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European CF Society Neonatal Screening Working Group (ECFS NSWG): Sabine Renner , Max Zeyda , Elke de Wachter , Luc Regal , Felix Votava, Andrea Holubova, Marianne Skov , Tessa Morgan, Paul Bregeaut , Loretta O'Grady, Ines Bucci , Stefano Pantano , Simonetta Simonetti, Domenica De Venuto, Donatello Salvatore, Nicola Perrotti, Mimma Caloiero, Giuseppe Castaldo, Antonella Tosco, Francesca Righetti, Giovanna Pisi, Fiorella Battistini, Antonio Angeloni, Giuseppe Cimino, Giovanni Fiocchi, Antonella Angiolillo, Michela Cassanello, Luisella Alberti, Laura E Claut, Raffaele Badolato, Enza Pavanello, Benedetta Fabrizzi, Elisabetta Bignamini, Anna Cardillo, Mariangela Lombardo, Letizia Cocciadiferro, Lisa Termini, Daniela Dolce, Vito Terlizzi, Anna Tamanini, Francesca Pauro, Giancarlo la Marca, Elina Aleksejeva, Dita Gaidule-Logina, Stoika Fustik, Violeta Anastasovska, Marelle Bouva, Alastair Reid, Jennifer Cundick, Emma Lundman, Egil Bakkeheim, Katarzyna Zybert, Mariusz Oltarzewski, Laura Vilarinho, Victoria Sherman, Elena Kondratyeva, Sarah Smith, Gordana Vilotijevic Dautovic, Maria Knapkova, Zuzana Mydlova, Rosa Mª López, Valle Velasco, Felicitas Díaz Flores, Cristóbal Colón Mejeras, Eva Sl Pedersen, Ugur Ozcelik, Bulent Karadag, Halyna Makukh, Moat Stuart. European CF Society Neonatal Screening Working Group (ECFS NSWG): INSA - Laura Vilarinho 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. Highlights: In 2022, newborn bloodspot screening (NBS) for CF is undertaken in 30 European countries, 26 of them are national programmes; Some programmes are still not achieving ECFS standards. Compared to 2014, there is an improvement in sensitivity but a deterioration in achieving a sufficient PPV; There continues to be a wide variety of approaches, but the majority of national programmes are now using DNA analysis as a 2nd tier; This survey demonstrates areas of good practice, but there is considerable scope for improvement in the quality of NBS for CF across Europe; The framework of the 20 parameters to calculate the 8 key outcomes should be part of any annual report of a CF NBS programme, and thus improve future surveys. The survey was funded by the European CF Society info:eu-repo/semantics/publishedVersion

Background Tezacaftor/ivacaftor is a CFTR modulator approved to treat people with cystic fibrosis (pwCF) who are homozygous (F/F) or heterozygous for the F508del-CFTR mutation and a residual function mutation (F/RF). This randomized, double-blind, placebo-controlled Phase 3 study evaluated the efficacy, safety, tolerability, and pharmacokinetics (PK) of tezacaftor/ivacaftor in participants ≥12 years of age heterozygous for the F508del-CFTR mutation and a minimal function mutation (F/MF), which produces no CFTR protein or a protein unresponsive to tezacaftor/ivacaftor in vitro. Methods Participants were randomized 1:1 to receive tezacaftor/ivacaftor or placebo for 12 weeks. The primary endpoint was the absolute change from baseline in percent predicted forced expiratory volume in 1 second (ppFEV1) between the tezacaftor/ivacaftor and placebo groups through week 12. Key secondary endpoints included absolute change from baseline in CF Questionnaire-Revised respiratory domain scores and the number of pulmonary exacerbations through week 12 and the absolute change from baseline in body mass index at week 12. A prespecified interim analysis (IA) for futility was conducted when approximately 50% of a planned enrollment of 300 participants reached week 12 of the study. Results At the time of the IA, 83 participants were randomized to tezacaftor/ivacaftor and 85 to placebo; 165 participants completed treatment. The study failed to demonstrate that tezacaftor/ivacaftor significantly improved ppFEV1 or any of the key secondary endpoints and was terminated for futility. The safety profile and PK parameters of tezacaftor/ivacaftor were similar to those reported in prior studies in participants ≥12 years of age with CF. Conclusions Tezacaftor/ivacaftor did not show a clinically meaningful benefit in participants with F/MF genotypes but was generally safe and well tolerated, consistent with the safety profile reported in other Phase 3 studies (NCT02516410).

OBJECTIVE To characterize the phenotypic expression of children with conductance regulator-related metabolic syndrome (CRMS)/cystic fibrosis screen positive inconclusive diagnosis (CFSPID) designation after positive newborn screening, reassign labeling if applicable and better define these children's prognosis. METHODS A multicenter cohort with CRMS/CFSPID designation was matched with cystic fibrosis (CF)-diagnosed cohort. Cohorts were prospectively compared on baseline characteristics, cumulative data and when they reached 6 to 7 years at endpoint assessment. RESULTS Compared to infants with CF (n = 63), the CRMS/CFSPID cohort (n = 63) had initially lower immunoreactive trypsinogen (IRT) and sweat chloride (SC) values, delayed visits, less symptoms, and better nutritional status; during follow-up, they had fewer hospitalizations, Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus identification, CF comorbidities, and treatment burden. At endpoint assessment, they presented a milder pulmonary phenotype on Brody computed tomography scores (0.0[0.0; 2.0] vs 13[2.0; 31.0]; P

Antibiotic eradication treatment is the standard-of-care for cystic fibrosis (CF) patients with early Pseudomonas aeruginosa (Pa)-infection; however, evidence from placebo-controlled trials is limited.This double-blind, placebo-controlled trial randomised CF patients7 years (N = 51) with early Pa-infection to tobramycin inhalation solution (TOBI 300 mg) or placebo (twice daily) for 28 days with an optional cross-over on Day 35. Primary endpoint was proportion of patients having throat swabs/sputum free of Pa on Day 29.On Day 29, 84.6% patients in the TOBI versus 24.0% in the placebo group were Pa-free (p 0.001). At the end of the cross-over period, 76.0% patients receiving TOBI in the initial 28 days were Pa-free compared to 47.8% receiving placebo initially. Adverse events were consistent with the TOBI safety profile with no differences between TOBI and placebo.TOBI was effective in eradicating early Pa-infection with a favourable safety profile in young CF patients.NCT01082367.

