Hemagglutination inhibiting (HI) antibody responses against influenza A(H3N2) vaccine strains decline with increasing years of vaccination. It is hypothesized that memory B cell dominance may direct antibody responses towards epitopes conserved with previously-encountered vaccine strains, including non-HI epitopes. To investigate this, we compared healthcare workers with zero versus five consecutive years of vaccination prior to enrolment in 2020 or 2021. We evaluated HI antibody reactivity across 25 A(H3N2) viruses spanning 2007-2022 and antibody binding to recombinant hemagglutinins (HA). HI antibody responses were poor across strains for participants vaccinated five compared to zero of five prior years, independent of pre-vaccination titre. HA and HA-stem binding antibody titre-rises were likewise attenuated in the repeatedly vaccinated group. These results provide no evidence that repeated vaccination promotes antibodies targeting conserved epitopes, rather, repeated vaccination broadly attenuates antibody responses. Work is ongoing to investigate whether attenuation reflects deficient memory B cell differentiation into plasmablasts.

BACKGROUND:Although uncommon, invasive meningococcal disease (IMD) results in death in 5%-10% of cases in healthy children and adolescents. This study aimed to examine demographics, clinical presentation, treatment and outcomes of Australian children hospitalized with IMD during the introduction of the meningococcal vaccine program, overall and by serogroup/disease severity. METHODS:This prospective, multicenter study was conducted through the Paediatric Active Enhanced Disease Surveillance network across 8 tertiary pediatric hospitals in Australia. Children 0-18 years of age with laboratory-confirmed IMD admitted between July 2016 and June 2022 were included. Clinical data were collected using standardized protocols. Logistic, quantile, negative binomial regression and univariate comparisons were used to compare characteristics by serogroup and to investigate factors associated with disease severity. RESULTS:Among 137 IMD cases included, 56% were male with a median age of 2 years, 37% were Aboriginal/Torres Strait Islander children and over half resided in socioeconomically disadvantaged areas. Meningococcal serogroup B (MenB) accounted for 55% of cases, followed by MenW (28%) and MenY (4%). The case fatality rate was 3%. Antibiotics were administered within 1 hour of presentation in 17% of cases. At discharge, 29% had ongoing sequelae, including scarring, arthritis, limb deformities or amputation. Most MenB cases were unvaccinated against MenB (93%), and only 1 MenY case had prior quadrivalent polysaccharide vaccination. CONCLUSIONS:This study highlights the continued burden of MenB disease, particularly among socioeconomically disadvantaged and Aboriginal and Torres Strait Islander children, underscores the importance of earlier recognition and treatment to reduce morbidity and mortality, and emphasizes the need for improving vaccine uptake and vaccine availability.

PURPOSE:Congenital cytomegalovirus (cCMV) is an important cause of long-term childhood disability. In Australia, the identification and treatment practices and the long-term clinical and neurodevelopmental outcomes of children with cCMV are unknown. The Australasian cCMV Register (ACMVR) is a longitudinal register and resource for research that aims to describe and explore, in Australian children with cCMV: (1) their clinical characteristics over time, (2) antiviral therapy use/prescribing up to 1 year of age and (3) risk factors and potential avenues for prevention of adverse sequelae of the virus. PARTICIPANTS:Children <18 years, with confirmed or probable cCMV infection, identified via medical records, community referral and physician referrals, in states with active study sites, are eligible for inclusion. The consent process is site-specific, reflecting local requirements and including both explicit consent and opt-out models. Participation in the ACMVR allows local site researchers to (1) collect specified demographic and clinical data from medical records, health professionals and families, (2) recontact parents/guardians to undertake developmental screening for their child at time-points up to 5 years of age, (3) share information with parents/guardians about relevant ethically approved research studies and (4) include participant data in ethically approved data linkage studies. FINDINGS TO DATE:Ethics and governance approvals, study database and a steering group have been established. Data collection is active in five sites across Australia. FUTURE PLANS:The ACMVR will inform our understanding of the long-term outcomes for children with cCMV in Australia and provide a sampling frame and resource for recruitment in future clinical and epidemiological research to inform practice and policy. New opportunities for the establishment of additional study sites and collaborations with Australian maternity and fetal medicine researchers and with cCMV registries in other countries are currently being explored.

