Data accuracy, consistency and completeness of the national Swiss cystic fibrosis patient registry: Lessons from an ECFSPR data quality project.

BACKGROUND: Good data quality is essential when rare disease registries are used as a data source for pharmacovigilance studies. This study investigated data quality of the Swiss cystic fibrosis (CF) registry in the frame of a European Cystic Fibrosis Society Patient Registry (ECFSPR) project aiming to implement measures to increase data reliability for registry-based research. METHODS: All 20 pediatric and adult Swiss CF centers participated in a data quality audit between 2018 and 2020, and in a re-audit in 2022. Accuracy, consistency and completeness of variables and definitions were evaluated, and missing source data and informed consents (ICs) were assessed. RESULTS: The first audit included 601 out of 997 Swiss people with CF (60.3 %). Data quality, as defined by data correctness ≥95 %, was high for most of the variables. Inconsistencies of specific variables were observed because of an incorrect application of the variable definition. The proportion of missing data was low with <5 % for almost all variables. A considerable number of missing source data occurred for CFTR variants. Availability of ICs varied largely between centers (10 centers had >5 % of missing documents). After providing feedback to the centers, availability of genetic source data and ICs improved. CONCLUSIONS: Data audits demonstrated an overall good data quality in the Swiss CF registry. Specific measures such as support of the participating sites, training of data managers and centralized data collection should be implemented in rare disease registries to optimize data quality and provide robust data for registry-based scientific research.

[Where we stand with asthma: optimized medical care and biologic therapy for children]. / Le point sur l'asthme en pédiatrie : optimisation de la prise en charge et thérapies biologiques.

Asthma recommendations are in constant evolution. Salbutamol exclusivity as the historical reference treatment for asthma exacerbations is now questioned. In case of light to moderate crisis, budesonide/formoterol, combining an inhaled corticosteroid and a fast acting long lasting beta2 agonist, can now be proposed as first line as needed treatment, for adolescents older than 12 years old. In addition, progress in fundamental research revealed the heterogeneous nature of asthma and allowed for the emergence of new-targeted therapies.

La prise en charge de l'asthme est en constante évolution. L'exclusivité du salbutamol, traitement historique de référence des exacerbations aiguës, même légères, est remise en question depuis plusieurs années. En cas de symptômes ou crise légère à modérée, le budésonide/formotérol, combiné de corticostéroïde inhalé et bronchodilatateur (ß2-agoniste) d'action rapide et prolongée, peut dorénavant être proposé en première intention, à la demande, y compris en pédiatrie, notamment à partir de 12 ans. De plus, les progrès en recherche fondamentale ont permis de révéler la nature hétérogène de l'asthme et de faire émerger de nouvelles cibles thérapeutiques. En particulier, les patients asthmatiques peuvent bénéficier de l'entrée des biologiques dans l'arsenal thérapeutique.

[Respiratory issues in children with severe neurological impairment]. / Atteinte respiratoire chez l'enfant en situation de polyhandicap sévère.

Respiratory problems have a significant impact on morbidity and mortality in children with severe neurological impairment. In particular, impaired airway clearance, recurrent respiratory infections, bronchial hyper reactivity can lead to acute decompensation and, with time, to chronic respiratory failure. Multiple coexisting and interacting factors that influence the respiratory status of these children should be recognized and effectively addressed to reduce respiratory morbidity and mortality. An accurate assessment involving a multidisciplinary approach and relatively simple interventions can lead to significant improvements in the quality of life of children as well as their parents and carers.

Les complications respiratoires ont un impact significatif sur la morbidité et la mortalité chez les enfants en situation de polyhandicap sévère. En particulier l'encombrement bronchique, les infections respiratoires récurrentes et l'hyperréactivité bronchique peuvent conduire à des décompensations aiguës et, avec le temps, à une insuffisance respiratoire chronique. De multiples facteurs coexistant et interagissant qui influencent l'état respiratoire de ces enfants doivent être reconnus et traités efficacement afin de réduire la morbidité et la mortalité respiratoires. Une évaluation précise impliquant une approche multidisciplinaire et des interventions relativement simples peuvent conduire à une amélioration significative de la qualité de vie de ces enfants ainsi que de leurs parents et tuteurs.

Unexpected associations between respiratory viruses and bacteria with Pulmonary Function Testing in children suffering from Cystic Fibrosis (MUCOVIB study).

