Elexacaftor/tezacaftor/ivacaftor (ETI) is a cystic fibrosis (CF) transmembrane conductance regulator modulator, which has shown efficacy in people with CF (pwCF) carrying the F508del (F) variant, both in homozygosity and heterozygosity with a minimal function (MF) variant. Limited data exist on the effects of ETI in pwCF with advanced lung disease. Our aim was to investigate ETI safety and effectiveness in this patient group in a real-life setting over 2 years. A multicenter observational cohort study was designed to gather real-world information on the effect of ETI treatment on CF patients (aged >12 years, genotype: F/MF mutation) with advanced lung disease as defined by a FEV1 < 40% predicted. Retrospective demographic and clinical data were recorded for the two years preceding and the two years following ETI initiation. The following outcomes were investigated: treatment-associated adverse events (AEs), drug interruptions (temporary or permanent), variations in percent predicted FEV1 (ppFEV1), sweat chloride concentration (SwCl), antibiotic use, body mass index (BMI), and quality of life. A total of 124 (51.6% males) pwCF were treated with ETI over 2 years. The median (IQR) age and ppFEV1 were 34 (26, 43) years and 34 (29, 41) percentage points, respectively. ETI was discontinued in two pwCF due to lung transplantation, and temporarily interrupted in two because of skin rash, and in three following elevated levels of aminotransferase. Most AEs were mild and short-lasting. In 12.1% pwCF, we registered an increase greater than twice the upper limit of the normal range in alanine aminotransferase, and in 16% we registered an increase in conjugated bilirubin with no increase in aminotransferase. Both increases were recurrent in about half of the subjects. The mean differences (95% CI) for ppFEV1 and SwCl, assessed as mean values in the pre-ETI and ETI treatment periods, were +11.8 (11.1 to 12.6) and -43.7 (-47.6 to -39.9) mmol/L. A modest increase in ppFEV1 persisted during the second year of treatment. Number of oral and IV antibiotic cycles/year, as well as hospitalizations/year, decreased significantly from 3.6 to 1.2, from 2.4 to 0.6, and from 2.1 to 0.5 during ETI treatment. A total of 8 of 16 (50%) pwCF were taken off the waiting list for lung transplantation, and significant reductions in the percentages of pwCF using long-term oxygen therapy and non-invasive ventilation were observed. A poor concordance between ppFEV1 and SwCl was found. In only 3/82 (3.7%), subjects with chronic airway infection by Pseudomonas aeruginosa cultures were always negative during ETI treatment. In CF patients with advanced lung disease on ETI treatment, we observed an improvement in a number of clinically significant outcomes over a 2-year study period. However, several additional observations, such as liver dysfunction, variable degrees of lung function improvement, and limited impact on chronic airway infection, underscore the fact that the benefit-risk profile of ETI treatment in cystic fibrosis patients with advanced lung disease has not been fully elucidated and warrants prolonged-term monitoring.

Pharmacological rescue of mutant cystic fibrosis transmembrane conductance regulator (CFTR) in cystic fibrosis (CF) depends on the specific defect caused by different mutation classes. We asked whether a patient with the rare p.Gly970Asp (c.2909G>A) mutation could benefit from CFTR pharmacotherapy since a similar missense mutant p.Gly970Arg (c.2908G>C) was previously found to be sensitive to potentiators in vitro but not in vivo. By complementary DNA transfection, we found that both mutations are associated with defective CFTR function amenable to pharmacological treatment. However, analysis of messenger RNA (mRNA) from patient's cells revealed that c.2908G>C impairs RNA splicing whereas c.2909G>A does not perturb splicing and leads to the expected p.Gly970Asp mutation. In agreement with these results, nasal epithelial cells from the p.Gly970Asp patient showed significant improvement of CFTR function upon pharmacological treatment. Our results underline the importance of controlling the effect of CF mutation at the mRNA level to determine if the pharmacotherapy of CFTR basic defect is appropriate.

