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Clinical trials demonstrate the short-term efficacy of dual CFTR modulators, but long-term real-world data is limited. We aimed to investigate the effects of 24-month lumacaftor/ivacaftor (LUM/IVA) therapy in pediatric CF patients (pwCF). This observational study included pwCF homozygous for F508del mutation treated between 2021 and 2023. We report data for the first 24 months from therapy initiation. Variables were analyzed separately for ages 2-5, 6-11, and over 12. Data from 49 pwCF (median age: 9.3 years (5.5-14.2)) showed that ppFEV1 values after a transient increase at 12 months, decreased from 102% (82-114) at baseline to 87% (74-96) at 24 months. The decrease was more pronounced with higher initial ppFEV1. Median sweat chloride concentration decreased from 75 mmol/L (69-82) to 57 mmol/L (43-70) without any association with respiratory function change. Median BMI z-score increased from - 0.81 (- 1.37-0.49) to - 0.39 (- 0.88 to  - 0.04) (p = 0.288), and the proportion of underweight and overweight children decreased. Skeletal muscle mass remained stable, while fat mass significantly increased (p = 0.011). Fecal elastase levels improved, especially among younger patients. These findings underscore the potential benefits of early initiation of CFTR modulator therapy in pediatric CF patients, highlighting improvements in nutritional status and pancreatic function., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Introduction: While the diagnosis of cystic fibrosis (CF) is often straightforward and reliant on correlation between genetic testing and clinical signs and symptoms, there is a subset where the distinction is not nearly as clearcut. This has previously been reported in patients identified through newborn screening but not meeting full CF diagnostic criteria, earning the label of CF Screen Positive, Inconclusive Diagnosis (CFSPID) instead. A homologous diagnostic category in adults is named CF Transmembrane Conductance Regulator-Related Disorder (CFTR-RD)., Methods: Through a retrospective chart review, this study reports on a relatively large adult cohort (n = 23) that presented to pulmonology clinic at a single center with intermediate or positive sweat chloride tests but non-diagnostic full CFTR gene analysis., Results: Median sweat chloride result was 48 mmol/L, and a majority of the cohort had chronic lung disease with atypical pathogens on sputum culture, including Pseudomonas aeruginosa, non-tuberculous Mycobacteria, Acinetobacter species, amongst others., Conclusions: This clinical picture suggests CFTR dysfunction or similar mechanism in the absence of an identified genetic cause. Alternate chloride channels and their respective genes or candidates of genetic modifiers to the CF-phenotype could be targets of further research in this cohort or similar patients. Such genetic modifiers include loci that have been implicated in inflammation, the CFTR interactome, and/or co-/post-translational modification of CFTR., (© 2025 The Author(s). Pediatric Pulmonology published by Wiley Periodicals LLC.)

Introduction: Lumacaftor/ivacaftor (lum/iva) was introduced in the Netherlands in 2017. We investigated 1-year efficacy of lum/iva on lung function and small airway and structural lung disease evaluated by multiple breath nitrogen washout and CT scan. Additionally, we investigated effects of lum/iva on exacerbations, anthropometry, sweat chloride and safety in children with CF in the Netherlands., Methods: Children with CF aged 6-18 years and homozygous for F508del treated in one of the seven Dutch CF centers for at least 12 months were eligible. Data were extracted from the Dutch CF Registry and electronic patient records. Primary outcome was change in percent predicted FEV 1 (ppFEV 1 ) after 12 months., Results: Nationwide, 247 children with CF were eligible for lum/iva. Eight patients discontinued lum/iva due to side effects. In total, 223/247 children (90.3%) were evaluated. Mean (range) age at baseline was 11.0 (6.0-17.1) years. There was no change in FEV 1 after 12 months of lum/iva. In a subgroup, markers of small airway function and structural lung disease, such as LCI (n = 28), mean change (SD) -10.0% (15.8), and bronchus-artery (BA) analysis on CT scan (n = 81), showed significant improvement (p < 0.01). Moreover, BMI (n = 192), exacerbations (n = 219) and sweat chloride measurements (n = 105) improved., Conclusion: Lum/iva was generally well tolerated in a real-life, nationwide pediatric cohort. The efficacy of lum/iva was comparable to phase 3 studies in children. LCI and BA analysis as markers of small airway and structural lung disease showed significant improvement which indicates the importance of these parameters to evaluate treatment effects of CF modulators in children., (© 2025 The Author(s). Pediatric Pulmonology published by Wiley Periodicals LLC.)

Background: Cystic Fibrosis is caused by recessively inherited variants of the cystic fibrosis transmembrane regulator. It is associated with diverse clinical presentations that can affect the respiratory, digestive, and reproductive systems and inhibit nutrient absorption and growth., Main Body: The current estimation of people affected by Cystic Fibrosis is likely underestimated as this disease remains undiagnosed in countries with limited diagnostic capacity. Recent evidence indicates that Cystic Fibrosis is more common than initially thought and is likely underreported in low- and middle-income countries. The sweat chloride test remains the gold standard for diagnosing Cystic Fibrosis. However, the costs of commercially available instruments, consumables, and laboratory reagents remain relatively high for widespread implementation in low- and middle-income countries., Conclusion: Alternative, cost-effective, and simpler approaches to sweat electrolyte measurement, may present more feasible options for CF diagnosis in the setting of low- and middle-income countries. Novel low-cost, point-of-care innovations for measuring sweat chloride should be explored and further validated as suitable alternatives. It will be important to consider how to implement these options and adjust the diagnostic algorithm to meet the needs of low- and middle-income countries. Future Cystic Fibrosis research in low- and middle-income countries should focus on finding a lower-cost and resource-intensive pathway for CF screening and diagnosis to improve its availability., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare that they have no competing interests., (© 2024. The Author(s).)