International audience; Background: Phase 3 trials have demonstrated the safety and efficacy of lumacaftor-ivacaftor (LUMA-IVA) in patients with cystic fibrosis (CF) homozygous for the Phe508del CFTR mutation and percent predicted forced expiratory volume in 1 s (ppFEV1) between 40 and 90. Marketing authorizations have been granted for patients at all levels of ppFEV1.Methods: To evaluate the safety and effectiveness of LUMA-IVA over the first year of treatment in patients with ppFEV1

An unintended consequence of newborn screening for cystic fibrosis (CF) is the identification of infants with a positive screening test but an inconclusive diagnostic testing. These infants are designated as CF transmembrane conductance regulator-related metabolic syndrome (CRMS) in the US and CF screen-positive, inconclusive diagnosis (CFSPID) in Europe. Recently, experts agreed on a unified international definition of CRMS/CFSPID which will improve our knowledge on the epidemiology and outcomes of these infants and optimize comparisons between cohorts. Many of these children will remain free of symptoms, but a number may develop clinical features suggestive of CFTR-related disorder (CFTR-RD) or CF later in life. Clinicians should to be prepared to identify these infants and communicate with parents about this challenging and stressful situation for both healthcare professionals and families. In this review, we present the recent publications on infants designated as CRMS/CFSPID, including the definition, the incidence across Europe, the assessment of the CFTR protein function, the outcomes with the rates of conversion to a final diagnosis of CF and their management.

International audience; Background: Major issues of newborn screening (NBS) for CF are the assessment of disease liability of variants and of the penetrance of clinical CF, notably in inconclusive diagnosis. The penetrance of CF is defined as the risk of a particular genotype to lead to a CF phenotype.Methods: We aimed to get insight into the penetrance of CF for fifteen CFTR variants: 5 frequent CF-causing and 10 classified as of varying clinical consequence (VCC) or associated with a CFTR-related disorder (CFTR-RD) in CFTR2 or CFTR-France databases. The penetrance was approached by: (1) comparison of variant allelic frequencies in CF patients (CFTR2) and in the general population; (2) estimation of the likelihood of a positive NBS test for the 14 compound heterozygous with F508del and the F508del homozygous genotypes, defined as the ratio of detected/expected number of neonates with a given genotype in the 2002-2017 period.Results: A full penetrance was observed for severe CF-causing variants. Five variants were more frequently found in the general population than in CF patients: TG11T5, TG12T5, TG13T5, L997F and R117H;T7. The likelihood of a positive NBS test was 0.03% for TG11T5, 0.3% for TG12T5, 1.9% for TG13T5, 0.6% for L997F, 11.7% for D1152H, and 17.8% for R117H;T7. Penetrance varied greatly for variants with discrepant classification between CFTR2 and CFTR-France: 5.1% for R117C, 12.3% for T338I, 43.5% for D110H and 52.6% for L206W.Conclusion: These results illustrate the contribution of genetics population data to assess the disease liability of variants for diagnosis and genetic counselling purposes.

Background Newborn screening (NBS) for cystic fibrosis (CF) is a well-established public health strategy with international standards. The aim of this study was to provide an update on NBS for CF in Europe and assess performance against the standards. Methods Questionnaires were sent to key workers in each European country. Results In 2016, there were 17 national programmes, 4 countries with regional programmes and 25 countries not screening in Europe. All national programmes employed different protocols, with IRT-DNA the most common strategy. Five countries were not using DNA analysis. In addition, the processing and structure of programmes varied considerably. Most programmes were achieving the ECFS standards with respect to timeliness, but were less successful with respect to sensitivity and specificity. Conclusions There has been a steady increase in national CF NBS programmes across Europe with variable strategies and outcomes that reflect the different approaches.

Resume Les tumeurs desmoides (TD) sont des tumeurs rares, infiltrant les tissus, denuees de potentiel metastatique. Elles sont le plus souvent sporadiques et dans 5 a 10 % des cas associees aux polyposes adenomateuses familiales (PAF). Elles apparaissent habituellement chez l’adulte jeune, plus rarement chez l’enfant. Nous rapportons le cas d’une adolescente de 14 ans qui avait subi une procto-colectomie totale en raison d’une PAF avec mutation de novo du gene APC, habituellement non associee aux TD. Trois ans plus tard, elle a presente des douleurs a la defecation. Le scanner a mis en evidence 2 TD intra-abdominales. Une exerese chirurgicale ayant ete ecartee en raison du risque de resection etendue du grele, un traitement par anti-estrogene et anti-inflammatoire non steroidien a ete instaure. Le scanner realise a 18 mois a montre une stabilisation des TD, mais l’adolescente gardait des douleurs chroniques difficiles a controler. Une surveillance radiologique reguliere a ete effectuee. Cette observation rappelle l’importance d’un depistage regulier des TD chez les sujets atteints de PAF, notamment apres une chirurgie, et ce quel que soit l’âge et le type de mutation. Des progres restent a faire pour determiner les facteurs de risque d’apparition d’une TD chez ces sujets et pour les traiter efficacement. La prise en charge therapeutique actuelle reste difficile du fait du caractere infiltrant et recidivant de ces tumeurs et necessite un avis pluridisciplinaire.

