Burden of antimicrobial prescribing in primary care attributable to sore throat: a retrospective cohort study of patient record data.

BACKGROUND: Reducing antibiotic use in Australia, and the subsequent impact on antimicrobial resistance, requires multiple, sustained approaches with appropriate resources and support. Additional strategies to reduce antibiotic prescribing include effective vaccines, against pathogens such as Streptococcus pyogenes, the most common bacterial cause of sore throat. As part of efforts towards assessing the benefits of introducing new strategies to reduce antimicrobial prescribing, we aimed to determine the burden of antimicrobial prescribing for sore throat in general practice. METHODS: General practice activity data from 2013 - 2017 derived from the first 8 practices participating in the 'Primary Care Audit, Teaching and Research Open Network' (Patron) program were analysed according to reason for visit (upper respiratory tract infection, URTI, or sore throat) and antibiotic prescription. The main outcome measures were percentage of sore throat or URTI presentations with antibiotic prescription by age. RESULTS: A total of 722,339 visits to general practice were made by 65,449 patients; 5.7% of visits were for URTI with 0.8% meeting the more specific criteria for sore throat. 66.1% of sore throat visits and 36.2% of URTI visits resulted in antibiotic prescription. Penicillin, the recommended antibiotic for sore throat when indicated, was the antibiotic of choice in only 52.9% of sore throat cases prescribed antibiotics. Broader spectrum antibiotics were prescribed more frequently in older age groups. CONCLUSIONS: Frequency of antibiotic prescribing for sore throat is high and broad, despite Australian Therapeutic guideline recommendations. Multiple, sustained interventions to reduce prescribing, including availability of effective S. pyogenes vaccines that could reduce the incidence of streptococcal pharyngitis, could obviate the need to prescribe antibiotics and support ongoing efforts to promote antimicrobial stewardship.

Strategic and scientific contributions of human challenge trials for vaccine development: facts versus fantasy.

The unprecedented speed of delivery of SARS-CoV-2 pandemic vaccines has redefined the limits for all vaccine development. Beyond the aspirational 100-day timeline for tomorrow's hypothetical pandemic vaccines, there is a sense of optimism that development of other high priority vaccines can be accelerated. Early in the COVID-19 pandemic, an intense and polarised academic and public discourse arose concerning the role of human challenge trials for vaccine development. A case was made for human challenge trials as a powerful tool to establish early proof-of-concept of vaccine efficacy in humans, inform vaccine down selection, and address crucial knowledge gaps regarding transmission, pathogenesis, and immune protection. We review the track record of human challenge trials contributing to the development of vaccines for 19 different pathogens and discuss relevant limitations, barriers, and pitfalls. This Review also highlights opportunities for efforts to broaden the scope and boost the effects of human challenge trials, to accelerate all vaccine development.

Geographic Expansion of Japanese Encephalitis Virus to Australia: Neuroinflammatory Sequelae and Consideration of Immunomodulation.

We report a child from Southern Australia (New South Wales) who presented during a La Niña event with encephalopathy and acute flaccid paralysis. Magnetic resonance imaging suggested Japanese encephalitis (JE). Steroids and intravenous immunoglobulin did not improve symptoms. Therapeutic plasma exchange (TPE) resulted in rapid improvement and tracheostomy decannulation. Our case illustrates the complex pathophysiology of JE, its' geographic expansion into Southern Australia and potential use of TPE for neuroinflammatory sequelae.

Increase in invasive group A streptococcal disease among Australian children coinciding with northern hemisphere surges.