BACKGROUND: Various bacterial and viral assemblages composing Cystic Fibrosis (CF) lung microbiota contribute to long-term lung function decline over time. Yet, the impact of individual microorganisms on pulmonary functions remains uncertain in children with CF. METHODS: As part of the 'Mucoviscidosis, respiratory VIruses, intracellular Bacteria and fastidious organisms'' project, children with CF were longitudinally followed in a Swiss multicentric study. Respiratory samples included mainly throat swabs and sputa samples for bacterial culture and 16S rRNA metagenomics and nasopharyngeal swabs for respiratory virus detection by molecular assays. Percentage of predicted Forced Expiratory Volume in one second (FEV1%) and Lung Clearance Index (LCI) were recorded. RESULTS: Sixty-one children, of whom 20 (32.8%) presented with at least one pulmonary exacerbation, were included. Almost half of the 363 nasopharyngeal swabs tested by RT-PCR were positive for a respiratory virus, mainly rhinovirus (26.5%). From linear mixed-effects regression models, P. aeruginosa (-11.35, 95%CI [-17.90; -4.80], p = 0.001) was significantly associated with a decreased FEV1%, whereas rhinovirus was associated with a significantly higher FEV1% (+4.24 95%CI [1.67; 6.81], p = 0.001). Compared to conventional culture, 16S rRNA metagenomics showed a sensitivity and specificity of 80.0% and 85.4%, respectively for detection of typical CF pathogens. However, metagenomics detected a bacteria almost twice more often than culture. CONCLUSIONS: As expected, P. aeruginosa impacted negatively on FEV1% while rhinovirus was surprisingly associated with better FEV1%. Culture-free assays identifie significantly more pathogens than standard culture, with disputable clinical correlation.

Chlamydia pneumoniae and Mycoplasma pneumoniae in children with cystic fibrosis: impact on bacterial respiratory microbiota diversity.

OBJECTIVES: The contribution of intracellular and fastidious bacteria in Cystic fibrosis (CF) pulmonary exacerbations, and progressive lung function decline remains unknown. This project aimed to explore their impact on bacterial microbiota diversity over time in CF children. METHODS: Sixty-one children enrolled in the MUCOVIB multicentre prospective cohort provided 746 samples, mostly nasopharyngeal swabs, throat swabs and sputa which were analysed using culture, specific real-time qPCRs and 16S rRNA amplicon metagenomics. RESULTS: Chlamydia pneumoniae (n = 3) and Mycoplasma pneumoniae (n = 1) were prospectively documented in 6.6% of CF children. Microbiota alpha-diversity in children with a documented C. pneumoniae was highly variable, similarly to children infected with Staphylococcus aureus or Pseudomonas aeruginosa. The transition from routine follow-up visits to pulmonary exacerbation (n = 17) yielded variable changes in diversity indexes with some extreme loss of diversity. CONCLUSIONS: The high rate of C. pneumoniae detection supports the need for regular screenings in CF patients. A minor impact of C. pneumoniae on the microbial community structure was documented. Although detected in a single patient, M. pneumoniae should also be considered as a possible aetiology of lung infection in CF subjects.

[Revolution in the treatment of cystic fibrosis]. / Révolution dans le traitement de la mucoviscidose.

Cystic Fibrosis is a genetic disorder resulting in the absence or dysfunction of the CFTR protein, a chloride channel present on the surface of epithelia, particularly respiratory. Until recently, treatments only concerned the consequences of the disease. But a new type of molecules called «â€…modulators ¼, is already available to some patients and targets the origin of the disease. «â€…Modulators ¼ are divided into «â€…potentiators ¼, which improve the transport of chloride by the CFTR protein, and «â€…correctors ¼, increasing the amount of CFTR proteins. An oral triple therapy combining a potentiator and two correctors has just been approved in the USA and will treat 85 % of patients. The clinical benefit of «â€…modulators ¼ is remarkable, and these drugs are revolutionizing the treatment of Cystic Fibrosis.

La mucoviscidose est une maladie génétique entraînant une absence ou des dysfonctions de la protéine Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), un canal chlore présent à la surface des épithélia, notamment respiratoire. Jusqu'à récemment, les traitements ne concernaient que les conséquences de la maladie. Mais un nouveau type de molécules appelées «â€…modulateurs ¼ est déjà à la disposition de certains patients et cible l'origine de la maladie. Les «â€…modulateurs ¼ sont divisés en «â€…potentiateurs ¼, permettant d'améliorer le transport du chlore par la protéine CFTR, et en «â€…correcteurs ¼, augmentant la quantité de protéines CFTR. Une trithérapie orale combinant un potentiateur et deux correcteurs vient d'être approuvée aux États-Unis et permettra de traiter 85 % des patients. Le bénéfice clinique des «â€…modulateurs ¼ est remarquable et ces médicaments bouleversent le traitement de la mucoviscidose.