Background: CFTR modulators are approved for approximately 90% of people with cystic fibrosis in the USA and provide substantial clinical benefit. N1303K (Asn1303Lys), one of the most common class 2 CFTR defects, has not been approved for these therapies by any regulatory agency. Preclinical investigation by our laboratories showed N1303K CFTR activation with elexacaftor-tezacaftor-ivacaftor (ETI). In this trial, we evaluate whether ETI improves CFTR function, measured by sweat chloride and other clinical outcomes, in people with cystic fibrosis and CFTR N1303K ., Methods: In this prospective, open-label, single-arm trial, participants aged 12 years or older with cystic fibrosis encoding at least one N1303K variant and at least one CFTR N1303K allele who were ineligible for modulator therapy by US Food and Drug Administration labelling were given ETI for 28 days followed by a 28-day washout period at two cystic fibrosis centres in the USA. Participants received two orally administered pills of 100 mg elexacaftor, 50 mg tezacaftor, and 75 mg ivacaftor once daily in the morning, and 150 mg ivacaftor once daily in the evening. The primary endpoint was mean change in sweat chloride from baseline up to day 28 compared with mixed-effects models. Secondary endpoints were changes in percentage of predicted FEV 1 (ppFEV 1 ), Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain, BMI, and weight after ETI therapy. Safety was assessed in all participants who received at least one dose of the study drug and primary and secondary analyses were performed in all participants who took the study drug per protocol. The trial was registered at ClinicalTrials.gov (NCT03506061) and remains open for reporting purposes., Findings: Between June 7, 2022, and Oct 20, 2023, 20 participants (ten male and ten female) were enrolled and received ETI treatment. One participant was lost to follow-up but was included in intention-to-treat analyses. At 28 days, the mean sweat chloride reduction was -1·1 mmol/L (95% CI -5·3 to 3·1; p=0·61) with only one participant showing a sweat chloride decrease greater than 15 mmol/L. There was a mean increase in ppFEV 1 from baseline at day 28 of 9·5 percentage points (6·7-12·3; p<0·0001) with 15 (75%) participants showing at least a 5% increase in ppFEV 1 . Improvements were also identified in mean CFQ-R respiratory domain score (20·8 increase [95% CI 11·9-29·8]; p<0·0001), BMI (0·4 kg/m 2 increase [0·2-0·7]; p=0·0017), and weight (1·0 kg increase [0·4-1·7]; p=0·0020) after 28 days of ETI treatment. 14 (70%) of 20 participants had adverse events (12 [60%] mild, one [5%] moderate), with one (5%) serious adverse event of hospitalisation attributed to pneumonia. No deaths were recorded in the study., Interpretation: Individuals with CFTR N1303K showed no change in sweat chloride after 28 days of treatment with ETI. However, there were improvements in secondary clinical endpoints, which suggest clinical efficacy. Our approach provides support for the use of in vitro model systems to inform clinical trials for rare CFTR variants., Funding: The Cystic Fibrosis Foundation and the US National Institutes of Health., Competing Interests: Declaration of interest GMS reports funding from the National Institutes of Health (NIH), the Cystic Fibrosis Foundation, the COPD Foundation, and the PCD Foundation; reports grants for clinical trials from Renovion, Vertex, Electromed, Insmed Pharmaceuticals, 4DMT, AstraZeneca, and BiomX for clinical trials; is a paid consultant for Insmed, Electromed, and Genetech; is on the steering committees for clinical trials for AstraZeneca, GlaxoSmithKline, and Genentech; is a member of the steering committee for the Bronchiectasis and NTM Research Registry; and has contracts for laboratory work from Renovion and ReCode, unrelated to the current manuscript. RWL reports grants paid to her institution from the Cystic Fibrosis Foundation and Vertex Pharmaceuticals; consulting fees from Vertex Pharmaceuticals; and support for travel to an investigator meeting from Vertex Pharmaceuticals. AS and EH report funding from the Cystic Fibrosis Foundation. WRH reports funding from NIH and the Cystic Fibrosis Foundation. JJB reports funding from NIH, the Cystic Fibrosis Foundation, and Cure Cystic Fibrosis, and has previously received honoraria for invited lectures from Vertex Pharmaceuticals. AR reports research support from NIH (HL-139876) and the Cystic Fibrosis Foundation. SPB reports grant funding from NIH and the Cystic Fibrosis Foundation. CM-B is a collaborator on the Cystic Fibrosis Foundation grant that funded this work. SS participates and has a key role in studies funded by the NIH and Cystic Fibrosis Foundation, and is an inventor on US Patent number 11 401 510 for the generation of airway basal stem cells from human pluripotent stem cells (issue date Aug 2, 2022). CB participates and has a key role in studies funded by NIH and the Cystic Fibrosis Foundation, and is an inventor on US Patent number 11 401 510. BRD has grants from NIH and the Cystic Fibrosis Foundation, and is an inventor on US Patent number 11 401 510. EJS reports funding from NIH (HL139876), the Cystic Fibrosis Foundation, and the Marcus Foundation; received an honorarium from the University of Iowa (Iowa City, IA, USA) for a talk regarding CFTR theratyping analysis; is working on novel compounds for treatment of cystic fibrosis that are not described or mentioned in this study but might have a future role against many CFTR mutations, including N1303K; and is a non-voting member of the Cystic Fibrosis Foundation board of directors (a not-for-profit organisation with no competing interests with this study). RR, BB, KV, ALW, JH, and CM declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Cystic fibrosis (CF) is a genetic disorder that primarily affects the respiratory, digestive, and reproductive systems. In the United States, approximately 32,000 individuals, spanning both children and adults, suffer from CF, and roughly 1,000 new cases are diagnosed annually. The current gold standard for CF diagnosis is the sweat test, yet this method is plagued by issues such as being time-consuming, expensive, challenging to replicate, and lacking treatment monitoring capabilities. In contrast, the emerging field of wearable sweat biosensors has gained significant attention due to their potential for noninvasive health monitoring. Despite this, there remains a conspicuous absence of a wearable sweat biosensor tailored specifically for CF diagnosis and monitoring. Here, this study introduces a flexible wearable sweat biosensor, named CFTrack, designed to address the unique challenges associated with CF. This proposed CFTrack biosensor not only facilitates CF diagnosis but also enables the monitoring of medication treatment effectiveness and tracks therapy activities. In addition, it operates in a self-powered and customized manner, ensuring seamless integration into the daily lives of individuals with CF. Given that sweat tests and fitness routines are the predominant methods for diagnosing and treating cystic fibrosis patients, respectively, the proposed CFTrack biosensor leverages ion concentration in sweat for diagnostic purposes. Additionally, it incorporates a motion-tracking function to monitor physical activity, providing a comprehensive approach to CF management. To evaluate the feasibility of the proposed CFTrack biosensor, a comprehensive evaluation has been performed including numerical simulations, theoretical analyses, and experimental tests. The results demonstrate the efficacy of the proposed CFTrack biosensor in diagnosing and monitoring CF conditions while also showcasing its ability to effectively track the progress of patients undergoing physical therapy. The proposed CFTrack biosensor resolves key issues associated with existing sweat sensors including high energy consumption, intricate fabrication procedures, and the absence of continuous monitoring capabilities. By addressing these challenges, the proposed sweat biosensor aims to revolutionize CF diagnosis and monitoring, offering a more efficient and user-friendly alternative to current methods.

Newborn screening for cystic fibrosis (CF-NBS) using an IRT-DNA algorithm with a 12 CFTR-variant panel and an IRT/IRT failsafe was officially implemented in the French-speaking Community of Belgium in January 2020. This screening protocol was evaluated after 4 years according to the criteria defined by the European Cystic Fibrosis Society's working group on neonatal screening. Immunoreactive trypsinogen concentration (IRT) was measured on dried blood spots collected between the second and the fourth day of life. CFTR variants genotyping was initiated when IRT ≥ 99th percentile (P99). If at least 1 variant was identified, the child was referred to a CF center for a sweat test (ST). If IRT ≥ 99.9th percentile with no variant identified, a failsafe was provided with IRT repeated on day 21 and subsequent ST in case of persistent IRT > P99. Extensive Gene Analysis was initiated if sweat chloride level was ≥ 30 mmol/L. Over a period of 4 years, 212.979 newborns were screened. Forty-two were diagnosed with CF: 34 by CF-NBS, 3 following a meconium ileus, 3 by family history and 2 missed cases. Additionally, 112 healthy carriers and 14 CFSPID were identified. The median age at the first consultation was 23 days. The sensitivity of our CF-NBS is 95% (target ≥ 95%), the positive predictive value 18% (target ≥ 30%) and CF/CFSPID ratio 2.8., Conclusion:  Although follow-up is limited, this first evaluation demonstrates encouraging sensitivity and early management before one month of age., What Is Known: • Newborn screening for cystic fibrosis improves the prognosis of patients., What Is New: • This article presents an initial assessment of our screening after 4 years., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

While Cystic Fibrosis is characterized by a high phenotypic variability, a correlation is reported between the pancreatic status and the CFTR genotype. Here we report an unusual case of a child with Cystic Fibrosis (F508del-duplication of exons 1-3 genotype) diagnosed at 8 years old for pancreatic insufficiency and non-pathological sweat test, in absence of respiratory symptoms and acute episodes of pancreatitis. Nasal potential differences and intestinal current measurements were normal, while the short-circuit current measured on patient-derived colonoids grown on Transwell ® indicated the presence of a reduced CFTR-dependent current relative to non-CF colonoids with, a modest improvement of CFTR activity record following treatment with elexacaftor/tezacaftor/ivacaftor.This case opens the discussion on the importance of performing CFTR sequencing and the search for large gene rearrangements in cases of pancreatic insufficiency of unclear etiology, also in the presence of non-pathological sweat test. Children with CF and non-pathological sweat chloride are likely to develop higher concentrations if they truly have CF., Competing Interests: Declarations. Ethics approval and consent to participate: An approval was obtained from the pediatric ethical committee of the Cystic Fibrosis center in Florence and for the Cystic Fibrosis Center AOUI of Verona (protocol#CFTR050). Consent for publication: Parents provided written informed consent for anonymous data processing and to participate in this case investigation. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Rationale: Clinical trials show that lumacaftor/ivacaftor (LUM/IVA) treatment has the potential to modify early cystic fibrosis (CF) disease progression in children as young as 2 years of age. Objectives: To assess the long-term impact of LUM/IVA treatment on CF disease progression in children aged 2-5 years. Methods: This phase 2 trial had two parts: part 1, a 48-week, randomized, double-blind, placebo-controlled study of LUM/IVA in children aged 2-5 years (previously reported) was followed by a 48-week open-label treatment period in which all children received LUM/IVA (part 2; reported here). Endpoints assessed in part 2 included absolute changes from baseline in chest magnetic resonance imaging (MRI) global score at Week 96; weight-for-age, stature-for-age, and body mass index (BMI)-for-age z -scores at Week 96; lung clearance index based on lung volume turnover required to reach 2.5% of starting N2 concentration (LCI 2.5 ) through Week 96; chest MRI morphological score, chest MRI perfusion score, weight, stature, BMI, and microbiology cultures (oropharyngeal swabs) at Week 96; sweat chloride, amount of immunoreactive trypsinogen, fecal elastase-1 concentration, and fecal calprotectin through Week 96; and number of pulmonary exacerbations, time to first pulmonary exacerbation, and number of CF-related hospitalizations. Results: Forty-nine children received one or more doses of LUM/IVA in the open-label period (33 in the LUM/IVA to LUM/IVA group and 16 in the placebo to LUM/IVA group), with a mean exposure of 47.1 (standard deviation [SD], 5.2) weeks. The mean absolute change in MRI global score (negative value indicates improvement) from baseline at Week 96 was -2.7 (SD, 7.0; 95% confidence interval [CI], -5.2 to -0.1) in the LUM/IVA to LUM/IVA group and -5.6 (SD, 6.9; 95% CI, -9.2 to -1.9) in the placebo to LUM/IVA group. Improvements in LCI 2.5 , sweat chloride concentration, and markers of pancreatic function and intestinal inflammation were also observed in both groups. Growth parameters remained stable in both groups. The majority of children had adverse events considered mild (38.8%) or moderate (40.8%). Two (4.1%) children discontinued LUM/IVA treatment because of adverse events (distal intestinal obstruction syndrome [ n  = 1] and alanine aminotransferase increase [ n  = 1]). Conclusions: These findings confirm the potential for early LUM/IVA treatment to alter the trajectory of CF disease progression, including CF lung disease, in children as young as 2 years of age. Clinical trial registered with ClinicalTrials.gov (NCT03625466).

