Intravenous tobramycin is a first-line treatment for Pseudomonas aeruginosa infection in people with cystic fibrosis (CF). Tobramycin exhibits concentration-dependent activity; however, excess drug exposure can lead to nephrotoxicity and ototoxicity. While dosing typically targets serum peak (Cmax) and trough (Cmin) concentrations, the area under the concentration-time curve over 24 h (AUC24) is also used to guide therapy. However, optimal exposure targets remain unclear, leading to variability in clinical practice and guidelines. This review aimed to determine the target tobramycin concentrations and exposure (Cmax, Cmin, AUC24) associated with clinical efficacy (lung function improvement) and/or toxicity (nephrotoxicity, ototoxicity) in CF. Four databases (PubMed, Medline, Embase and Cochrane) were searched and identified studies involving CF patients receiving intravenous tobramycin, recorded tobramycin drug concentration/exposure alongside either clinical efficacy or drug-related toxicity outcomes. Studies with ≤10 patients, in vitro studies and reviews were excluded. The Newcastle-Ottawa Scale was used to assess risk of bias. A meta-analysis was not conducted. Twenty-six studies were included; efficacy was reported in 17, nephrotoxicity in 16 and ototoxicity in 17. Both Cmax and AUC24 were associated with efficacy, with AUC24 being the more reliable predictor. Cmin and AUC24 were associated with toxicity. Only 11 studies reported AUC24, and the overall quality of evidence was poor (21 with medium/high risk of bias, 5 low bias). Current therapeutic Cmax (20-40 mg/L) and Cmin (<1 mg/L) targets remain appropriate. Evidence suggests AUC24-guided dosing for improved efficacy and safety; however, further research is needed to confirm the optimal AUC24 target (80-120 mg/L·h).

BACKGROUND:Pulmonary exacerbations pose a significant clinical burden on people with cystic fibrosis (pwCF). Whether management of exacerbations should change in the context of modulator therapy is unclear. We describe the characteristics, treatment and lung function outcomes of pulmonary exacerbations requiring intravenous antibiotic therapy (PERITs) in a contemporary Australian cohort of pwCF, in an era of rapidly broadening access to modulator therapy. METHODS:PwCF receiving care at 11 Australian specialist centres were prospectively enrolled between 14 October 2020 and 9 October 2024. Spirometry data and treatments received during a PERIT were collected systematically. RESULTS:A total of 982 pwCF were enrolled, with 593 PERITs recorded in 323 individuals. The median (interquartile range) age at PERIT start was 12 (7-17) years and the mean±sd baseline forced expiratory volume in 1 s (FEV1) % predicted across PERITs was 80±21%. Approximately 62% (n=366) of PERITs occurred in people receiving modulator therapy. Intravenous tobramycin (63%) and piperacillin-tazobactam (43%) were the most frequently used antibiotics. Among participants with spirometry at baseline and at Day 7 (n=296) or Day 60 (n=383), 41% (n=120) and 44% (n=169) were below their baseline at Day 7 and Day 60 after commencing treatment, respectively; 8% were >10% below their baseline FEV1 % predicted at both time-points. Recovery patterns were consistent regardless of baseline lung function, Pseudomonas aeruginosa colonisation or modulator use. CONCLUSION:The pattern and magnitude of lung function impairment during PERITs is similar among those receiving and not receiving modulator therapy. This underscores the continued need for evidence to help clinicians balance treatment burden against the risk of irreversible loss of lung function.

ABSTRACT Co-designed research in paediatric HSCT is limited. We sought to determine research priorities which represent the shared priorities of patients, parents, carers, and healthcare professionals (HCP) within Australia, New Zealand, the Netherlands and United Kingdom. An international, multiphase priority-setting methodology was implemented in partnership with the James Lind Alliance and delivered over an 18-month period. Part 1: an international scoping survey asked respondents to submit their research uncertainties related to paediatric HSCT. Part 2: summarising and evidence-checking the submitted uncertainties. Part 3: interim prioritisation survey. Part 4: consensus workshop. In the first international scoping survey, 667 topic ideas were suggested (45% by consumers, 55% by HCP), which were categorized into 80 summary questions. After systematic literature review, 35 summary questions were judged to be true uncertainties (i.e. not answered by existing evidence). These 35 uncertainties were included in a second interim prioritisation survey, completed by 224 participants. From those, a shortlist of 19 questions was drawn. After a multistakeholder workshop, consensus was reached on the top 10 priorities. The PSP identified important research gaps in the management of paediatric HSCT. Priority areas included: implementing personalised medicine approaches, improving immune recovery and adjunct interventions such as exercise, nutrition and microbiome-directed strategies.