Background Cystic fibrosis (CF) is the most common autosomal recessive disease in Caucasian population. Due to its pathological mechanism, chronic rhino sinusitis (CRS) associated or not with nasal polyposis usually occurs in adults and affects close to one-half of all CF patients. The goal of our work was to evaluate the impact of endoscopic sinus surgery (ESS) in the quality of life (QoL) of the CF patients and demonstrate an improvement of the functional outcomes in the patients undergoing the surgical procedure rather than in the not treated ones. Methodology: We studied 54 adult patients affected by CF. Lund–Kennedy, Lund–Mackay scores, and Sino-Nasal Outcome Test-22 (SNOT-22) were analyzed. Results Twenty-two (40.7%) of the 54 CF patients underwent ESS. This group presented more likely complaints consistent with CRS. Lund–Kennedy and Lund–Mackay scores appeared higher in the ESS group: 10 (range of 6–12) and 16 (range of 12–20), respectively. SNOT-22 showed median values for non-ESS and ESS group of 17.5 (range of 3–68) and 44 (range of 10–73), respectively. Conclusions ESS represents the best option to improve clinical QoL of CF patients who do not response to conventional medical therapy.

BACKGROUND:Ivacaftor is a significant innovation in the treatment of cystic fibrosis (CF) with gating mutations. A substantial percentage of patients with CF have severe lung involvement, but these patients are usually excluded from phase III clinical trials. Thus, the effectiveness of ivacaftor in this population has not been fully determined. METHODS:Data were collected from Italian CF centers with patients enrolled in an ivacaftor compassionate use programme (percent predicted [pp] forced expiratory volume in 1 second [FEV1 ] < 40%, or on lung transplant waiting list, or with a fast worsening trend of lung function). Data were collected for 1 year before and 1 year after ivacaftor commencement. RESULTS:Thirteen patients received ivacaftor for a median of 320 days. Mean (SD) ppFEV1 increased from 35.1% (14.3%) before treatment to 46.6% (18.8%) after 12 months of treatment (absolute increase 11.5%, relative increase 32.8%). Mean distance of the 6-minute walking test improved significantly, from 535.1 m before to 611.6 m after 12 months of treatment (P = .002). The number of pulmonary exacerbations decreased significantly, from 57 during the year before ivacaftor to 28 in the year following ivacaftor (P = .0048). Five of the 13 patients (38.5%) had no exacerbations during the 12 months after starting ivacaftor. Median weight increased significantly, from 52.7 kg to 55.6 kg (P = .0031). Mean (SD) sweat chloride concentration decreased significantly, from 99.5 (22.8) mmol/L to 39.3 (15.8) mmol/L (P < .0001). No safety concerns were registered. CONCLUSIONS:Ivacaftor was safe and effective in patients with CF with severe lung disease and non-G551D gating mutations.

Background Few studies, based on a limited number of patients using non-uniform therapeutic protocols, have analyzed Methicillin-resistant Staphylococcus aureus (MRSA) eradication. Methods In 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. Results Sixty-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. Conclusions Although 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.

The Lung Clearance Index (LCI) is an index derived from washout recordings, able to detect early peripheral airway damage in subjects with cystic fibrosis (CF) with a greater sensitivity than spirometry.LCI is a marker of overall lung ventilation inhomogeneity; in fact, as pulmonary ventilation worsens, the number of tidal breaths and the expiratory volumes required to clear the lungs of a marker gas are increased, as documented by a greater value.In the field of CF, LCI allows indirect investigation of the small airways (< 2 mm) the site where, from a pathophysiologic point of view, the disease begins due to the defect of the CF transmembrane-conductance regulator (CFTR) protein. Infant pulmonary function changes seem to occur before clinically overt symptoms of lower respiratory illness occur.When performing the test, it is important to refer to the American Thoracic Society and European Respiratory Society consensus statements and apply a strict standardization.In Italy the first tests were carried out in 2014 for research purpose and now approximately 10 centers are collecting data and are experiencing a consistency in repeating exams.Currently in Italian centers children at pre-school age are the main target: in this population it is important to have a sensitive and feasible test, non-invasive, that can be performed at tidal volume without sedation, and requiring minimal cooperation and coordination, and that can be used longitudinally over time. Another target could be the transplanted subjects to detect early signs of lung function decline.The content of this paper captures the experience and discussions among some of the Italian centers where LCI is currently used for research and/or in clinical practice about the method and the need to have a common approach.The aim of this paper is not to describe the methodology of MBW, but to inform the pediatric community about the possible application of LCI in CF.