Cryptococcal post-infectious inflammatory response syndrome (PIIRS) is a rare but described complication of the treatment of Cryptococcus gattii meningitis in immunocompetent patients. The presentation mimics worsening infection including visual loss, headaches and meningism. There is no established guideline for the management of PIIRS, however corticosteroids and aggressive management of intracranial pressure (ICP) have been utilised in adult patients. In this report we present the case of a previously well Aboriginal male with Cryptococcal meningitis (CM) complicated by early neurological sequelae that were successfully treated with high-dose steroids. A 15-year-old previous healthy Aboriginal male from a regional community presented with a 2-week history of frontal headaches, vomiting and episodes of reduced level of consciousness. He was reviewed multiple times before being transferred to a tertiary children's hospital with a new lateral rectus nerve palsy, right sided upper limb weakness and ataxia. The initial non-contrast magnetic resonance imaging (MRI) did not show any acute ischaemia or haemorrhage. He was admitted and treated with chlorpromazine for presumed hemiplegic migraine without improvement. He progressed to having bilateral sixth cranial nerve (CN) palsy and dysphasia with reduced sensorium, at which point he was admitted to the Intensive Care Unit (ICU) for observation. He was also complaining of acute right sided hearing impairment which was consistent with new sensorineural hearing loss on formal testing. An ophthalmology consult revealed bilateral mildly swollen optic discs and normal visual acuity. A repeat MRI with contrast was concerning for raised ICP and an elevated opening pressure of 90 cm H2O was noted at lumbar puncture (LP). Cerebrospinal fluid (CSF) showed an elevated white cell count of 56 (95% monocytes) and Cryptococcus gattii was identified on multiplex polymerase chain reaction (PCR) testing as well as fungal culture. Both serum and CSF cryptococcal antigen were positive with titres of > 1:2048. Human immunodeficiency virus (HIV) antigen testing was negative and lymphocyte subsets revealed a borderline low CD3 and CD4+/CD3+ count (0.69 and 0.36 respectively) but normalised on repeat testing. The patient had a paediatric immunology review and ongoing surveillance which has not revealed any abnormalities and he appears to be immune-competent. After the diagnosis of Cryptococcal gattii meningitis was made and with direct questioning, the patient provided a history of smoking eucalyptus leaves in the weeks preceding his presentation. Induction therapy commenced with intravenous liposomal amphotericin (4 mg/kg) and fluconazole (800 mg) daily before being transitioned to oral flucytosine (25 mg/kg) every 6h via NGT. The patient continued to have significant neurological symptoms including right sided sensorineural hearing loss, altered behaviour and mentation, all of which responded partially to repeated LPs. On day 3 of ICU admission, the patient subsequently developed acute right sided vision loss (hand movement only) and examination and imaging were consistent with optic perineuritis. A lumbar drain was inserted on day 3 of admission due to ongoing high opening pressures (> 100 cm H2O). His vision remained poor despite initiation of antifungal therapy and insertion of lumbar drain. Given the MRI findings and acute deterioration in vision despite ICP control, he was treated with 3 days of pulse methylprednisolone at 3 mg/kg followed by a steroid weaning plan for presumed PIIRS. Within 24h his visual acuity had improved to 6/30 and returned to 6/6 within 6 days of treatment with high-dose steroids. The lumbar drain was removed on day 10 of treatment as it was no longer patent. He required two further LPs for management of ICP and culture. In week 4 of treatment, the patient was transferred back to his local hospital for ongoing induction therapy with daily liposomal amphotericin infusions and oral flucytosine. CSF was confirmed to be culture negative on day 38 of treatment. He was transitioned to consolidation therapy with fluconazole monotherapy during week 5 of treatment. During week 6 of treatment, correlating with cessation of steroids, he had a neurological deterioration with worsening headaches, vomiting and high opening pressures. It was at this time that the patient was first diagnosed with PIIRS and treated with 60 mg of oral prednisolone with limited improvement in his symptoms leading to subsequent insertion of VP shunt for ICP control. Pain and vision improved significantly with insertion of shunt, and he was discharged with a steroid weaning plan and ongoing follow up from the infectious diseases, ophthalmology and neurosurgical team. Unfortunately, the patient has had three further episodes of PIIRS characterised by severe headaches, vision loss and optic neuritis whenever steroids were weaned. These symptoms resolve with stress dose steroids. He also has ongoing hearing loss and has been fitted with a hearing aid. At the time of publication, our patient is on a prolonged weaning course of hydrocortisone over several months with a plan for a short synacten test prior to ceasing completely. CM is an important opportunistic infection causing significant morbidity and mortality worldwide. CM can be caused by either Cryptococcus neoformans or Cryptococcus gattii. Cryptococcus neoformans has a global distribution and more commonly occurs in immunocompromised individuals [1]. C. gattii is more common in tropical and subtropical regions and commonly infects immunocompetent patients [1]. C. gattii is present in a range of environmental sources including the bark and flowers of Eucalyptus trees [2]. The inhalation of C. gattii is the most common route for invasive disease in both humans and animals. Immune reconstitution inflammatory syndrome (IRIS) is a recognised complication of the treatment of Cryptococcus in HIV-infected patients. IRIS describes an inflammatory disorder associated with paradoxical worsening of infectious processes following the commencement of antiretroviral therapy (ART) in HIV-infected patients. A similar, but distinctly separate, entity of PIIRS has been described in non-HIV-infected patients following treatment of Cryptococcus. The inflammatory response tends to occur after adequate mycologic control with negative cultures but pleocytosis [3]. It has been postulated that the inflammatory response occurs in response to release of cryptococcal antigen resulting in proliferation of CD4+ and CD8+ T cells in the central nervous system. This switch is associated with a change from an anti-inflammatory Th2 immune response to a Th1 or proinflammatory response [4]. There are no established risk factors for the development of PIIRS however there have been recent studies that revealed a correlation between baseline hearing impairment and high CSF pressures HIV-negative immunocompetent patients, both of which our patient had [5]. PIIRS typically presents with a paradoxical worsening of symptoms or poor recovery with negative cultures and usually at least 1 month of fungicidal therapy. The exact mechanism is not understood, however given the recent recognition of the role of host-initiated immune damage in the symptomology of CM it is possible this host response was at least partially responsible for the early neurological symptoms in our patient. In our case, the presence of early, asymmetrical visual loss which was not responsive to measures used to control ICP pointed towards an alternative cause for visual loss, either direct invasion by Cryptococcus or an inflammatory response causing optic neuritis. The rapid response to steroids favours an inflammatory reaction. To our knowledge, this case was one of the earliest presentations of PIIRS with optic neuritis and vision loss treated with high-dose steroids. Ocular complications in CM are often attributed to raised ICP, however there is growing evidence that inflammation and neuritis could play a role in rapid visual loss, meaning corticosteroids are a promising treatment option [6]. The risks of using immunosuppression in the setting of active infection must be weighed against long-term neurological sequalae. In our patient, time to CSF clearance was markedly longer than other case reports (38 days cf. 7–21 days) [7] and studies in HIV positive patients have reported worse long-term outcomes in patients when CSF sterilisation is beyond 14 days [8]. CM in immunocompetent children can present with subtle symptoms and it is important that providers are aware of the risk of PIIRS. In addition to aggressive management of ICP, dampening immune-mediated inflammation may play a role in improving visual outcomes in children who present with rapid visual loss and signs of neuritis. This case report was reviewed and endorsed by Children's Health Queensland Hospital and Health Service Human Research Ethics Committee on the 2 May 2024. We would like to acknowledge the patient and family for providing written informed consent for publications of this case report. The authors declare no conflicts of interest.