The chloride (Cl-) sweat test remains the reference test in the diagnosis of cystic fibrosis, allowing direct assessment of CFTR (Cystic Fibrosis Transmembrane conductance Regulator) channel function. Under highly effective modulators such as the combination of Elexacaftor, Tezacaftor and Ivacaftor (ETI), the Cl- level in sweat significantly improves, as shown in our cohort of patients when ETI was introduced. In addition to its role in the diagnosis of the disease, the sweat test is also important for individual clinical trials (n-of-1) in patients not eligible for ETI and for newborn screening for cystic fibrosis.

Background: Highly effective modulators of the CFTR channel have been demonstrated to dramatically impact disease progression and outcome. However, real-world data indicates that the magnitude of the clinical benefit is not equal among all patients receiving the treatment. We aimed to assess the variability in treatment response (as defined by the 6-month change in sweat chloride concentration, forced expiratory volume in one second [ppFEV1], body mass index [BMI], and CF Questionnaire-Revised [CFQ-R] respiratory domain score) and identify potential predictors in a group of patients receiving Elexacaftor-Tezacaftor-Ivacaftor (ETI) triple combination therapy., Methods: This was a single-center, prospective cohort study enrolling adults with CF at a major center in Italy. We used linear regression models to identify a set of potential predictors (including CFTR genotype, sex, age, and baseline clinical characteristics) and estimate the variability in treatment response., Results: The study included 211 patients (median age: 29 years, range: 12-58). Median changes (10-90th percentile) from baseline were: - 56 mEq/L (-76; -27) for sweat chloride concentration, +14.5 points (2.5; 32.0) for ppFEV1, +0.33 standard deviation scores (-0.13; 1.05) for BMI and +17 points (0; 39) for the CFQ-R respiratory domain score. The selected predictors explained 23 % of the variability in sweat chloride concentration changes, 18 % of the variability in ppFEV1 changes, 39 % of the variability in BMI changes, and 65 % of the variability in CFQ-R changes., Conclusions: This study highlights a high level of heterogeneity in treatment response to ETI, which can only be partially explained by the baseline characteristics of the disease., Competing Interests: Declaration of competing interest AG, CL, VD and FB reported honoraria for lectures from Vertex; AG reported honoraria for lectures from Zambon, Foodar, Insmed; FB reported honoraria for lectures from Viatris, Zambon, Foodar, Chiesi, Insmed; AG and VD reported travel support from Neupharma; AG and FB reported travel support from Viatris., (Copyright © 2024. Published by Elsevier B.V.)

Background: Elexacaftor-tezacaftor-ivacaftor (ETI) is a highly effective cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulating therapy for people with CF and at least one F508del variant. However, there is limited data about the safety and efficacy of this therapy in pediatric populations and in real-world settings. This study aimed at evaluating the effectiveness, tolerability, and safety of ETI in children with CF., Methods: This was a prospective observational study including all children aged 6-11 years who initiated ETI therapy between October 2022 and March 2023 at the Pediatric CF Center of Milan (Italy). Study outcomes included changes in sweat chloride concentration, FEV 1 , LCI 2.5 , body mass index (BMI), tolerance, and safety. Mean changes in study outcomes from baseline through 24 weeks were estimated using mixed-effects regression models., Results: The study included 34 children with CF (median age: 8.3 years). At Week 12, we observed an average decrease in LCI 2.5 of 2.3 units (95% confidence interval [CI]: -3.1; -1.5). At Week 24, sweat chloride concentration decreased by 63 mEq/L (95% CI: -69; -58), FEV 1 increased by 8.8 percentage point (95% CI: 3.7; 13.9) and BMI increased by 0.15 standard deviation scores (95% CI: 0.04; 0.25). Skin rashes appeared in 6 patients which spontaneously resolved within a few days. One month after treatment initiation, one patient experienced an elevation in liver function test results, which subsequently decreased during follow-up visits without necessitating discontinuation of therapy., Conclusions: Our data indicate that ETI therapy is well tolerated by children with CF and is effective in improving signs of lung function abnormalities from early childhood., (© 2024 The Author(s). Pediatric Pulmonology published by Wiley Periodicals LLC.)

Background: New York (NY) State implemented a new cystic fibrosis (CF) newborn screen (NBS) algorithm in December 2017 with improvement in positive predictive value and unanticipated increased identification of infants with cystic fibrosis transmembrane conductance regulator (CFTR)-related metabolic syndrome (CRMS). Repeat sweat testing is recommended in infants with CRMS. During the COVID-19 pandemic infants with CRMS were lost to follow up. With this quality improvement (QI) initiative, we aimed to perform repeat sweat testing in 25% of infants lost to follow up. We also describe consensus recommendations for CRMS from the NY CF NBS Consortium., Methods: Our QI team identified the primary drivers contributing to absent follow up, outreached to families, and created a questionnaire to evaluate parental understanding of CRMS using QI-based strategies., Results: Of 350 infants diagnosed with CRMS during the study period, 179 (51.1%) infants were lost to follow up. A total of 31 (17.3%) were scheduled for repeat sweat tests and followed up at CF Centers. Families reported high satisfaction with the CRMS knowledge questionnaire., Conclusions: With this QI-based approach, we effectively recaptured infants with CRMS previously lost to follow up during the COVID-19 pandemic. Ongoing concerns about infection risk and lack of understanding on the part of families and pediatricians likely contributed to patients with CRMS lost to follow up. Consensus recommendations for CRMS include annual visits with repeat sweat testing until 2-6 years of age and education for adolescents about clinical and reproductive implications of CRMS., (© 2024 Wiley Periodicals LLC.)

Background: It is difficult to determine CFTR activity following highly effective CFTR modulator therapies (HEMT). The sweat gland provides two biomarkers of CFTR activity: a linear readout via the β-sweat rate and a logarithmic readout via sweat chloride concentration (SCC). In prior work, different logarithmic functions were generated to calibrate SCC with the percent of healthy control CFTR activity (HCCFTR). Two functions, A and B, were fit to SCC means from healthy controls set = 100 % and CF carriers measured as 50 % HCCFTR. A and B differ in the % HCCFTR activity assigned to SCC for minimal function mutations = 0.01 % for A and 1 % for B., Methods: Here, the functions are evaluated based on retrospective analysis of three multi-center studies of CF subjects with one or two F508del mutations treated with Elexacaftor/Tezacaftor/Ivacaftor (ETI). Predictions of the percent HCCFTR activity for one vs two mutations were compared for the two functions. The expectation is that after ETI treatment, subjects with two responsive mutations will have 2-fold higher HCCFTR activity than subjects with only one. The hypothesis is that the SCCHCCFTR function that most closely fits that expectation provides the more accurate prediction of CFTR activity., Results: In two separate comparisons, function B most accurately predicted a 2-fold (1.9, 2.3-fold) higher level of HCCFTR activity in subjects on ETI with two vs. one responsive mutation. Function A predicted a 4, 5.5-fold higher level., Conclusions: Function B predicts that 60 mmol/L SCC, the cutoff for a CF diagnosis, is associated with 10 % HCCFTR activity. Comparing HEMT effects on subjects with one or two mutations provides an additional tool for calibrating SCC to CFTR activity., Competing Interests: Declaration of competing interest I, the author Jeffrey J. Wine declare that no conflict of interest exists., (Copyright © 2024 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Sweat chloride concentration, a diagnostic feature in cystic fibrosis (CF), reflects CF transmembrane conductance regulator (CFTR) activity. CFTR modulator therapies, especially elexacaftor/tezacaftor/ivacaftor (ETI), has improved CF outcomes. We report nationwide, real-world data on sweat chloride concentration in people with CF (pwCF) with and without modulator therapies. All Danish pwCF with a minimum of one F508del allele were included. Sweat chloride measurements were stratified by genotype and modulator treatment. Differences were assessed using mixed-effects models. We included 977 sweat chloride measurements from 430 pwCF, 71% of which were F508del homozygous. Heterozygous and homozygous ETI-treated pwCF had an estimated mean sweat chloride concentration of 43 mmol/L (95% confidence interval: 39; 48) and 43 mmol/L (39; 47), respectively-48% and 59% lower than those without treatment. High variation in concentrations remained regardless of treatment status. Despite ETI treatment, 27% heterozygous and 23% homozygous pwCF had elevated concentrations (≥60 mmol/L). These real-world data confirm a substantial decrease in sweat chloride concentration during modulator treatment, especially ETI, where mean concentrations halved. However, large variation remained, including persistently high concentrations. These findings emphasize the potential of sweat chloride concentration as a treatment response biomarker and the need to explore its heterogeneity and relationship with clinical outcomes., (© 2024 The Author(s). APMIS published by John Wiley & Sons Ltd on behalf of Scandinavian Societies for Pathology, Medical Microbiology and Immunology.)