The Lung Clearance Index (LCI) is an index derived from washout recordings, able to detect early peripheral airway damage in subjects with cystic fibrosis (CF) with a greater sensitivity than spirometry. LCI is a marker of overall lung ventilation inhomogeneity; in fact, as pulmonary ventilation worsens, the number of tidal breaths and the expiratory volumes required to clear the lungs of a marker gas are increased, as documented by a greater value. In the field of CF, LCI allows indirect investigation of the small airways (< 2 mm) the site where, from a pathophysiologic point of view, the disease begins due to the defect of the CF transmembrane-conductance regulator (CFTR) protein. Infant pulmonary function changes seem to occur before clinically overt symptoms of lower respiratory illness occur. When performing the test, it is important to refer to the American Thoracic Society and European Respiratory Society consensus statements and apply a strict standardization. In Italy the first tests were carried out in 2014 for research purpose and now approximately 10 centers are collecting data and are experiencing a consistency in repeating exams. Currently in Italian centers children at pre-school age are the main target: in this population it is important to have a sensitive and feasible test, non-invasive, that can be performed at tidal volume without sedation, and requiring minimal cooperation and coordination, and that can be used longitudinally over time. Another target could be the transplanted subjects to detect early signs of lung function decline. The content of this paper captures the experience and discussions among some of the Italian centers where LCI is currently used for research and/or in clinical practice about the method and the need to have a common approach. The aim of this paper is not to describe the methodology of MBW, but to inform the pediatric community about the possible application of LCI in CF.

Objective: The implementation of cystic fibrosis (CF) newborn screening (NBS) has led to identification of infants with a positive NBS test but inconclusive diagnosis classified as "CF screen positive, inconclusive diagnosis" (CFSPID). We retrospectively evaluated the prevalence and clinical outcome of CFSPID infants diagnosed by 2 NBS algorithms in the period from 2011 to 2016 in the Tuscany region of Italy. Methods: In 2011-2016, we assessed the diagnostic impact of DNA analysis on the NBS 4-tier algorithm [immunoreactive trypsin (IRT) - meconium lactase - IRT2 - sweat chloride (SC)]. All CFSPID patients repeated SC testing every 6 months, and CFTR gene analysis was performed (detection rate 98%). We reclassified children as: CF diagnosis in presence of at least 2 pathological SC results; healthy carrier or healthy in presence of at least 2 normal SC results for age and either 1 or 0 CF-causing mutations, respectively. Results: We identified 32 CF and 50 CFSPID cases: 20/50 (40%) were diagnosed only by the IRT-DNA-SC algorithm and 16/50 (32%) only by IRT-meconium lactase-IRT2-SC. Both protocols identified the remaining 14 cases (28%). Thirty-seven of 50 (74%) CFSPID patients had a conclusive diagnosis on December 31, 2017:5 (10%) CF, 17 (34%) healthy and 15 (30%) healthy carriers; 13/50 (26%) cases were asymptomatic with persistent intermediate SC and followed as CFSPID (CF:CFSPID ratio 2.85:1). Conclusions: In 6 years, the CF:CFSPID ratio modified from 0.64:1 to 2.85:1, and 10% of CFSPID cases progressed to CF. Genetic analysis improved positive predictive value and identified a higher number of CFSPID infants progressing to CF. (C) 2019 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Background A clinical heterogeneity was reported in patients with Cystic Fibrosis (CF) with the same CFTR genotype and between siblings with CF. Methods We investigated all clinical aspects in a cohort of 101 pairs of siblings with CF (including 6 triplets) followed since diagnosis. Results Severe lung disease had a 22.2% concordance in sib-pairs, occurred early and the FEV 1 % at 12 years was predictive of the severity of lung disease in the adulthood. Similarly, CF liver disease occurred early (median: 15 years) and showed a concordance of 27.8% in sib-pairs suggesting a scarce contribution of genetic factors; in fact, only 2/15 patients with liver disease in discordant sib-pairs had a deficiency of alpha-1-antitrypsin (a known modifier gene of CF liver phenotype). CF related diabetes was found in 22 pairs (in 6 in both the siblings). It occurred later (median: 32.5 years) and is strongly associated with liver disease. Colonization by P. aeruginosa and nasal polyposis that required surgery had a concordance > 50% in sib-pairs and were poorly correlated to other clinical parameters. The pancreatic status was highly concordant in pairs of siblings (i.e., 95.1%) but a different pancreatic status was observed in patients with the same CFTR mutations. This suggests a close relationship of the pancreatic status with the “whole” CFTR genotype, including mutations in regulatory regions that may modulate the levels of CFTR expression. Finally, a severe course of CF was evident in a number of patients with pancreatic sufficiency. Conclusions Physicians involved in care of patients with CF and in genetic counseling must be aware of the clinical heterogeneity of CF even in sib-pairs that, at the state of the art, is difficult to explain.

