Standards for the care of people with cystic fibrosis (CF); Planning for a longer life.

This is the final of four papers updating standards for the care of people with CF. That this paper "Planning a longer life" was considered necessary, highlights how much CF care has progressed over the past decade. Several factors underpin this progress, notably increased numbers of people with CF with access to CFTR modulator therapy. As the landscape for CF changes, so do the hopes and aspirations of people with CF and their families. This paper reflects the need to consider people with CF not as a "problem" to be solved, but as a success, a potential and a voice to be heard. People with CF and the wider CF community have driven this approach, reflecting many of the topics in this paper. This exercise involved wide stakeholder engagement. People with CF are keen to contribute to research priorities and be involved in all stages of research. People with CF want healthcare professionals to respect them as individuals and consider the impact of our actions on the world around us. Navigating life presents challenges to all, but for people with CF these challenges are heightened and complex. In this paper we highlight the concerns and life moments that impact people with CF, and events that the CF team should aim to support, including the challenges around having a family. People with CF and their care teams must embrace the updated standards outlined in these four papers to enjoy the full potential for a healthier life.

Long-term pulmonary outcomes of young adults born prematurely: a Polish prospective cohort study PREMATURITAS 20.

BACKGROUND: The long-term consequences of prematurity are often not sufficiently recognized. To address this gap, a prospective cohort study, which is a continuation of the multicenter Polish study PREMATURITAS, was conducted, utilizing unique clinical data from 20 years ago. OBJECTIVE: The main goal was to evaluate lung function, detect any structural abnormalities using lung ultrasound, and assess psychological well-being in young adults born between 24 and 34 weeks of gestational age (GA). Additionally, the study aimed to investigate potential associations between perinatal risk factors and abnormalities observed in pulmonary function tests (PFTs) during adulthood. METHODS: The young survivors underwent a comprehensive set of PFTs, a lung ultrasound, along with the quality of life assessment. Information regarding the neonatal period and respiratory complications was obtained from the baseline data collected in the PREMATURITAS study. RESULTS: A total of 52 young adults, with a mean age of 21.6 years, underwent PFTs. They were divided into two groups based on GA: 24-28 weeks (n = 12) and 29-34 weeks (n = 40). The subgroup born more prematurely had significantly higher lung clearance index (LCI), compared to the other subgroup (p = 0.013). LCI ≥ 6.99 was more frequently observed in the more premature group (50% vs. 12.5%, p = 0.005), those who did not receive prenatal steroids (p = 0.020), with a diagnosis of Respiratory Distress Syndrome (p = 0.034), those who received surfactant (p = 0.026), and mechanically ventilated ≥ 7 days (p = 0.005). Additionally, elevated LCI was associated with the diagnosis of asthma (p = 0.010). CONCLUSIONS: The findings suggest pulmonary effects due to prematurity persist into adulthood and their insult on small airway function. Regular follow-up evaluations of young survivors born preterm should include assessments of PFTs. Specifically, the use of LCI can provide valuable insights into long-term pulmonary impairment.

Cystic Fibrosis Cases Missed by Newborn Bloodspot Screening-Towards a Consistent Definition and Data Acquisition.

Repeated European surveys of newborn bloodspot screening (NBS) have shown varied strategies for collecting missed cases, and information on data collection differs among countries/regions, hampering data comparison. The ECFS Neonatal Screening Working Group defined missed cases by NBS as either false negatives, protocol-related, concerning analytical issues, or non-protocol-related, concerning pre- and post-analytical issues. A questionnaire has been designed and sent to all key workers identified in each NBS programme to assess the feasibility of collecting data on missed cases, the stage of the NBS programme when the system failed, and individual patient data on each missed case.

Parents' Knowledge of the Impact of Cystic Fibrosis on the Quality of Life of Children and Adolescents Suffering from This Disease as an Element of Patient Safety.