Since screening for cystic fibrosis (CF) was incorporated into the newborn screening program, the number of recognised variants in the CF transmembrane conductance regulator (CFTR ) gene has significantly increased. This has led to the discovery of combinations of gene variants with an uncertain prognosis. One outcome is the designation of 'cystic fibrosis screen positive inconclusive diagnosis' (CFSPID). While the majority of these children are expected to be unaffected by their CFTR variants, a small proportion have been seen to develop symptoms or increasing sweat chloride levels over time, which may reflect dysfunction of the CFTR protein.As the number of children with CFSPID increases, paediatricians and those working in primary care are more likely to encounter them in their practice. It is important that professionals have an understanding of CFSPID: what it is and, importantly, what it is not (ie, they do not have CF). In this article, we hope to explore this using some example cases, illustrating the ways in which these children may present symptomatically and how to manage them., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Acrolein, an aldehyde in smoke from tobacco products, inhibits CFTR function in vitro. Ivacaftor is an FDA-approved potentiator that improves mutant CFTR function. This human clinical study investigated the relationship between two urinary markers of tobacco smoke exposure - the acrolein metabolite 3-HPMA and the nicotine metabolite NNAL - and sweat chloride response to ivacaftor in the G551D Observational Trial (GOAL)., Methods: 3-HPMA (low: <50th centile; moderate: 50-75th centile; high: >75th centile) and NNAL (detectable/undetectable) in GOAL samples was quantified with LC-MS/MS. Self-report of tobacco smoke exposure (Y/N) served as a subjective measure. Change in sweat chloride from pre- to 6 months post-ivacaftor treatment (ΔSC) was the primary CFTR-dependent readout., Results: The sample included 151 individuals, mean age 20.7 (SD 11.4) years, range 6-59 years. Smoke exposure prevalence was 15 % per self-reports but 27 % based on detectable NNAL. 3-HPMA was increased in those reporting tobacco smoke exposure (607 vs 354 ng/ml, p = 0.008), with a higher proportion of smoke-exposed in the high- vs low-acrolein group (31 % vs 9 %, p=0.040). Compared to low-acrolein counterparts, high-acrolein participants experienced less decrease in sweat chloride (-35.2 vs -48.2 mmol/L; p = 0.020) and had higher sweat chloride values (50.6 vs 37.6 mmol/L; p = 0.020) 6 months post-ivacaftor. The odds of ivacaftor-mediated potentiation to near normative CFTR function (defined as SC 6mo <40 mmol/L) was more than twice as high in the low-acrolein cohort (OR: 2.51, p = 0.026)., Conclusions: Increased urinary 3-HPMA, an acrolein metabolite of tobacco smoke, is associated with a diminished sweat chloride response to ivacaftor potentiation of CFTR function., Competing Interests: Declaration of competing interest None., (Copyright © 2024 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Objectives: Aim of this study was to identify risk factors for a progression to cystic fibrosis (CF) in individuals detected as CF Screening Positive, Inconclusive Diagnosis (CFSPID)., Methods: This is a systematic review through literature databases (2015-2023). Blood immunoreactive trypsinogen (b-IRT) values, CFTR genotype, sweat chloride (SC) values, isolation of Pseudomonas aeruginosa (Pa) from respiratory samples, Lung Clearance Index (LCI) values in CFSPIDs who converted to CF (CFSPID > CF) and age at CF transition were assessed., Results: Percentage of CFSPID > CF varies from 5.3 % to 44 %. Presence of one CF-causing CFTR variant in trans with a variant with variable clinical consequences (VVCC), an initial SC ≥ 40 mmol/L, an increase of SC > 2.5 mmol/L/year and recurrent isolation of pseudomonas aeruginosa (Pa) from airway samples could allow identification of subjects at risk of progression to CF., Conclusions: CFSPIDs with CF causing variant/VVCC genotype and first SC in the higher borderline range may require more frequent and prolonged clinical follow-up., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Diagnosing cystic fibrosis (CF) is not always straightforward, in particular when sweat chloride concentration (SCC) is intermediate and <2 CF-causing CFTR variants are identified. The physiological CFTR assays proposed in the guidelines, nasal potential difference and intestinal current measurement, are not readily available nor feasible at all ages. Rectal organoid morphology analysis (ROMA) was previously shown to discriminate between organoids from subjects with and without CF based on a distinct phenotypical difference: compared with non-CF organoids, CF organoids have an irregular shape and lack a visible lumen. The current study serves to further explore the role of ROMA when a CF diagnosis is inconclusive., Methods: Organoid morphology was analysed using the previously established ROMA protocol. Two indices were calculated: the circularity index to quantify the roundness of organoids and the intensity ratio as a measure of the presence of a central lumen., Results: Rectal organoids from 116 subjects were cultured and analysed together with the 189 subjects from the previous study. ROMA almost completely discriminated between CF and non-CF. ROMA indices correlated with SCC, pancreatic status and genetics, demonstrating convergent validity. For cases with an inconclusive diagnosis according to current guidelines, ROMA provided additional diagnostic information, with a diagnostic ROMA classification for 18 of 24 (75%)., Discussion: ROMA provides additional information to support a CF diagnosis when SCC and genetics are insufficient for diagnostic classification. ROMA is standardised and can be centralised, allowing future inclusion in the diagnostic work-up as first-choice physiological assay in case of an unclear diagnosis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The cystic fibrosis transmembrane conductance regulator (CFTR) mutation I1234V (I1234V, p.Ile1234Val, c.3700A>G), is a missense-mutation that creates a cryptic splice site, with the formation of a protein lacking 6 amino acids, that is misfolded and misprocessed. The in vitro effects of CFTR modulator (CFTRm) therapies on human bronchial cell models and intestinal organoids carrying this mutation are conflicting. The aim of this study was therefore to explore the clinical efficacy of CFTRm in people with cystic fibrosis (pwCF) carrying this mutation., Methods: This was a retrospective descriptive study of the clinical records of homozygous and compound heterozygous (none F508del) pwCF, for the I1234V mutation, that received CFTRm. Parameters explored were body mass index (BMI), forced expiratory volume in one second percent predicted (FEV 1 %), lung clearance index (LCI) and quantitative sweat chloride measurements., Results: Mean age was 38.6 ± 14 years (range 21-60). Two subjects were homozygous and five compound heterozygous, with minimal function mutations. Four were pancreatic insufficient and three pancreatic sufficient. The two homozygous subjects received Tezacaftor/Ivacaftor, the remaining Elexacaftor/Tezacaftor/Ivacaftor (ETI); treatment ranged from 6 to 12 months. Mean BMI score increased from 21.7 ± 1.3 to 23.6 ± 2.1 kg/m 2 (p = 0.04); FEV 1 (%pred) increased by 20.14±10.2while mean change in FEV 1 in the year prior to CFTRm initiation was -0.14±1.18 (p = 0.0001). Additionally, LCI 2.5% decreased from 18.7 to 14.5 (p = 0.07); sweat chloride decreased from 116±10 to 90±17 mEq/L (p = 0.017) and chronic pseudomonas airway infection was eradicated in one subject., Conclusions: This study supports a clinical benefit for CFTRm therapy in pwCF carrying the I1234V mutation., Competing Interests: Declaration of competing interest All authors have no conflict of interests to declare., (Copyright © 2024. Published by Elsevier B.V.)

