION: First VP-SE was predominantly associated with a measles-containing vaccine at 12-months of age. Seizure severity was no different between first VP-SE and first NVP-SE. In children with VP-SE, subsequent seizure admissions and epilepsy diagnosis were associated with having seizure prior to their first SE.

COVID-19 vaccination in children and adolescents aged 5 years and older undergoing treatment for cancer and non-malignant haematological conditions: Australian and New Zealand Children's Haematology/Oncology Group consensus statement.

INTRODUCTION: The Australian Technical Advisory Group on Immunisation and New Zealand Ministry of Health recommend all children aged ≥ 5 years receive either of the two mRNA COVID-19 vaccines: Comirnaty (Pfizer), available in both Australia and New Zealand, or Spikevax (Moderna), available in Australia only. Both vaccines are efficacious and safe in the general population, including children. Children and adolescents undergoing treatment for cancer and immunosuppressive therapy for non-malignant haematological conditions are particularly vulnerable, with an increased risk of severe or fatal COVID-19. There remains a paucity of data regarding the immune response to COVID-19 vaccines in immunosuppressed paediatric populations, with data suggestive of reduced immunogenicity of the vaccine in immunocompromised adults. RECOMMENDATIONS: Considering the safety profile of mRNA COVID-19 vaccines and the increased risk of severe COVID-19 in immunocompromised children and adolescents, COVID-19 vaccination is strongly recommended for this at-risk population. We provide a number of recommendations regarding COVID-19 vaccination in this population where immunosuppressive, chemotherapeutic and/or targeted biological agents are used. These include the timing of vaccination in patients undergoing active treatment, management of specific situations where vaccination is contraindicated or recommended under special precautions, and additional vaccination recommendations for severely immunocompromised patients. Finally, we stress the importance of upcoming clinical trials to identify the safest and most efficacious vaccination regimen for this population. CHANGES IN MANAGEMENT AS A RESULT OF THIS STATEMENT: This consensus statement provides recommendations for COVID-19 vaccination in children and adolescents aged ≥ 5 years with cancer and immunocompromising non-malignant haematological conditions, based on evidence, national and international guidelines and expert opinion. ENDORSED BY: The Australian and New Zealand Children's Haematology/Oncology Group.

Revaccination with Bacille Calmette-Guérin (BCG) is associated with an increased risk of abscess and lymphadenopathy.

The reported frequency and types of adverse events following initial vaccination and revaccination with Bacille Calmette-Guérin (BCG) varies worldwide. Using active surveillance in a randomised controlled trial of BCG vaccination (the BRACE trial), we determined the incidence and risk factors for the development of BCG injection site abscess and regional lymphadenopathy. Injection site abscess occurred in 3% of 1387 BCG-vaccinated participants; the majority (34/41, 83%) resolved without treatment. The rate was higher in BCG-revaccinated participants (OR 3.6, 95% CI 1.7-7.5), in whom abscess onset was also earlier (median 16 vs. 27 days, p = 0.008). No participant with an abscess had a positive interferon-gamma release assay. Regional lymphadenopathy occurred in 48/1387 (3%) of BCG-vaccinated participants, with a higher rate in revaccinated participants (OR 2.1, 95% CI 1.1-3.9). BCG-associated lymphadenopathy, but not injection site abscess, was influenced by age and sex. A previous positive tuberculin skin test was not associated with local reactions. The increased risk of injection site abscess or lymphadenopathy following BCG revaccination is relevant to BCG vaccination policy in an era when BCG is increasingly being considered for novel applications.

Revaccination outcomes of children with vaccine proximate seizures.