Importance:Generic pediatric patient-reported outcome measures (P-PROMs) have the potential to enhance care and patient-clinician interactions in specialty hospital settings. However, evidence about their feasibility and acceptability is lacking. Objective:To identify the feasibility and acceptability of a P-PROM at the point of care among children receiving outpatient care from selected specialty clinics. Design, Setting, and Participants:This nonblinded, pilot feasibility and acceptability randomized clinical trial was conducted from February to June 2024 across 4 pediatric specialty clinics (asthma, sleep, encopresis, and chronic constipation) at The Royal Children's Hospital in Melbourne, Victoria, Australia. Children aged 4 to 17 years (and their caregivers) were eligible for inclusion if they had an appointment at one of the participating clinics during the trial period. Patients and their caregivers were randomly assigned to the intervention or control group. Clinicians (physicians, nurses, and allied health staff) providing specialty care services to eligible patients were also invited to participate. Intervention:Children and/or their caregivers assigned to the intervention arm were asked to complete a generic P-PROM-the EuroQoL 5-Dimensional Questionnaire for Youth, 5 Levels (EQ-5D-Y-5L)-7 days before their appointment and to indicate which EQ-5D-Y-5L items they would like to discuss with their clinician during their appointment. Responses to the completed P-PROM were displayed to clinicians in the electronic medical record, and children and their caregivers received information to act on the P-PROM items. Clinicians received training, clinical decision support, and resources to support patient actions. Patients assigned to the control arm received standard outpatient care, which excluded completing a P-PROM. Main Outcomes and Measures:Primary outcomes were feasibility and acceptability of the P-PROM. Results:Of 170 eligible patients, 87 children (51.2%) and their caregivers were randomly assigned to the intervention arm (n = 43) or control arm (n = 44). Patients included 44 females (50.6%) with a mean (SD) age of 8.8 (3.2) years, and caregivers included 82 females (94.3%) with a mean (SD) age of 41.8 (6.9) years. Of the 17 eligible clinicians, 14 were included in the study; they reported working in a specialty clinic for a mean (SD) of 9.7 (8.4) years. Thirty-three of 37 caregivers (89.2%) in the intervention arm and 9 of 14 clinicians (64.3%) reported that the P-PROM was acceptable. A P-PROM completion rate of 93.0% (40 of 43 patients) was achieved, indicating feasibility. Conclusions and Relevance:In this pilot randomized clinical trial, the collection and use of the EQ-5D-Y-5L was feasible and acceptable in routine outpatient specialty pediatric care. Further study should examine the quantitative impacts of the intervention on quality of care and outcomes as well as the impacts over time. Trial Registration:ISRCTN Identifier: ISRCTN16030620.

The lung alveoli are continually exposed to inhaled pathogens and environmental hazards and rely on coordinated communication between alveolar macrophages and type 2 alveolar epithelial cells (AT2s) to maintain homeostasis. Disruption of these interactions can impair immunity and repair, contributing to acute and chronic respiratory diseases. To better define these mechanisms and support therapeutic discovery, we established a human iPSC-derived air-liquid interface platform that captures key features of AT2-macrophage crosstalk. Using this system, we show that coculture enhances AT2-specific transcriptional programs including lipid synthesis, while macrophages actively phagocytose AT2-derived surfactant. iPSC-derived macrophages adopt an alveolar macrophage-like phenotype and respond to AT2-derived M-CSF. During respiratory infection, macrophages play a crucial role in modulating epithelial inflammatory responses, augmenting antiviral immunity, and limiting viral replication. We further identify a role for macrophages in epithelial repair, where VEGF-mediated signaling to macrophages increases epithelial permeability during viral infection. Together, these findings reveal dimensions of AT2-macrophage cooperation in homeostasis, infection, and repair, and demonstrate how this iPSC-derived platform can be used to dissect mechanisms that may initiate or drive the progression of respiratory diseases.

