Srdjan Micic

Background: Flexible bronchoscopy (FB) is widely used in the management of children with Cystic Fibrosis (CF) to visualize airway abnormalities, assess inflammation and detect infection. While previous scoring systems have been proposed to quantify visual airway findings in general pediatric populations, no standardized tool exists for assessing airway inflammation specific to CF. Methods: We modified the previously proposed pediatric bronchoscopy scoring tool by adding four features relevant to CF pathology: mucus plugging, secretion viscosity, bleeding, and vascular drawing (abnormal or enhanced visualization of airway mucosal vessels, reflecting neovascular remodeling associated with inflammation). Eighty bronchoscopy recordings (50 CF, 30 non‐CF) were retrospectively scored by four raters blinded to the clinical information, and ten visual features were assessed: six from the previously proposed score (secretion amount and color, mucosal edema, erythema, ridging, and pallor) and the four CF‐specific additions. Inter‐rater reliability was assessed using Gwet's AC2 coefficient. Results: Agreement between raters varied across features. Mucus plugging (AC2 = 0.94) and bleeding (0.80), both CF‐specific, were among the most reliably scored features, while secretion viscosity (0.47) and vascular drawing (0.50) showed the lowest agreement. The expanded score demonstrated comparable or improved reliability for overlapping features from earlier scoring systems. Conclusion: The modified bronchoscopy score demonstrated moderate to excellent inter‐rater reliability and added clinically relevant features specific to CF. It may serve as a standardized method to assess bronchoscopy for pediatric CF lung disease, although further validation is needed for features with lower inter‐rater reliability.

Diffusing capacity for carbon monoxide (DLco) testing is widely used in adult respiratory medicine, but its role in pediatric care remains unclear. This st

Background: Childhood interstitial lung diseases (chILD) encompass a diverse group of rare, chronic respiratory disorders. While treatment options are limited, evaluating health-related quality of life (HRQoL) has become a vital approach for clinical monitoring. This study aims to enhance our understanding of the medical and sociodemographic factors influencing HRQoL in chILD. Methods: This study used prospectively obtained data from the chILD-EU Register. Caregivers were handed validated, age-specific HRQoL questionnaires (the chILD-specific questionnaire and the generic Pediatric Quality of Life Questionnaire (PedsQL) 4.0 questionnaire). The scores were linearly transformed from a 5-point scale to a percentage scale ranging from 0% to 100%. We used exploratory univariate analyses and multivariable ordinary least squares (OLS) regression models on cross-sectional data to investigate the associations between subjects’ clinical features and HRQoL scores. Results: 424 patients from 10 European countries and 48 study sites were included in the final analysis. The most relevant factors associated with lower HRQoL scores for the chILD-specific questionnaire and the PedsQL 4.0 Total Score, as identified in the univariate analysis and confirmed in the multivariable OLS regression model, were “inpatient medical care in the last 3 months” (−13.6%; p<0.0001 and −11.4%; p<0.0001, respectively) and “failure to thrive” (−9.1%; p=0.0014 and −12.1%; p<0.0001, respectively). Among subjects old enough for pulmonary function testing (PFT) (n=162), we observed only a weak correlation between PFT results and different HRQoL scores. Conclusions: The main factors linked to reduced HRQoL scores were prior inpatient treatment and failure to thrive. Further interventional studies should determine whether addressing these factors can enhance HRQoL scores and potentially improve quality of life in chILD.

Background: The rising prevalence of paediatric liver disease, including metabolic dysfunction- associated steatotic liver disease, highlights the need for reliable, non-invasive diagnostic tools. Advanced ultrasound techniques such as shear wave elastography (SWE), shear wave dispersion (SWD), and attenuation imaging (ATI) offer promising alternatives to biopsy or magnetic resonance imaging, but normative paediatric values remain limited. Objective: This study aimed to establish age-specific reference values for SWE, SWD, and ATI in healthy children and to assess potential influencing factors such as age, sex, body mass index (BMI), and fasting duration. Materials and methods: In this retrospective study, 264 children (135 female, median age 11.5 years) without known liver disease were selected from a cohort of 734. Each child underwent liver ultrasound using a standardized protocol with five ATI and ten SWE/SWD measurements. Only high-quality data were included. Statistical analyses examined correlations between imaging parameters and patient characteristics. Results: The median ATI was 0.54 dB/cm/MHz [interquartile range (IQR):0.50–0.58], SWE was 1.24 m/s (IQR:1.14–1.33) and SWD was 11.70 (m/s)/kHz (IQR:10.84–12.13). ATI and SWD values showed significant negative correlations with age ( P < 0.001 and P = 0.0048, respectively). SWD also correlated negatively with BMI z -score ( P < 0.001) and was significantly lower in females ( P = 0.001). SWE showed only a weak positive correlation with measurement depth ( P = 0.0261). Fasting duration had no significant impact on any measurement. Conclusion: This study provides reference values for SWE, SWD, and ATI in children. Age and sex influence SWD and ATI values, underscoring the importance of age-specific interpretation in paediatric liver ultrasound. Graphical