Successful home respiratory polygraphy to investigate sleep-disordered breathing in children.

OBJECTIVE: Sleep-disordered breathing (SDB) in children is common. Interest in sleep tests, such as polygraphy (PG), which can be performed in a non-attended setting, are gaining is increasing. PG has, however, been little studied in children with co-morbidities other than obstructive sleep apnea (OSA), and in particular, if performed in a non-attended setting. We report on the feasibility and interpretability of implementing PGs at home versus in hospital. METHODS: PGs were analyzed according to the setting (hospital or home) and sequence (initial or subsequent) in which they were performed. Non-interpretability was defined as absent or unreliable oxygen saturation by pulse oximetry (SpO2), or airflow and respiratory inductance plethysmography flow trace signals during the time analyzed. RESULTS: We retrospectively analyzed 400 PGs; 332/400 were initial PGs. Indications were: suspected OSA (65%), obesity (13%), craniofacial malformations (5%), neuromuscular disease (4%), and other (13%) which included prematurity. 16% were recorded in hospitals and 84% at home. The mean age was 5.7 ± 5.8 years and 7.3 ± 4.5 years for the hospital and home groups, respectively. Interpretability was similar in both settings (87%). In the 68 subsequent PGs, interpretability was 84% when performed for follow-up and 96% when repeated for non-interpretability. Non-interpretability was predominantly due to a failure of the SpO2 channel. CONCLUSIONS: PG performed at home is both feasible and interpretable for a variety of indications. Non-interpretability was not predictable in association with the setting, anthropometric data, or indication, independently of the sequence (initial or subsequent PG) in which the parameters were analyzed.

Combined Pancreatic Islet-Lung-Liver Transplantation in a Pediatric Patient with Cystic Fibrosis-Related Diabetes.

BACKGROUND: Cystic fibrosis-related diabetes (CFRD) is the most frequent extrapulmonary complication of cystic fibrosis (CF). METHODS: We report the first combined pancreatic islet-lung-liver transplantation in a 14-year-old adolescent. CFTR was analyzed by Sanger sequencing. Further genes were analyzed by high-throughput sequencing. RESULTS: The patient was diagnosed with CF at the age of 14 months. Nine years later, after diagnosis of CFRD, the patient's BMI and lung function began to decline. Bilateral lung transplantation with simultaneous liver transplantation was performed at the age of 14.5 years. The first islet transplantation (IT) was carried out 10 days later. Six months later, C-peptide secretion after arginine stimulation showed peak values of 371 pmol/L (vs. 569 pmol/L before IT) and insulin doses had slightly increased (1.40 vs. 1.11 units/kg/day before IT). A second IT was performed at the age of 15 years, a third at 16 years. Two years after the first IT, arginine-stimulated C-peptide secretion increased to 2,956 pmol/L and insulin doses could be reduced to 0.82 units/kg/day. HbA1c decreased from 7.3% (57.4 mmol/mol) to 5.9% (41.0 mmol/mol). CONCLUSION: IT following lung and liver transplantation, with injection of islets into a transplanted organ, is feasible. It improves C-peptide secretion, decreases insulin needs, and lowers HbA1c.

Safely Decreasing Rigid Bronchoscopies for Foreign-Body Aspiration in Children: An Algorithm for the Emergency Department.

