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.

A novel drive-through approach to vaccination of children and young people with neurodevelopmental disability.

Disparities in preventative health care likely contribute to comorbidities associated with neurodevelopmental disability. These comorbidities are risk factors for poor outcomes of COVID-19, making COVID-19 vaccination a priority for this population. In mid-2021, the Australian Technical Advisory Group (ATAGI) recommended the COVID-19 vaccination rollout include children and young people at risk of severe COVID-19 associated disease. This cohort included children/young people severely immunocompromised, with disability, and/or complex, multiple health conditions. Children and young people with neurodevelopmental disability can be challenging to vaccinate in conventional clinic environments and may experience exacerbation of behaviours posing barriers to vaccination. Remaining unvaccinated for COVID-19 increased risk of secondary complications and affected access to carers and respite facilities. This paper describes a novel, individualised approach to safe vaccination for this cohort. In consultation with stakeholders, a drive-through clinic vaccination model was developed and implemented for children/young people with neurodevelopmental disability. The model prioritised person-centred care and minimised triggering factors experienced in community clinics. Data were collected on successfully administered vaccine doses; administration safety and adverse events following immunisation. Parents/carers and staff provided reflective feedback. Twenty-four children and young people used the model with successful vaccination rate of 96% (n = 23). Most patients received multiple doses through the clinic (n = 16). Some patients were vaccinated after unsuccessful attempts elsewhere. Feedback from carers and staff was positive and no adverse events were reported. This model is generalisable to other health services and may be applied to other vaccinations for people of all ages with neurodevelopmental disabilities.

Inborn Errors of Immunity in Children With Invasive Pneumococcal Disease: A Multicenter Prospective Study.

BACKGROUND: In settings with universal conjugate pneumococcal vaccination, invasive pneumococcal disease (IPD) can be a marker of an underlying inborn error of immunity. The aim of this study was to determine the prevalence and characterize the types of immunodeficiencies in children presenting with IPD. METHODS: Multicenter prospective audit following the introduction of routinely recommended immunological screening in children presenting with IPD. The minimum immunological evaluation comprised a full blood examination and film, serum immunoglobulins (IgG, IgA and IgM), complement levels and function. Included participants were children in whom Streptococcus pneumoniae was isolated from a normally sterile site (cerebrospinal fluid, pleura, peritoneum and synovium). If isolated from blood, features of sepsis needed to be present. Children with predisposing factors for IPD (nephrotic syndrome, anatomical defect or malignancy) were excluded. RESULTS: Overall, there were 379 episodes of IPD of which 313 (83%) were eligible for inclusion and 143/313 (46%) had an immunologic evaluation. Of these, 17/143 (12%) were diagnosed with a clinically significant abnormality: hypogammaglobulinemia (n = 4), IgA deficiency (n = 3), common variable immunodeficiency (n = 2), asplenia (n = 2), specific antibody deficiency (n = 2), incontinentia pigmenti with immunologic dysfunction (n = 1), alternative complement deficiency (n = 1), complement factor H deficiency (n = 1) and congenital disorder of glycosylation (n = 1). The number needed to investigate to identify 1 child presenting with IPD with an immunologic abnormality was 7 for children under 2 years and 9 for those 2 years old and over. CONCLUSIONS: This study supports the routine immune evaluation of children presenting with IPD of any age, with consideration of referral to a pediatric immunologist.

Immunogenicity and safety of vaccination in children with paediatric rheumatic diseases: a scoping review.