Parental perspective on the health, safety, and quality of life in children and adolescents with cystic fibrosis (CF). AIM OF THE STUDY: Assessment of the impact of a chronic disease such as cystic fibrosis (CF) on the quality of life and safety of children and adolescents as perceived by parents/caretakers. METHODS: The study was conducted at the Department of Lung Diseases of the Institute of Mother and Child, a branch of the Cystic Fibrosis Centre Children of Warsaw SZPZOZ in Dziekanów Lesny, the largest pediatric CF center in Poland, and in the Rodzinamuko group on Facebook. A total of 139 parents participated in the study. The study was conducted using the diagnostic survey method with the use of the Kid- & Kiddo-KINDLR questionnaire for examining the quality of life of children and adolescents and a demographic questionnaire. RESULTS: The perception of cystic fibrosis (CF) as a chronic disease varies based on parental residence and professional status. The well-being of children and adolescents with CF is tied to their parents' employment, particularly regarding schooling. Social interactions are influenced by the level of parental education. The quality of life in children and adolescents with CF is age-dependent, with younger children exhibiting higher quality of life. This age-quality of life relationship extends to physical well-being, emotional well-being, and school-related aspects. Furthermore, the emotional dimension of quality of life is affected by the child's age at the time of diagnosis. CONCLUSIONS: The Kid- & Kiddo-KINDLR QoL Questionnaire for children with cystic fibrosis is a good tool to measure parental knowledge. The study shows the need for the whole family to understand and be aware of the impact of CF on family life. Parents may be tired or may misunderstand or miscommunicate the medical team's instructions, which may affect both family life and patient safety. To ensure patient safety, parents should work with healthcare professionals at hospitals or clinics but also at home. They should also account for the family as a whole, not just for the problems of the child with CF.

Pulmonary Function Tests in the Evaluation of Early Lung Disease in Cystic Fibrosis.

BACKGROUND: Properly evaluating respiratory system dysfunction is essential in children with cystic fibrosis (CF). This prospective study aimed to assess the course of early lung disease based on multiple breath nitrogen washout (MBNW), impulse oscillometry (IOS), and conventional techniques, such as spirometry and body plethysmography. METHODS: Over a 2 year recruitment period, subjects with CF aged 7-18 performed pulmonary function tests (PFTs). Moreover, the nutritional and microbiological status, frequency of pulmonary exacerbations (PExs), and patients' health-related quality of life (HRQoL) were assessed. RESULTS: The mean age of the children (n = 69) was 14.09 ± 3.26 years; F/M 37/32. Spirometry-based diagnoses of normal lung function (forced expiratory volume in 1 s, FEV1 ≥ 90%pred), mild (FEV1 70-89%pred) and moderate (FEV1 40-69%pred) lung diseases were established in 34 (49.3%), 25 (36.2%), and 10 (14.5%) patients, respectively. An elevated lung clearance index (LCI > 6.98) was observed in 85% of the subjects with normal FEV1. The presence of Pseudomonas aeruginosa infection (n = 16) and the number of PExs treated with IV antibiotics were associated with significantly worse PFT results. CONCLUSIONS: MBNW and IOS are more helpful tools than conventional techniques in assessing early lung disease in CF. LCI is a more useful parameter for detecting functional abnormalities than FEV1 in school-age children.

Lung Ultrasound in the Evaluation of Lung Disease Severity in Children with Clinically Stable Cystic Fibrosis: A Prospective Cross-Sectional Study.

With the increasing longevity of cystic fibrosis (CF), there is a growing need to minimise exposure to ionising radiation in patients who undergo regular imaging tests while monitoring the course of the lung disease. This study aimed to define the role of lung ultrasounds (LUS) in the evaluation of lung disease severity in children with clinically stable CF. LUS was performed on 131 patients aged 5 weeks to 18 years (study group) and in 32 healthy children of an equivalent age range (control group). Additionally, an interobserver study was performed on 38 patients from the study group. In CF patients, the following ultrasound signs were identified: I-lines; Z-lines; single, numerous and confluent B-lines; Am-lines; small and major consolidations; pleural line abnormalities and small amounts of pleural fluid. The obtained results were evaluated against an original ultrasound score. LUS results were correlated with the results of chest X-ray (CXR) [very high], pulmonary function tests (PFTs) [high] and microbiological status [significant]. The interobserver study showed very good agreement between investigators. We conclude that LUS is a useful test in the evaluation of CF lung disease severity compared to routinely used methods. With appropriate standardisation, LUS is highly reproducible.

Efficacy of the Simeox® Airway Clearance Technology in the Homecare Treatment of Children with Clinically Stable Cystic Fibrosis: A Randomized Controlled Trial.