Streszczenie Specjalistyczna opieka nad chorymi na mukowiscydoze doprowadzila do znaczącej poprawy przezycia: w ciągu ostatnich czterech dekad bylo ono istotnie wyzsze niz wśrod ogolnej populacji pacjentow w analogicznym wcześniejszym okresie. Wprowadzenie badan przesiewowych noworodkow w wielu krajach Europy sprawilo, ze w coraz wiekszej liczbie ośrodkow prowadzeni są pacjenci z minimalnymi zmianami plucnymi w momencie rozpoznania, ktorzy w efekcie mogą potencjalnie cieszyc sie doskonalą jakością zycia i wyzszą średnią dlugością zycia niz w przeszlości. W celu zapewnienia wysokiej jakości opieki medycznej w Europie, w 2005 roku opublikowano przelomową prace ustanawiającą standardy opieki. Niniejszy artykul opiera sie na tamtym dokumencie, wyznaczając standardy dotyczące najlepszych praktyk dla kluczowych aspektow leczenia mukowiscydozy. Celem naszej pracy jest zapewnienie szerokiego przeglądu standardow dotyczących badan przesiewowych, diagnostyki, leczenia ograniczajacego chorobe pluc, zywienia, leczenia powiklan, przeszczepienia, opieki u schylku zycia i wsparcia psychologicznego. W tabeli I umieszczono odniesienia do najnowszego konsensusu europejskiego, wytycznych i innych dokumentow zawierających kompleksowe informacje dotyczące opieki medycznej w mukowiscydozie. Mamy nadzieje, ze niniejszy dokument opisujący najlepsze praktyki bedzie uzytecznym narzedziem dla zespolow klinicznych zarowno w krajach, w ktorych opieka nad pacjentami z mukowiscydozą jest dopiero rozwijana, jak i tych, w ktorych istnieją juz specjalistyczne ośrodki.

To evaluate nutritional status and associated factors in a cystic fibrosis (CF) cohort diagnosed by newborn screening and followed up to month 24.A prospective longitudinal multicenter study assessing nutritional status according to pancreatic status, feeding modalities, prescriptions, pulmonary outcome, and biological nutritional parameters.One hundred and five infants were recruited and 99 completed the study. Nutritional care management prevented undernutrition and stunting in those with exocrine pancreatic sufficiency (EPS), but affected (13/87) 15% and (21/86) 24%, respectively, of infants with exocrine pancreatic insufficiency (EPI). The logistic regression model found a positive association between both weight and length z scores "at risk" at month 24, and initial pulmonary symptoms (odds ratio [OR] 0.06, P 0.01 and OR 0.08, P 0.01, respectively); these symptoms were less frequent when age at first visit was earlier than 1.2 months (33% vs 67%, P = 0.02); stunting was also associated with high-calorie density intake and Staphylococcus aureus (OR 0.05, P = 0.01 and OR 0.17, P 0.01). Pulmonary outcome did not differ according to pancreatic status; breast-feeding for at least 3 months delayed first acquisition of Pseudomonas aeruginosa. Despite sodium and fat-soluble vitamin supplementation, half of both cohorts had low urinary sodium output and half of the EPI cohort had low vitamin D levels.Our data shed light on the fact that stunting was more frequent than undernutrition, while both parameters involved only patients with pancreatic insufficiency. Modalities of feeding were not associated with nutritional status; breast-feeding may provide some protection against acquisition of P aeruginosa.

Developments in managing CF continue to drive dramatic improvements in survival. As newborn screening rolls-out across Europe, CF centres are increasingly caring for cohorts of patients who have minimal lung disease on diagnosis. With the introduction of mutation-specific therapies and the prospect of truly personalised medicine, patients have the potential to enjoy good quality of life in adulthood with ever-increasing life expectancy. The landmark Standards of Care published in 2005 set out what high quality CF care is and how it can be delivered throughout Europe. This underwent a fundamental re-write in 2014, resulting in three documents; center framework, quality management and best practice guidelines. This document is a revision of the latter, updating standards for best practice in key aspects of CF care, in the context of a fast-moving and dynamic field. In continuing to give a broad overview of the standards expected for newborn screening, diagnosis, preventative treatment of lung disease, nutrition, complications, transplant/end of life care and psychological support, this consensus on best practice is expected to prove useful to clinical teams both in countries where CF care is developing and those with established CF centres. The document is an ECFS product and endorsed by the CF Network in ERN LUNG and CF Europe.

Summary Clinical studies in patients with cystic fibrosis and G551D-CFTR showed that the group treated with ivacaftor had improved clinical outcomes. To better understand the effect of ivacaftor therapy across the distribution of individual FEV1 responses, data from Phase 3 studies (STRIVE/ENVISION) were re-examined. In this post-hoc analysis of patients (n = 209) who received 48 weeks of ivacaftor or placebo, patients were assigned to tertiles according to FEV1 response. These groups were then used to evaluate response (FEV1, sweat chloride, weight, CFQ-R, and pulmonary exacerbation). The number needed to treat (NNT) was calculated for specific thresholds for each outcome. Across all tertiles, numerical improvements in FEV1, sweat chloride, CFQ-R and the frequency of pulmonary exacerbations were observed in ivacaftor-treated patients: the treatment difference versus placebo was statistically significant for all outcomes in the upper tertile and for some outcomes in the lower and middle tertiles. The NNT for a ≥ 5% improvement in %predicted FEV1 was 1.90, for a ≥ 5% body weight increase was 5.74, and to prevent a pulmonary exacerbation was 3.85. This analysis suggests that the majority of patients with clinical characteristics similar to STRIVE/ENVISION patients have the potential to benefit from ivacaftor therapy. Pediatr Pulmonol. 2015; 50:447–455. © 2015 Wiley Periodicals, Inc.

Background and Aims Catheter venous thrombosis may result in life-threatening embolic complications. Recently, a thrombophilic tendency was described in cystic fibrosis (CF), the significance of which remains unclear. The aims of this study were to (1) document the frequency of catheter venous thrombosis detected by colour-Doppler-ultrasound (Doppler-US), (2) assess genetic and acquired thrombophilia risk factors for catheter venous thrombosis and hypercoagulability status and (3) provide recommendations on laboratory screening when considering insertion of a totally implantable vascular access device (TIVAD) in CF patients. Methods We designed a multicentre prospective study in patients selected at the time of catheter insertion. Doppler-US was scheduled at 1 and 6months after insertion and before insertion in case of a previous central line. Blood samplings were drawn at insertion and at 1 and 6months later. Results One-hundred patients received a TIVAD and 90 completed the 6-month study. Prevalence of thrombophilia abnormalities and hypercoagulability was found in 50% of the cohorts. Conversely, catheter venous thrombosis frequency was low (6.6%). Conclusion Our data do not support biological screening at the time of a TIVAD insertion. We emphasise the contribution of a medical history of venous thromboembolism and prospective Doppler-US for identifying asymptomatic catheter venous thrombosis to select patients who may benefit from biological screening and possible anticoagulant therapy.