Aberrant inflammation and structural lung damage occurs early in life for people with cystic fibrosis (CF). Even in the era of CFTR modulators, anti-inflammatory therapy may still be needed to prevent establishment and lifelong consequences of bronchiectasis. In this study, we integrated transcriptome-wide single-cell RNA sequencing data and highly multiplexed surface protein expression to create the largest comprehensive paediatric lower airway atlas of >190,000 cells from 45 bronchoalveolar lavage (BAL) samples resulting in 43 immune and epithelial cell populations, all available for exploration on CELLxGENE. We then investigated inflammatory cell responses in children with CF to show widespread gene expression dysregulation of macrophage populations in the preschool CF lung. This included alterations in pathways associated with TNF and IFN signalling, cholesterol homeostasis, as well as pulmonary fibrosis, that were further altered by the early development of bronchiectasis. We showed that the CFTR modulator ivacaftor restores some of these macrophage-related functional deficits and reduces expression of pathways associated with neutrophil infiltration, however the modulator lumacaftor/ivacaftor did not result in any detectable changes in transcriptional response. This work represents a comprehensive, multi-omic single-cell analysis of BAL from preschool children and the results may inform the future development of anti-inflammatory therapy for children with CF.

OBJECTIVES:To compare the measurement properties of paediatric patient-reported outcome measures (P-PROMs) used in clinical trials and practice for common conditions. DESIGN:Data from the Australian Paediatric Multi-Instrument Comparison study were used, including children aged 5-18 years with autism spectrum disorder (ASD) (n=510), asthma (n=487), eating disorder(s) (n=216), epilepsy (n=298), recurrent abdominal pain (n=392), sleep problems (n=346), dental problems (n=490), type 1 diabetes (T1D) (n=67), enuresis (n=182) and no health conditions (reference group) (n=1259). The acceptability, response distribution (floor/ceiling effects), known-groups validity, test-retest reliability, responsiveness and convergent validity of the Paediatric Quality of Life Inventory (PedsQL), EuroQol Group's Youth instruments with three and five response options (EQ-5D-Y-3L and EQ-5D-Y-5L), Child Health Utility 9D (CHU9D), Assessment of Quality of Life 6D (AQoL-6D), Health Utilities Index Mark 3 and Patient-Reported Outcomes Measurement Information System Paediatric Profile 25 (PROMIS-25) were assessed. RESULTS:PedsQL, EQ-5D-Y-3L, EQ-5D-Y-5L, CHU9D and PROMIS-25 were easy and quick to complete, indicating acceptability. Only the EQ-5D-Y-3L and EQ-5D-Y-5L demonstrated ceiling effect issues. All measures were able to differentiate between children with no health conditions and children with each condition (p<0.001, effect sizes between 0.47 and 3.5), indicating known-groups validity. Test-retest reliability varied by condition; however, the PedsQL and EQ-5D-Y-5L were the most reliable. CONCLUSIONS:Certain P-PROMs may be preferred in different conditions, that is, ASD (PedsQL and EQ-5D-Y-5L), asthma (PedsQL), eating disorder(s) (PedsQL and CHU9D), epilepsy (PedsQL and CHU9D), recurrent abdominal pain (PedsQL, EQ-5D-Y-5L and CHU9D), sleep problems (PedsQL), dental problems (PedsQL), T1D (PedsQL and CHU9D) and enuresis (PedsQL). Notably, the PedsQL performed favourably in all conditions assessed. More evidence is required on the responsiveness of P-PROMs to changes in child health. TRIAL REGISTRATION NUMBER:ACTRN12621000657820.