Background: Sweat chloride (SC) concentrations in people with cystic fibrosis (PwCF) reflect relative CF transmembrane conductance regulator (CFTR) protein function, the primary CF defect. Populations with greater SC concentrations tend to have lesser CFTR function and more severe disease courses. CFTR modulator treatment can improve CFTR function within specific CF genotypes and is commonly associated with reduced SC concentration. However, SC concentrations do not necessarily fall to concentrations seen in the unaffected population, suggesting potential for better CFTR treatment outcomes. We characterized post-modulator SC concentration variability among CHEC-SC study participants by genotype and modulator., Methods: PwCF receiving commercially approved modulators for ≥90 days were enrolled for a single SC measurement. Clinical data were obtained from chart review and the CF Foundation Patient Registry (CFFPR). Variability of post-modulator SC concentrations was assessed by cumulative SC concentration frequencies., Results: Post-modulator SC concentrations (n = 3787) were collected from 3131 PwCF; most (n = 1769, 47 %) were collected after elexacaftor/tezacaftor/ivacaftor (ETI) treatment. Modulator use was associated with lower SC distributions, with post-ETI concentrations the lowest on average. Most post-ETI SC concentrations were <60 mmol/L (79 %); 26 % were <30 mmol/L. Post-ETI distributions varied by genotype. All genotypes containing at least one F508del allele had individuals with post-ETI SC ≥60 mmol/L, with the largest proportion being F508del/minimal function (31 %)., Conclusions: Post-modulator SC concentration heterogeneity was observed among all genotypes and modulators, including ETI. The presence of PwCF with post-modulator SC concentrations within the CF diagnostic range suggests room for additional treatment-associated CFTR restoration in this population., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Inflammation is a key driver in the pathogenesis of cystic fibrosis (CF). We assessed the effectiveness of elexacaftor/tezacaftor/ivacaftor (ETI) therapy on downregulating systemic and immune cell-derived inflammatory cytokines. We also monitored the impact of ETI therapy on clinical outcome. Adults with CF, heterozygous for F508del (n = 19), were assessed at baseline, one month and three months following ETI therapy, and clinical outcomes were measured, including sweat chloride, lung function, weight, neutrophil count and C-reactive protein (CRP). Cytokine quantifications were measured in serum and following stimulation of peripheral blood mononuclear cells (PBMCs) with lipopolysaccharide (LPS) and adenosine triphosphate and analysed using LEGEND plex™ Human Inflammation Panel 1 by flow cytometry (n = 19). ASC specks were measured in serum and caspase-1 activity and mRNA levels determined from stimulated PBMCs were determined. Patients remained stable over the study period. ETI therapy resulted in decreased sweat chloride concentrations (p < 0.0001), CRP (p = 0.0112) and neutrophil count (p = 0.0216) and increased percent predicted forced expiratory volume (ppFEV1) (p = 0.0399) from baseline to three months, alongside a trend increase in weight. Three months of ETI significantly decreased IL-18 (p< 0.0011, p < 0.0001), IL-1β (p<0.0013, p = 0.0476), IL-6 (p = 0.0109, p = 0.0216) and TNF (p = 0.0028, p = 0.0033) levels in CF serum and following PBMCs stimulation respectively. The corresponding mRNA levels were also found to be reduced in stimulated PBMCs, as well as reduced ASC specks and caspase-1 levels, indicative of NLRP3-mediated production of pro-inflammatory cytokines, IL-1β and IL-18. While ETI therapy is highly effective at reducing sweat chloride and improving lung function, it also displays potent anti-inflammatory properties, which are likely to contribute to improved long-term clinical outcomes., Competing Interests: Conflict of Interest DP: speaker/board honoraria from Vertex This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Jarosz-Griffiths et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: To verify the rate and predictors of 'quantity not sufficient' (QNS) among Brazilian infants younger than 3 months with positive newborn screening (NBS) for cystic fibrosis (CF)., Design: Prospective, population-based study., Setting: Public Statewide Newborn Screening Programme where the incidence rate of CF is ≈1:11 000., Patients: Subjects with positive two-tiered immunoreactive trypsinogen., Interventions: Sweat induction and collection were performed in the same facility; one sweat sample was obtained per individual., Main Outcome Measures: The QNS rate and its predictors; analysis corresponded to the day of sweat collection., Results: Among the 975 participants, QNS rates for 10 and 15 µL were 3.6% (95% CI 2.5% to 4.9%) and 8.3% (95% CI 6.6% to 10.2%). Infants weighing >3056 and >3845 g and with gestational age higher than 37 weeks had a greater likelihood (5.5 and 6.7, and 2.7 and 5.8 times more, respectively) of avoiding QNS than their peers., Conclusion: QNS rates fulfilled the requirements, but predictors differed from those recommended by the Cystic Fibrosis Foundations guidelines., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Guidelines for sweat chloride testing endorse a minimum sweat rate for reporting results. Bilateral sweat collection is recommended, but if both sites fail to meet the minimum rate (quantity not sufficient, QNS), the test should be repeated. In this study, we examine the correlation between sweat rate and sweat chloride concentration ([Cl-]), assess the accuracy of specimens collected at suboptimal rates, and investigate the use of pooled bilateral specimens for chloride measurement., Methods: Pearson correlation was employed to analyze the relationship between sweat rate and chloride concentration, [Cl-], in 674 macroduct collections. Weighted kappa was evaluated to determine cystic fibrosis (CF) diagnostic classification concordance for 18 tests with paired arms above vs below the minimum sweat rate. Deming regression was applied to compare [Cl-] from pooled bilateral specimens vs neat specimens in 27 collections with residual volume available after clinical testing., Results: Pearson correlation of sweat rate vs [Cl-] was minimal (r = -0.0735) across specimens with varying rates and [Cl-]. There was substantial agreement in CF diagnostic classification between arms for bilateral collections with discordant sweat rates. Regression analysis of [Cl-] in pooled vs nonpooled specimens revealed a slope of 0.984 and an intercept of 0.796., Conclusions: Negligible correlation of sweat rate and [Cl-] suggests the minimum sweat rate for macroduct collectors may be overly stringent. Reporting of [Cl-] in specimens with ≥10 µL (rate ≥0.3 µL/min) may reduce QNS rates without compromising diagnostic accuracy. Preliminary data suggests pooling of bilateral collections may be a feasible option to achieve the required volume for testing., (© Association for Diagnostics & Laboratory Medicine 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Sweat pH is an important indicator for diagnosing disease states, such as cystic fibrosis. However, conventional pH sensors are composed of large brittle mechanical parts and need additional instruments to read signals. These pH sensors have limitations for practical wearable applications. In this study, we propose wearable colorimetric sweat pH sensors based on curcumin and thermoplastic-polyurethane (C-TPU) electrospun-fibers to diagnose disease states by sweat pH monitoring. This sensor aids in pH monitoring by changing color in response to chemical structure variation from enol to di-keto form via H-atom separation. Its chemical structure variation changes the visible color due to light absorbance and reflectance changes. Furthermore, it can rapidly and sensitively detect sweat pH due to its superior permeability and wettability. By O 2 plasma activation and thermal pressing, this colorimetric pH sensor can be easily attached to various fabric substrates such as swaddling and patient clothing via surface modification and mechanical interlocking of C-TPU. Furthermore, the diagnosable clothing is durable and reusable enough to neutral washing conditions due to the reversible pH colorimetric sensing performance by restoring the enol form of curcumin. This study contributes to the development of smart diagnostic clothing for cystic fibrosis patients who require continuous sweat pH monitoring.

Objectives Cystic fibrosis (CF) is a debilitating genetic disorder that benefits from early detection. CF diagnosis relies on measuring elevated sweat chloride that is difficult in neonates with low sweat rates. We introduce a new method for sweat chloride determination from volume-limited specimens, and explore the potential utility of sweat bicarbonate in neonatal CF screening. Methods A rapid assay (< 5 min) was developed to analyze chloride and bicarbonate using capillary electrophoresis with indirect UV detection (CE-iUV). Pilocarpine-stimulated sweat samples from screen-positive CF infants were collected at two hospital sites, including confirmed CF (n = 12), CF screen-positive inconclusive diagnosis (n = 4), and unaffected non-CF cases (n = 37). All sweat chloride samples were analyzed by a coulometric titrator and CE-iUV, and the viability to measure acid-labile bicarbonate was also evaluated. Results Stability studies revealed that bicarbonate can be reliably assessed in sweat if acidification and heating were avoided. Method validation demonstrated that sweat chloride and bicarbonate were quantified with acceptable accuracy (recovery of 102%), precision (CV = 3.7%) and detection limits (∼ 0.1 mM). An inter-laboratory comparison confirmed a mean bias of 6.5% (n = 53) for sweat chloride determination by CE-iUV relative to a commercial chloridometer. However, sweat bicarbonate did not discriminate between CF and non-CF infants (AUC = 0.623, p = 0.215) unlike chloride (AUC = 1.00, p = 3.00 × 10 -7 ). Conclusions CE-iUV offers a robust method for sweat chloride testing from presumptive CF infants that may reduce testing failure rates. However, sweat bicarbonate does not have clinical value in newborn CF diagnosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Objectives: Two CFTR-dependent β-adrenergic sweat rate tests applying intradermal drug injections were reported to better define diagnosis and efficacy of CFTR-directed therapies. The aim of this work was to develop and test a needle-free image-based test and to provide an accurate analysis of the responses., Methods: The modified method was conducted by applying two successive iontophoresis sessions using the Macroduct device. Efficiency of drug delivery was tested by evaporimetry. Cholinergically stimulated sweating was evoked by pilocarpine iontophoresis. β-adrenergically stimulated sweating was obtained by iontophoresis of isoproterenol and aminophylline in the presence of atropine and ascorbic acid. A nonlinear mixed-effects (NLME) approach was applied to model volumes of sweat and subject-specific effects displaying inter- and intra-subject variability., Results: Iontophoresis provided successful transdermal delivery of all drugs, including almost neutral isoproterenol and aminophylline. Pilocarpine was used at a concentration ∼130-times lower than that used in the classical Gibson and Cooke sweat test. Addition of ascorbic acid lowered the pH of the solution, made it stable, prevented isoproterenol degradation and promoted drug iontophoresis. Maximal secretory capacity and kinetic rate of β-adrenergic responses were blunted in CF. A cutoff of 5.2 minutes for ET50, the time to reach the half maximal secretion, discriminated CF from controls with a 100% sensitivity and specificity. Heterozygous showed an apparently reduced kinetic rate and a preserved secretory capacity., Conclusion: We tested a safe, well-tolerated needle-free image-based sweat test potentially applicable in children. Modelling responses by NLME allowed evaluating metrics of CFTR-dependent effects reflecting secretory capacity and kinetic rate., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: The cystic fibrosis (CF) sweat gland is defective in β-adrenergically-stimulated sweat secretion in the coil and chloride reabsorption in the duct. Whereas chloride reabsorption is regularly assessed by quantitative pilocarpine iontophoresis (QPIT), the measurement of β-adrenergic sweat secretion is not yet established in clinical practice., Methods: A novel sweat bubble imaging protocol was developed that determines sweat secretion rates by automatic recording, processing and quality control of the kinetics of sweat droplet formation., Results: Treatment of CF patients with the CFTR modulators elexacaftor, tezacaftor and ivacaftor reduced the sweat chloride concentration measured in QPIT in the majority of patients to values in the intermediate or normal range. In contrast, the β-adrenergically-stimulated sweat secretion rate assayed by the automated bubble sweat test was normalized in only 3 patients, slightly increased in 12 patients and remained undetectable in 8 patients., Conclusions: β-adrenergic sweat stimulation in the coil is apparently rather stringent in its requirements for a wild type CFTR conformation whereas chloride reabsorption in the duct tolerates residual structural and functional deficits of native or pharmacologically rescued mutant CFTR in the apical membrane., Competing Interests: Declaration of Competing Interests None of the authors has any competing financial interests related to the material present in this manuscript., (Copyright © 2021. Published by Elsevier B.V.)