Children with paediatric rheumatic diseases (PRDs) are at increased risk of vaccine-preventable disease. Safe and effective vaccination is central to preventive care in PRD patients; however, uncertainty surrounding immunogenicity and safety has contributed to suboptimal vaccination. The aim of this study was to evaluate treatment effect on immunogenicity to vaccination in PRD patients and assess vaccine safety, specifically adverse events following immunisation (AEFI) and disease flare. Scoping review. In this scoping review, a systematic search of PubMed, CINAHL and Embase databases was conducted from 2014 to 23 August 2022 to identify observational studies evaluating the immunogenicity and safety of commonly used vaccinations in PRD patients. The primary outcome was immunogenicity (defined as seroprotection and protective antibody concentrations), with secondary outcomes describing AEFI and disease flare also extracted. Due to extensive heterogeneity related to diagnostic and vaccination variability, narrative synthesis was used to describe the findings of each study. Study quality was assessed via the Mixed Methods Appraisal Tool. The review was prospectively registered with PROSPERO (CRD42022307212). The search yielded 19 studies evaluating immunogenicity to vaccination and incidence of AEFI and disease flares in this population, which were of acceptable quality. Corticosteroids did not have deleterious effects on vaccine response. Treatment with conventional disease-modifying antirheumatic drugs (DMARDs) and biologic DMARDs generally had no effect immunogenicity in PRD patients. While patients exhibited adequate seroprotection, protective antibody levels were lower in patients on some immunosuppressant agents. Varicella infections were recorded post vaccination in several patients with low protective antibody levels undergoing treatment with DMARDs and corticosteroids. Most vaccines appear safe and effective in PRD patients, despite immunosuppressant treatment. Booster vaccinations should be considered with some studies highlighting inadequate seroprotection following primary course of vaccinations with acceleration of antibody decline over time. There was limited evidence to support avoiding live vaccines in PRD patients.

A multicentre, retrospective audit of fosfomycin use for urinary tract infections in Australian children and adolescents.

BACKGROUND: Urinary tract infections (UTIs) due to MDR organisms are increasingly common. The lack of paediatric data on efficacious antibiotics makes UTI treatment particularly challenging. Data on the efficacy of fosfomycin use for UTI in children are variable. METHODS: We conducted a retrospective audit of children aged 0-18 years who were treated with fosfomycin for UTI at seven tertiary paediatric hospitals in Australia over a 7 year period, from 2014 to 2020. RESULTS: Ninety-one children with a median age of 5 years (range 2 months to 18 years) received oral fosfomycin for UTI. The majority (57/91, 63%) had one or more comorbidity, with the most common being renal tract anomalies (24/91, 26%). Fifty-nine (65%) had febrile UTI, 14/91 (15%) had pyelonephritis and 1/91 (1%) was bacteraemic. A majority (80/91, 88%) of urinary cultures had an ESBL-producing Gram-negative pathogen isolated. Fosfomycin susceptibility was evident in all 80 isolates tested. For uncomplicated UTI, the most common dose in children aged <1, 1-12 and >12 years was 1, 2 and 3 g, respectively. For complicated UTI, doses of 2 and 3 g were most common. The median duration of fosfomycin administration was 5 days (range 1-82). Clinical cure was achieved in 84/90 (93%); the six with treatment failure had underlying comorbidities. Overall, 2/91 (2%) children experienced drug-related adverse effects comprising gastrointestinal symptoms in both, which resolved after treatment discontinuation. CONCLUSIONS: Fosfomycin is well tolerated and associated with favourable treatment outcomes in children with UTI. Further research on the optimal dosing strategy is required.

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.

The impact of a multidisciplinary care package for vaccination in needle phobic children: An observational study.

AIMS: Children with severe needle phobia find vaccination extremely distressing and can remain unvaccinated, which puts them at an increased risk of contracting and transmitting vaccine preventable disease. Referral to a specialist or hospital service may occur when they cannot be safely vaccinated in the community, but engagement of allied health services can be inconsistent. The aim of the study was to assess the impact of a multidisciplinary, consumer-oriented model of care on vaccinations for needle phobic children. METHODS: Needle phobic children aged between 6 and 16 years attended multidisciplinary consultation, as part of a care package, to assess previous experiences and determine the level of intervention that was required to support vaccination. A multidisciplinary case meeting followed this appointment and an individualised plan formulated for each patient. The main outcome of the project was rate of successful vaccination. RESULTS: The care package resulted in a successful vaccination rate of 83% (n = 20) with 69 vaccines administered across three clinics. Of those successful, 90% required multiple injections per visit. The majority of patients indicated moderate to high level of anxiety. Supportive care was escalated and de-escalated as tolerated. CONCLUSIONS: Results demonstrate the diversity of patients presenting with needle phobia and indicate an individualised, collaborative approach is preferable to a 'one size fits all' model of care. The study highlights a need for the development of guidelines that streamline the assessment and individualisation of procedural anxiety plans to meet patient needs and embed these processes into standard care.