BACKGROUND: Seizures, whether febrile or afebrile, occurring within 14 days following vaccination can be considered as vaccine proximate seizures (VPSs). While the attributable risk and clinical severity of first febrile VPS is well known, the risk and clinical outcomes of VPS recurrence is less well defined. METHODS: We conducted a retrospective review of revaccination management and outcomes in children who experienced a VPS as their first seizure seen in Australian Specialist Immunisation Clinics between 2013 and 2017. Vaccination outcomes were compared between children who had a VPS as their only seizure (VPS only) and children who had further non-vaccine proximate seizures following their initial VPS (VPS+) prior to review at the clinic. RESULTS: We identified 119 children with a VPS as their first seizure, of which 61 (51%) went on to have other seizures (VPS+). Children with VPS+ were more likely to present at a younger age (6.2 vs 12.5 months, P = 0.03), with afebrile seizures (42.6% vs 15.5%, P = 0.002) compared to VPS only children. VPS recurrence on revaccination was uncommon in both groups, but more common in VPS+ children (12.5% vs 2.4%, P = 0.07). Having an epilepsy diagnosis, specifically Dravet syndrome, was associated with VPS recurrence (P < 0.001). Of the four children with Dravet syndrome who had VPS recurrence, all had status epilepticus following revaccination. CONCLUSION: In children who presented with a single VPS as their only seizure, VPS recurrence on revaccination was uncommon. Children who had multiple non-vaccine proximate seizures following their initial VPS (VPS+) were more likely to present with afebrile VPS, at a younger age and have a VPS recurrence with vaccination. In these children, particularly those aged < 12 months, assessment and investigation for diagnosis of Dravet syndrome should be considered and additional precautions for revaccination undertaken as they are at highest risk of VPS recurrence.

Immunogenicity of the inactivated influenza vaccine in children who have undergone allogeneic haematopoietic stem cell transplant.

Influenza vaccination is recommended for children following allogeneic haematopoietic stem cell transplant (HSCT), however there is limited evidence regarding its benefit. A prospective multicentre study was conducted to evaluate the immunogenicity of the inactivated influenza vaccine in children who have undergone HSCT compared with healthy age-matched controls. Participants were vaccinated between 2013 and 2016 according to Australian guidelines. Influenza-specific hemagglutinin inhibition antibody titres were performed prior to each vaccination and 4 weeks following the final vaccination. A nasopharyngeal aspirate for influenza was performed on participants that developed influenza-like illness. There were 86 children recruited; 43 who had undergone HSCT and 43 controls. For the HSCT group, seroprotection and seroconversion rates were 81.4% and 60.5% for H3N2, 41.9% and 32.6% for H1N1, and 44.2% and 39.5% for B strain respectively. There was a significant geometric mean fold increase to the H3N2 (GMFI 5.80, 95% CI 3.68-9.14, p < 0.001) and B (GMFI 3.44, 95% CI 2.36-5.00, p = 0.048) strains. Serological response was superior in age-matched controls to all vaccine strains. There were no serious adverse events following vaccination. For children who underwent HSCT, incidence of laboratory-proven influenza infection was 2.3%. Overall, this study provides evidence to support annual inactivated influenza vaccine administration to children following HSCT.

Randomised Controlled Trial Comparing Daily Versus Depot Vitamin D3 Therapy in 0-16-Year-Old Newly Settled Refugees in Western Australia Over a Period of 40 Weeks.

Vitamin D deficiency is highly prevalent in newly settled refugees in Western Australia (WA). If adherence to daily vitamin D therapy is problematic, depot therapy is a therapeutic alternative. The aim of this study was to compare daily versus depot treatment and factors influencing the therapeutic outcome. Newly settled refugees (n = 151) with 25(OH)D levels less than 78 nmol/L were randomised to receive daily or depot vitamin D therapy with eight weekly interval follow up to 40 weeks. Biochemical and clinical parameters were collected at each visit. Generalized Linear Mixed Models (GLMM) examined the longitudinal changes over time controlling for confounders including age, gender, treatment arm, season, country of refuge/origin and sun exposure score. Participants were aged 5.5 months to 16.0 years (75 males, 83 females). Both treatment groups achieved vitamin D sufficiency. The daily treatment group had significantly higher 25(OH)D levels at each visit post baseline and a higher proportion of participants with levels above 50 nmol/L at all time points. Time, treatment group, calcium and sun exposure score were significant predictors of 25(OH)D serum levels. Depot vitamin D therapy is an alternative to daily treatment in this at-risk group of children and adolescents in whom treatment adherence is problematic.

A 15-Year Old Burmese Girl With Hemoptysis: A Case Report.