Background: Recurrent (RP) and chronic pancreatitis (CP) may complicate Cystic Fibrosis (CF). It is still unknown if mutations in genes involved in the intrapancreatic activation of trypsin (IPAT) or in the pancreatic secretion pathway (PSP) may enhance the risk for RP/CP in patients with CF. Methods: We enrolled: 48 patients affected by CF complicated by RP/CP and, as controls 35 patients with CF without pancreatitis and 80 unrelated healthy subjects. We tested a panel of 8 genes involved in the IPAT, i.e. PRSS1, PRSS2, SPINK1, CTRC, CASR, CFTR, CTSB and KRT8 and 23 additional genes implicated in the PSP. Results: We found 14/48 patients (29.2%) with mutations in genes involved in IPAT in the group of CF patients with RP/CP, while mutations in such genes were found in 2/35 (5.7%) patients with CF without pancreatitis and in 3/80 (3.8%) healthy subjects (p < 0.001). Thus, we found mutations in 12 genes of the PSP in 11/48 (22.9%) patients with CF and RP/CP. Overall, 19/48 (39.6%) patients with CF and RP/CP showed one or more mutations in the genes involved in the IPAT and in the PSP while such figure was 4/35 (11.4%) for patients with CF without pancreatitis and 11/80 (13.7%) for healthy controls (p < 0.001). Conclusions: The trans-heterozygous association between CFTR mutations in genes involved in the pathways of pancreatic enzyme activation and the pancreatic secretion may be risk factors for the development of recurrent or chronic pancreatitis in patients with CF.