Background: The sweat test has been the "gold standard" diagnostic test for cystic fibrosis for more than 40 years. We hypothesized that there would be a change in the pattern of sweat testing in Ireland since the introduction of cystic fibrosis newborn screening in 2011, when practices were last reviewed. This is a follow up survey looking at sweat testing numbers and practices., Methods: A national survey compiled data on sweat collection, conductivity and sweat chloride testing in all hospitals previously identified as performing sweat tests., Results: All 13 centres in Ireland performing sweat testing in 2018 responded to the survey (100% return rate). Our results indicate that 1007 sweat tests were performed in 2018 compared to 2555 in 2011, equating to a 61% reduction. Seven out of 13 centres are performing less than 50 sweat tests per year. Nine out of 13 centres (69%) had a sweat test failure rate greater than the recommended allowable rate of ≤ 10%. We detected a trend of sweat testing in patients with an existing diagnosis of CF who had commenced cystic fibrosis transmembrane conductance regulator (CFTR) modulators., Conclusions: There has been a significant reduction in the number of sweat tests performed in Ireland since the introduction of newborn screening for CF. There remains a lack of standardisation in many aspects of the service ranging from sample collection to reporting of results. We have identified a new trend of sweat testing in the cystic fibrosis transmembrane conductance regulator modulator era., Competing Interests: Declaration of Competing Interest No conflict of interest is declared by the authors., (Copyright © 2021. Published by Elsevier B.V.)

Background and Objectives: Cystic fibrosis (CF) screen-positive infants with an inconclusive diagnosis (CFSPID) are infants in whom sweat testing and genetic analysis does not resolve a CF diagnosis. Lack of knowledge about the health outcome of these children who require clinical follow-up challenges effective consultation. Early predictive biomarkers to delineate the CF risk would allow a more targeted approach to these children., Methods: Prospective, longitudinal, multicenter, Canada-wide cohort study of CF positive-screened newborns with 1 to 2 cystic fibrosis transmembrane conductance regulator gene variants, of which at least 1 is not known to be CF-causing and/or a sweat chloride between 30 and 59 mmol/L. These were monitored for conversion to a CF diagnosis, pulmonary, and nutritional outcomes., Results: The mean observation period was 7.7 (95% confidence interval 7.1 to 8.4) years. A CF diagnosis was established for 24 of the 115 children with CFSPID (21%) either because of reinterpretation of the cystic fibrosis transmembrane conductance regulator genotype or because of increase in sweat chloride concentration ≥60 mmol/L. An initial sweat chloride of ≥40 mmol/l predicted conversion to CF on the basis of sweat testing. The 91 remaining children with CFSPID were pancreatic sufficient and showed normal growth until school age. Pulmonary function as well as lung clearance index in a subgroup of children with CFSPID were similar to that of healthy controls., Conclusions: Children with CFSPID have good nutritional and pulmonary outcomes at school age, but rates of reclassifying the diagnosis are high. The initial sweat chloride test can be used as a biomarker to predict the risk for CF in CFSPID., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2021 by the American Academy of Pediatrics.)

Background: The Characterizing CFTR Modulated Changes in Sweat Chloride and their Association with Clinical Outcomes (CHEC-SC) study is a large epidemiologic study designed to determine the relationship between sweat chloride response and clinical outcomes in people with cystic fibrosis (CF) on commercially approved CFTR modulators. A challenge to study feasibility was capturing sweat chloride measurements before modulator initiation. We tested the hypothesis that historic sweat chloride approximated contemporary pre-modulator values to estimate CFTR modulator-induced changes, allowing a single-visit study design., Methods: GOAL and PROSPECT were multi-center prospective studies of individuals initiating ivacaftor or lumacaftor-ivacaftor. At enrollment, pre-modulator sweat chloride was measured and historic results recorded. Post-modulator sweat chloride was measured at 1, 3 and 6 months. For this analysis, differences between historic and pre-modulator sweat chloride were estimated. CFTR modulator-induced sweat chloride mean changes were compared using historic and pre-modulator sweat chloride., Results: Paired historic and pre-modulator sweat chloride (n=406 participants) revealed a non-significant mean change of -1.0 mmol/L (95% CI: -2.71, 0.66) over an average of 17.2 years. Calculating sweat response to ivacaftor or lumacaftor-ivacaftor using historic or pre-modulator values resulted in similar estimates of modulator response. Based on these results, the CHEC-SC study was designed with a single, post-modulator sweat chloride measurement., Conclusions: Historic sweat chloride values provide a reliable estimate of pre-modulator sweat chloride for people starting on modulator therapy. The CHEC-SC study anticipates capturing approximately 5,000 sweat chloride values, providing an unprecedented understanding of sweat chloride across the CF population in the era of CFTR modulators., Competing Interests: Declaration of Competing Interest ETZ, NMH, DRV, SMR, MWK: grants or consulting CFF; DRV consults for aMoon, Arrevus, Eloxx, Enbiotix, Felix, Ionis, Matinas, Merck, Polyphor, Respirion, Savara; SMR consults for Vertex; MWK consults for Anthera, AzurRx, Celtaxsys, Chiesi, Ionis, Kala, Laurent, Merck, Paranta, pH Pharma, Santhera, Vertex; JPC, KOD and MS: none., (Copyright © 2021. Published by Elsevier B.V.)

Background: Early diagnosis via newborn screening is crucial to improve clinical outcomes in patients with cystic fibrosis (CF). In resource-limited areas where newborn screening is unavailable and CF-related morbidity is high, clinical tools such as palmar aquagenic wrinkling (AW) have been considered. We report the utility of AW for possible early identification of CF in children <2 years old., Methods: This pilot case-control study included 55 total children, 20 with confirmed CF, 10 CF carriers, and 25 healthy controls. The time to wrinkling (TTW) after hand immersion in water was recorded, and relationships between TTW, demographic and clinical variables, and validated diagnostic tests were analyzed., Results: Wrinkling was observed in children <2 years of age, and median TTW was significantly lower among those with CF (3 min) compared to carriers or healthy controls (12 and 14 min, respectively). Higher immunoreactive trypsinogen and sweat chloride levels were associated with lower TTW (p < 0.001). In this predominantly Caucasian cohort, children with F508del had the lowest TTW. Six minutes of hand immersion offered a sensitivity of 85% and a specificity of 91%, suggesting a practical and effective test duration for this age. There was no evidence that nutritional status affected TTW., Conclusion: Our data confirm the role of AW in CF, validate test utility among young children, and analyze relationships between TTW, immunoreactive trypsinogen, sweat chloride levels, and CF-causing mutations. Despite test limitations, in children with suspected CF from non-screened populations, utility of AW in enabling early referral and diagnosis needs further exploration., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: Elexacaftor-tezacaftor-ivacaftor is a small-molecule cystic fibrosis transmembrane conductance regulator (CFTR) modulator regimen shown to be efficacious in patients with at least one Phe508del allele, which indicates that this combination can modulate a single Phe508del allele. In patients whose other CFTR allele contains a gating or residual function mutation that is already effectively treated with previous CFTR modulators (ivacaftor or tezacaftor-ivacaftor), the potential for additional benefit from restoring Phe508del CFTR protein function is unclear., Methods: We conducted a phase 3, double-blind, randomized, active-controlled trial involving patients 12 years of age or older with cystic fibrosis and Phe508del -gating or Phe508del -residual function genotypes. After a 4-week run-in period with ivacaftor or tezacaftor-ivacaftor, patients were randomly assigned to receive elexacaftor-tezacaftor-ivacaftor or active control for 8 weeks. The primary end point was the absolute change in the percentage of predicted forced expiratory volume in 1 second (FEV 1 ) from baseline through week 8 in the elexacaftor-tezacaftor-ivacaftor group., Results: After the run-in period, 132 patients received elexacaftor-tezacaftor-ivacaftor and 126 received active control. Elexacaftor-tezacaftor-ivacaftor resulted in a percentage of predicted FEV 1 that was higher by 3.7 percentage points (95% confidence interval [CI], 2.8 to 4.6) relative to baseline and higher by 3.5 percentage points (95% CI, 2.2 to 4.7) relative to active control and a sweat chloride concentration that was lower by 22.3 mmol per liter (95% CI, 20.2 to 24.5) relative to baseline and lower by 23.1 mmol per liter (95% CI, 20.1 to 26.1) relative to active control (P<0.001 for all comparisons). The change from baseline in the Cystic Fibrosis Questionnaire-Revised respiratory domain score (range, 0 to 100, with higher scores indicating better quality of life) with elexacaftor-tezacaftor-ivacaftor was 10.3 points (95% CI, 8.0 to 12.7) and with active control was 1.6 points (95% CI, -0.8 to 4.1). The incidence of adverse events was similar in the two groups; adverse events led to treatment discontinuation in one patient (elevated aminotransferase level) in the elexacaftor-tezacaftor-ivacaftor group and in two patients (anxiety or depression and pulmonary exacerbation) in the active control group., Conclusions: Elexacaftor-tezacaftor-ivacaftor was efficacious and safe in patients with Phe508del -gating or Phe508del -residual function genotypes and conferred additional benefit relative to previous CFTR modulators. (Funded by Vertex Pharmaceuticals; VX18-445-104 ClinicalTrials.gov number, NCT04058353.)., (Copyright © 2021 Massachusetts Medical Society.)

