Carolina Constant

The implementation of newborn screening (NBS) has revolutionized the diagnostic landscape of cystic fibrosis (CF). In Portugal, NBS was initiated in October 2013 through a pilot study and was subsequently fully integrated into a nationwide program by December 2018. Infants with positive screening results are referred to a specialized CF reference center for diagnostic confirmation, employing Sweat Chloride Testing (SCT) and genetic testing for CFTR variants. We aimed to analyze infants with a positive CF screening and determine the false positive and false negative rates, as well as to calculate the positive predictive value and sensitivity of our NBS program. A retrospective nationwide analysis was conducted on infants with a positive NBS for CF between October 2013 and February 2023. Two hundred and forty infants were referred from the NBS program; 74 (30.8%) were confirmed to have CF through SCT and genetic testing. Sensitivity was 93.2%, and the positive predictive value (PPV) was 30.8%. In addition, 48.5% were homozygous for F508del variants, and 87.8% had at least one F508del variant. Guidelines set forth by the European Cystic Fibrosis Society advise NBS programs to achieve a minimum PPV of 30% and a minimum sensitivity of 95%. Our report demonstrated good compliance with these recommendations.

Background: The extent to which changes in lung function are due to natural variability in patients with primary ciliary dyskinesia (PCD) is unknown. We aimed to assess intra-individual variability in forced expiratory volume in 1 s (FEV₁) derived from spirometry to define the extent to which the observed changes were due to test variability in clinically stable PCD patients.Methods: PROVALF-PCD (Prospective Observational Multicentre Study on Variability of Lung Function in Stable PCD Patients) was a large international prospective cohort conducted in 2017–2019. We included patients aged ≥5 years who were clinically stable at two or more consecutive visits and provided spirometry-derived lung function measurements. To calculate the upper limit of normal (ULN), we fitted an unadjusted multilevel mixed-effect model, and to determine the absolute change in FEV₁z-scores, we calculated the coefficient of repeatability (CR). We performed sensitivity analyses by stratifying relative change by age (adultsversuschildren), number of measurements (at least four), and time between measurements (25% between visits in stable PCD patients lie beyond the expected test variability and therefore could be considered physiologically relevant. These findings inform the selection of end-points for pulmonary intervention trials in PCD, as they suggest that FEV₁is not a sensitive test for monitoring lung health in PCD.

Introduction: Respiratory pathogens are frequently isolated from airway samples in primary ciliary dyskinesia (PCD) patients. Few studies have investigated associations between these pathogens and lung function, with current management based on evidence from cystic fibrosis. We investigated the association between commonly isolated respiratory pathogens and lung function in PCD patients.Methods: Using a cross-sectional design, we prospectively collected clinical and concurrent microbiology data from 408 participants with probable or confirmed PCD, aged ≥5 years, from 12 countries. We used Global Lung Function Initiative 2012 references to calculate forced expiratory volume in 1 s (FEV₁) z-scores. For 351 patients (86%) with complete data, we assessed the association of the four most frequently isolated pathogens with lung function by fitting multilevel linear models with country as random intercept, adjusted for age at diagnosis, age at lung function, use of antibiotic prophylaxis and body mass index z-scores.Results: Individuals withPseudomonas aeruginosagrowth in culture had significantly lower FEV₁z-scores (β= −0.87, 95% CI −1.40– −0.34), adjusted for presence ofHaemophilus influenzae, methicillin-sensitiveStaphylococcus aureusandStreptococcus pneumoniae, and for covariates. When stratified by age, associations remained strong for adults but not for children. Results were similar when ciliary defects by transmission electron microscopy were included in the models and when restricting analysis to only confirmed PCD cases.Conclusions: We found thatP. aeruginosawas associated with worse lung function in individuals with PCD, particularly adults. These findings suggest that it is prudent to aim forP. aeruginosaeradication in the first instance, and to treat exacerbations promptly in colonised patients.

Introduction: People living with PCD are frequently acutely infected or chronically colonised by respiratory pathogens. Few studies investigated the effect of these pathogens on lung function, with current management based on evidence from cystic fibrosis. Aims: We investigated the association between airway microbiology and FEV1 z-scores in PCD patients. Methods: We collected clinical and microbiology data at baseline from 333 patients aged >5 years from 12 countries. We used Global Lung Function Initiative 2012 references to calculate FEV1 z-scores. We assessed the effect of the 3 most isolated pathogen on lung function by fitting multilevel linear models with country as random effect, adjusted for age at diagnosis, source of microbiological sample, use of antibiotic prophylaxis, presence of respiratory exacerbation, age at lung function, and BMI z-scores. Results: Most patients were children (n=280, 68.6%). Median FEV1 z-score was -1.72 (IQR -2.74 to -0.65) and varied per country. The most isolated pathogen was H. influenzae (36%, 101 children and 19 adults), followed by methicillin-sensitive S. aureus (MSSA) (15%) and P. aeruginosa (9%, 9 children and 21 adults). Those with a positive culture for P. aeruginosa had significantly lower FEV1 z-scores (β = -0.76, 95%CI -1.30 to -0.21), adjusted for presence of H. influenzae (β = -0.05, 95%CI -0.38 to 0.29), MSSA (β = 0.04, 95%CI -0.40 to 0.48), and other co-variates. Results were similar when restricting analysis to adults. Conclusions: Our findings suggest P. aeruginosa but not H. Influenzae or MSSA are associated with worse lung function in PCD, regardless of exacerbation status.