INTRODUCTION:Mycobacteroides abscessus (MABS) is within the non-tuberculous mycobacteria family. It inhabits soil and water, exhibits multi-antibiotic resistance and causes opportunistic lung infections, which may progress to symptomatic MABS-pulmonary disease (MABS-PD) associated with substantial morbidity, increased healthcare utilisation, impaired quality of life and increased mortality. Treatment regimens for MABS-PD are highly variable, not evidence-based and involve complex, expensive drug combinations administered for prolonged periods (>12 months) with frequent adverse effects and treatment failure. There is an urgent need for safe, efficacious and cost-effective MABS-PD therapy. Here, we describe the Master Protocol for the Finding the Optimal Regimen for Mycobacteroides abscessus Treatment (FORMaT) trial. FORMaT aims to determine the most effective and best tolerated treatment for MABS-PD as defined by MABS clearance from respiratory samples with good treatment tolerance. METHODS AND ANALYSIS:FORMaT is an international multicentre, adaptive platform trial evaluating treatment combinations for MABS-PD. Participants are randomised multiple times during the trial, with assessment of the primary outcome of clearance of MABS infection with good treatment tolerance. Initially, therapies recommended in international consensus guidelines are being tested. Data obtained will eliminate therapies lacking efficacy or causing unacceptable toxicity. Novel treatments can then be added and tested against previously determined optimal approaches, leading in an iterative fashion to improved microbiological clearance and health outcomes. In parallel, an Observational cohort and several integrated and discovery studies are embedded in FORMaT to identify biomarkers of MABS-PD and MABS clearance, clinical and radiographic treatment response, drug pharmacokinetics and Mycobacteroides genomics and resistome. ETHICS AND DISSEMINATION:The FORMaT Master Protocol and related documents are approved by regulatory authorities in each participating jurisdiction and/or site. Results will be published in peer-reviewed journals and presented at scientific meetings. De-identified, aggregated data will be shared on an approved online platform. TRIAL REGISTRATION NUMBERS:NCT04310930, ANZCTR12618001831279, 2020-000050-10, ISRCTN67303903.