We report the case of a 15-year-old Burmese girl who presented with hemoptysis 3 years after immigrating to Australia with a background of previously treated pulmonary tuberculosis at 6 years of age. Cavitation in the right upper lobe had originally been identified on her baseline chest radiograph following arrival to Australia; extensive investigations were conducted thereafter to exclude causes of cavitary lung disease; these were negative. Paragonimus westermani was finally diagnosed on serological grounds 3 years after this child's original presentation, with subsequent identification of P. westermani ova in sputum and in stool. Clinicians should be alert to the possibility of Paragonimiasis in children who have traveled to or originate from endemic countries who present with a clinically compatible illness. Treatment is simple and effective. Failure to consider this pathogen early may result in unnecessary investigative workup and delayed diagnosis.

Immunogenicity and clinical effectiveness of the trivalent inactivated influenza vaccine in immunocompromised children undergoing treatment for cancer.

Influenza is associated with significant morbidity and mortality in children receiving therapy for cancer, yet recommendation for, and uptake of the seasonal vaccine remains poor. One hundred children undergoing treatment for cancer were vaccinated with the trivalent inactivated influenza vaccine according to national guidelines in 2010 and 2011. Influenza-specific hemagglutinin inhibition antibody titers were performed on blood samples taken prior to each vaccination and 4 weeks following the final vaccination. A nasopharyngeal aspirate for influenza was performed on all children who developed an influenza-like illness. Following vaccination, seroprotection and seroconversion rates were 55 and 43% for H3N2, 61 and 43% for H1N1, and 41 and 33% for B strain, respectively. Overall, there was a significant geometric mean fold increase to H3N2 (GMFI 4.56, 95% CI 3.19-6.52, P < 0.01) and H1N1 (GMFI 4.44, 95% CI 3.19-6.19, P < 0.01) strains. Seroconversion was significantly more likely in children with solid compared with hematological malignancies and in children <10 years of age who received a two-dose schedule compared to one. Influenza infection occurred in 2% of the vaccinated study population, compared with 6.8% in unvaccinated controls, providing an adjusted estimated vaccine effectiveness of 72% (95% CI -26-94%). There were no serious adverse events and a low reactogenicity rate of 3%. The trivalent inactivated influenza vaccine is safe, immunogenic, provides clinical protection and should be administered annually to immunosuppressed children receiving treatment for cancer. All children <10 years of age should receive a two-dose schedule.

Immunogenicity of a monovalent 2009 influenza A(H1N1) vaccine in infants and children: a randomized trial.

CONTEXT: In the ongoing influenza pandemic, a safe and effective vaccine against 2009 influenza A(H1N1) is needed for infants and children. OBJECTIVE: To assess the immunogenicity and safety of a 2009 influenza A(H1N1) vaccine in children. DESIGN, SETTING, AND PARTICIPANTS: Randomized, observer-blind, age-stratified, parallel group study assessing 2 doses of an inactivated, split-virus 2009 influenza A(H1N1) vaccine in 370 healthy infants and children aged 6 months to less than 9 years living in Australia. INTERVENTION: Intramuscular injection of 15 microg or 30 microg of hemagglutinin antigen dose of monovalent, unadjuvanted 2009 influenza A(H1N1) vaccine in a 2-dose regimen, administered 21 days apart. MAIN OUTCOME MEASURES: Hemagglutination inhibition assay to estimate the proportion of participants with antibody titers of 1:40 or greater, seroconversion, or a significant antibody titer increase, and factor increase in geometric mean titer. Assessments of solicited adverse events during 7 days and unsolicited adverse events for 21 days after each vaccination. RESULTS: Following the first dose of vaccine, antibody titers of 1:40 or greater were observed in 161 of 174 infants and children in the 15-microg group (92.5%; 95% confidence interval [CI], 87.6%-95.6%) and in 168 of 172 infants and children in the 30-microg group (97.7%; 95% CI, 94.2%-99.1%). Corresponding seroconversion rates were 86.8% (95% CI, 80.9%-91.0%) and 94.2% (95% CI, 89.6%-96.8%), and factor increases in geometric mean titer were 13.6 (95% CI, 11.8-15.6) and 18.3 (95% CI, 15.7-21.4). All participants demonstrated antibody titers of 1:40 or greater after the second vaccine dose. Immune responses were robust regardless of age, baseline serostatus, or seasonal influenza vaccination status. The majority of adverse events were mild to moderate in severity. CONCLUSION: One 15-microg dose of vaccine was immunogenic in infants and children starting at 6 months of age and vaccine-associated reactions were mild to moderate in severity. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00940108.