The recently published report by Farrell et al introduces some important revisions to Cystic Fibrosis Foundation Guidelines published in 2008 for screened, cystic fibrosis transmembrane conductance regulator (CFTR)–related metabolic syndrome/cystic fibrosis–screen positive, inconclusive diagnosis (CF-SPID) and nonscreened populations.1Farrell P.M. White T.B. Ren C.L. Hempstead S.E. Accurso F. Derichs N. et al.Diagnosis of cystic fibrosis: consensus guidelines from the Cystic Fibrosis Foundation.J Pediatr. 2017; 181S: S4-15Abstract Full Text Full Text PDF PubMed Scopus (435) Google Scholar, 2Farrell P.M. Rosenstein B.J. White T.B. Accurso F.J. Castellani C. Cutting G.R. et al.Guidelines for diagnosis of cystic fibrosis in newborns through older adults: Cystic Fibrosis Foundation consensus report.J Pediatr. 2008; 153: S4-14Abstract Full Text Full Text PDF PubMed Scopus (815) Google Scholar One revision, which harmonizes US and European procedures, is in regard to the new level of sweat chloride below which cystic fibrosis is considered unlikely. In the US, the new suggested limit is 30 mmol/L for all age groups, which differs from the previous guidelines for individuals >6 months of age (the previous limit was 40 mmol/L). This decision was based on the data coming from the CFTR2 database, which contains phenotypic and functional information of CFTR variants and in which some cases of patients >6 months of age have been included definitively in cystic fibrosis registries as cystic fibrosis, combining clinical information and gene variant combination with chloride values in the range 30-39 mmol/L.3Sosnay P.R. Salinas D.B. White T.B. Ren C.L. Farrell P.M. Raraigh K.S. et al.Applying cystic fibrosis transmembrane conductance regulator genetics and CFTR2 data to facilitate diagnoses.J Pediatr. 2017; 181S: S27-S32Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar In our opinion, the decision to lower the upper normal sweat chloride value to 30 mmol/L for all ages raises several concerns. First of all, the CFTR2 project assembles data from national registries of patients with cystic fibrosis, as well as large clinical databases from countries without a national registry, including individuals with different criteria used for the definition of the cystic fibrosis disease. Ren et al revealed that data from 40.8% of infants classified as CFTR-related metabolic syndrome were entered into the US registry with a clinical diagnosis of cystic fibrosis.4Ren C.L. Fink A.K. Petren K. Borowitz D.S. McColley S.A. Sanders D.B. et al.Outcomes of infants with indeterminate diagnosis detected by cystic fibrosis newborn screening.Pediatrics. 2015; 135: e1386-e1392Crossref PubMed Scopus (62) Google Scholar Thomas et al and Naehrlich et al confirmed these data in 4 European cystic fibrosis registries and the German cystic fibrosis registry.5Thomas M. Lemonnier L. Gulmans V. Naehrlich L. Vermeulen F. Cuppens H. et al.Is there evidence for correct diagnosis in cystic fibrosis registries?.J Cyst Fibros. 2014; 13: 275-280Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar, 6Naehrlich L. Bagheri-Behrouzi A. German CF Quality Assurance GroupMisdiagnosis of cystic fibrosis: experience from Germany.J Cyst Fibros. 2013; 12: 68-73Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar In Italy, the ICFS Sweat Test Working Group conducted a retrospective analysis of children >6 months of age with their first sweat chloride value in the range 30-39 mmol/L, collecting data from 10 Italian cystic fibrosis centers. Sweat tests were performed with the Gibson-Cooke recommended method. Repeated sweat tests in the same subjects were excluded, as were sweat samples with insufficient sweat (<75 mg) and sweat results from subjects treated with CFTR-modulation therapies (Table). Among subjects sweat tested in the past years and managed as recommended in the diagnostic guidelines and the EU standards of care,2Farrell P.M. Rosenstein B.J. White T.B. Accurso F.J. Castellani C. Cutting G.R. et al.Guidelines for diagnosis of cystic fibrosis in newborns through older adults: Cystic Fibrosis Foundation consensus report.J Pediatr. 2008; 153: S4-14Abstract Full Text Full Text PDF PubMed Scopus (815) Google Scholar, 7Kerem E. Conway S. Elborn S. Heijerman H. Consensus CommitteeStandards of care for patients with cystic fibrosis: a European consensus.J Cyst Fibros. 2005; 4: 7-26Abstract Full Text Full Text PDF PubMed Scopus (343) Google Scholar, 8Smyth A.R. Bell S.C. Bojcin S. Bryon M. Duff A. Flume P. et al.European Cystic Fibrosis Society Standards of Care: Best Practice guidelines.J Cyst Fibros. 