Background Ivacaftor has been shown to improve lung function and body weight in patients with CF and a gating mutation. Real-world evaluation is warranted to examine its safety and effectiveness over the long term. Methods A retrospective observational multicentre study collected clinical data in the year before and the 2years after ivacaftor initiation in patients with CF and a Gly551Asp- CFTR mutation. Results Fifty-seven patients were included. Mean absolute change in FEV 1 % predicted improved from baseline to Year 1 (8.4%; p Pseudomonas aeruginosa and Staphylococcus aureus positive cultures, and decreased IV antibiotics and maintenance treatment prescriptions (including azithromycin, Dornase alpha and nutritional supplements). No significant adverse events were reported. Conclusion The clinical benefits of ivacaftor reported in previous clinical trials were confirmed in a real-world setting two years post-initiation, also reducing treatment burden.

Objective An unintended consequence of cystic fibrosis (CF) newborn screening (NBS) is the identification of infants with a positive NBS test but inconclusive diagnostic testing. These infants are classified as CF transmembrane conductance regulator-related metabolic syndrome (CRMS) in the US and CF screen positive, inconclusive diagnosis (CFSPID) in other countries. Diagnostic and management decisions of these infants are challenges for CF healthcare professionals and stressful situations for families. As CF NBS has become more widespread across the world, increased information about the epidemiology and outcomes of these infants is becoming available. These data were reviewed at the 2015 CF Foundation Diagnosis Consensus Conference, and a harmonized definition of CRMS and CFSPID was developed. Study design At the consensus conference, participants reviewed published and unpublished studies of CRMS/CFSPID and used a modified Delphi methodology to develop a harmonized approach to the definition of CRMS/CFSPID. Results Several studies of CRMS/CFSPID from populations around the world have been published in the past year. Although the studies vary in the number of infants studied, study design, and outcome measures, there have been some consistent findings. CRMS/CFSPID occurs relatively frequently, with CF:CRMS that ranges from 3 to 5 cases of CF for every 1 case of CRMS/CFSPID in regions where gene sequencing is not used. The incidence varies by NBS protocol used, and in some regions more cases of CRMS/CFSPID are detected than cases of CF. The majority of individuals with CRMS/CFSPID do not develop CF disease or progress to a diagnosis of CF. However, between 10% and 20% of asymptomatic infants can develop clinical features concerning for CF, such as a respiratory culture positive for Pseudomonas aeruginosa . Most studies have only reported short-term outcomes in the first 1-3 years of life; the long-term outcomes of CRMS/CFSPID remain unknown. The European CF Society definition of CFSPID and the CF Foundation definition of CRMS differ only slightly, and the consensus conference was able to create a unified definition of CRMS/CFSPID. Conclusions CRMS/CFSPID is a relatively common outcome of CF NBS, and clinicians need to be prepared to counsel families whose NBS test falls into this classification. The vast majority of infants with CRMS/CFSPID will remain free from disease manifestations early in life. However, a small proportion may develop clinical features concerning for CF or demonstrate progression to a clinical phenotype compatible with a CF diagnosis, and their long-term outcomes are not known. A consistent international definition of CRMS/CFSPID will allow for better data collection for study of outcomes and result in improved patient care.

Introduction Inhaled mannitol has beneficial effects on lung function, mucociliary clearance, quality of life and sputum properties. This trial examined the efficacy of inhaled mannitol in children with cystic fibrosis (CF). Methods The efficacy of inhaled mannitol in children with CF aged 6–17years was assessed in a phase 2, randomised, placebo-controlled crossover study. Subjects were randomly assigned to mannitol 400mg every 12h or matching placebo for 8weeks, followed by an 8week washout and an 8week period with the alternate treatment. The primary endpoint was the absolute change from baseline in ppFEV1 (percent predicted FEV1). Results A total of 92 subjects were studied, with a mean age of 12years and mean baseline ppFEV1 of 72.2%. During mannitol treatment ppFEV1 was 3.42% (p=0.004) higher compared to placebo or a 4.97% (p=0.005) relative difference; relative change from baseline FEF25-75 was 10.52% (p=0.013). During mannitol treatment, acute post-treatment sputum weight was higher (p=0.012). In pre-specified subgroups (rhDNase use, age, and disease severity), the treatment differences consistently favoured mannitol. The most common AEs were cough and pulmonary exacerbations. Pulmonary exacerbation AEs were approximately 30% lower in the mannitol group. Conclusions In children with CF, inhaled mannitol was associated with significant improvements in lung function and sputum weight, irrespective of rhDNase use, age or disease severity. Inhaled mannitol was well tolerated and was associated with a reduced incidence of pulmonary exacerbation AEs. (Clinical Trials.Gov: NCT 01883531)

Resume Ces recommandations sont destinees a harmoniser les procedures concernant la prise en charge des nourrissons de moins de 2 ans atteints de formes typiques de mucoviscidose et diagnostiques par depistage neonatal. Elles ont ete elaborees par le Groupe de travail « depistage neonatal de la mucoviscidose » de la Federation des centres de ressources et de competences de la mucoviscidose (CRCM) et validees selon la methodologie Delphi par des pediatres impliques dans le suivi au quotidien de ces nourrissons. Elles concernent la prise en charge au moment du diagnostic a la fois sur le plan de l’organisation des soins que du bilan initial et definissent le cadre du suivi du nourrisson depiste au plan nutritionnel, digestif et respiratoire pendant les 2 premieres annees de vie.

Specialised CF care has led to a dramatic improvement in survival in CF: in the last four decades, well above what was seen in the general population over the same period. With the implementation of newborn screening in many European countries, centres are increasingly caring for a cohort of patients who have minimal lung disease at diagnosis and therefore have the potential to enjoy an excellent quality of life and an even greater life expectancy than was seen previously. To allow high quality care to be delivered throughout Europe, a landmark document was published in 2005 that sets standards of care. Our current document builds on this work, setting standards for best practice in key aspects of CF care. The objective of our document is to give a broad overview of the standards expected for screening, diagnosis, pre-emptive treatment of lung disease, nutrition, complications, transplant/end of life care and psychological support. For comprehensive details of clinical care of CF, references to the most up to date European Consensus Statements, Guidelines or Position Papers are provided in Table 1. We hope that this best practice document will be useful to clinical teams both in countries where CF care is developing and those with established CF centres.