BACKGROUND: Cystic fibrosis (CF) patients require regular airway clearance therapy (ACT). The aim of this study was to evaluate homecare therapeutic effects of a new ACT (Simeox®) added to the optimal standard of care, including home chest physiotherapy, in the treatment of clinically stable children. METHODS: Forty pediatric CF patients (8-17 years old) with stable disease were randomized 1:1 in a single-center, prospective, open-label, cross-over trial into two groups: with or without Simeox®. Lung function (impulse oscillometry, spirometry, body plethysmography, multi-breath nitrogen washout) results, health-related quality of life, and safety were assessed during the study after 1 month of therapy at home. RESULTS: A significant decrease in proximal airway obstruction (as supported by improvement in airway resistance at 20 Hz (R20Hz) and maximum expiratory flow at 75% of FVC (MEF75)) compared to the control group was observed after 1 month of therapy with the device. Lung-clearance index was stable in the study group, while it worsened in the control group. In addition, the device group demonstrated a significant increase in the Cystic Fibrosis Questionnaire-Revised (CFQ-R) physical score. No side effects were identified during the study. CONCLUSIONS: Simeox® may improve drainage of the airways in children with clinically stable CF and could be an option in chronic treatment of the disease.

European survey of newborn bloodspot screening for CF: opportunity to address challenges and improve performance.

BACKGROUND: The aim of this study was to record the current status of newborn bloodspot screening (NBS) for CF across Europe and assess performance. METHODS: Survey of representatives of NBS for CF programmes across Europe. Performance was assessed through a framework developed in a previous exercise. RESULTS: In 2022, we identified 22 national and 34 regional programmes in Europe. Barriers to establishing NBS included cost and political inertia. Performance was assessed from 2019 data reported by 21 national and 21 regional programmes. All programmes employed different protocols, with IRT-DNA the most common strategy. Six national and 11 regional programmes did not use DNA analysis. CONCLUSIONS: Integrating DNA analysis into the NBS protocol improves PPV, but at the expense of increased carrier and CFSPID recognition. Some programmes employ strategies to mitigate these outcomes. Programmes should constantly strive to improve performance but large datasets are needed to assess outcomes reliably.

Improving nutrition in cystic fibrosis: A systematic literature review.

With increasing life expectancy of patients with cystic fibrosis (CF), gastrointestinal manifestations of the disease have been increasingly brought into focus. This was a systematic review of the PubMed database and ongoing phase III clinical trials that aimed to summarize recent (published after June 1 2016) studies reporting the effects of nutritional interventions on anthropometric measures (weight, height, and body mass index) in patients with CF. Two ongoing trials and 40 published studies (18 interventional and 22 observational) were identified. Key results supported the benefits of comprehensive, individualized nutritional plans, high-fat, high-calorie diet including high-quality carbohydrates, and enteric tube feeding (albeit the latter was derived from observational studies only). In contrast, the supplementation of probiotics, lipids, docosahexaenoic, glutathione, or antioxidant-enriched multivitamin appeared to have little effect on anthropometric measures.

Clinical complications in children with false-negative results in cystic fibrosis newborn screening

Abstract Objective: To present signs and symptoms and clinical course in cystic fibrosis patients with false-negative newborn screening (CF NBS). Materials and methods: All children presented in this paper were covered by CF NBS. The group of 1.869.246 newborns was screened in the Institute of Mother and Child in Warsaw within a period of 01.01.1999 - 31.05.2019. Screening protocols evolved over time from IRT/IRTto IRT/DNA/EGA. Results: The authors identified 11 patients with false-negative NBS, in whom CF was diagnosed based on clinical symptoms or the examination of siblings with positive CF NBS. In the study group, the diagnosis was made significantly later in comparison to positive CF NBS patients ranging from 2 months to 15 years of age. CF NBS strategy does not significantly affect the sensitivity of the screening. Conclusion: In the presence of clinical symptoms, additional diagnostics must be implemented, in spite of the negative screening results. At first, the sweat test should be conducted, followed by a DNA analysis of the most common mutations in the given population. The diagnostic process requires searching for CFTR mutations not typically associated with a high chloride concentration in sweat. Repetition of sweat chloride concentration enables the diagnosis in children whose initial chloride values in sweat are borderline, and no CF-causing mutations are detected. In strong clinical indications, the extension of DNA analysis (EGA) is recommended in order to identify rare CF variants. In children with meconium ileus, genetic analysis is mandatory.