Background: Increases in invasive group A streptococcal disease (iGAS) have recently been reported in multiple countries in the northern hemisphere, occurring during, and outside of, typical spring peaks. We report the epidemiology of iGAS among children in Australia from 1 July 2018 to 31 December 2022. Methods: The Paediatric Active Enhanced Disease Surveillance (PAEDS) Network prospectively collected iGAS patient notifications for children and young people aged less than 18 years admitted to five major Australian paediatric hospitals in Victoria, Queensland, Western Australia and the Northern Territory. Patients were eligible for inclusion if they had GAS isolated from a normally sterile body site, or met clinical criteria for streptococcal toxic shock syndrome or necrotising fasciitis with GAS isolated from a non-sterile site. We report patients' clinical and demographic characteristics, and estimate minimum incidence rates. Findings: We identified 280 paediatric iGAS patients, median age 4.5 years (interquartile range 1.4-6.4). We observed a pre-pandemic peak annualised incidence of 3.7 per 100,000 (95% CI 3.1-4.4) in the 3rd quarter of 2018, followed by a decline to less than 1.0 per 100,000 per quarter from 2020 to mid-2021. The annualised incidence increased sharply from mid-2022, peaking at 5.2 per 100,000 (95% CI 4.4-6.0) in the 3rd quarter and persisting into the 4th quarter (4.9 per 100,000, 95% CI 4.2-5.7). There were 3 attributable deaths and 84 (32%) patients had severe disease (overall case fatality rate 1%, 95% CI 0.2-3.3). Respiratory virus co-infection, positive in 57 of 119 patients tested, was associated with severe disease (RR 1.9, 95% CI 1.2-3.0). The most common emm-type was emm-1 (60 of 163 isolates that underwent emm-typing, 37%), followed by emm-12 (18%). Interpretation: Australia experienced an increase in the incidence of iGAS among children and young people in 2022 compared to pandemic years 2020-2021. This is similar to northern hemisphere observations, despite differences in seasons and circulating respiratory viruses. Outbreaks of iGAS continue to occur widely. This emphasises the unmet need for a vaccine to prevent significant morbidity associated with iGAS disease. Funding: Murdoch Children's Research Institute funded open access publishing of this manuscript.

The utility of chest x-ray and lung ultrasound in the management of infants and children presenting with severe pneumonia in low-and middle-income countries: A pragmatic scoping review.

Background: Chest x-ray (CXR) is commonly used (when available) to support clinical management decisions for child pneumonia and provide a reference standard for diagnosis in research studies. However, its diagnostic and technical limitations for both purposes are well recognised. Recent evidence suggests that lung ultrasound (LUS) may have diagnostic utility in pneumonia. This systematic scoping review of research on the utility of CXR and LUS in the management of severe childhood pneumonia aims to inform pragmatic guidelines for low- and middle-income countries (LMICs) and identify gaps in knowledge. Methods: We included peer-reviewed studies published between 2000 and 2020 in infants and children aged from one month to nine years, presenting with severe pneumonia. CXR studies were limited to those from LMICs, while LUS studies included any geographic region. LUS and CXR articles were mapped into the following themes: indications, role in diagnosis, role in management, impact on outcomes, and practical considerations for LMIC settings. Results: 85 articles met all eligibility criteria, including 27 CXR studies and 58 LUS studies. CXR studies were primarily observational and examined associations between radiographic abnormalities and pneumonia aetiology or outcomes. The most consistent finding was an association between CXR consolidation and risk of mortality. Difficulty obtaining quality CXR images and inter-reader variability in interpretation were commonly reported challenges. Research evaluating indications for CXR, role in management, and impact on patient outcomes was very limited. LUS studies primarily focused on diagnostic accuracy. LUS had higher sensitivity for identification of consolidation than CXR. There are gaps in knowledge regarding diagnostic criteria, as well as the practical utility of LUS in the diagnosis and management of pneumonia. Most LUS studies were conducted in HIC settings with experienced operators; however, small feasibility studies indicate that good inter-operator reliability may be achieved by training of novice clinicians in LMIC settings. Conclusions: The available evidence does not support the routine use of CXR or LUS as essential tools in the diagnosis and initial management of severe pneumonia. Further evaluation is required to determine the clinical utility and feasibility of both imaging modalities in low-resource settings.

A systematic review of clinical, epidemiological and demographic predictors of tuberculosis in children with pneumonia.

Background: Tuberculosis (TB) can present as acute, severe pneumonia in children, but features which distinguish TB from other causes of pneumonia are not well understood. We conducted a systematic review to determine the prevalence and to explore clinical and demographic predictors of TB in children presenting with pneumonia over three decades. Methods: We searched for peer-reviewed, English language studies published between 1990 and 2020 that included children aged between 1 month and 17 years with pneumonia and prospectively evaluated for TB. There were 895 abstracts and titles screened, and 72 full text articles assessed for eligibility. Results: Thirteen clinical studies, two autopsy studies and one systematic review were included in analyses. Majority of studies were from Africa (12/15) and included children less than five years age. Prevalence of bacteriologically confirmed TB in children with pneumonia ranged from 0.2% to 14.8% (median = 3.7%, interquartile range (IQR) = 5.95) and remained stable over the three decades. TB may be more likely in children with pneumonia if they have a history of close TB contact, HIV infection, malnutrition, age less than one year or failure to respond to empirical antibiotics. However, these features have limited discriminatory value as TB commonly presents as acute severe pneumonia - with a short duration of cough, and clinical and radiographic features indistinguishable from other causes of pneumonia. Approximately half of patients with TB respond to initial empirical antibiotics, presumably due to bacterial co-infection, and follow-up may be critical to detect and treat TB. Conclusion: TB should be considered as a potential cause or comorbidity in all children presenting with pneumonia in high burden settings. Clinicians should be alert to the presence of known risk factors for TB and bacteriological confirmation sought whenever possible. Quality data regarding clinical predictors of TB in childhood pneumonia are lacking. Further, prospective research is needed to better understand predictors and prevalence of TB in childhood pneumonia, particularly in TB endemic settings outside of Africa and in older children. Children of all ages with pneumonia should be included in research on improved, point-of-care TB diagnostics to support early case detection and treatment.