This randomized clinical trial examines the feasibility and acceptability of using the self-reported EuroQoL 5-Dimensional Questionnaire for Youth, 5 Levels tool at routine outpatient pediatric specialty care visits. QuestionWhat is the feasibility and acceptability of using a pediatric patient-reported outcome measure (P-PROM), EuroQoL 5-Dimensional Questionnaire for Youth, 5 Levels (EQ-5D-Y-5L), in routine outpatient specialty care?FindingsIn this pilot randomized clinical trial with 87 pediatric patients and their caregivers, use of EQ-5D-Y-5L, implemented in a P-PROM intervention, was reported as feasible by most participants and acceptable by a majority of caregivers and clinicians.MeaningThe findings of this study suggest that use of EQ-5D-Y-5L in specialty care is feasible and acceptable and that future research is needed into the quantitative impacts of the intervention on quality of care and outcomes. ImportanceGeneric pediatric patient-reported outcome measures (P-PROMs) have the potential to enhance care and patient-clinician interactions in specialty hospital settings. However, evidence about their feasibility and acceptability is lacking.ObjectiveTo identify the feasibility and acceptability of a P-PROM at the point of care among children receiving outpatient care from selected specialty clinics.Design, Setting, and ParticipantsThis nonblinded, pilot feasibility and acceptability randomized clinical trial was conducted from February to June 2024 across 4 pediatric specialty clinics (asthma, sleep, encopresis, and chronic constipation) at The Royal Children's Hospital in Melbourne, Victoria, Australia. Children aged 4 to 17 years (and their caregivers) were eligible for inclusion if they had an appointment at one of the participating clinics during the trial period. Patients and their caregivers were randomly assigned to the intervention or control group. Clinicians (physicians, nurses, and allied health staff) providing specialty care services to eligible patients were also invited to participate.InterventionChildren and/or their caregivers assigned to the intervention arm were asked to complete a generic P-PROM-the EuroQoL 5-Dimensional Questionnaire for Youth, 5 Levels (EQ-5D-Y-5L)-7 days before their appointment and to indicate which EQ-5D-Y-5L items they would like to discuss with their clinician during their appointment. Responses to the completed P-PROM were displayed to clinicians in the electronic medical record, and children and their caregivers received information to act on the P-PROM items. Clinicians received training, clinical decision support, and resources to support patient actions. Patients assigned to the control arm received standard outpatient care, which excluded completing a P-PROM.Main Outcomes and MeasuresPrimary outcomes were feasibility and acceptability of the P-PROM.ResultsOf 170 eligible patients, 87 children (51.2%) and their caregivers were randomly assigned to the intervention arm (n = 43) or control arm (n = 44). Patients included 44 females (50.6%) with a mean (SD) age of 8.8 (3.2) years, and caregivers included 82 females (94.3%) with a mean (SD) age of 41.8 (6.9) years. Of the 17 eligible clinicians, 14 were included in the study; they reported working in a specialty clinic for a mean (SD) of 9.7 (8.4) years. Thirty-three of 37 caregivers (89.2%) in the intervention arm and 9 of 14 clinicians (64.3%) reported that the P-PROM was acceptable. A P-PROM completion rate of 93.0% (40 of 43 patients) was achieved, indicating feasibility.Conclusions and RelevanceIn this pilot randomized clinical trial, the collection and use of the EQ-5D-Y-5L was feasible and acceptable in routine outpatient specialty pediatric care. Further study should examine the quantitative impacts of the intervention on quality of care and outcomes as well as the impacts over time.Trial RegistrationISRCTN Identifier: ISRCTN16030620

Bronchiolitis obliterans syndrome (BOS) represents a significant source of morbidity and non-relapse mortality among children and young adults treated with allogeneic hematopoietic stem cell transplantation (aHSCT). Pulmonary function testing (PFT) pre- and post-aHSCT may allow for pre-symptomatic detection of BOS, and thus early intervention. Current guidelines and practices vary regarding which tests to perform and timing relative to transplant. A systematic review evaluating PFT before and after pediatric aHSCT was conducted to inform American Thoracic Society clinical practice guidelines on detection of BOS. To determine the optimal approach to conducting PFT prior to and after pediatric aHSCT. We performed a systematic review of the literature to identify studies of PFT in human aHSCT recipients < 25 years of age to address two questions: (1) Should pre-transplant screening PFT be performed in pediatric patients who will undergo aHSCT? (2) At what frequency should pediatric patients who have had aHSCT undergo PFT? We searched in Medline through August 2022 for studies that enrolled patients < 25 years of age being treated with aHSCT for whom PFT data were reported before or after transplant. The 30 studies with pre-transplant PFT data showed a wide range of findings, with the majority demonstrating abnormalities. In studies reporting respiratory symptoms, 85–100