Clinical complications in children with false-negative results in cystic fibrosis newborn screening.

OBJECTIVE: To present signs and symptoms and clinical course in cystic fibrosis patients with false-negative newborn screening (CF NBS). MATERIALS AND METHODS: All children presented in this paper were covered by CF NBS. The group of 1.869.246 newborns was screened in the Institute of Mother and Child in Warsaw within a period of 01.01.1999 - 31.05.2019. Screening protocols evolved over time from IRT/IRT to IRT/DNA/EGA. RESULTS: The authors identified 11 patients with false-negative NBS, in whom CF was diagnosed based on clinical symptoms or the examination of siblings with positive CF NBS. In the study group, the diagnosis was made significantly later in comparison to positive CF NBS patients ranging from 2 months to 15 years of age. CF NBS strategy does not significantly affect the sensitivity of the screening. CONCLUSION: In the presence of clinical symptoms, additional diagnostics must be implemented, in spite of the negative screening results. At first, the sweat test should be conducted, followed by a DNA analysis of the most common mutations in the given population. The diagnostic process requires searching for CFTR mutations not typically associated with a high chloride concentration in sweat. Repetition of sweat chloride concentration enables the diagnosis in children whose initial chloride values in sweat are borderline, and no CF-causing mutations are detected. In strong clinical indications, the extension of DNA analysis (EGA) is recommended in order to identify rare CF variants. In children with meconium ileus, genetic analysis is mandatory.

Reclassifying inconclusive diagnosis after newborn screening for cystic fibrosis. Moving forward.

BACKGROUND: Newborn screening for Cystic Fibrosis (CF) is associated with situations where the diagnosis of CF or CFTR related disorders (CFTR-RD) cannot be clearly ruled out. MATERIALS/PATIENTS AND METHODS: We report a case series of 23 children with unconclusive diagnosis after newborn screening for CF and a mean follow-up of 7.7 years (4-13). Comprehensive investigations including whole CFTR gene sequencing, in vivo intestinal current measurement (ICM), nasal potential difference (NPD), and in vitro functional studies of variants of unknown significance, helped to reclassify the patients. RESULTS: Extensive genetic testing identified, in trans with a CF causing mutation, variants with varying clinical consequences and 3 variants of unknown significance (VUS). Eighteen deep intronic variants were identified by deep resequencing of the whole CFTR gene in 13 patients and were finally considered as non-pathogenic. All patients had normal CFTR dependent chloride transport in ICM. NPD differentiated 3 different profiles: CF-like tracings qualifying the patients as CF, such as F508del/D1152H patients; normal responses, suggesting an extremely low likelihood of developing a CFTR-RD such as F508del/TG11T5 patients; partial CFTR dysfunction above 20% of the normal, highlighting a remaining risk of developing CFTR-RD such as F508del/F1052V patients. The 3 VUS were reclassified as variant with defective maturation (D537N), defective expression (T582I) or with no clinical consequence (M952T). CONCLUSION: This study demonstrates the usefulness of combining genetic and functional investigations to assess the possibility of evolving to CF or CFTR-RD in babies with inconclusive diagnosis at neonatal screening.

Nebulisation therapy in patients with cystic fibrosis - consensus of the Polish Cystic Fibrosis Society.

INTRODUCTION: Nebulisation therapy plays a key role in the treatment of cystic fibrosis (CF). Its effectiveness depends on obtaining a high concentration of drugs in the respiratory tract. Particle deposition is determined by many factors resulting, inter alia, from the essence of the lung disease (mucus, structural changes such as bronchiectasis, fibrous changes, cirrhosis) and the quality of the aerosol and breathing techniques during the procedure. AIM OF THE GUIDELINES: A large variety of available drugs that can be used in the form of aerosols (bronchodilators, mucolytics, antibiotics), a wide range of devices for their delivery, and a different approach to the practical aspect related to the use of inhalation, makes it necessary to systematize knowledge in order to optimize nebulisation therapy. The paper presents an overview of inhaled drugs used in cystic fibrosis and their administration devices. RESULTS: The principles of inhalation antibiotic therapy, which constitute the basis for the treatment of primary and chronic respiratory tract infections of Pseudomonas aeruginosa etiology, are discussed in detail. A very important issue was raised related to the proper selection of devices and their proper operation. In the context of the key role of nebulisation therapy in cystic fibrosis, a huge problem is the limited availability of inhaled antibiotics in Poland. CONCLUSIONS: The possibility of choosing an antibiotic and using alternating therapy increases the effectiveness of inhalation treatment, which results in slowing down the progress of bronchopulmonary disease and extending the life of patients.