BACKGROUND:Health care-associated infections (HAIs) continue to contribute significantly to Australia's burden of disease. In Queensland, varied surveillance protocols exist contributing to unnecessary complexity. With end-user partners, we defined a minimum dataset to support the public reporting of HAI surveillance data. METHODS:A modified, 2-round Delphi study was conducted with field experts. In Round 1, infection control professionals and infectious disease physicians rated HAI measures on importance, feasibility, usefulness, and case definition acceptability using Likert scales. Measures meeting predefined thresholds progressed to Round 2, where a panel of experts achieved ≥70% consensus on the final dataset. RESULTS:Forty-nine infection control professionals (nurses and physicians) responded in Round 1. From the originally proposed 36 HAI measures, 17 achieved consensus for importance, usefulness and feasibility. In Round 2, 14 experts (11 infection control practitioners; 3 physicians) met to review the 17 measures retained from Round 1. Final measures (n=13), meeting Round 2 consensus, included bloodstream infections, selected surgical site infections, and significant organisms. CONCLUSIONS:We developed a 13-item minimum dataset with standardized definitions to support consistent, state-wide HAI surveillance and reporting. The dataset supports efficient data aggregation and will inform targeted prevention activities.

AIMS:Primary aim was to review severe acute respiratory infections (SARI) hospitalisations caused by respiratory syncytial virus (RSV) in children aged < 2 years in paediatric hospitals in Australia. Secondary aims included RSV subtyping, assessing RSV seasonality and contributing to the World Health Organisation's RSV surveillance programme. METHODS:We prospectively reviewed the medical records of children (< 2 years of age) with a confirmed SARI who were admitted to one of four major Australian paediatric hospitals and had a respiratory sample analysed by Polymerase Chain Reaction (PCR). A detailed dataset was completed for RSV positive cases. RESULTS:Between 1 January 2021 and 31 December 2022, 2290 RSV (laboratory-confirmed) admissions were identified (53.4% of all SARI admissions). Approximately 50% of all RSV cases were aged 0-6 months. RSV-A predominated in 2021 with peak infections observed in summer while in 2022 RSV-B predominated with peak infections in the more traditional winter months. The median total length of stay (LOS) for RSV positive admissions was 46 h (IQR: 22-82 h). 9% of these children required an ICU admission with a prolonged median LOS 68 h (IQR: 40-112 h). Respiratory support utilisation was consistent over the 2 years. 1.8% required mechanical ventilation; 4.6% continuous positive airway pressure; 23.3% high flow oxygen; and 50.8% low flow oxygen. CONCLUSIONS:RSV in children continues to cause a significant disease burden at Australian tertiary paediatric centres. Ongoing hospital surveillance is required to document the impact of RSV preventative therapies that have become available in 2024.

BACKGROUND:Management and outcomes of children hospitalised with acute SARS-CoV-2 infection may differ throughout the pandemic or with admission type (clinical COVID-19, incidental COVID-19 or nosocomial infection). OBJECTIVES:Describe the severity, management and outcomes of hospitalised children with acute SARS-CoV-2 infection in Australia across the first 4 years of the pandemic and compare between admission types, SARS-CoV-2 variants, age groups and immune status. STUDY DESIGN:A multi-centre prospective cohort study of 6009 children aged 0-16 years between January 2020 and June 2023. RESULTS:Most children (84.3 %) did not receive respiratory support, 33.4 % received antibiotics and 8 % were admitted to intensive care unit (ICU). Infants <6 months old were more likely to be admitted with clinical COVID than older children (12-16 years). Older children were more likely to receive antibiotics (27.8 % vs 43.9 %), corticosteroids (11.3 % vs 34.1%) or ICU admission (5.2 % vs 13.5 %). Compared to immunocompetent children, the immunosuppressed (7.7 %) were more likely to have nosocomial infection (9.5 % vs 3.9 %), receive antibiotics (57 % vs 25 %) or antivirals (18 % vs 4.4 %), but less likely to require respiratory support (93.4 % vs 83.8 %) or ICU admission (3.5 % vs 8 %). Children with nosocomial SARS-CoV-2 infection had higher rates of invasive ventilation (8 %) and ICU admission (21 %) compared to those with clinical (2.1 % and 7.1 % respectively) or incidental COVID-19 (4.8 % and 9.1 % respectively). CONCLUSIONS:Acute COVID-19 generally caused mild disease in hospitalised children, with management and outcomes differing by age and admission type. Similar outcomes were observed across the pandemic. Nosocomial SARS-CoV-2 infection was associated with more severe disease.