An update for the standardization of spirometry was published in 2019, to take full advantage of current technical capabilities, which includes enhanced quality assurance approaches. Aims: Determine the impact of the different quality control (QC) criteria between the 2005 and the 2019 ATS/ERS guidelines and describe the success rate in spirometry execution in a paediatric lung function lab; report compliance with QC criteria and identify the least fulfilled criteria. Methods: For each spirometry: start of test criteria (SOT), end of test criteria (EOT), number of acceptable, reproducible manoeuvres according to 2005 and 2019 guidelines were considered. Spirometry’s QC fulfilled criteria were quantified and compared (χ2test, McNemara test; SPSS®2021). Results: 404 spirometries were analysed of which 237 (59%) were from male children, median age 12 (4-18) years old. Acceptability and repeatability were met in 300 (74%) by 2005 and 335 (83%) by 2019 guidelines, which was significantly different (p<0.01). For both analyses, SOT was met by more than 90% and extrapolation volume was achieved in almost 80% of exams. EOT was the least met criteria. 104 (26%) spirometries did not reach QC according to 2005 guidelines, compared to 69 (17%) as per 2019 guidelines. With the introduction of usability criteria, 17 (25%) were classified as uninterpretable and 52 (75%) met some QC criteria. Conclusion: More than two thirds of all children attained QC criteria. Performing good quality spirometry in pediatrics is possible. The new 2019 guidelines overcome difficulties encountered over the years in children. The objective quantification of quality and the reformulation of acceptability and repeatability is a clear step forward.

Improving paediatric bronchiectasis outcomes requires high-quality research containing endpoints that meet study objectives and are meaningful for parents/patients. We developed a core-outcome set (COS) incorporating parent/patients’ perspectives. Methods: An international, multidisciplinary panel of specialists in paediatric and adult respiratory medicine, infectious disease, physiotherapy, primary care, nursing, radiology, methodology, patient advocacy and parents whose children had bronchiectasis was assembled. We undertook a systematic review from which the panel constructed an outcome list of 21 items and developed separate surveys for parents/patients (European Lung Foundation [ELF] and Panel member networks) and health professionals (European Respiratory Society members and global experts). The results were presented to the ELF patient advisory group and expert panel to achieve a consensus COS for paediatric bronchiectasis. Results: There were 562 survey respondents (361 health professionals; 201parent/patients). The three highest ranked outcomes were common to both groups (quality-of-life [QoL], exacerbations and hospitalisations). The consensus COS (QoL, symptoms, exacerbations, hospitalisations, lost days [school/work], adverse-events, lung function, burden of therapy) was based upon the top 10 outcomes chosen by parents/patients, the remaining were selected according to intervention and discovery type studies. Interpretation: This international, parent and patient-informed consensus paediatric bronchiectasis COS ensures studies have clinically meaningful outcomes that improve systematic reviews and GRADE-informed guidelines.

Background: Most people with PCD have impaired lung function, which deteriorates over time. Longitudinal research of lung function is scarce and there is a lack of guidance on intra-individual variability during routine clinical surveillance. Aims: In this prospective study, we aimed to assess the variability of forced expiratory volume in the first second (FEV1) at routine appointments whilst stable over 18 months, across BEAT-PCD centres. Methods: We analysed 1297 measurements from 302 individuals, ages 5 to 70 years (median = 37.5) from 12 countries in 2017 and 2018. We used Global Lung Function Initiative 2012 references to calculate FEV1 z-scores. To model the variability of lung function over time, we fitted linear mixed-effects models with random effects at country and patient level, with relevant adjustments. Results: The coefficient of variation, which indicates the intra-individual variability of repeated FEV1 measurements, was 10%. Whilst stable, the 95% upper limit of normal for relative changes in FEV1 between visits was 26%. There was minimal change of average FEV1 z-scores over a year (-0.008; 95%CI -0.016 to -0.0003), although there was inter-individual variability in this rate of change. Conclusions: Between visits when stable, 95% of relative changes were <26%. This suggests large intra-individual variability of FEV1 when stable and monitoring lung function must take this into account.

The bronchodilator responsiveness testing (BDR) is of great value for clinical decision-making. In children, the BDR interpretation differs depending on the guidelines. A new method was recently proposed based on ΔFVC and/or ΔFEV1>P10% (ATS/ERS 2021). Objectives: To compare the different methods for valuing BDR in children with normal spirometry and different degrees of bronchial obstruction and to study if BDR interpretation through fixed volume and FVC cut-offs in children is of value. Methodology: Data from 2272 tests performed at a Pediatric Lung Function Lab in 4 years (2017-2020) were reviewed. Descriptive and comparative analysis of different equations for FEV1 and FVC variations, as recommended by different societies was done: 1. ATS/ERS 2005: ΔFVC and/or ΔFEV1 ≥I(initial)12% and ≥200ml; 2. ATS/ERS 2021: ΔFVC and/or ΔFEV1 >P10%; 3. GINA 2022: ΔFEV1 >P12%; 4. NAEPP 2007: ΔFEV1 ≥I12% and >200ml; 5. SATS 2013: ΔFEV1 and/or ΔFVC ≥I12% or >200ml; 6. BTS 2019: ΔFEV1 ≥I12% (Student9s T-tests; Q-Crochan and ANOVA; SPSS v.25). Results: From 2201 tests, 56% were from male children, mean age 12 (±3) years. Predominant referral diagnosis was Asthma (1718; 78%). In basal spirometries, the variation of the mean values for FEV1 and FVC significantly increased with age. For BDR, significant differences between the different equations were found. The FEV1≥200ml criterion was the most often criteria for a positive test followed by ∆>10%P. Conclusion: Due to differences in lung volumes with increasing age, the use of fixed volume cut-offs in children as positivity criteria for the BDR should be discontinued. The new ERS/ATS 2021 interpretative criteria based on ∆>10%P seem to be more appropriate.