Gram-negative neonatal sepsis in low- and lower-middle-income countries and WHO empirical antibiotic recommendations: A systematic review and meta-analysis.

BACKGROUND: Neonatal sepsis is a significant global health issue associated with marked regional disparities in mortality. Antimicrobial resistance (AMR) is a growing concern in Gram-negative organisms, which increasingly predominate in neonatal sepsis, and existing WHO empirical antibiotic recommendations may no longer be appropriate. Previous systematic reviews have been limited to specific low- and middle-income countries. We therefore completed a systematic review and meta-analysis of available data from all low- and lower-middle-income countries (LLMICs) since 2010, with a focus on regional differences in Gram-negative infections and AMR. METHODS AND FINDINGS: All studies published from 1 January 2010 to 21 April 2021 about microbiologically confirmed bloodstream infections or meningitis in neonates and AMR in LLMICs were assessed for eligibility. Small case series, studies with a small number of Gram-negative isolates (<10), and studies with a majority of isolates prior to 2010 were excluded. Main outcomes were pooled proportions of Escherichia coli, Klebsiella, Enterobacter, Pseudomonas, Acinetobacter and AMR. We included 88 studies (4 cohort studies, 3 randomised controlled studies, and 81 cross-sectional studies) comprising 10,458 Gram-negative isolates from 19 LLMICs. No studies were identified outside of Africa and Asia. The estimated pooled proportion of neonatal sepsis caused by Gram-negative organisms was 60% (95% CI 55% to 65%). Klebsiella spp. was the most common, with a pooled proportion of 38% of Gram-negative sepsis (95% CI 33% to 43%). Regional differences were observed, with higher proportions of Acinetobacter spp. in Asia and Klebsiella spp. in Africa. Resistance to aminoglycosides and third-generation cephalosporins ranged from 42% to 69% and from 59% to 84%, respectively. Study limitations include significant heterogeneity among included studies, exclusion of upper-middle-income countries, and potential sampling bias, with the majority of studies from tertiary hospital settings, which may overestimate the burden caused by Gram-negative bacteria. CONCLUSIONS: Gram-negative bacteria are an important cause of neonatal sepsis in LLMICs and are associated with significant rates of resistance to WHO-recommended first- and second-line empirical antibiotics. AMR surveillance should underpin region-specific empirical treatment recommendations. Meanwhile, a significant global commitment to accessible and effective antimicrobials for neonates is required.

Optimising immunisation in children with 22q11 microdeletion.

BACKGROUND: The condition known as 22q11 microdeletion syndrome has a broad phenotypic spectrum, with many affected individuals experiencing mild-to-moderate immunodeficiency. Currently, there are significant variations in live vaccine practices and immunological testing prior to live vaccine administration due to safety concerns and limited established guidelines. METHODS: Queensland Children's Hospital (QCH) Child Development Unit, offers a state-wide 22q11 microdeletion clinic. This is a retrospective single-centre review, capturing the majority of children with 22q11 microdeletion in Queensland, Australia. We describe the live vaccination status of 134 children, age 0 to 18 years under our care between 2000 and 2018, adverse events following immunisation (AEFI) and the proportion of children who received additional pneumococcal coverage. An immunological investigation pathway prior to live vaccine administration is proposed. RESULTS: Of the 134 children, 124 were eligible for live vaccinations as per the Australian National Immunisation Program: 82% had received dose one of measles, mumps and rubella (MMR) vaccine, 77% had completed MMR dose two and 66% had completed varicella immunisation. There were no AEFI notifications reported. Of the total sample of children, 18% received a fourth dose of conjugate pneumococcal vaccine (Prevenar 7 or 13) and 16% received a dose of Pneumovax 23 from 4 years of age. Immunology workup practices were demonstrated to vary widely prior to live vaccine administration. Most patients' immune profiles were consistent with mild-to-moderate immunodeficiency. CONCLUSION: We propose an immunological investigation and vaccination pathway with the aim of providing guidance and consistency to clinicians caring for children with 22q11 microdeletion.