BACKGROUND:Variations in neonatal aciclovir prescribing for suspected herpes simplex virus (HSV) disease are well-known, but there are limited data describing aciclovir prescribing in older children. METHODS:Medical records of neonates (≤28 days) and children (29 days to 18 years) prescribed intravenous aciclovir for suspected HSV disease (1 January 2019-12 December 2019) in eight Australian and New Zealand hospitals were reviewed. Prescribing indication, HSV testing, aciclovir prescription details, adverse events and discharge diagnosis were recorded. RESULTS:1426 received empirical aciclovir. For neonates (n = 425), the median duration was 1 day (IQR 1-3), 411/425 underwent HSV investigations and 13/425 had HSV disease (two with disseminated encephalitis, four with encephalitis and seven with skin, eye, mouth disease). Of the 1001 children, 906 were immunocompetent. 136/906 suspected of mucocutaneous disease received aciclovir for a median of 2 days (1-2), 121/136 underwent HSV testing, and 69/136 had proven disease. 770/906 received aciclovir for suspected disseminated disease or encephalitis for a median of 1 day (1-2), 556/770 underwent HSV testing, and 5/770 had disseminated disease or encephalitis. Among 95 immunocompromised children, 53/58 with suspected mucocutaneous disease had HSV testing and this was confirmed in 22. Disseminated disease or encephalitis was suspected in 37/95, HSV testing conducted in 23/37 and detected in one. The median aciclovir duration was 3 (2-7) days for immunocompromised children. Nephrotoxicity occurred in 7/1426 and 24/1426 had an extravasation injury. CONCLUSION:Frequent and often unnecessary intravenous aciclovir prescribing for suspected HSV encephalitis or disseminated disease occurred in children, as evidenced by incomplete HSV investigations and only 5/770 older children having the diagnosis confirmed.

BACKGROUND:Visitor restrictions and mask-wearing may reduce hospital-acquired infections (HAI) as part of infection control bundles. The impact of a strict visitor policy and compulsory surgical mask wearing implemented during the SARS-CoV-2 pandemic, but prior to any local community circulating SARS-CoV-2, on the rates of hospital-acquired respiratory viral infections (HA-RVI) was assessed. METHODS:Retrospective audit of a local HAI database for HA-RVI from 1st April 2019 to 29th March 2021 in a tertiary children's hospital. HA-RVI were standardized against occupied bed days (OBD) and admitted community acquired infections (CAI). Rates of HA-RVI were compared during 52 weeks of SARS-CoV-2-associated enhanced control periods (visitor restrictions with and without universal surgical masking), against 52 weeks standard practice. Total respiratory virus infections, respiratory syncytial virus (RSV), and rhinovirus infections were analysed. RESULTS:Comparing standard practice with enhanced measures, 42 v 15 HA-RVI and 1517 v 691 CAI were noted. Enhanced infection controls resulted in significant reductions in total HA-RVI when adjusted for OBD (p = 0.0038) and CAI (p = 0.0122). Non-significant decreases were seen in hospital-acquired respiratory syncytial virus (HA-RSV) adjusted for both CAI and OBD. Visitor restrictions combined with universal surgical masks significantly decreased adjusted total HA-RVI compared with visitor restrictions alone (adjusted for OBD p = 0.0123; adjusted for CAI p = 0.0429). HA-RSV decreased non-significantly when mask wearing was combined with visitor restrictions compared with visitor restrictions alone. HA-rhinovirus infections did not decrease with the addition of masks to visitor restrictions. CONCLUSION:Enhanced infection control measures introduced with SARS-CoV-2 pandemic decreased some HA-RVI. Universal surgical mask wearing decreased HAI rates more than visitor restrictions alone, except for rhinovirus where the HAI rate remained unchanged.

