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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

BackgroundFew studies, based on a limited number of patients using non-uniform therapeutic protocols, have analyzed Methicillin-resistant Staphylococcus aureus (MRSA) eradication.MethodsIn a randomized multicenter trial conducted on patients with new-onset MRSA infection we evaluated the efficacy of an early eradication treatment (arm A) compared with an observational group (B). Arm A received oral rifampicin and trimethoprim/sulfamethoxazole (21 days). Patients' microbiological status, FEV1, BMI, pulmonary exacerbations and use of antibiotics were assessed.ResultsSixty-one patients were randomized. Twenty-nine (47.5%) patients were assigned to active arm A and 32 (52.5%) patients to observational arm B. Twenty-nine (47.5%) patients, 10 patients in arm A and 19 in arm B, dropped out of the study. At 6 months MRSA was eradicated in 12 (63.2%) out of 19 patients in arm A while spontaneous clearance was observed in 5 (38.5%) out of 13 patients in arm B. A per-protocol analysis showed a 24.7% difference in the proportion of MRSA clearance between the two groups (z = 1.37, P(Z>z) = 0.08). Twenty-seven patients, 15 (78.9%) out of 19 in arm A and 12 (92.3%) out of 13 in arm B, were able to perform spirometry. The mean (±SD) FEV1 change from baseline was 7.13% (±14.92) in arm A and -1.16% (±5.25) in arm B (p = 0.08). In the same period the BMI change (mean ±SD) from baseline was 0.54 (±1.33) kg/m2 in arm A and -0.38 (±1.56) kg/m2 in arm B (p = 0.08). At 6 months no statistically significant differences regarding the number of pulmonary exacerbations, days spent in hospital and use of antibiotics were observed between the two arms.ConclusionsAlthough the statistical power of the study is limited, we found a 24.7% higher clearance of MRSA in the active arm than in the observational arm at 6 months. Patients in the active arm A also had favorable FEV1 and BMI tendencies.

Summary Background Long-term complications of cystic fibrosis include osteoporosis and fragility fractures, but few data are available about effective treatment strategies, especially in young patients. We investigated treatment of low bone mineral density in children, adolescents, and young adults with cystic fibrosis. Methods We did a multicentre trial in two phases. We enrolled patients aged 5–30 years with cystic fibrosis and low bone mineral density, from ten cystic fibrosis regional centres in Italy. The first phase was an open-label, 12-month observational study of the effect of adequate calcium intake plus calcifediol. The second phase was a 12-month, double-blind, randomised, placebo-controlled, parallel group study of the efficacy and safety of oral alendronate in patients whose bone mineral apparent density had not increased by 5% or more by the end of the observational phase. Patients were randomly assigned to either alendronate or placebo. Both patients and investigators were masked to treatment assignment. We used dual x-ray absorptiometry at baseline and every 6 months thereafter, corrected for body size, to assess lumbar spine bone mineral apparent density. We assessed bone turnover markers and other laboratory parameters every 3–6 months. The primary endpoint was mean increase of lumbar spine bone mineral apparent density, assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01812551. Findings We screened 540 patients and enrolled 171 (mean age 13·8 years, SD 5·9, range 5–30). In the observational phase, treatment with calcium and calcifediol increased bone mineral apparent density by 5% or more in 43 patients (25%). 128 patients entered the randomised phase. Bone mineral apparent density increased by 16·3% in the alendronate group (n=65) versus 3·1% in the placebo group (n=63; p=0·0010). 19 of 57 young people (33·3%) receiving alendronate attained a normal-for-age bone mineral apparent density Z score. In the observational phase, five patients had moderate episodes of hypercalciuria, which resolved after short interruption of calcifediol treatment. During the randomised phase, one patient taking alendronate had mild fever versus none in the placebo group; treatment groups did not differ significantly for other adverse events. Interpretation Correct calcium intake plus calcifediol can improve bone mineral density in some young patients with cystic fibrosis. In those who do not respond to calcium and calcifediol alone, alendronate can safely and effectively increase bone mineral density. Funding Telethon Foundation (Italy).

