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Background: Lung infections antibiotic treatment in Cystic Fibrosis patients (pwCF) is often complicated by bacterial persisters, including the so-called Viable but Non Culturable (VBNC) forms, live cells undetected by the routine cultural microbiological methods. This study investigated the occurrence of VBNC cells of five CF bacterial pathogens in 94 pwCF over one year and the possible associations with the patients' clinical features., Methods: Sputum samples, recovered at routine visits and during exacerbation episodes, were analyzed for the presence of the five pathogens by both routine culture-based assays and species-specific qPCR. VBNC cells were estimated as the difference between molecular and cultural counts and their presence was matched with the clinical data in particular the therapeutic regimens., Results: All but ten pwCF showed the presence of VBNC cells at least once during the study. Pseudomonas aeruginosa and methicillin-susceptible Staphylococcus aureus were the species most frequently found in the VBNC state. Only the former showed a significant association between chronic infection and VBNC cells presence; VBNC-MSSA positive patients significantly increased overtime. The presence of non culturable bacteria was generally concurrent with poor lung functionality and more frequent pulmonary exacerbations. No significant association with modulator treatment was evidenced., Conclusions: The obtained data demonstrated the overwhelming occurrence of bacterial VBNC cells in CF lung infections, warranting a constant monitoring of pwCF and underlining the need of implementing the routine culture-based assays with culture-independent techniques. This is pivotal to understand the CF bacterial population dynamics and to efficiently contrast the lung infection progression and worsening., Competing Interests: Declaration of competing interest The authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

More than five decades after the introduction of the quantitative pilocarpine iontophoresis technique, surveys still highlight inconsistencies in the performance and reporting of sweat tests in Europe. The sweat test remains key for the Cystic Fibrosis (CF) diagnostic pathway for all age groups, as it reflects the basic pathophysiological defect in the sweat gland. It is also critical following newborn screening as a confirmatory diagnostic step. Despite its importance, sweat test quality is variable whether performed in the laboratory or as a point of care test. The ECFS DNWG aims to improve sweat test performance, taking into account the barriers and issues identified in the European survey; the previous step in the ECFS sweat test project. This manuscript proposes a grading of sweat test guidance from "acceptable" to "optimal", aiming to pragmatically improve quality while taking into account local situations, especially in resource-limited settings., Competing Interests: Declaration of Competing Interest No conflict of interest is declared by the authors., (Copyright © 2022 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Objective: We evaluated the prevalence, Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene profile, clinical data, management and outcome for infants with a CFTR-related metabolic syndrome/CF Screen Positive, Inconclusive Diagnosis (CRMS/CFSPID) designation from six Italian centres., Methods: All newborn bloodspot screening (NBS) positive infants born from January 2011 to August 2018 with a CF diagnosis or a CRMS/CFSPID designation were enrolled. Data on sweat testing, genetics, clinical course and management were collected., Results: We enrolled 257 CF patientsand 336 infants with a CRMS/CFSPID designation (CF: CRMS/CFSPID ratio of 1:1.30).Blood immuno-reactive trypsinogen (IRT) was significantly lower in CRMS/CFSPID infants and the F508del variant accounted for only 20% of alleles. Children with CRMS/CFSPID showed a milder clinical course, pancreatic sufficiency compared to CF infants. Varied practice across centres was identified regarding sweat testing, chest radiograph (8-100%) and salt supplementation (11-90%). Eighteen (5.3%) CRMS/CFSPID infants converted or were reclassified to diagnosis of CF. Four infants (1.3%) developed a clinical feature consistent with a CFTR-related disorder (1.2%). Twenty-seven were re-classified as healthy carriers (8.0%) and 16 as healthy infants (4.8%)., Conclusions: We have identified considerable variability in the evaluation and management of infants with an inconclusive diagnosis following NBS across six Italian centres. CRMS/CFSPID is more regularly seen in this population compared to countries with higher prevalence of F508del.Conversion to a CF diagnosis was recorded in 18 (5.3%) of CRMS/CFSPID infants and in 16 was as a result of increasing sweat chloride concentration., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest and no financial relationships relevant to this article to disclose., (Copyright © 2021 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: Meconium ileus (MI) is a risk factor for poor outcomes in cystic fibrosis (CF) patients. The aim of this study was to identify the risk factors for poor 12-month clinical outcomes in MI-CF newborns., Methods: This retrospective, multicentre, observational study of MI-CF infants born 2009-2015 recorded their pre- and neonatal histories, intestinal occlusion treatments, post-surgical history, nutrition, CF diagnosis, and compared the patients with 12-month faltering growth or chronic Pseudomonas aeruginosa respiratory infection (cases) with the others (controls)., Results: About 25% of the 85 patients enrolled by 13 Italian CF centres (24% premature, 18% of low birth weight) had prenatally diagnosed bowel obstruction, and 39% had complex MI. Seventy-one required surgery (the 33 with complex MI and 38 with simple MI), of whom 58 (82%) required post-surgical intensive care, including 25 (35%) needing ventilatory support. Forty-six (54%) were breastfed; exclusively parenteral nutrition was started in 52 (61%). Cholestasis was diagnosed in 21%. Thirty-one (37%) experienced negative outcomes: the only risk factors were prenatally diagnosed intestinal obstruction and a need for intensive care and oxygen therapy. The cases had significantly higher first blood immunoreactive trypsinogen (b-IRT) levels (P = .008). Logistic regression showed that the probability of having negative outcome is decreased in the absence of cholestasis (Odds Ratio = 0.125) and a need for intensive therapy (OR = 0.141), and increased by not having been breastfed (OR = 2.921)., Conclusions: High b-IRT levels, prenatally diagnosed intestinal obstruction, a severe post-surgical clinical picture and early liver disease are risk factors for negative outcomes. Breastfeeding may be protective., (Copyright © 2019. Published by Elsevier B.V.)