Influenza vaccine effectiveness and immunogenicity can be compromised with repeated vaccination. We assessed immunological markers in a cohort of healthcare workers (HCW) from six public hospitals around Australia during 2020-2021. Sera were collected pre-vaccination and ~14 and ~180 days post-vaccination and assessed in haemagglutination inhibition assay against egg-grown vaccine and equivalent cell-grown viruses. Responses to vaccination were compared by the number of prior vaccinations. Baseline sera were available for 595 HCW in 2020 and 1031 in 2021. 5% had not been vaccinated during five years prior to enrolment and 55% had been vaccinated every year. Post-vaccination titres for all vaccine antigens were lowest among HCW vaccinated in all 5-prior years and highest among HCW with 0 or 1 prior vaccinations, even after adjustment. This was observed for both influenza A subtypes and was dependent on pre-vaccination titre. Expanded cohorts are needed to better understand how this translates to vaccine effectiveness.

BACKGROUND:We aimed to describe the clinical spectrum and burden of COVID-19-associated neurologic disease in Australian children. METHODS:We extracted Australian national sentinel site surveillance data on COVID-19-associated neurologic disease in children hospitalized in the Paediatric Active Enhanced Disease Surveillance network, 2020-2023. Neurologic complications included encephalitis, encephalopathy, Guillain-Barre syndrome, seizures and cerebrovascular accident among others. We calculated the proportion of hospitalized pediatric COVID-19 cases associated with neurologic disease and described the spectrum of presentations including clinical features and severity. We calculated incidence rates of neurologic disease within COVID-19 variant eras among hospitalized patients. RESULTS:We identified 311 cases of SARS-CoV-2 infection with neurologic disease among 4616 hospitalized pediatric cases of COVID-19 reported through the surveillance network, representing 5.3 cases per 100 pediatric COVID-19 admissions. The most common COVID-19-associated neurologic presentations were seizures (n = 215), including febrile seizures. Nonspecific encephalopathy (n = 62), encephalitis, Guillain-Barre Syndrome, acute cerebellar syndromes, acute demyelinating encephalomyelitis and cerebrovascular accident were also reported. Almost 60% of children were ≤4 years, approximately 30% had pre-existing neurologic conditions and almost half had other medical comorbidities. COVID-19-associated neurologic complications infrequently led to death, although 25% (n = 2/8) of children with COVID-19 encephalitis died. The incidence rate of COVID-19-associated neurologic disease was lowest during the late Omicron era. CONCLUSIONS:Neurologic complications among COVID-19 hospitalized children are relatively frequent. While most neurologic complications are transient, including seizures, encephalitis remains a cause of significant morbidity. Children with pre-existing neurologic disease and other comorbidities are at higher risk.

BACKGROUND:The widespread use of pneumococcal conjugate vaccines (PCV) has changed the epidemiology of invasive pneumococcal disease (IPD) in children globally. METHODS:Multicentre prospective audit of IPD episodes from five paediatric hospitals in Australia over 5.5 years between 2016 and June 2021. Children (<18 years) with Streptococcus pneumoniae isolated from a sterile site were included. RESULTS:There were 377 IPD episodes in 375 children: 338 (90%) had received ≥3 PCV doses; 42 (11%) had IPD risk factors. The most common presentations were complicated pneumonia (254, 67%), bacteraemia (65, 17%) and meningitis (29, 8%). Five (1%) children died.Serotype information was available for 230 (61%) episodes; 140 (61%) were 13vPCV vaccine serotypes (VTs). The majority (85%) of episodes of complicated pneumonia were due to a VT; predominantly 3, 19A, 19F. Children with risk factors were more likely to present with bacteraemia ± sepsis (42% vs 12%) and to have a non-vaccine serotype (NVT) (74% vs 32%). Resistance to ceftriaxone (meningitis cut-off) occurred in 17% of 23B isolates (n=12) and accounted for 22% (5/23) of meningitis cases. CONCLUSIONS:Complicated pneumonia is the most common IPD presentation. NVTs account for the majority of bacteraemia and meningitis episodes. High rates of ceftriaxone resistance for NVT 23B support the addition of vancomycin for empiric treatment of suspected meningitis.

Background Invasive fungal disease (IFD) is a significant complication for children receiving treatment for leukaemia, contributing to morbidity and mortality. Recent regional paediatric epidemiological IFD data are lacking. Additionally uncertainty remains regarding the optimal prophylactic approach in this context. Methods In a multi-centre Australian cohort study of children diagnosed with de novo acute leukaemia between 1st January 2017 and 30th June 2020, we characterised antifungal prophylaxis prescribing and IFD prevalence. Impact of antifungal prophylaxis was assessed using Kaplan Meier curves and Cox-proportional hazards regression adjusting for known IFD risk factors. Findings A total of 434 children were included (47.2% female; median age 5.0 years, median follow-up 240 days). This cohort included 351 children with ALL (214 high-risk [HR-ALL]; 137 standard-risk [SR-ALL]), and 73 with AML. The prevalence of proven/probable IFD was 6.8% for AML, 14.0% for HR-ALL and 4.4% for SR-ALL. A mould was implicated as the causative pathogen in almost two thirds of cases. Antifungal prophylaxis was prescribed in 98.7% of chemotherapy cycles for AML, 56.7% for HR-ALL and 14.9% for SR-ALL. A mould-active agent was used in 77.4% of AML cycles and 21.2% of HR-ALL cycles. Mould-active prophylaxis was associated with a lower risk of IFD overall and increased IFD-free survival in AML. Interpretation These data demonstrate the persistent high regional burden of IFD in children with HR-ALL, and the potential for mould-active prophylaxis to ameliorate this. Strategies to increase uptake of appropriate prophylaxis are required in this cohort. Funding This study was supported by a Perth Children’s Hospital Foundation grant (PCHF9973).