Background Distal intestinal obstruction syndrome (DIOS) is a specific complication of cystic fibrosis. Methods A study was performed in 10 countries to prospectively evaluate the incidence, associated factors, and treatment modalities in children and adults. Results 102 patients presented 112 episodes. The incidence of DIOS was similar in children and adults. Medical treatment failed only in cases of complete DIOS (11%). Children with meconium ileus had a higher rate of surgery for DIOS (15% vs. 2%, p = 0.02). Complete DIOS entailed longer hospitalisation (4 [3; 7] days vs. 3 [1; 4], p = 0.002). Delayed arrival at hospital and prior weight loss had a significant impact on the time needed for DIOS resolution. Associated CF co-morbidities for DIOS included meconium ileus (40% vs. 18%, p < 0.0001), exocrine pancreatic insufficiency (92% vs. 84%, p = 0.03), liver disease (22% vs. 12%, p = 0.004), diabetes mellitus (49% vs. 25%, p = 0.0003), and Pseudomonas aeruginosa (68% vs. 52%, p = 0.01); low fibre intake and insufficient hydration were frequently observed. Female gender was associated with recurrent DIOS (75% vs. 52%, p = 0.04), constipation with incomplete episodes (39% vs. 11%, p = 0.03), and poor patient compliance in taking pancreatic enzyme therapy during complete episodes (25% vs. 3%, p = 0.02). Conclusion DIOS is a multifactorial condition having a similar incidence in children and adults. We show that delayed arrival at hospital after the initial symptoms causes significant morbidity. Early recognition and treatment would improve the prognosis.

Background Little data exist on causes of death in cystic fibrosis (CF) patients in the era of lung transplantation. Methods Deaths in CF patients in France (2007–2010) were identified using the French CF Registry and causes of deaths were determined based on medical files by a mortality adjudication committee. Results Of 256 deaths, half occurred after lung transplantation and were related to early or late complications of transplantation, whereas half occurred in patients who did not receive lung transplantation and were primarily related to respiratory failure or massive hemoptysis. Among patients who did not receive lung transplantation, only 19% died while waiting on a lung transplantation list. Lack of listing for lung transplantation was primarily related to late, or to lack of transplantation referral, rather than to contraindication to transplantation. Conclusions These data suggest that improvement in transplantation referral strategies may result in transplantation-related survival benefits.

Background Newborn screening (NBS) for cystic fibrosis (CF) results in the recognition of a number of infants with a positive NBS result, but an inconclusive diagnosis. Varied practice exists with respect to the management of these infants. Methods A Delphi consensus approach was used to determine agreement on statements generated by a core group of specialists. A designation (naming) exercise was required after Round 1 and further expert opinion was sought to guide that process. After Round 2, a sensitivity analysis was undertaken to assess the impact of attrition on subsequent agreement levels. Results Infants were divided into group A (normal sweat chloride and two CFTR mutations, at least one of which has unclear phenotypic consequences) and group B (intermediate sweat chloride and one or no CFTR mutations). 32 statements were produced for Round 1 and 24 achieved consensus. After Round 1, a designation exercise was undertaken and the term "CF Screen Positive, Inconclusive Diagnosis (CFSPID)" was suggested for Round 2. Agreement was achieved for this statement and for all other statements aside from the need for routine respiratory culture, on which there was divided opinion. The core group advocated local practice for this issue. A sensitivity analysis demonstrated that consensus for Round 2 was achieved by change in opinion rather than attrition. Conclusion We have generated a new designation and statements to guide the management of infants with CFSPID through a robust international Delphi process. These statements will be a valuable tool for CF teams and will improve the consistency of management of these infants.

To retrospectively assess, in a pediatric multicenter cohort, guidelines for the management of familial adenomatous polyposis (FAP).Ten centers from the French-speaking Pediatric Gastroenterology Hepatology and Nutrition Group provided follow-up data on patients up to 18 years of age. Clinical records, genetic test results, endoscopy with histopathology examination, and therapeutic modalities were reviewed.A total of 70 children from 47 families were included. When initial consultation resulted from a surveillance program because of an affected family member, 12 of 59 children were already symptomatic. Among 11 patients whose initial consultation was based only on symptoms, families were unaware at the time of a familial FAP history for 7 children, whereas only 4 cases were sporadic. A panel of 27 different pathogenic adenomatous polyposis coli (APC) germ-line mutations and large genomic deletions were identified in 43 families. Extracolonic manifestations were found in half of the patients. As part of the standard practice for initial screening, the entire cohort underwent colonoscopy, which revealed adenoma above an intact rectosigmoid in 8 cases. Prophylactic colectomy was performed in 42 cases; high-grade dysplastic adenoma and 1 invasive carcinoma were detected in 6 children. For timing of surgery, indications were in accordance with recent international guidelines.Defining optimal screening and therapeutic modalities in pediatric FAP cohorts is a challenge. Specific advice for genetic screening, endoscopy surveillance, and type of surgery based on recent guidelines is recommended.

Resume Ces recommandations sont destinees a harmoniser les procedures concernant le test de la sueur dans le cadre du depistage neonatal de la mucoviscidose en France. Elles ont ete elaborees par le groupe de travail « depistage neonatal de la mucoviscidose » de la federation des Centres de ressources et de competences de la mucoviscidose (CRCM). Le test de la sueur est pratique chez le nouveau-ne lorsqu’il a atteint le poids de 3 kg et qu’il est âge de plus de 3 semaines d’âge reel. La stimulation de la production de sueur est realisee par administration transdermique de la pilocarpine par iontophorese. Le recueil de sueur s’effectue de facon preferentielle en collecteur capillaire. Seul le dosage specifique de l’ion chlorure est retenu comme methode diagnostique. Un dosage de chlorure sudoral inferieur a 30 mmol/l elimine a priori une mucoviscidose. Un dosage de chlorure sudoral superieur ou egal a 60 mmol/l confirme une mucoviscidose. Le test est dit intermediaire entre ces 2 valeurs.