INTRODUCTION:Pulmonary complications due to infection contribute significantly to post-haematopoietic stem cell transplant (HCT) morbidity and mortality. Standard microbiological investigations, when performed on bronchoalveolar lavage (BAL) fluid, can take days to weeks to confirm a diagnosis. We aimed to determine the diagnostic performance of the BioFire FilmArray pneumonia panel plus (FA-PP), a multiplex polymerase chain reaction (PCR) panel that detects 18 bacterial and nine viral targets, when applied to BAL obtained by flexible bronchoscopy, in children undergoing HCT. METHODS:We performed a single-centre prospective observational study in children undergoing allogeneic HCT, who underwent BAL pre- and post-HCT. To determine the diagnostic performance of the FA-PP, we measured the positive and negative concordance, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV), compared with standard microbiological investigations, which was considered the gold standard. The clinical impact of the FA-PP was also qualitatively measured. RESULTS:This study enrolled 16 children who had 31 BAL samples collected, both pre- and post-HCT. In total, there were seven patients who underwent eight BALs while symptomatic, and 50% (4/8) of these results were concordant between FA-PP and standard microbiological investigations. In the 13 patients who had 23 BALs collected while asymptomatic, 78% (18/23) of these results were concordant. In the cohort as a whole, sensitivity, specificity, PPV and NPV were 100%, 78%, 54% and 100%, respectively. In 50% (4/8) of patients who underwent a BAL while symptomatic, the FA-PP resulted in a hypothetical or actual clinical change, compared to 22% (5/23) of patients who underwent an asymptomatic BAL. CONCLUSION:In conclusion, we report the first prospective evaluation of the diagnostic performance of the FA-PP in BAL, in a high-risk paediatric HCT cohort. We demonstrate that the FA-PP is a potentially useful adjunct to traditional standard microbiological investigations that can provide clinically impactful diagnostic information.

Tobramycin is commonly used for the treatment of pulmonary exacerbations in children with cystic fibrosis (CF). Currently, a standard dose of 10 mg/kg daily is used in all children. We aim to develop a population pharmacokinetic (popPK) model of tobramycin in children with CF and determine the: (i) effect of cystic fibrosis transmembrane conductance regulator (CFTR) modulators on tobramycin pharmacokinetics (PK); (ii) attainment of the commonly used serum steady state area under the concentration-time curve target (AUC24,ss) of 80-110 mg/L⋅h with standard dosing; and (iii) generate an optimized fully individualized dosing strategy to improve target attainment. Multicenter prospective observational study of children with CF aged 0-19 years receiving IV tobramycin who had ≥1 serum concentration measured. A popPK model was developed using nonlinear mixed-effect modeling, and simulations were performed to assess study aims. Overall, 63 children had 450 serum tobramycin concentrations. A one-compartment popPK model, including age, weight, a renal maturation model, and estimated glomerular filtration rate as covariates, was developed. With standard dosing, 1/3 of children achieved the target AUC24,ss with younger children (<2 years) having the lowest probability of target attainment (PTA) (15%). The optimized dosing regimen improved target attainment in all children, increasing the PTA in children <2 years to 62%. CFTR modulator drugs did not affect tobramycin PK. Standard tobramycin dosing in children with CF achieves poor attainment of target serum AUC24,ss, particularly in children <2 years. A fully individualized approach (available at https://www.kidscalc.org/) improved target attainment in all children. CFTR modulators had a negligible effect on tobramycin PK.

Objectives:Lung complications occur commonly post-haematopoietic stem cell transplant (HCT) in children and contribute significantly to mortality. The development of biomarkers predictive of post-HCT lung complications may improve outcomes for these children. Therefore, the primary objective of this study was to identify pre-transplant plasma biomarkers predictive of lung complications in children undergoing HCT. Methods:Plasma samples from 117 pre-HCT patients were used to measure 78 soluble immune analytes, and extensive clinical metadata were retrospectively collected from the electronic medical record, including clinical characteristics of the post-HCT lung complications. Results:Firstly, we showed that the plasma cytokine signature of children undergoing HCT differed significantly between children depending on the indication for HCT (malignant vs non-malignant). Secondly, we found that the plasma cytokine signature changed with the age of the patient. Thirdly, we showed that elevated pre-HCT plasma levels of CXCL9 and Chitinase 3-like 1, both induced by IFN-γ, were predictive of post-HCT lung complications in patients with a malignant indication for HCT [area under the curve (AUC): 0.70, P = 0.0007 and AUC: 0.68, P = 0.0016, respectively]. Conclusion:In conclusion, we have identified two potential biomarkers of post-HCT lung disease in paediatric patients and these require validation in future cohorts.