Introduction: Enhancing paediatric asthma diagnosis is crucial. Molecular analysis of exhaled breath is a rapidly evolving field aimed at harnessing established and innovative technologies for clinical applications. This study evaluates the feasibility of using online proton-transfer-reaction mass spectrometry (PTR-MS) to identify distinctive breath signatures in children with allergic asthma. Methods: Exhaled breath samples of 81 children (41 with allergic asthma and 40 healthy controls) were analysed using the Vocus CI-TOF mass spectrometer (Tofwerk AG, Switzerland), with mass spectra acquired in H ₃ O ⁺ and NH ₄ ⁺ ionisation modes. Significant mass-to-charge (m/z) features were extracted using the Wilcoxon rank-sum test. Molecular identification was conducted using two-dimensional gas chromatography time-of-flight mass spectrometry (GCxGC-Q-TOF). Results: Statistical analysis revealed 89 significant m/z features associated with paediatric allergic asthma, 66 in H ₃ O ⁺ mode and 23 in NH ₄ ⁺ mode. Supervised machine learning achieved an average accuracy of 74.7% in distinguishing between the groups. GCxGC-QTOF analysis identified a subset of significant features, including four previously reported asthma predictors in breath analysis studies. 16 novel asthma predictor candidates were additionally detected, including 7 likely endogenous, 4 unknowns and 3 exogenous. The main group of breath metabolites was structurally related fatty acids, methyl esters and aldehydes, including four known biomarkers of lipid peroxidation. Conclusion: Our findings demonstrate the suitability of PTR-MS for real-time breath analysis in paediatric populations. Moreover, the identification of distinct breath signatures exclusive to allergic asthma in children suggests the potential of leveraging such technology for non-invasive diagnostic applications.

Background: The CFTR modulator Elaxacaftor/Tezacaftor/Ivacaftor (ETI) has been shown to remarkably improve health condition in people with CF (pwCF) in clinical studies. We assessed the efficacy of ETI in a registry-based pharmacovigilance project since its market introduction in 2021. Methods: Clinical outcomes of pwCF receiving ETI were assessed at baseline (before ETI start) and at subsequent follow-up medical visits (FUs) every three months in a longitudinal observational study on Swiss data from the European Cystic Fibrosis Society Patient Registry. Changes in sweat chloride concentration, BMI and FEV_1pp over time were analyzed using mixed-effects models for repeated measures and stratified according to age (6-11 vrs, 12-17 yrs, ≥18 yrs). Results are presented as means (95% CI). Results: 424 pwCF, including 127 children 6-17yrs, were involved. The majority had four FUs. Sweat chloride decreased from 97 mmol/l (96-99) to 45 mmol/l (43-47; p2 (1.0-1.5; p1pp was highly significant between baseline and FU1 (+11.6%; 10.6-12.5; p1pp increase did not differ between age groups despite adults having a significant lower FEV1pp at baseline. Discussion: Introduction of ETI resulted in a significant decrease of sweat chloride concentration and a significant and sustainable increase of BMI and FEV_1pp independent of age. Real world evidence demonstrates equal efficacy of ETI throughout different age groups.

Background: Discovery of asthma linked biomarkers in exhaled breath of children shows promise, however, biomarker validation remains limited. This study aimed to address this by validating previously identified m/z features as potential asthma biomarkers from an exploratory pilot study using secondary electro-spray ionization high-resolution mass spectrometry (SESI-HRMS). Methods: Two years after the pilot study, an independent cohort of 88 children (46 asthmatic and 42 healthy controls, aged 7-17) was recruited for validation. The breath measurements were performed on an AB SCIEX TripleTOF 5600+ HRMS coupled to SUPER-SESI, consistent with the pilot study. The previously identified 149 m/z features were analyzed for their presence, statistical significance, and diagnostic ability using supervised machine learning. Results: Over 70% (102) of the m/z features were successfully replicated in the validation cohort (mass tolerance ≤ 0.001). Of these, 68 were found to be significant again (FDR adjusted p < 0.05), confirming many of the previously detected metabolic pathways and chemical families including lysine degradation, tyrosine metabolism, 2-oxocarboxylic acid metabolism, fatty acid metabolites and monosaccharides. Furthermore, when applied to the new cohort, a disease prediction model trained on the pilot study data resulted in a ROC AUC of 0.79 (accuracy: 77%, sensitivity: 86%, specificity: 67%), demonstrating similar diagnostic performance as in the pilot study. Conclusion: This study represents the first successful validation of a subset of asthma associated biomarkers through real-time breath analysis using SESI-HRMS. The rich set of markers showed a promising diagnostic ability on previously unseen data.

Environmental volatile organic compounds (VOCs) from the ambient air potentially influence on-line breath analysis measurements by secondary electrospray ionization high-resolution mass spectrometry (SESI-HRMS). The aim of this study was to investigate how inhaling through a VOC filter affects the detected breath profiles and whether it is feasible to integrate such filters into routine measurements. A total of 24 adult participants performed paired breath analysis measurements with and without the use of an activated carbon filter for inspiration. Concordance correlation coefficients (CCCs) and the Bland–Altman analysis were used to assess the agreement between the two methods. Additionally, the effect on a selection of known metabolites and contaminants was analyzed. Out of all the detected features, 78.3% showed at least a moderate agreement before and after filter usage (CCC > 0.9). The decrease in agreement of the remaining m/z features was mostly associated with reduced signal intensities after filter usage. Although a moderate-to-substantial concordance was found for almost 80% of the m/z features, the filter still had an effect by decreasing signal intensities, not only for contaminants, but also for some of the studied metabolites. Operationally, the use of the filter complicated and slowed down the conductance of measurements, limiting its applicability in clinical studies.