Progress and Pitfalls in the Quest for Effective SARS-CoV-2 (COVID-19) Vaccines.

There are currently around 200 SARS-CoV-2 candidate vaccines in preclinical and clinical trials throughout the world. The various candidates employ a range of vaccine strategies including some novel approaches. Currently, the goal is to prove that they are safe and immunogenic in humans (phase 1/2 studies) with several now advancing into phase 2 and 3 trials to demonstrate efficacy and gather comprehensive data on safety. It is highly likely that many vaccines will be shown to stimulate antibody and T cell responses in healthy individuals and have an acceptable safety profile, but the key will be to confirm that they protect against COVID-19. There is much hope that SARS-CoV-2 vaccines will be rolled out to the entire world to contain the pandemic and avert its most damaging impacts. However, in all likelihood this will initially require a targeted approach toward key vulnerable groups. Collaborative efforts are underway to ensure manufacturing can occur at the unprecedented scale and speed required to immunize billions of people. Ensuring deployment also occurs equitably across the globe will be critical. Careful evaluation and ongoing surveillance for safety will be required to address theoretical concerns regarding immune enhancement seen in previous contexts. Herein, we review the current knowledge about the immune response to this novel virus as it pertains to the design of effective and safe SARS-CoV-2 vaccines and the range of novel and established approaches to vaccine development being taken. We provide details of some of the frontrunner vaccines and discuss potential issues including adverse effects, scale-up and delivery.

Pediatric Neuroschistosomiasis: A Case Report and Review of the Literature.

Neuroschistosomiasis is a rare but severe manifestation of Schistosoma infection. Diagnosis is challenging and surgical biopsy is often required to confirm diagnosis and exclude malignancy. We present a pediatric case of presumed pseudotumoral cerebral schistosomiasis secondary to Schistosoma mansoni with an excellent therapeutic response to empirical praziquantel and corticosteroid treatment.

In utero exposure to biologic disease-modifying anti-rheumatic drugs and effects to the infant: infectious complications, vaccine response, and safety of live vaccine administration.

INTRODUCTION: Biologic disease-modifying anti-rheumatic drugs (bDMARDS) are increasingly used in clinical practice for a variety of conditions. Due to concerns surrounding persistence of drug levels and resulting immunosuppression, current case reports recommend against live vaccine administration in the first year of life for an infant exposed to perinatal bDMARDS. As a result, this significantly impacts receipt of rotavirus vaccination, a vaccine recommended in many countries' national immunization program. Area covered: We have reviewed all available published literature to explore the effect of peripartum bDMARDS exposure on infant immune responses, safety of live vaccines, and vaccine efficacy in the first year of life. Expert opinion: We recommend that otherwise healthy newborns with a history of perinatal exposure to bDMARDS should receive rotavirus vaccinations as per the recommended schedule. Bacille Calmette et Guerin vaccine should be withheld in the first year of life. No additional booster doses of inactivated vaccines are required as they appear to mount adequate immune responses to the routine schedule.

Improved Clinical Outcome After Treatment of Mycobacterium abscessus Complex Pulmonary Disease in Children With Cystic Fibrosis.

BACKGROUND: Mycobacterium abscessus complex pulmonary disease (M. abscessus PD) in cystic fibrosis (CF) is challenging to treat. Current guideline therapeutic regimens involving an intensive phase of intravenous (IV) antibiotics followed by a consolidation phase of inhaled and oral antibiotics are not evidence-based. The objectives of this study were to characterize the clinical outcomes and clearance of Mycobacterium abscessus complex (M. abscessus) from respiratory cultures in children with CF M. abscessus PD. METHODS: This retrospective longitudinal cohort analysis evaluated the first course of treatment for M. abscessus PD in 33 children in Queensland, Australia between 2001 and 2015. Spirometry and nutritional outcomes 2 years pretreatment and 1 year posttreatment were compared with clearance or relapse/persistence of Mycobacterium abscessus complex from respiratory cultures. RESULTS: Nine of 18 children who completed therapy, cleared infection. Three of 7 children who completed only intensive therapy cleared sputum compared with 0/8 children who did not. The trajectory of the percent predicted forced expiratory volume in 1 s and age standardized body mass index significantly improved posttreatment in those that cleared sputum (P < 0.0001). CONCLUSIONS: These results suggest that current treatment recommendations for M. abscessus PD are associated with some success in clearing infection in children with CF and improvement in lung function and body mass index. Clinical trials are required to determine the best treatment approaches.