CONTEXT:Central venous access device (CVAD) locks are routine interventions used to prevent and treat complications, such as infection, thrombosis, and catheter occlusion. OBJECTIVE:To compare and rank lock-solutions for prevention or treatment of complications in pediatrics. Design Systematic review and network meta-analysis. DATA SOURCES:Five databases and 2 clinical trial registries were searched. STUDY SELECTION:Published and unpublished randomized controlled trials that enrolled pediatric patients with a CVAD and compared the effectiveness of lock-solutions. DATA EXTRACTION:Data extraction was conducted by 2 reviewers. Odds ratio (OR) for prevention or treatment of CVAD-associated bloodstream infection (BSI), thrombosis, occlusion, CVAD-failure, and mortality were calculated, with point estimates ranking lock-solutions. RESULTS:Twenty-nine studies were included. Chelating agents and antibiotic locks given as prevention were associated with lower odds (OR: 0.11; 95% confidence interval [CI]: 0.02-0.67; moderate-quality; OR: 0.19; 95% CI: 0.05-0.79, high-quality, respectively) of CVAD-associated BSI compared with heparinized saline (reference). Preventative thrombolytic agents had lower odds (OR: 0.64, 95% CI: 0.44-0.93; low-quality) of CVAD occlusion, whereas ethanol had higher odds (OR: 2.84, 95% CI: 1.31-6.16; high-quality) compared with heparinized saline (reference). No lock solution had effects on thrombosis prevention or treatment, CVAD-failure, CVAD-associated BSI treatment failure, or mortality. LIMITATIONS:There was substantial uncertainty around the point estimates because of the limited number of studies for outcomes and study heterogeneity. More high-quality studies are needed to confirm the efficacy of lock solutions. CONCLUSIONS:Chelating agents and antibiotic locks may be effective for CVAD-associated BSI prevention in pediatrics. Thrombolytic agents can be an option for CVAD occlusion prevention, whereas ethanol may not be recommended.

Early recognition and effective treatment of sepsis improves outcomes in critically ill patients. However, antibiotic exposures are frequently suboptimal in the intensive care unit (ICU) setting. We describe the feasibility of the Bayesian dosing software Individually Designed Optimum Dosing Strategies (ID-ODS™), to reduce time to effective antibiotic exposure in children and adults with sepsis in ICU. A multi-centre prospective, non-randomised interventional trial in three adult ICUs and one paediatric ICU. In a pre-intervention Phase 1, we measured the time to target antibiotic exposure in participants. In Phase 2, antibiotic dosing recommendations were made using ID-ODS™, and time to target antibiotic concentrations were compared to patients in Phase 1 (a pre–post-design). 175 antibiotic courses (Phase 1 = 123, Phase 2 = 52) were analysed from 156 participants. Across all patients, there was no difference in the time to achieve target exposures (8.7 h vs 14.3 h in Phase 1 and Phase 2, respectively, p = 0.45). Sixty-one courses in 54 participants failed to achieve target exposures within 24 h of antibiotic commencement (n = 36 in Phase 1, n = 18 in Phase 2). In these participants, ID-ODS™ was associated with a reduction in time to target antibiotic exposure (96 vs 36.4 h in Phase 1 and Phase 2, respectively, p < 0.01). These patients were less likely to exhibit subtherapeutic antibiotic exposures at 96 h (hazard ratio (HR) 0.02, 95