Background: The sweat chloride test (ST) is the gold standard for cystic fibrosis (CF) diagnosis in symptomatic patients, within the newborn screening and in the follow-up of CF patients during molecular therapies. However, false positives have been reported in patients with different diseases. We describe and discuss 4 cases due to different clinical conditions in which we recorded false positive ST, and the test remained altered for a period of varying length., Cases Presentation: Case 1: Eight months old female child suffering from constipation, recurrent vomiting and failure to thrive, family history of recurrent pancreatitis without mutations in the PRSS1 and SPINK1 genes. Both ST and fecal elastase were altered although no CFTR gene mutations were found. Due to rapid clinical deterioration, celiac disease was suspected and diagnosed by laboratory tests and intestinal biopsy. After 2 weeks of gluten-free diet ST and fecal elastase normalized. Case 2: 14 months old male suffering from bilateral renal dysplasia, episodes of metabolic alkalosis, recurrent respiratory infections and recurrent vomiting. The child had more ST positives, but no CFTR mutations were found. During follow-up, he developed sensorineural hearing loss and an atrial septic defect was found. Finally, a diagnosis of Klinefelter was made, but the ST normalized several years later. Case 3 and 4: Two boys with stubborn constipation and fecal occlusion treated with Poly Ethylene Glycol (PEG) with salts showed pathological ST. The test returned normal a few days after stopping treatment., Conclusions: We hypotesized the possible causes of ST alteration in these conditions: in celiac disease it could be due to a transient dysregulation of the aquaporins, rapidly reversed by the diet; in Klinefelter, it may be due to stable pubertal hypoandrogenism; while, the PEG formulation itself contains salts that can temporarily alter ST.

Cystic fibrosis (CF) is a genetic disease caused by a bi-allelic mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. When the diagnosis cannot be confirmed by a positive sweat test or/and the identification of two CF-causing variants, international guidelines recommend the use of CFTR functional assays. These tests assess whether CFTR activity is normal or diminished/absent through measurement of CFTR-mediated chloride secretion/absorption. CFTR functional assays are not only useful for diagnostic purposes but can also serve as a surrogate outcome for clinical trials of CFTR modulators, which are emerging therapeutic agents designed to correct the malfunctioning protein. In the near future they could also be used as precision-medicine techniques, to help guidance and optimisation of treatment. Until now, sweat testing has been the only CFTR functional assay available in Switzerland. Since 2020, the Centre Hospitalier Universitaire Vaudois (CHUV) at Lausanne and the Lucerne Children&rsquo;s Hospital perform nasal potential difference measurement. Moreover, The Ecole Polytechnique F&eacute;d&eacute;rale de Lausanne (EPFL) established a reliable procedure to generate adult intestinal organoids, i.e., stem cell-derived in-vitro grown mini tissues, extracted from rectal biopsies, which can be used to assess CFTR function in vitro. This narrative review describes the most popular CFTR functional assays, as well as their indications, limitations and availability in Switzerland.

Objective: Wales has an immunoreactive trypsin (IRT)-DNA cystic fibrosis (CF) newborn screening (NBS) programme. Most CF NBS false negative cases are due to an IRT concentration below the screening threshold. The accuracy of IRT results is dependent on the quality of the dried bloodspot (DBS) sample. The aim of this study was to determine the cause of false negative cases in CF NBS and their relationship to DBS quality., Design: Longitudinal birth cohort., Setting: Wales 1996-2016., Patients: Children with CF., Interventions: Identification of all CF patients with triangulation of multiple data sources to detect false negative cases., Main Outcome Measures: False negative cases., Results: Over 20 years, 673 952 infants were screened and 239 were diagnosed with CF (incidence 1:2819). The sensitivity of the programme was 0.958, and positive predictive value was 0.476. Eighteen potential false negatives were identified, of whom eight were excluded: four screened outside Wales, two had complex comorbidities, no identified cystic fibrosis transmembrane conductance regulator (CFTR) variants on extended analysis and thus not considered to have CF and two were diagnosed after their 16th birthday. Of the 10 false negatives, 9 had a low DBS IRT and at least one common CFTR variant and thus should have received a sweat test under the programme. DBS cards were available for inspection for five of the nine false negative cases-all were classified as small/insufficient or poor quality., Conclusions: The majority of false negatives had a low bloodspot IRT, and this was associated with poor quality DBS. The optimal means to improve the sensitivity of our CF NBS programme would be to improve DBS sample quality., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Case Presentation: A 14-year old girl presented with history of productive cough since the age of 3 years. For the past 6 years, she complained of chest tightness and wheezing. There was also nasal stuffiness and discharge for the past 6 years. She denied history of hemoptysis, ear discharge, or chest pain. There was no history of respiratory distress at the time of birth. Her brother also suffered from productive cough and wheezing since the age of 3 years. However, both her parents were asymptomatic., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Cystic fibrosis transmembrane conductance regulator (CFTR) gating mutations (GMs) result in CFTR that is present at the cell surface but nonfunctional. Patients with the G551D mutation, the most prevalent worldwide, have been well studied. Italian GM patients have mainly non-G551D mutations. We studied their epidemiology and clinical characteristics in the period spanning the pre/post ivacaftor introduction to the Italian market., Methods: Data from the Italian CF Registry were used to describe patients with GMs and compare them with F508del homozygous (F/F) patients., Results: In total, 186 patients with GMs (median [range] age, 21.96 [0.13-63.38] years) were identified among the 5552 patients included in the study (3.3%). They had lower sweat chloride values at diagnosis than the F/F and a lower ratio of males. In the GM group, examining the data of the years 2012 and 2017 and comparing with F/F, lung infection by Staphylococcus aureus and diabetes became less prevalent, and better FEV 1 and nutritional status were observed in 2017. The cross-sectional evaluation year-by-year from 2012 to 2017 of the GM group showed improving trends in lung function and body mass index, and the decreasing prevalence of diabetes compared with F/F. Longitudinal evaluation of GM patients showed improvement in percent predicted (pp)FEV 1 and nutrition in the 2012-2017 period. These variations correspond to the introduction of treatment with the CFTR potentiator ivacaftor (2014/2015)., Conclusions: Italian patients with GMs are few and are characterized by milder phenotypes than F/F patients. Improved outcomes are likely influenced by treatment with ivacaftor., (© 2020 Wiley Periodicals LLC.)

Aim: To explore which patient-related factors influence sweat test response to CFTR modulators, as well as examining the correlation between the sweat chloride response and ppFEV 1 or BMI response, using systematically collected real-life clinical data., Methods: 160 CF patients were identified who had used lumacaftor/ivacaftor for at least six months. Of these patients, age, sweat chloride levels, ppFEV 1 weight and BMI at the start of treatment and after 6 months were collected retrospectively. Pearson and Spearman tests were performed to assess correlations., Results: Females compared to males in this group showed a larger response in sweat chloride (mean difference 10.6 mmol/l, 95% CI: 5.7-15.4) and BMI (mean difference 0.27 kg/m 2 , 95% CI: 0.01-0.54). A modest but significant correlation was found between patient weight and sweat chloride response (Pearson R = 0.244, p = 0.001), which diminished upon correction for the other factors. The correlation between sex and sweat chloride response remained; R = 0.253, p = 0.001. Sweat chloride response did not correlate with ppFEV 1 change or BMI change at 6 months after start of therapy., Conclusion: Sweat chloride response is larger in females compared to males, which also explains the negative correlation of weight with the response in sweat chloride concentration after start of lumacaftor/ivacaftor. Sweat chloride response does not correlate with the responses in ppFEV 1 and BMI. This information may help the interpretation of sweat test results acquired for the follow up and evaluation of CFTR modulating treatments, and warrants further investigation into the underlying mechanisms of sex differences in response to CFTR modulators., Competing Interests: Declaration of Competing Interest HGM Heijerman has provided assistance to Vertex pharmaceuticals, the manufacturer of lumacaftor/ivacaftor, as member of the advisory board, speaker and investigator in clinical studies. HGM Arets also is a member of the advisory board and has been investigator in clinical studies for Vertex. KM de Winter-de Groot works presently as an investigator in a clinical study for Vertex. BL Aalbers has assisted in clinical trials for Vertex as a sub-investigator. CK van der Ent reports grants from Vertex, outside the submitted work., (Copyright © 2020. Published by Elsevier B.V.)