Various definitions for distal intestinal obstruction syndrome (DIOS), meconium ileus equivalent, and constipation in patients with cystic fibrosis (CF) are used. However, an unequivocal definition for DIOS, meconium ileus equivalent, and constipation is preferred. The aims of this study were, therefore, to seek consensus on the definitions for DIOS and constipation in patients with CF and to determine the incidence, characteristics, and treatment of DIOS in a cohort of paediatric patients with CF.During the 2005 European Society for Paediatric Gastroenterology, Hepatology, and Nutrition meeting in Porto a group of paediatric gastroenterologists discussed the definition of DIOS and constipation in CF. Subsequently, all patients younger than or equal to 18 years with complete DIOS according to the definition agreed upon and diagnosed during the years 2001 to 2005 in 8 CF centres were studied.Distal intestinal obstruction syndrome was defined as an acute complete or incomplete faecal obstruction in the ileocaecum, whereas constipation was defined as gradual faecal impaction of the total colon. Fifty-one episodes of DIOS in 39 patients were recorded, giving an overall incidence of 6.2 (95% confidence interval, 4.4-7.9) episodes per 1000 patient-years. Of the 39 patients with DIOS, 20% experienced a relapse, 92% were pancreatic insufficient, 44% had a history of meconium ileus at birth, and 82% had a severe genotype. Conservative treatment was effective in 49 of 51 DIOS episodes (96%).The European Society for Paediatric Gastroenterology, Hepatology, and Nutrition CF Working Group definitions of DIOS and constipation in CF are specific and make a clear distinction between these 2 entities. The incidence of DIOS in the present study was considerably higher than reported previously.

Background Cystic fibrosis (CF) is a recessively inherited condition caused by mutation of the CFTR gene. Newborn infants with CF have raised levels of immuno-reactive trypsinogen (IRT) in their serum. Measurement of IRT in the first week of life has enabled CF to be incorporated into existing newborn screening (NBS) blood spot protocols. However, IRT is not a specific test for CF and NBS therefore requires a further tier of tests to avoid unnecessary referral for diagnostic testing. Following identification of the CFTR gene, DNA analysis for common CF-associated mutations has been increasingly used as a second tier test. The aim of this study was to survey the current practice of CF NBS programmes in Europe. Method A questionnaire was sent to 26 regional and national CF NBS programmes in Europe. Results All programmes responded. The programmes varied in number of infants screened and in the protocols employed, ranging from sweat testing all infants with a raised first IRT to protocols with up to four tiers of testing. Three different assays for IRT were used; in the majority (24) this was a commercially available kit (Delfia™). A number of programmes employed a second IRT measurement in the 4th week of life (as the IRT is more specific at this point). Nineteen programmes used DNA analysis for common CFTR mutations on samples with a raised first IRT. Three programmes used a second IRT measurement on infants with just one recognised mutation to reduce the number of infants referred for sweat testing. Referral to clinical services was prompt and diagnosis was confirmed by sweat testing, even in infants with two recognised mutations in most programmes. Subsequent clinical pathways were less uniform. Multivariate analysis demonstrated a relationship between the age of diagnosis and the timing of the first IRT. More sweat tests were undertaken if the first IRT was earlier and the diagnosis was later. Conclusions Annually these programmes screen approximately 1,600,000 newborns for CF and over 400 affected infants are recognised. The findings of this survey will guide the development of European evidence based guidelines and may help new regions or nations in the development and implementation of NBS for cystic fibrosis.

Objective This matched case-control study compared the nutritional and the pulmonary long-term outcomes of cystic fibrosis (CF) patients presenting a history of meconium ileus (MI) with early-diagnosed symptomatic CF without MI (non-MI). Material and Method Twenty-six patients with CF treated for MI between 1980 and 1997 have been matched for sex, birth date, and earliest CF symptomatic diagnosis for the children with non-MI CF. Clinical characteristics, genotype and complications were evaluated as well as the progression of the CF disease from infancy to 15 years old by nutritional status ( z score weight, z score height), pulmonary function tests (PFTs) (FVC and FEV 1 ), and Pseudomonas aeruginosa acquisition. Results Median duration of the follow-up was 12.5 years (range, 10-17 years). Genotype identification showed no significant difference. Further on, the rate of complications and the occurrence of chronic P aeruginosa colonization did not differ. At age of 15 years (n = 13), nutritional status and PFTs did not demonstrate any significant difference. Conclusion These results suggest that adequate initial nutritional and medical management of MI allows further similar nutritional status and PFTs compared with other early-diagnosed symptomatic CF patients. In this study, MI did not represent an additional risk factor for the patient's life.

Children with cystic fibrosis commonly experience abdominal pain; however this remains poorly characterised. This prospective cross-sectional study with a longitudinal design, examined the prevalence, causes and effect of pain management via daily diaries, validated questionnaires for pain characteristics, anxiety status and quality of life. One hundred and thirty CF patients aged 8 to 18years, regularly followed at our centre, were questioned on recurrent abdominal pain. Eight patients fulfilled the criteria; all wished to enter the study. Pain management included behavioural intervention with effective pain relief, and had a positive impact on anxiety and quality of life. This study is the first one to prospectively assess recurrent abdominal pain in CF. We documented a very low prevalence of 6%. We suggest that, ruling out abdominal discomfort, only a minority of CF children presented recurrent abdominal pain with a true negative impact on daily life. We emphasise the need for further studies including larger cohorts.