2014; 13: S23-S42Abstract Full Text Full Text PDF PubMed Scopus (400) Google Scholar a minority received a diagnosis of cystic fibrosis (range 0.0-7.5%), CFTR-related disorders (range 0.0-14.7%), or CF-SPID (range 0.0%-3.7%). Only 1.3% of subjects were labeled as having cystic fibrosis, whereas 2.7% received a diagnosis of CFTR-related disorders or CF-SPID (1:2) based on their first sweat chloride test. The majority of all subjects did not receive any further diagnostic follow-up (range 83.4%-98.7%) because no sign or symptom of disease appeared through the follow-up or because a differential diagnosis was posed.TableDiagnostic data collected from 10 Italian cystic fibrosis centersCystic fibrosis centersTime periodNo. subjects with their first sweat chloride in the range 30-39 mmol/L (>6 mo of age)Cystic fibrosisCystic fibrosis, %CFTR-related disordersCFTR-related disorders, %CF-SPIDCF-SPID, %No further diagnostic follow-upNo further diagnostic follow-up, %Ancona2008-201713821.41712.342.911583.4Bari2010-20173400514.7002985.3Brescia2011-20174524.424.4004191.2Firenze2008-201721731.483.783.719891.2Messina2007-20174037.500003792.5Milano2006-201731882.582.50030295Napoli2008-201713153.81410.732.310983.2Parma2009-201614321.3000014198.7Roma Bambino Gesù2008-2016146415160.4161.1142797.5Torino2008-201796360.670.730.394798.4Total3493461.3591.7341334696 Open table in a new tab Seia et al demonstrated that 39 mmol/L was the best threshold for sweat chloride to optimize the accuracy of CF diagnosis.9Seia M. Costantino L. Paracchini V. Porcaro L. Capasso P. Coviello D. et al.Borderline sweat test: utility and limits of genetic analysis for the diagnosis of cystic fibrosis.Clin Biochem. 2009; 42: 611-616Crossref PubMed Scopus (12) Google Scholar In several patients with a clinical picture strongly suggestive of cystic fibrosis, the identification of CFTR mutations/variants is not associated with CFTR dysfunction as sweat chloride results in the normal range and even lower than 30 mmol/L.10Castellani C. Cuppens H. Macek Jr, M. Cassiman J.J. Kerem E. Durie P. et al.Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice.J Cyst Fibros. 2008; 7: 179-196Abstract Full Text Full Text PDF PubMed Scopus (453) Google Scholar, 11Lucarelli M. Bruno S.M. Pierandrei S. Ferraguti G. Stamato A. Narzi F. et al.A genotypic-oriented view of CFTR genetics highlights specific mutational patterns underlying clinical macrocategories of cystic fibrosis.Mol Med. 2015; 21: 257-275Crossref PubMed Scopus (31) Google Scholar The diagnosis of cystic fibrosis remains a clinical decision; therefore, interpretation of sweat chloride value should be performed in the context of patient's clinical presentation, family history, newborn screening results, and associated comorbidities. Based on these considerations, we wonder whether lowering the borderline cut-off for sweat chloride is the best option to improve the diagnostic accuracy of sweat chloride. It may be better to recommend extended clinical monitoring of subjects with an early sweat chloride value in the range 30-39 mmol/L without any signs or symptoms of cystic fibrosis. In this way, many genetic analyses, which harbor a significant economic impact and possible inconclusive results, would be avoided. We confirm our concern regarding the new recommended upper normal limit of sweat chloride lowered from 40 to 30 mmol/L for all ages; In our opinion it can complicate the diagnostic process, which may become more complex and inconclusive. To address these questions and better understand the real impact of this new lower borderline limit for sweat chloride extended to all ages and the consequent risk to over- or underestimate the very wide disease spectrum of cystic fibrosis, the ICFS Sweat Test Working Group is planning to conduct a multicenter prospective analysis adding CFTR-extensive genetic analysis to all subjects with their first sweat chloride between 30 and 39 mmol/L.

On behalf of SIFC working group for the revision of Consensus document about genetic analysis in cystic fibrosis.pathogen detection, point-of-care (POC) testing and clinical isolate identification with MALDI-TOF MS.Despite the advent of cutting edge molecular-based (real time PCR, 16S rRNA sequencing, next-generation sequencing) and protein-based microbial identification tools, there is an enormous need to continue culture-based testing to assess susceptibility to all antimicrobials and to identify pathogens with mutations that may escape detection by new technologies.Rapid detection and identification of infectious agents in clinical specimens are mandatory to implement appropriate therapeutic measures.For this purpose it is clear that combining culture based methods and molecular techniques can contribute to clinical management of airway infection, highlighting the importance of making these two methods complementary.

An increasing number of patients have been described as having a number of Cystic Fibrosis Transmembrane conductance Regulator (CFTR) variants for which it lacks a clear genotype–phenotype correlation. We assesses the clinical features of patients bearing the S737F (p.Ser737Phe) CFTR missense variant and evaluated the residual function of CFTR protein on nasal epithelial cells (NEC).