Lung Clearance Index in Children with Cystic Fibrosis during Pulmonary Exacerbation.

(1) Background: Pulmonary exacerbation (PEx) is one of the main factors affecting the quality of life and life expectancy in patients with cystic fibrosis (CF). Our study aimed to evaluate the change in selected pulmonary function parameters, including lung clearance index (LCI), in patients with CF diagnosed with PEx. (2) Methods: We enrolled 40 children with CF aged 6-17. They performed spirometry and multiple breath nitrogen washout (MBNW) tests during a stable condition period at the beginning and the end of intravenous antibiotic treatment. (3) Results: LCI increased by 65% and FEV1 decreased by ≥10% in 40% of patients with CF during PEx. An absolute change in LCI between a stable condition period and PEx was 1.05 (±1.92) units, which corresponds to a relative change of 11.48% (±18.61) of the baseline. The relative decrease in FEV1 was -9.22% (±12.00) and the z-score was -0.67 (±1.13). After the PEx treatment, FEV1 increased by 11.05% (±9.04) on average, whereas LCI decreased by 1.21 ± 1.59 units on average, which represented 9.42% ± 11.40 compared to the value at the beginning of PEx. (4) Conclusions: The change in LCI captures a higher proportion of events with functional impairment than FEV1 in school-age children with CF.

Metabolomics Comparison of Drug-Resistant and Drug-Susceptible Pseudomonas aeruginosa Strain (Intra- and Extracellular Analysis).

Pseudomonas aeruginosa is a common human pathogen belonging to the ESKAPE group. The multidrug resistance of bacteria is a considerable problem in treating patients and may lead to increased morbidity and mortality rate. The natural resistance in these organisms is caused by the production of specific enzymes and biofilm formation, while acquired resistance is multifactorial. Precise recognition of potential antibiotic resistance on different molecular levels is essential. Metabolomics tools may aid in the observation of the flux of low molecular weight compounds in biochemical pathways yielding additional information about drug-resistant bacteria. In this study, the metabolisms of two P. aeruginosa strains were compared-antibiotic susceptible vs. resistant. Analysis was performed on both intra- and extracellular metabolites. The 1H NMR method was used together with multivariate and univariate data analysis, additionally analysis of the metabolic pathways with the FELLA package was performed. The results revealed the differences in P. aeruginosa metabolism of drug-resistant and drug-susceptible strains and provided direct molecular information about P. aeruginosa response for different types of antibiotics. The most significant differences were found in the turnover of amino acids. This study can be a valuable source of information to complement research on drug resistance in P. aeruginosa.

Long-term amikacin liposome inhalation suspension in cystic fibrosis patients with chronic P. aeruginosa infection.

BACKGROUND: . In CLEAR-108-a phase 3, randomised, open-label study-once-daily amikacin liposome inhalation suspension (ALIS) was noninferior to twice-daily tobramycin inhalation solution (TIS) in improving lung function in patients with cystic fibrosis (CF) and chronic Pseudomonas aeruginosa infection after 3 treatment cycles (28 days on/28 days off). The CLEAR-110 extension study (ClinicalTrials.gov: NCT01316276; EudraCT: 2011-000443-24) assessed long-term safety, tolerability, and efficacy of ALIS in eligible patients who completed CLEAR-108. METHODS: . Patients received once-daily ALIS 590 mg for 12 treatment cycles (96 weeks). Patients were grouped by prior treatment: the "prior-ALIS" cohort received ALIS in CLEAR-108, and the "ALIS-naive" cohort received TIS in CLEAR-108. RESULTS: . Overall, 206 patients (prior-ALIS, n=92; ALIS-naive, n=114) entered CLEAR-110 and received ≥1 dose of ALIS. Most patients (88.8%) experienced ≥1 treatment-emergent adverse event (TEAE) through day 672 (end of year 2). Most TEAEs (72.3%) were mild or moderate in severity. Severe TEAEs were reported in 31 patients (15.0%). Two life-threatening TEAEs (haemoptysis; intestinal obstruction) and 1 death (cardiac failure) were reported. Twenty-one patients (10.2%) discontinued treatment due to a TEAE (mostly infective pulmonary exacerbation of CF). Mean change from baseline in forced expiratory volume in 1 second percent predicted at day 672 was -3.1% (prior-ALIS, -4.0%; ALIS-naive, -2.3%). Mean change from baseline in sputum density of P. aeruginosa at day 672 was 0.02 (prior-ALIS, -0.16; ALIS-naive, 0.19) log CFU/g. CONCLUSIONS: . Long-term treatment with ALIS was well tolerated with a favourable adverse event profile and demonstrated continued antibacterial activity in CF patients with chronic P. aeruginosa infection.