INTRODUCTION: Rigid bronchoscopy was traditionally performed in the management of foreign-body aspiration (FBA). More recently, since development of a less invasive method, flexible bronchoscopy has been proposed in some centers for the management of FBA. For the past few years, we have applied a decisional algorithm, privileging flexible bronchoscopy for diagnosis and, in some cases, for extraction of foreign body (FB). Our aims are first to analyze our current management of FBA and second to examine the bronchoscopic findings and complications. MATERIALS AND METHODS: Retrospective medical chart review of all patients with clinical suspicion of FBA who underwent bronchoscopy (flexible and/or rigid) from 2009 through 2014. RESULTS: An FB was found in 23 (33%) of the 70 patients included in the study (45 boys, 25 girls; median age: 21.5 months). Diagnosis of FBA was made on first intention in 22/23 (96%) and extraction was performed in 7/23 (30%) by flexible bronchoscopy. Rigid bronchoscopy was necessary for the extraction of the 16/23 (70%) remaining FBs. The rigid procedure was performed as first intention in only two (3%) patients, and one of the two was negative. Among the clinical signs of FBA, none were > 90% specific except for apnea (100%), but which was poorly sensitive (22%). Seven clinical and radiologic signs were found to be significantly different between FB+ and FB- groups: sudden choking, cyanosis, apnea, decreased breath sounds, atelectasis, mediastinal shift, and air trapping. Conversely, when none of these symptoms or signs and no clear history of sudden choking were present (in 15/70 patients), no FB was found. No life-threatening complications or death were observed. CONCLUSION: Our current management of FBA allows us to avoid almost all negative rigid bronchoscopies. In addition, we identified some symptoms and clinical and radiologic signs whose absence was highly predictive of negative bronchoscopy. We propose a novel algorithm for management of FBA that will help decrease the number of negative bronchoscopies.

Elevated lung clearance index in infants with cystic fibrosis shortly after birth.

It is not known at what age lung function impairment may arise in children with cystic fibrosis (CF). We assessed lung function shortly after birth in infants with CF diagnosed by newborn screening.We performed infant lung function measurements in a prospective cohort of infants with CF and healthy controls. We assessed lung clearance index (LCI), functional residual capacity (FRC) and tidal breathing parameters. The primary outcome was prevalence and severity of abnormal lung function (±1.64 z-scores) in CF.We enrolled 53 infants with CF (mean age 7.8 weeks) and 57 controls (mean age 5.2 weeks). Compared to controls, LCI and FRC were elevated (mean difference 0.30, 95% CI 0.02-0.60; p=0.034 and 14.5 mL, 95% CI 7.7-21.3 mL; p<0.001, respectively), while ratio of time to peak tidal expiratory flow to expiratory time was decreased in infants with CF. In 22 (41.5%) infants with CF, either LCI or FRC exceeded 1.64 z-scores; three infants had both elevated LCI and FRC.Shortly after birth, abnormal lung function is prevalent in CF infants. Ventilation inhomogeneity or hyperinflation may serve as noninvasive markers to monitor CF lung disease and specific treatment effects, and could thus be used as outcome parameters for future intervention studies in this age group.

Successful Lung Transplant After Prolonged Extracorporeal Membrane Oxygenation (ECMO) in a Child With Pulmonary Hypertension: A Case Report.

INTRODUCTION: The use of extracorporeal membrane oxygenation (ECMO) is considered a risk factor for, or even a potential contraindication to, lung transplantation. However, only a few pediatric cases have been described thus far. CASE PRESENTATION: A 9-year-old boy with idiopathic pulmonary arterial hypertension developed cardiac arrest after the insertion of a central catheter. ECMO was used as a bridge to lung transplantation. However, after prolonged resuscitation, he developed medullary ischemia and medullary syndrome. After 6 weeks of ECMO and triple combination therapy for pulmonary hypertension, including continuous intravenous prostacyclin, he was weaned off support, and after 2 weeks, bilateral lung transplantation was performed. At 4 years post-transplant, he has minimal problems. The medullary syndrome has also alleviated. He is now back to school and can walk with aids. CONCLUSIONS: Increasing evidence supports the use of ECMO as a bridge to LT, reporting good outcomes. In the modern era of PAH therapy, it is feasible to use prolonged ECMO support as a bridge to lung transplant, with the aim of weaning off this support; however, its use requires more experience and knowledge of long-term outcomes.

[Implementation of the neonatal cystic fibrosis screening program in Switzerland: beginning January 2011]. / Dépistage néonatal systématique de la mucoviscidose en Suisse: dès janvier 2011.

The diagnosis of cystic fibrosis (CF) is often delayed because of the nonspecificity of a wide variety of clinical symptoms at disease onset. Newborn screening for CF has been advocated to reduce delays in diagnosis, facilitating preventive care for early respiratory and nutritional involvement. According to American and European consensus and experience of existing programs, a Swiss Nationwide Cystic Fibrosis Newborn Screening Program started in January 2011. Screening strategy combines two steps: an immunoreactive trypsinogen assay and DNA mutation analysis in dried blood samples at day 4 (Guthrie cards).