BACKGROUND:Early-life inflammation has long been recognised as a key pathophysiological process in the evolution of cystic fibrosis (CF) lung disease. Despite this, no CF-specific anti-inflammatory treatments have been developed. This is crucial even in the era of highly effective modulator therapy as recent evidence suggests that modulators alter, but may not fully resolve, pulmonary inflammation. METHODS:In this study, we used clinical microbiology data, high-dimensional flow cytometry and multiplex immunoassays to compare pulmonary (bronchoalveolar lavage (BAL)) and systemic immunity in 70 preschool children with CF and a total of 32 age-matched preschool controls. RESULTS:We show that inflammation in the early-life CF lung is characterised by innate cell infiltration (neutrophils: 31.31 vs 1.8% of BAL in CF compared with controls, FDRp=0.0001; eosinophils: 0.55 vs 0.06%, FDRp=0.001, and monocytes: 1.91 vs 0.45%, FDRp=0.004) and widespread upregulation of both traditional and type 2 inflammatory soluble signatures (40 analytes significantly elevated in BAL of CF compared with controls, all FDRp<0.1). Key targetable features of this response included pulmonary interleukin (IL)-8 and IL-13 which were most significantly associated with neutrophilic and eosinophilic infiltration, respectively (IL-8 and neutrophils; Spearman rho=0.68, FDRp=0.002: IL-13 and eosinophils; Spearman rho=0.75, FDRp=0.01). Signatures of type 2 inflammation, as identified by REACTOME pathway analysis, including IL-4, IL-13 and FGF-2, were highly elevated in both the lungs and circulation in early CF. When exploring the efficacy of Cystic Fibrosis Transmembrane Conductance Regulator modulators to resolve pulmonary and systemic inflammation in early life, we showed that different classes of modulators have varying effects on inflammation, with ivacaftor showing a more significant effect in the lungs and circulation than lumacaftor/ivacaftor. Finally, we showed that CF children with pathogen colonisation had similar levels of pulmonary inflammation as CF children without pathogen colonisation (no significant differences), and that inflammation was evident during infancy even without evidence of colonisation (as observed by significant increases in levels of SDF-1alpha, M-CSF, IL-2, IL-9, IL-12p40, IL-17, MCP-1 and LIGHT/TNFSF14, all FDRp<0.1), highlighting a role for intrinsic dysregulation of inflammation that begins in early life. CONCLUSIONS:We provide a rationale for targeted anti-inflammatory intervention in early-life CF.

Background Telehealth has been widely incorporated into cystic fibrosis (CF) care in Australia and other countries, with a largely hybrid approach of multidisciplinary telehealth alongside traditional in-person care. While feasibility and acceptability of telehealth-based care has been established, the impact on CF-related health outcomes has not been comprehensively assessed. Methods Retrospective cohort study using national Australian Cystic Fibrosis Registry Data (ACFDR). Primary outcomes were change in percent predicted forced expiratory volume in one second (ppFEV1) in adults and body mass index (BMI) z-score in children. Secondary outcomes included lung function, BMI, microbiology and hospital admissions. Telehealth use was stratified according to percentage of telehealth visits out of total CF clinic visits during the study period, examined as quartiles. Analyses were conducted using Analysis of Covariance (ANCOVA) and logistic regression, to isolate the effect of telehealth use quartile on outcomes after adjusting for confounders. Results Complete data from 1250 patients, (646 < 18 yr, 594 ≥ 18 yrs), were analysed. There was less decline in ppFEV1 in adults (β = 6.06, p < 0.001), and lower detection of Pseudomonas aeruginosa in adults (OR = 0.419, p = 0.035) and children (OR = 0.182, p = 0.011) who received greater than 75% of visits via telehealth. However, high telehealth use was associated with reduced microbiological sampling. Telehealth was not associated with change in BMI or hospitalisations. Conclusions Population level data from the ACFDR demonstrates that higher telehealth usage was not associated with adverse health outcomes and was associated with a reduced decline in ppFEV1 in adults.