Background Prompt antibiotic administration for febrile neutropenia (FN) is standard of care, and targets of time to antibiotics (TTA) <60 min are common. We sought to determine the effect of TTA >= 60 versus <60 min on adverse outcomes (intensive care unit (ICU) admission or death) in children with cancer and FN. Effect modification by a decision rule that predicts infection (AUS-rule) and bacteraemia were also investigated. Methods The prospective, multi-centre (n = 8), Australian PICNICC study dataset was analysed. To control for confounding, we used outcome regression adjusted for propensity score modelled as restricted cubic spline with two degrees of freedom. The propensity score was estimated from a logistic regression model for the exposure on the confounders, identified a priori (age, sex, severely unwell, disease, chemotherapy intensity and site). TTA was defined as time from from emergency triage to first antibiotic dose. Findings 1685 FN episodes in 976 patients were included. Median TTA was 53 min (IQR 37-77 min, 1542 (92%) <120 min). An adverse outcome occurred in 43 (2.6%) episodes (39 ICU; 5 deaths). The confounder-adjusted point estimate suggested a lower risk for adverse outcome associated with TTA >= 60 min (RR 0.62, 95% CI 0.32-1.21), but the wide 95% CI precluded definitive judgement about strength and direction of the effect (unadjusted RR 0.52; 95% CI 0.26, 1.05). Similarly, although the point estimates were suggestive of a null association or reduced risk for adverse outcome associated with TTA >= 60 min for all comparisons across bacteraemia or AUS-rule strata, the 95% CIs were imprecise. Interpretation For children with FN, there was no definite evidence that TTA >= 60 min from hospital triage (but within 2 h), increased risk of adverse outcome or prolonged hospital admission. This study has important implications for FN TTA mandates, suggesting a more nuanced approach is required.

Abstract The World Health Organization, in response to the growing burden of fungal disease, established a process to develop a fungal priority pathogens list. This systematic review aimed to evaluate the epidemiology and impact of eumycetoma. PubMed and Web of Science were searched to identify studies published between 1 January 2011 and 19 February 2021. Studies reporting on mortality, inpatient care, complications and sequelae, antifungal susceptibility, risk factors, preventability, annual incidence, global distribution, and emergence during the study time frames were selected. Overall, 14 studies were eligible for inclusion. Morbidity was frequent with moderate to severe impairment of quality of life in 60.3%, amputation in up to 38.5%, and recurrent or long-term disease in 31.8%–73.5% of patients. Potential risk factors included male gender (56.6%–79.6%), younger age (11–30 years; 64%), and farming occupation (62.1%–69.7%). Mycetoma was predominantly reported in Sudan, particularly in central Sudan (37%–76.6% of cases). An annual incidence of 0.1/100 000 persons and 0.32/100 000 persons/decade was reported in the Philippines and Uganda, respectively. In Uganda, a decline in incidence from 3.37 to 0.32/100 000 persons between two consecutive 10-year periods (2000–2009 and 2010–2019) was detected. A community-based, multi-pronged prevention programme was associated with a reduction in amputation rates from 62.8% to 11.9%. With the pre-specified criteria, no studies of antifungal drug susceptibility, mortality, and hospital lengths of stay were identified. Future research should include larger cohort studies, greater drug susceptibility testing, and global surveillance to develop evidence-based treatment guidelines and to determine more accurately the incidence and trends over time.

AimAs herpes simplex virus (HSV) in infancy is not a mandatory notifiable condition in Australia, completeness of ascertainment by the Australian Paediatric Surveillance Unit (APSU) has been difficult to evaluate to date. We evaluated case capture in Queensland (QLD) and Western Australia (WA) using statewide laboratory and clinical data and complementary surveillance data collected via the APSU.MethodsHSV polymerase chain reaction positive results in infants (0–3 months) from 2007 to 2017 were obtained from statewide public pathology providers in QLD and WA. Clinical data were extracted from patient records and compared to APSU reported cases.ResultsA total of 94 cases of HSV disease in infancy (70 QLD; 24 WA) were identified from laboratory data sets, compared to 36 cases (26 QLD; 10 WA) reported to the APSU. In total there was 102 unique cases identified; 28 cases were common to both data sets (seven skin eye mouth (SEM) disease, 13 central nervous system (CNS) disease and eight disseminated disease). Active surveillance captured 35% (36/102) of cases overall including 74% (14/19) of CNS, 71% (10/14) of disseminated and 17% (12/69) of SEM disease cases, respectively. Surveillance reported cases had a higher case‐fatality rate compared to those not reported (14% vs. 3%, P = 0.038). Neurological sequelae at discharge were comparable between the groups.ConclusionActive surveillance captures one third of hospitalised HSV cases in QLD and WA, including the majority with severe disease. However, morbidity and mortality remain high. Future studies on HSV will rely on observational studies. Enhanced case ascertainment through combined laboratory and surveillance data is essential for better understanding and improving outcomes.