The aim of this report is to assess whether the research issues priorities are perceived differently according to the Stakeholders (SH)'s individual knowledge of research topics and degree of training in biomedical research. Four groups of SH were enrolled in this study: 1. Skilled SH, specifically trained in biomedicine; 2. Unskilled untrained SH who responded to a written questionnaire in 2015; 3. SH who were trained for one year in a course delivered by professionals; 4. Untrained SH who responded to an online questionnaire in 2017. The large ranking order variability observed among groups addresses the question that the choices are markedly influenced by the SH's backgrounds. Such results emphasize the need to consider the education level and the delivery of ad hoc training activities by professionals to broaden the base of SH who may be considered qualified to transfer the Patient Centered Outcome Research principles into practice., (Copyright © 2018 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Evidence based guidelines exist for sweat testing, which remains a key component of a diagnosis of cystic fibrosis (CF), especially following newborn bloodspot screening (NBS). There are emerging challenges with respect to maintaining a valid sweat test service, notably a smaller number of sweat tests ordered in regions with established NBS programmes where Pediatricians refer less children for sweat testing, younger patients and equipment becoming obsolete. The ECFS Diagnostic Network Working Group has undertaken a comprehensive survey to better define sweat test practice across Europe. The survey was completed by 136 European respondents representing a CF center or laboratory providing a sweat test service (65% from regions with NBS for CF). There was considerable variance in practice, often not consistent with guidelines. In particular collection of sweat from two sites was rarely reported in European centres in contrast to US guidelines. There was a range of different references quoted for cut-off for both a positive and intermediate test. Most responses suggest cost is becoming an increasing issue and is not sufficiently reimbursed. This work will inform best practice guidelines and resources to sustain and improve sweat testing in Europe., (Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: Discordant results were reported on the clinical expression of subjects bearing the D1152H CFTR mutation, and also for the small number of cases reported so far., Methods: A retrospective review of clinical, genetic and biochemical data was performed from individuals homozygous or compound heterozygous for the D1152H mutation followed in 12 Italian cystic fibrosis (CF) centers., Results: 89 subjects carrying at least D1152H on one allele were identified. 7 homozygous patients had very mild clinical expression. Over half of the 74 subjects compound heterozygous for D1152H and a I-II-III class mutation had borderline or pathological sweat test and respiratory or gastrointestinal symptoms; one third had pulmonary bacteria colonization and 10/74 cases had complications (i.e. diabetes, allergic bronchopulmonary aspergillosis, and hemoptysis). However, their clinical expression was less severe as compared to a group of CF patients homozygous for the F508del mutation. Finally, 8 subjects compound heterozygous for D1152H and a IV-V class mutation showed very mild disease., Conclusions: The natural history of subjects bearing the D1152H mutation is widely heterogeneous and is influenced by the mutation in trans., (Copyright © 2014 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: In 2001 Liou published a 5-year survival model using CFF Registry data., Aims: To evaluate its validity in predicting survival in Italian CF patients., Methods: In a retrospective study on 945 patients, the 9 variables selected by Liou were analyzed, vital status on December 2008 recorded and observed and expected deaths compared. To develop a new model, patients were randomly divided into a derivation (n=475) and a validation sample (n=470)., Results: A significant difference was found between observed and expected deaths based on Liou's model (62 vs 94), with a 34% reduction in mortality (p<0.05). A new model (based on FEV1, Staphylococcus aureus and Burkholderia cepacia complex infection, number of pulmonary exacerbations/year) was generated, that correctly predicted survival in the validation sample (31 observed vs 29 expected deaths, p=0.660)., Conclusions: The Liou model did not adequately predict 5-year survival in our CF population that, compared to the one in which it was originally tested, could benefit from 10 years of improvement in treatments and practice patterns. A new generated model, based on only four variables, was more accurate in predicting 5-year survival in Italian CF patients., (Copyright © 2011 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: Cystic Fibrosis diagnosis is confirmed using sweat test. The aim of our study was to evaluate current techniques and methodologies in use at Italian CF Care Centres., Methods: A series of questions related to the performance of the sweat test was collected by all CF Care Centres in Italy. Answers were compared with UK and NCCLS guidelines., Results: 39/41 Centres replied to the questionnaire. A good adherence to guidelines was registered for storing samples before analysis in 90.9%, while performing CF diagnosis by at least two sweat tests, and chloride analysis were reported respectively in 100% and 75.7% of Centres. Some inconsistencies were registered for minimum acceptable sweat quantity and time to collect sweat inadequate in respectively 42.5% and 24.2% of Centres, while performing quality control procedures and referring to an external quality assessment scheme were found inadequate in respectively 54.6% and 100%. 57.6% didn't provide any appropriate analytical ranges and only 15.1% of Centres offered proper information to patients/parents. A report form, including sweat quantity, reference ranges and interpretation, was adequate only for 9.4 up to 41.4% of CF Centres., Conclusions: Our study showed areas of inconsistencies in sweat testing current practices in Italy and highlights the need for evidence based national guidelines to improve practice and management strategies.