Non-typhoidal Salmonella infections in children: Review of literature and recommendations for management.

Non-typhoidal Salmonellae are a major cause of infectious diarrhoea worldwide and can cause invasive diseases, including bacteraemia, meningitis and osteomyelitis. Young or immunocompromised children and those with underlying conditions such as sickle cell disease are particularly vulnerable to invasive disease. There has been an increase in the rate of resistant non-typhoidal Salmonella, which is associated with invasive disease and hospitalisation. The intracellular nature of non-typhoidal Salmonella protects against extracellular antibiotics and can facilitate disease relapse, particularly meningitis. Effective antimicrobial agents with good intracellular penetration include azithromycin, fluoroquinolones and third-generation cephalosporins. Antibiotic treatment of non-typhoidal Salmonella gastroenteritis is only indicated if there are risk factors for invasive disease as it can prolong excretion and does not shorten the duration of gastrointestinal symptoms. Optimal choice and length of therapy for gastroenteritis and invasive disease in children is not clear. Here, we provide a review of the literature and treatment recommendations.

Tetanus in New Zealand children: Intensive care management of a vaccine preventable disease.

AIM: To review management of children admitted with tetanus to Starship Children's Hospital from 2000 to 2013. METHODS: Retrospective chart review of children aged 0-15 years admitted to Starship Children's Hospital with tetanus from 2000 to 2013. Follow-up of immunisation status was via the National Immunisation Register and/or phone contact with patient's primary health care provider. RESULTS: Four cases of tetanus occurred, all in unimmunised children. All four required paediatric intensive care unit admission (length of stay (LOS) 2.5-7 weeks) for ventilatory support; three required tracheostomy. Specific tetanus treatment included metronidazole, tetanus immunoglobulin and antispasmodic medications such as magnesium sulphate and benzodiazepines. Three remain partially or unimmunised following discharge. CONCLUSION: Tetanus in children is a rare but preventable life-threatening disease, requiring costly intensive care management. Immunisation is cheap and effective in preventing tetanus and should be offered to all children, including tetanus cases for their future protection.

Prospective surveillance of hospitalisations associated with varicella in New Zealand children.

AIM: Varicella is a vaccine-preventable disease not notifiable in New Zealand (NZ), and varicella vaccine is not funded in the National Immunisation Schedule (NIS). Hospitalisations can occur because of bacterial secondary infection and other complications, which can result in long-term sequelae. Varicella may not be acknowledged in discharge coding when complications occur weeks after infection. Using the New Zealand Paediatric Surveillance Unit (NZPSU), the aim of this study was to document the hospitalisation burden of this disease. METHODS: Cases (0-14 years) of varicella and post-varicella complications requiring hospitalisation, including stroke syndromes where varicella occurred in the preceding 6 months, were notified to NZPSU between 1 November 2011 and 31 October 2013. Herpes zoster cases were excluded. Questionnaires were used to capture demographics, clinical features, management and short-term outcomes. RESULTS: One hundred seventy-eight notifications were received and 144 were confirmed cases. Overall incidence was 8.3/100,000 children per year. Fifty-two percent were women with a median age of 2.4 years. Maori and Pacific Island (PI) children accounted for 74% of hospitalisations, with incidence rate ratios compared with European children of 2.8 and 3.9, respectively (P < 0.01). Complications included: infection (75%), respiratory (11%), neurological (11%), electrolyte disturbance (6%) and haemorrhagic varicella (4%). Nine percent were immunocompromised. Median duration of hospital admission was 4 days with 9% requiring intensive care admission. There were no reported deaths; however, 19% had ongoing problems at discharge. CONCLUSION: Varicella has more associated morbidity than commonly perceived in immunocompetent children. Maori and PI children are more likely to have complications. This surveillance gives support for inclusion of universal varicella vaccine in the NZ NIS.