The effects of the addition of a new airway clearance device to chest physiotherapy in children with cystic fibrosis pulmonary exacerbations.

BACKGROUND: Chest physiotherapy plays a crucial role in managing cystic fibrosis, especially during pulmonary exacerbations. This study evaluated the effects of adding a new airway clearance device to chest physiotherapy in subjects with cystic fibrosis hospitalised due to pulmonary exacerbations. METHODS: This prospective open-label study was carried out at the Pediatric Cystic Fibrosis Centre in Poland between October 2017 and August 2018. Cystic fibrosis patients aged 10 to 18 years who were admitted to the hospital and required intravenous antibiotic therapy due to pulmonary exacerbations were consecutively allocated (1:1) to either chest physiotherapy alone or chest physiotherapy with a new airway clearance device (Simeox; PhysioAssist). Patients performed spirometry and multiple-breath nitrogen washout for lung clearance index assessment upon admission and prior to discharge. RESULTS: Forty-eight cystic fibrosis patients were included (24 in each group). Spirometry parameters in both groups improved significantly after intravenous antibiotic therapy. A significant improvement in the maximum expiratory flow at 25% of forced vital capacity was observed only in the group with a new airway clearance device (p < 0.01 vs. baseline). Trends towards a lower lung clearance index ratio were similar in both groups. No adverse events were observed in either group. CONCLUSIONS: Spirometry parameters increased significantly in cystic fibrosis patients treated for pulmonary exacerbations with intravenous antibiotic therapy and intensive chest physiotherapy. The new airway clearance device was safe and well tolerated when added to chest physiotherapy and may be another option for the treatment of pulmonary exacerbation in cystic fibrosis.

What Is Most Suitable for Children With Cystic Fibrosis-The Relationship Between Spirometry, Oscillometry, and Multiple Breath Nitrogen Washout.

INTRODUCTION: In cystic fibrosis (CF), pathological lung changes begin early in life. The technological progress currently gives many diagnostic possibilities. However, pulmonary function testing in children remains problematic. OBJECTIVES: Our study aimed to correlate the results of impulse oscillometry (IOS) with those of multiple breath nitrogen washout (MBNW) in our pediatric CF population. We also compared those parameters between the groups with and without spirometric features of obturation. METHODS: We collected 150 pulmonary function test sets, including spirometry, IOS, and MBNW in patients with CF aged 12.08 ± 3.85 years [6-18]. The study group was divided into two subgroups: IA (without obturation) and IB (with obturation). We also compared Sacin, Scond, and oscillometry parameters of 20 patients aged 14-18 years who reached the appropriate tidal volume (VT) during MBNW. RESULTS: Statistical analysis showed a negative correlation between lung clearance index (LCI) and spimoetric parameters. Comparison of subgroups IA (n = 102) and IB (n = 48) indicated a statistically significant difference in LCI (p < 0.001) and FEV1z-score (p < 0.001), FEV1% pred (p < 0.001), MEF25z-score (p < 0.001), MEF50 z-score (p < 0.001), MEF75 z-score (p < 0.001), R5% pred (p < 0.05), and R20% pred (p < 0.01). LCI higher than 7.91 was found in 75.33% of the study group, in subgroup IB-91.67%, and IA-67.6%. CONCLUSIONS: LCI derived from MBNW may be a better tool than IOS for assessing pulmonary function in patients with CF, particularly those who cannot perform spirometry.