Some studies have shown a direct relationship between nutritional status and survival in Cystic Fibrosis (CF) patients. Body wasting, defined as a percentage of the ideal body weight for age, has been shown to be an independent predictor of mortality in CF. With respect to height only two studies were performed and these studies suggested that stunting is an important determinant of survival but both did not adjust statistical analysis for confounding variables. We aimed at determining the association between stunting and risk of mortality in CF patients.393 CF patients older than 6 years of age, 95 deceased, as cases, and 298 live, as controls, were enrolled in a nested case-control study. Stunting was defined by a height percentile5th. We performed a multivariate statistical analysis including height percentile and the following possible confounding variables: age, gender, Body Mass Index (BMI), Forced Expiratory Volume in 1 s (FEV1), genotype, pancreatic status, CF-related diabetes, colonization with Pseudomonas aeruginosa and/or Burkholderia cepacia.In the adjusted analyses stunting (OR 2.22 [IC 95%1.10-4.46]), wasting (OR 5.27 [IC 95% 2.66-10.41]), and FEV1 40% of predicted (OR 10.60 [IC 95% 5.43-20.67]) resulted the covariates that significantly predict the risk of mortality.Our study shows, for the first time, that stunting is a significant and independent risk factor for mortality in CF patients, and warrants an intervention of nutritional rehabilitation. Considering that nutritional interventions in stunted patients should be prolonged, are invasive and expensive, and might affect self-esteem and body image, their efficacy should be fully assessed by Randomised Controlled Trials.

Very few studies have been performed on the long-term clinical advantages of neonatal screening programs for cystic fibrosis (CF) and these have been inconclusive. This is a preliminary report of two observational cohort studies on this subject.In the first study, CF patients born between 1973 and 1981 in northeastern Italy were split into 4 groups according to the modality of diagnosis: screening by meconium test (58 patients); meconium ileus (45 patients); symptoms and pancreatic insufficiency (PI; 75 patients), or symptoms and pancreatic sufficiency (PS; 19 patients). The patients were followed for up to 26 years by three CF centers sharing common treatment protocols. In the second study, two cohorts of CF patients born between 1983 and 1992 were compared. Patients from one cohort (126 patients) were born in the Veneto region, where a neonatal screening program had been established based on immunoreactive trypsinogen. Patients from the other cohort (152 patients) were born in Sicily, where an intensive program of early diagnosis by symptoms was implemented. The cohorts were comparable for CF incidence, CFTR genotypes, gender proportion and common treatment protocols. Statistical analyses were performed by Kaplan-Meier survival curves, a Cox proportional hazard model for survival and cross-sectional comparisons by 2-year periods for weight z score, height z score and body mass index.In the first study, the patients detected by newborn screening (PI) showed better survival and nutritional status compared to patients diagnosed through meconium ileus or symptom presentation with PI. PS patients diagnosed by symptoms showed the best outcome, but most of them had a mild genotype. In the second study, the Veneto cohort showed better outcome with regard to survival and nutritional status over 16 years of follow-up.Observational cohort studies cannot give definitive evidence of the clinical benefit of neonatal CF screening; however, data have been accumulated which strongly suggest a better clinical outcome for CF patients born in an area where a screening program is performed.

We report the case of a 17-year-old boy with cystic fibrosis (CF) who presented with persistent cough; after starting intravenous antibiotics for Pseudomonas aeruginosa he underwent a computed tomography (CT) scan of the chest. CT revealed extensive consolidation in the right lower lobe with relative bronchus obstruction; the cause of bronchial obstruction was detected in the mediastinal window, corresponding to a bronchial tree-shaped, thick, tenacious mucous plug. This was extracted 48 h after unresponsive bronchial washing and endobronchial instillation of rhDNAse, using foreign-body forceps, with subsequent resolution of cough. This case, which is the second report of plastic bronchitis in CF, was resolved by mechanical removal of the mucous plug, suggesting that a careful observation of CT imaging may guide intervention aimed at resolution of atelectasis.

Aims: To study the predictive value of predefined symptoms and signs for allocating children into one of two groups: nonorganic and organic failure to thrive. Patients and Methods: Two hundred eight outpatients (6 months–14 years old) suffering from failure to thrive (FTT) were included in the study. Predefined symptoms and signs were considered as potential predictors of organic/nonorganic failure to thrive. All patients underwent an established diagnostic work up in order to exclude organic causes of FTT. Results: The percentage of patients without any organic symptom (negative predictive value), who were diagnosed as NOFTT was 92%; the percentage of patients having nonorganic symptoms only (positive predictive value), who were diagnosed as NOFTT was 96%, while their absence does not exclude a NOFTT diagnosis as well (negative predictive value = 41%). Conclusion: The detection of at least one nonorganic symptom or sign, with the exclusion of any organic symptom, can support a diagnosis of nonorganic FTT and therefore only few laboratory investigations seem to be warranted.