The Impact of Antimicrobial Stewardship in Children in Low- and Middle-income Countries: A Systematic Review.

BACKGROUND: Antimicrobial stewardship (AMS) is central to the World Health Organisation Global Action Plan against antimicrobial resistance (AMR). If antibiotics are used without restraint, morbidity and mortality from AMR will continue to increase. In resource-rich settings, AMS can safely reduce antibiotic consumption. However, for children in low- and middle-income countries (LMIC), the impact of different AMS interventions is unknown. AIM: To determine the impact of different AMS interventions on antibiotic use and clinical and microbiologic outcomes in children in LMIC. METHODS: MEDLINE, Embase and PubMed were searched for studies of AMS interventions in pediatric population in LMIC settings. Controlled trials, controlled before-and-after studies and interrupted time series studies were included. Outcomes assessed were antibiotic use, multidrug-resistant organism (MDRO) rates, clinical outcomes and cost. RESULTS: Of 1462 studies, 34 met inclusion criteria including a total population of >5,000,000 in 17 countries. Twenty were in inpatients, 2 in ED, 10 in OPD and 2 in both. Seven studies were randomized controlled trials. All types of interventions reported a positive impact on antibiotic prescribing. AMS bundles with education, and clinical decision tools appeared more effective than guidelines alone. AMS interventions resulted in significantly decreased clinical infections (4/4 studies) and clinical failure (2/2) and reduced MDRO colonization rate (4/4). There was no concomitant increase in mortality (4/4 studies) or length of stay (2/2). CONCLUSION: Multiple effective strategies exist to reduce antibiotic consumption in LMIC. However, marked heterogeneity limit conclusions regarding the most effective approach, particularly regarding clinical outcomes. Overall, AMS strategies are important tools in the reduction of MDRO-related morbidity in children in LMIC.

Infliximab for Paradoxical Reactions in Pediatric Central Nervous System Tuberculosis.

Paradoxical reactions in central nervous system tuberculosis (CNS-TB) are associated with significant morbidity and mortality. We describe 4 HIV-uninfected children treated for CNS-TB with severe paradoxical reactions unresponsive to corticosteroids. All made recovery after treatment with infliximab, highlighting the safety and effectiveness of infliximab for this complication, and need for prospective trials.

COVID-19 public health measures and respiratory viruses in children in Melbourne.

AIM: To describe the epidemiology of respiratory viruses in children before and during the 2020 SARS-CoV-2 pandemic and the relationship to public health measures instituted by the Victorian government. METHODS: Retrospective audit of respiratory viruses at a tertiary paediatric hospital in Melbourne from January 2015 up to week 47, 2020 in children under 18 years of age. The proportion of positive cases in weeks 1-47 in 2015-2019 (period 1) were compared to weeks 1-47, 2020 (period 2), and reviewed in the context of public health restrictions in Victoria. RESULTS: An annual average of 4636 tests were performed in period 1 compared to 3659 tests in period 2. Proportions of positive influenza A virus, influenza B virus, respiratory syncytial virus (RSV) and human parainfluenza virus were significantly reduced in period 2 compared to period 1: 77.3, 89.4, 68.6 and 66.9% reductions, respectively (all P < 0.001). From week 12-47, 2020, 28 893 SARS-CoV-2 tests were performed with a 0.64% positivity rate. Influenza viruses were not detected after week 17, RSV was not detected after week 35. CONCLUSIONS: Strict public health measures and border closures were successful in eliminating community transmission of SARS-CoV-2 in Melbourne. This was associated with a significant reduction in other respiratory virus infections in children. Identifying sustainable and effective ongoing public health interventions to reduce transmission of RSV and influenza could result in reduced morbidity and mortality in children and requires further research.

Rare Infant Case of Pulmonary Aspergilloma Highlighting Common Challenges With Voriconazole Dosing.