Resume Objectif – L’atteinte pancreatique au cours des maladies inflammatoires chroniques de l’intestin de l’enfant n’a ete rapportee que de facon anecdotique. Les donnees chez l’adulte revelent une frequence de 2 % des pancreatites aigues symptomatiques et de 8 a 21 % des formes asymptomatiques. Le but de ce travail etait d’etudier la frequence de l’atteinte pancreatique au cours des maladies inflammatoires du tube digestif de l’enfant, d’en preciser les caracteristiques et d’en determiner les causes. Patients et methodes – Cent vingt-quatre dossiers d’enfants atteints de maladies inflammatoires du tube digestif ont ete repris de facon retrospective. Le critere diagnostique de l’atteinte pancreatique etait une amylasemie ≥ + 2 ET de la normale avec des signes cliniques evocateurs (formes symptomatiques) ou sans signe clinique (formes asymptomatiques). Resultats. – La frequence de l’atteinte pancreatique au cours des maladies inflammatoires du tube digestif de l’enfant etait de 27 % dont 14,5 % etaient symptomatiques et 12,5 % asymptomatiques. Les filles etaient plus souvent touchees que les garcons (p = 0,04). Les pancreatites aigues etaient relativement benignes, non compliquees et souvent recidivantes, elles survenaient frequemment au cours d’une poussee digestive. La maladie sous-jacente etait severe (p = 0,006), c’est-a-dire a evolution continue ou intermittente selon les criteres de Binder. Les localisations digestives des maladies inflammatoires du tube digestif n’etaient pas statistiquement differentes entre les cas avec ou sans pancreatite. Une origine medicamenteuse etait retrouvee chez 27 % des patients ayant une pancreatite symptomatique, essentiellement liee a l’azathioprine et aux anti-inflammatoires non steroidiens. D’autres facteurs etaient egalement frequents : une localisation duodenale de la maladie ou une atteinte hepatobiliaire (18 et 15 % respectivement : NS). Conclusion – Ce travail suggere l’importance de la surveillance du bilan pancreatique au cours des maladies inflammatoires du tube digestif de l’enfant pour ne pas meconnaitre une pancreatite. Il faut en determiner les causes, souvent multifactorielles et intriquees, pour eviter de suspecter a tort des pancreatites medicamenteuses risquant ainsi de se retrouver dans une impasse therapeutique injustifiee.

Resume Les lymphangiectasies intestinales primitives ou maladie de Waldmann entrainent des symptomes d’enteropathie exsudative variables dans leur severite. Peu d’etudes concernent l’evolution de long cours des patients. Nous rapportons le suivi retrospectif de six enfants pour lesquels le diagnostic a ete porte a l’âge moyen de 17 ± 12 mois et qui ont ete suivis sur une periode moyenne de 11 ± 4,9 ans. Observations. – Des le diagnostic pose, les patients ont ete mis au regime sans graisses, enrichi en proteines et triglycerides a chaine moyenne avec des perfusions regulieres de lipides associes a des vitamines liposolubles. Ce regime a permis la disparition des symptomes cliniques chez tous les patients tandis que les signes biologiques de fuite lymphatique ont persiste chez cinq enfants sur six. Un seul enfant a normalise les parametres biologiques et a tolere un regime normal avec quatre ans de recul ; l’abandon du regime par deux enfants qui conservaient une hypoalbuminemie et une lymphopenie a provoque une rechute clinique majeure difficilement controlable 14 et 17 ans apres les symptomes revelateurs. Trois patients poursuivent le regime en restant asymptomatiques. Conclusion. – Le maintien du regime d’exclusion des graisses semble justifie chez les patients meme asymptomatiques des lors que persistent des anomalies biologiques. Les rechutes cliniques peuvent etre tres bruyantes et difficiles a controler lors d’elargissement, souvent autoprescrit, du regime.

Malnutrition is a common complication of chronic diseases in children and may lead to growth impairment (stunting). Malnutrition in cystic fibrosis (CF) results from increased energy expenditure, decreased energy intakes, malabsorption of ingested nutrients because of pancreatic insufficiency and chronic inflammation. Malnutrition and high levels of inflammatory cytokines affect IGF-1 production through interrelated mechanisms. Nutritional support was shown to improve both nutritional status and outcome in CF. However, some nutrients have a direct effect on the disease. n-3 fatty acids supplementation is able to correct lipid abnormalities resulting from a primary mechanism. Moreover, n-3 fatty acids have a direct effect on the inflammatory response, decreasing eicosanoid synthesis and modulating nuclear transcriptional factors nuclear factor ĸB and peroxisome proliferator-activated receptors γ. Nutritional support may be considered part of the care of the CF patient together with antibiotics, pancreatic enzymes and physiotherapy, influencing significantly the evolution of the disease.

Objective Cystic fibrosis (CF) can be difficult to diagnose, even when newborn screening (NBS) tests yield positive results. This challenge is exacerbated by the multitude of NBS protocols, misunderstandings about screening vs diagnostic tests, and the lack of guidelines for presumptive diagnoses. There is also confusion regarding the designation of age at diagnosis. Study design To improve diagnosis and achieve standardization in definitions worldwide, the CF Foundation convened a committee of 32 experts with a mission to develop clear and actionable consensus guidelines on diagnosis of CF with an emphasis on screened populations, especially the newborn population. A comprehensive literature review was performed with emphasis on relevant articles published during the past decade. Results After reviewing the common screening protocols and outcome scenarios, 14 of 27 consensus statements were drafted that apply to screened populations. These were approved by 80% or more of the participants. Conclusions It is recommended that all diagnoses be established by demonstrating dysfunction of the CF transmembrane conductance regulator (CFTR) channel, initially with a sweat chloride test and, when needed, potentially with newer methods assessing membrane transport directly, such as intestinal current measurements. Even in babies with 2 CF-causing mutations detected via NBS, diagnosis must be confirmed by demonstrating CFTR dysfunction. The committee also recommends that the latest classifications identified in the Clinical and Functional Translation of CFTR project [http://www.cftr2.org/index.php] should be used to aid with CF diagnosis. Finally, to avoid delays in treatment, we provide guidelines for presumptive diagnoses and recommend how to determine the age of diagnosis.

Chronic infection by Pseudomonas aeruginosa (PA) in patients with cystic fibrosis (CF) is preceded by a period of colonization and acute infection. Early aggressive antibiotic treatment of initial colonisation may prevent or at least delay chronic pulmonary infection. We initiated treatment with a combination of IV beta-lactam tobramycin, followed by nebulized colistin when PA was first isolated from patients with CF. Subsequent serial PA isolates obtained from these colonized CF patients were characterized by means of molecular methods to determine whether they were genetically related to the initial strain. Initial colonization was eradicated in all 19 patients. All patients reacquired PA within 3-25 months during the 3 years of follow-up. Fourteen patients acquired a new PA strain with a distinct genotypic profile, suggesting a new source of contamination. Five patients had two PA isolates with identical genotypes, suggesting either previous undetected respiratory tract colonization or a persistent environmental source of contamination.