The current guidelines for sweat chloride analysis identify the procedures for sweat collection, but not for chloride assay, which is usually performed by methods originally not aiming at the low concentrations of chloride found in sweat. To overcome this limitation, we set up, characterized, and adopted an original inductively coupled plasma mass spectrometry (ICP-MS) method for sweat chloride determination, which was designed for its easy use in a clinical laboratory. The method was linear in the range 8.5E-3 to 272.0E-3 mM, precision exhibited a relative standard deviation < 6%, and accuracy was in the range 99.7-103.8%. Limit of blank, limit of detection, and limit of quantitation were 2.1 mM, 3.2 mM, and 7.0 mM, respectively, which correspond to real concentrations injected into the mass spectrometer of 3.9E-3 mM for LOD and 8.5E-3 mM for LOQ. At first, the method was tested on 50 healthy volunteers who exhibited a mean chloride concentration of 15.7 mM (25-75th percentile 10.1-19.3 mM, range 2.8-37.4 mM); then, it was used to investigate two patients with suspected cystic fibrosis, who exhibited sweat chloride values of 65.6 mM and 81.2 mM, respectively. Moreover, the method was cross-validated by assaying 50 samples with chloride concentration values in the range 10-131 mM, by both ICP-MS and coulometric titration, which is the technology officially used in Tuscany for cystic fibrosis newborn screening. The reference analytical performances and the relatively low cost of ICP-MS, accompanied by the advantageous cost of a single sweat chloride assay, make this technology the best candidate to provide a top reference method for the quantification of chloride in sweat. The method that we propose was optimized and validated for sweat samples ≥ 75 mg, which is the minimum amount requested by the international protocols. However, the method sensitivity and, in addition, the possibility to reduce the sample dilution factor, make possible the quantification of chloride even in samples weighting < 75 mg that are discarded according to the current guidelines. Graphical abstract.

Patients with cystic fibrosis (CF) have a two- to four-fold higher sodium chloride sweat content compared with healthy controls. This high sweat salt loss increases the risk for electrolyte disturbances, associated with subacute or chronic complications. Sodium status therefore needs to be adequately monitored and salt intake adjusted to individual needs. The lack of current evidence to formulate specific recommendations and assess sodium status is reflected in a variability of recommendations in international guidelines. This narrative review presents an overview of the current evidence. Infants with CF in particular are at risk for severe sodium deficiency, potentially leading to metabolic alkalosis due to low intake and high sweat losses. More research on the assessment of sodium status and efficacy of sodium chloride supplements in the population of patients with CF, especially given the changing era of CF transmembrane conductance regulator modulatory treatment, is warranted., (Copyright © 2020 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.)

Introduction: Cystic fibrosis (CF) is a life-limiting autosomal recessive disorder as a result of CF transmembrane conductance regulator gene mutation. It has a wide range of disease severity in patients with the same genotype., Case Report: A 5-year-old Malay boy with a history of recurrent pneumonia, presented with productive cough, fever and worsening tachypnoea. Physical examination revealed coarse crepitations, reduced breath sounds and clubbing. Biochemical investigations showed that he had respiratory type 2 failure as a result of bronchiectasis. Sweat conductivity done twice was raised supporting a diagnosis of CF. Other investigations such as bronchoscopy to look for congenital anomaly of the lung, infectious disease screening and tuberculosis, fungal and viral culture and sensitivity were negative. Further cascade screening revealed high sweat conductivity results in his siblings., Discussion: Although CF prevalence is low in Malaysia, it is nevertheless an important diagnosis to be recognised as it is associated with increased morbidity.

Objective: To assess the performance of a newly developed skin wipe test (SWT) for the diagnosis of cystic fibrosis (CF)., Study Design: Spontaneously formed sweat from the forearm was wiped by a cotton swab moistened with 100 µL of deionized (DI) water and extracted into 400 µL of DI water (SWT). The conventional Macroduct sweat test (ST) was performed simultaneously. SWT samples of 114 CF patients, 76 healthy carriers, and 58 controls were analyzed by capillary electrophoresis with contactless conductivity detection and Cl - /K + and (Cl -  + Na + )/K + ion ratios were evaluated. Chloride concentrations from Macroduct ST were analyzed coulometrically., Results: Analysis of 248 SWT samples and simultaneous Macroduct ST samples showed comparable method performance. Two ion ratios, Cl - /K + and (Cl -  + Na + )/K + , from the SWT samples and Cl - values from the ST samples were evaluated to diagnose CF. Sensitivity of the SWT method using the Cl - /K + ratio (cutoff value 3.9) was 93.9%, compared to 99.1% when using the (Cl -  + Na + )/K + ratio (cutoff value 5.0) and 98.3% in using Macroduct Cl - (cutoff value higher or equal to 60 mmol/L). The methods' specificities were 97.8%, 94.0%, and 100.0%, respectively., Conclusions: The developed SWT method with capillary electrophoretic analysis for CF diagnosis performs comparably to the conventional Macroduct ST. The SWT method is simple, fast, inexpensive, and completely noninvasive. Use of an ion ratio in obtained SWT samples is proposed as a new diagnostic parameter that shows significant promise in CF diagnostics., (© 2020 Wiley Periodicals, Inc.)

Objective: The first available CFTR modulator combination for homozygous F508del patients, lumacaftor/ivacaftor, has not been tested in patients with percentage predicted (pp)FEV 1  > 90 in the phase III trials. The objective of this study is to share real life experience about treatment results in this group., Methods: In this retrospective observational study, patients aged 6 years or older starting on lumacaftor/ivacaftor in standard care were in strict follow up. For these patients, data were obtained about FEV 1 , BMI, CFQ-R and sweat chloride before start and after 6 months of treatment, and data about FEV 1 and BMI were recorded every 3 months. Exacerbations were recorded continuously., Results: We identified 40 patients with a ppFEV 1  ≥ 90 at the start of lumacaftor/ivacaftor who had been in follow up for at least 12 months. After 12 months, ppFEV 1 was unchanged, whereas mean absolute change in BMI was +0.88 (p = 0.001) with a mean change in SDS for BMI of +0.26 (p = 0.014). Mean CFQ-R overall score at 6 months improved by 2.6% (p = 0.004) and mean decrease in sweat chloride was -27.3 mEq/L (p = 0.000). Exacerbation rate declined from 1.03 to 0.53/person/year (p = 0.003). One patient discontinued treatment in the first 12 months because of progression of CFRLD, two paused treatment but resumed later., Conclusion: Homozygous F508del patients starting lumacaftor/ivacaftor at ppFEV 1  ≥ 90 improved significantly in nutritional status, sweat chloride levels and exacerbation rate, but did not respond in ppFEV 1 . Treatment is well tolerated in this patient group. These effects make it worth considering to treat this group of patients with lumacaftor/ivacaftor., Competing Interests: Declaration of Competing Interest HGM Heijerman has provided assistance to Vertex pharmaceuticals, the manufacturer of lumacaftor/ivacaftor, as member of the advisory board, speaker and principal investigator in clinical studies. HGM Arets also is a member of the national advisory board and has been principal investigator in several clinical studies for Vertex. KM de Winter-de Groot will work as an principal investigator in a clinical study for Vertex in the near future. CK van der Ent reports grants from Vertex, outside the submitted work., (Copyright © 2020. Published by Elsevier B.V.)

Background: 5T polymorphism is a CFTR mutation with unclear clinical consequences: the phenotype varies from healthy individuals to Cystic Fibrosis (CF). The aim of this study was to evaluate if nasal potential difference (NPD) and sweat testing correlate with symptoms and CF diagnosis in 5T patients., Methods: 86 patients with 5T who had undergone NPD measurement, were included (6 homozygous (5T/5T), 41 with a PI-CF causing mutation in trans (5T/PI-CF), 11 with a PS-CF causing mutation in trans (5T/PS-CF) and 28 without a known mutation in trans (5T/?). Data including age, phenotype, sweat chloride and follow up were collected., Results: 33% of the 5T/5T patients had abnormal NPD results, compared to 70% in 5T/PI-CF; 33% in 5T/PS-CF and 29% in 5T/?. The percentage of high or borderline sweat chloride was highest in 5T/PI-CF, and 5T/?, compared to 5T/5T and 5T/PS-CF (91, 96, 80, and 63%, respectively). TGm (number of TG repeats in intron 8) analysis was performed in 21 5T/PI-CF patients. TG11 was associated with lower sweat chloride, lower percentage of abnormal NPD and less progression of symptoms compared to TG12 and TG13., Conclusion: There is much variation in clinical status among 5T patients. All patients in this study with 5T/PS CF, all patients with both normal NPD and sweat test, and most patients with TG11 were stable or improving over time. Therefore, NPD measurement and TGm status aid to assess if a patient is at high risk for developing CF or CFTR-related disease and if specific follow up in a CF center is required., (Copyright © 2019 European Cystic Fibrosis Society. All rights reserved.)

Introduction: The cystic fibrosis (CF) clinical profile and associated CFTR mutation spectrum is poorly understood in the South Asian population. This is likely due to the lack of diagnostic resources and the absence of a centralised CF database and screening programme, despite a relatively large proportion of the global population., Methods: Following identification of a previously unreported CFTR mutation (c.2805&#95;2810delinsTCAGA; p.(Pro936Ginfs*6)) in a newly diagnosed patient of Indian descent, we interrogated national registries for other cases., Results: We identified three European-born subjects of South Asian descent with CF due to a novel CFTR mutation. All three subjects presented in infancy and each had a severe phenotype with intestinal complications as a presenting feature. Two subjects were diagnosed prior to the advent of universal screening. Preliminary genetic screening failed to identify the causative mutation in all three patients., Conclusion: Our work highlights the value of extended or targeted genotyping in selected populations. It also demonstrates the benefit of routine collaboration between national registries. This will promote the identification of novel mutations; leading to greater understanding of genotype-phenotype associations, improved individual prognostication and ultimately the improved availability of novel precision therapies. This collaboration is essential if we are to achieve health equality for people with CF living in resource-limited settings., (© 2020 John Wiley & Sons Ltd.)