We describe a 6-week-old male-term infant with a pulmonary aspergilloma diagnosed following lobectomy for suspected pleuropulmonary blastoma, with characteristic histopathologic findings and Aspergillus detected by polymerase chain reaction. Intensive testing did not reveal primary or secondary immunodeficiency. During 5 weeks treatment with voriconazole including regular therapeutic drug monitoring and dose adjustment, a level in the target range was never achieved. When the patient developed photosensitivity, treatment was stopped without relapse over 12 months follow-up. Voriconazole dosing is notoriously challenging in children. We review the cumulative published experience with voriconazole use in infants to highlight even greater difficulty in infants. Pulmonary aspergillosis is typically a disease affecting immunocompromised or critically ill patients. In children, it is well described in those with chronic granulomatous disease (CGD) as a complication of immunosuppressive antineoplastic chemotherapy and rarely in extremely- or very-low birthweight premature neonatal intensive care patients. The diagnosis is extremely rare in children without underlying risk factors. To our knowledge, this is the first report of a pulmonary aspergilloma in an immunocompetent infant.

A case report describing the immune response of an infant with congenital heart disease and severe COVID-19.

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

Tuberculous Meningitis in Children: Reducing the Burden of Death and Disability.

Tuberculous meningitis disproportionately affects young children. As the most devastating form of tuberculosis, it is associated with unacceptably high rates of mortality and morbidity even if treated. Challenging to diagnose and treat, tuberculous meningitis commonly causes long-term neurodisability in those who do survive. There remains an urgent need for strengthened surveillance, improved rapid diagnostics technology, optimised anti-tuberculosis drug therapy, investigation of new host-directed therapy, and further research on long-term functional and neurodevelopmental outcomes to allow targeted intervention. This review focuses on the neglected field of paediatric tuberculous meningitis and bridges current clinical gaps with research questions to improve outcomes from this crippling disease.

Feasibility of Continuous Infusions of Acyclovir.

Current guidelines for severe herpes simplex virus infection recommend 21 days of intravenous therapy. The thrice-daily administration of intravenous acyclovir makes it challenging to deliver as outpatient therapy. We describe 2 cases with confirmed or presumed neonatal herpes simplex virus encephalitis treated with acyclovir administered as a continuous-infusion at home and review the pharmacologic and clinical evidence for continuous infusions of acyclovir.

Successful Treatment of a Severe Vision-Threatening Paradoxical Tuberculous Reaction with Infliximab: First Pediatric Use.

A 7-year-old girl with tuberculous (TB) meningitis developed optochiasmatic arachnoiditis, a vision-threatening paradoxical reaction, after starting TB treatment including adjunctive steroid therapy. She was treated with infliximab with complete recovery. This is the first report of the use of a tissue necrosis factor α inhibitor for the treatment of a severe paradoxical TB reaction in a child.

Paediatric Integrase Inhibitor Use in a Real-Life Setting: A Single-Centre Cohort Experience 2009-2018.

BACKGROUND AND OBJECTIVE: Integrase strand transfer inhibitors (INSTIs) have become the preferred first-line antiretroviral therapy in adults. There is paucity of published data on their use in children outside of clinical trials, particularly long-term safety and tolerability. This study aimed to describe INSTI use including the number of, and reasons for INSTI discontinuation. METHODS: We conducted a retrospective cohort analysis by database and electronic record review of children aged under 18 years with perinatally acquired human immunodeficiency virus who started INSTI-based antiretroviral therapy between May 2009 and March 2018, in a single tertiary centre. RESULTS: Fifty-six INSTI-based regimens were prescribed in 54 children, 64.9% from 2015 onwards. Twenty-one of 56 (37.5%) regimens commenced with raltegravir, 29 (51.8%) with dolutegravir and six (10.7%) with elvitegravir. The median age at the start of treatment was 15 years (interquartile range 13.5-16.4) with a median duration of INSTI-antiretroviral therapy of 1.65 years (range 0.01-8.8). Twenty-four children had a detectable viral load at the start INSTI therapy; 20 (83%) achieving viral suppression in a median of 26 days (interquartile range 19.5-34.5). There were 26 discontinuations of INSTI-based antiretroviral therapy after a median of 183 days; 9/26 because of adverse events. Four of nine adverse events were attributed to INSTI use, all in patients taking dolutegravir and the adverse events were neuropsychiatric and gastrointestinal in nature. CONCLUSIONS: INSTI-based regimens were generally efficacious and well tolerated in this paediatric cohort, with 4/26 discontinuations due to INSTI-attributed adverse events. Further post-marketing surveillance of INSTI use in children is warranted.