In cystic fibrosis (CF), approximately 5–8% of the patients develop multilobular cirrhosis during the first decade of life. Annual screening (clinical examination, liver biochemistry, ultrasonography) is recommended in order to identify early signs of liver involvement, initiate ursodeoxycholic acid therapy and detect complications (portal hypertension and liver failure). Management should focus on nutrition and prevention of variceal bleeding.The gut may also be involved in children with CF. Gastroesophageal reflux is frequent, although often neglected and should be investigated by pH monitoring and impedancemetry, if available. Acute pancreatitis occurs in patients with persistent exocrine pancreatic activity. Intussusception, appendicular mucocele, distal intestinal occlusion syndrome, small bowel bacterial overgrowth and Clostridium difficile colitis should be considered in case of abdominal pain.Preventive nutritional support should be started as soon as possible after diagnosis of CF. Attainment of normal growth is one of the main goals and can be achieved with hypercaloric and salt supplemented food. Pancreatic enzyme replacement therapy should be started as soon as exocrine pancreatic insufficiency is confirmed and ingested immediately prior to meals with intake of fat-soluble vitamins. Curative nutritional interventions are more likely to be effective in the early stages of pulmonary disease.Feeding disorders, related to the physiopathology and the psychologic aspects of the disease are frequent. Repeated corporeal aggressions, associated with inappropriate medical and parental pressure, may increase the child's refusal of food. The multidisciplinary team should guide parents in order to avoid all intrusive feeding practices and promote pleasant mealtimes.; Environ 5 à 8% des patients atteints de mucoviscidose développent une cirrhose multilobulaire au cours de la première décennie. Le dépistage annuel de signes d'atteinte hépatique par l'examen clinique, les tests biologiques hépatiques, l'échographie et le suivi sont recommandés afin d'instaurer un traitement par acide ursodésoxycholique et d'identifier les complications: hypertension portale et insuffisance hépatocellulaire. La correction de la malnutrition et la prévention de l'hémorragie digestive sont les principaux objectifs de la prise en charge.Différentes atteintes digestives peuvent être rencontrées chez ces enfants. Le reflux gastro-œsophagien, très fréquent mais souvent négligé, doit être recherché par pH-métrie couplée éventuellement à une impédancemétrie. Des épisodes de pancréatite aigüe peuvent survenir chez des patients ayant une activité pancréatique exocrine résiduelle suffisante. Invagination intestinale aigüe, mucocèle appendiculaire (accumulation de mucus épais dans l'appendice), syndrome d'occlusion intestinale distale (impaction de selles et de mucus au niveau iléo-caecal), syndrome de pullulation bactérienne de l'intestin grêle et colite à Clostridium difficile sont à évoquer devant des douleurs abdominales.Sur le plan nutritionnel, la prise en charge préventive et la surveillance attentive de la croissance débutent dès le diagnostic. L'alimentation, tout en restant équilibrée, doit être hyper-énergétique et supplémentée en sel. Les extraits pancréatiques lors des repas sont prescrits dès l'insuffisance pancréatique exocrine confirmée, de même que les vitamines liposolubles. En cas de dénutrition, la prise en charge nutritionnelle curative par assistance nutritionnelle est d'autant plus efficace qu'elle est précoce, chez des patients à l'état respiratoire satisfaisant.Les difficultés d'alimentation sont très fréquentes, liées à la physiopathologie de la maladie mais également à son retentissement psychologique. Le vécu corporel négatif de l'enfant, la pression médicale et parentale parfois excessive peuvent majorer les refus alimentaires. L'équipe multidisciplinaire doit veiller à proscrire toute attitude contre-productive de nourrissage intrusif et valoriser l'instauration d'un climat de plaisir au cours des repas.

Since the discovery of chloride secretion by the Cystic Fibrosis Transport regulator CFTR in 1983, and CFTR gene in 1989, knowledge about CFTR synthesis, maturation, intracellular transfer and function has dramatically expanded. These discoveries have led to the distribution of CF mutations into 6 classes with different pathophysiological mechanisms. In this article we will explore the state of art on CFTR synthesis and its chloride secretion function. We will then explore the consequences of the 6 classes of mutations on CFTR protein function and we will describe the new therapeutic developments aiming at correcting these defects.

Resume Les manifestations digestives de la mucoviscidose, en dehors de l'insuffisance pancreatique externe et de l'ileus meconial, sont rares et de gravite variable. Observation Un enfant souffrant de mucoviscidose a, a l'âge de 4,5 ans, une invagination ileocolique. Sa recidive justifie une appendicectomie, qui permet le diagnostic de mucocele appendiculaire. Neanmoins, les episodes d'invaginations se reproduisent et necessitent une resection ileocolique droite, 2 ans plus tard, emportant le moignon appendiculaire obstrue. Conclusion La mucocele appendiculaire peut etre responsable d'invagination ileocolique. L'exerese d'une collerette c˦cale lors de l' appendicectomie pourrait etre utile pour eviter que la mucocele ne se reforme a partir du moignon appendiculaire.

Resume Les localisations gastro-intestinales de la maladie de Recklinghausen (MR) sont rares chez l'enfant, longtemps latentes et de pronostic reserve du fait des rectidives locales et du risque de transformation maligne. Observation. — Un garcon de 13 ans a presente une hematernese revellatrice d'un ulcere gastrique. Une recidive hemorragique a permis d'identifier une tumefaction gastrique sessile chez ce garcon, par ailleurs porteur de nombreuses taches cutanees caracteristiques de MR. Un nouvel episode de deglobulisation a fait realiser une laparotomie exploratrice qui decouvre une infiltration etendue de la face anterieure de l'estomac dont l'exerese partielle a permis le diagnostic histologique de neurofibrome. L'absence de compaliance a la surveillance echoendoscopique et une recidive symptomatique ont finalement conduit a une gastrectomie totale; le controle histologique ne montrait pas de signes de degenerescence. Conclusion. — L'endoscopie est un moyen important d'investigation de la tumeur ou de l'infiltration, mais seule l'echoendoscopie permet de faire le bilan de l'extension parietale.