Sweat Chloride: The Critical Biomarker for Cystic Fibrosis Trials

Objective. As part of a study to determine population-based frequencies of CFTR mutations in an ethnically diverse, midwestern cystic fibrosis (CF) population, clinical histories were studied in 119 CF patients. Methodology. We sought to examine the association between genotype as characterized by the ΔF508 and 11 other commonly occurring mutations and clinical parameters including age at diagnosis, clinical presentation, sweat chloride level, chest roentgenogram score, clinical scores, pulmonary function test results, percent weight for height, and presence of associated CF complications. Results. Age at diagnosis of CF was significantly associated with homozygosity for ΔF508 (mean age at diagnosis ± SE: 1.7 ± 0.3 years for ΔF508/ΔF508 vs 3.9 ± 0.9 years for ΔF508/other and other/other; P = .03). No other age-adjusted clinical parameter was significantly associated with ΔF508 or any other genotype. Conclusion. These data suggest that in this sample of CF patients, ΔF508 genotype is not predictive of disease severity. The lack of association between disease severity and genotype in this ethnically diverse sample may reflect the presence of more severe undetected mutations in our sample, or the effects of modifying genes at other, non-CF loci.

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Rectal organoid morphology analysis (ROMA) as a promising diagnostic tool in cystic fibrosis

Thorax ◽

10.1136/thoraxjnl-2020-216368 ◽

2021 ◽

pp. thoraxjnl-2020-216368

Author(s):

Senne Cuyx ◽

Anabela Santo Ramalho ◽

Nikky Corthout ◽

Steffen Fieuws ◽

Eva Fürstová ◽

...

Keyword(s):

Cystic Fibrosis ◽

Image Analysis ◽

Diagnostic Tool ◽

Automated Image Analysis ◽

Sweat Chloride ◽

Morphology Analysis ◽

Morphological Differences ◽

Two Parameters ◽

Analysis Protocol

Diagnosing cystic fibrosis (CF) when sweat chloride is not in the CF range and less than 2 disease-causing CFTR mutations are found requires physiological CFTR assays, which are not always feasible or available. We developed a new physiological CFTR assay based on the morphological differences between rectal organoids from subjects with and without CF. In organoids from 167 subjects with and 22 without CF, two parameters derived from a semi-automated image analysis protocol (rectal organoid morphology analysis, ROMA) fully discriminated CF subjects with two disease-causing mutations from non-CF subjects (p<0.001). ROMA, feasible at all ages, can be centralised to improve standardisation.

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Atypical cystic fibrosis of the pancreas with normal levels of sweat chloride and minimal pancreatic lesions

The Journal of Pediatrics ◽

10.1016/s0022-3476(79)80830-6 ◽

1979 ◽

Vol 94 (2) ◽

pp. 237-239 ◽

Cited By ~ 20

Author(s):

Dale S. Huff ◽

Nancy N. Huang ◽

James B. Arey

Keyword(s):

Cystic Fibrosis ◽

Sweat Chloride

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Elexacaftor-Tezacaftor-Ivacaftor: The First Triple-Combination Cystic Fibrosis Transmembrane Conductance Regulator Modulating Therapy

The Journal of Pediatric Pharmacology and Therapeutics ◽

10.5863/1551-6776-25.3.192 ◽

2020 ◽

Vol 25 (3) ◽

pp. 192-197 ◽

Cited By ~ 4

Author(s):

Kaden Ridley ◽

Michelle Condren

Keyword(s):

Cystic Fibrosis ◽

Clinical Trials ◽

Genetic Mutations ◽

Transmembrane Conductance Regulator ◽

Triple Combination ◽

Transmembrane Conductance ◽

Sweat Chloride ◽

Cystic Fibrosis Transmembrane

Elexacaftor-tezacaftor-ivacaftor is a newly approved triple-combination cystic fibrosis transmembrane conductance regulator (CFTR) modulating therapy that contains 2 correctors and a potentiator of the CFTR channel. Its labeled indication for use is for persons 12 years of age and older with at least 1 F508del mutation for the CFTR gene. This drug combination provides potential therapy to many patients who had previously been excluded from CFTR modulation therapy due to the nature of their genetic mutations. The efficacy demonstrated in clinical trials surpasses the currently available therapies related to lung function, quality of life, sweat chloride reduction, and reducing exacerbations. The most common adverse events seen in clinical trials included rash and headache, and laboratory monitoring is recommended to evaluate liver function. Continued evaluation of patient data is needed to confirm its long-term safety and efficacy. Elexacaftor-tezacaftor-ivacaftor is a monumental and encouraging therapy for cystic fibrosis; however, approximately 10% of the CF population are not candidates for this or any other CFTR modulation therapy.

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Revisiting sweat chloride test results based on recent guidelines for diagnosis of cystic fibrosis

Practical Laboratory Medicine ◽

10.1016/j.plabm.2018.01.001 ◽

2018 ◽

Vol 10 ◽

pp. 34-37 ◽

Cited By ~ 8

Author(s):

Jayson V. Pagaduan ◽

Mahesheema Ali ◽

Michael Dowlin ◽

Liye Suo ◽

Tabitha Ward ◽

...

Keyword(s):

Cystic Fibrosis ◽

Test Results ◽

Sweat Chloride

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A European regulatory perspective on cystic fibrosis: current treatments, trends in drug development and translational challenges for CFTR modulators

European Respiratory Review ◽

10.1183/16000617.0124-2017 ◽

2018 ◽

Vol 27 (148) ◽

pp. 170124 ◽

Cited By ~ 8

Author(s):

Stefano Ponzano ◽

Giulia Nigrelli ◽

Laura Fregonese ◽

Irmgard Eichler ◽

Fabio Bertozzi ◽

...

Keyword(s):

Cystic Fibrosis ◽

Drug Development ◽

Forced Expiratory Volume ◽

The European Union ◽

End Points ◽

Sweat Chloride ◽

European Regulatory ◽

Clinical Models ◽

Cf Transmembrane Conductance Regulator ◽

Cftr Modulators

In this article we analyse the current authorised treatments and trends in early drug development for cystic fibrosis (CF) in the European Union for the time period 2000–2016. The analysis indicates a significant improvement in the innovation and development of new potential medicines for CF, shifting from products that act on the symptoms of the disease towards new therapies targeting the cause of CF. However, within these new innovative medicines, results for CF transmembrane conductance regulator (CFTR) modulators indicate that one major challenge for turning a CF concept product into an actual medicine for the benefit of patients resides in the fact that, although pre-clinical models have shown good predictability for certain mutations, a good correlation to clinical end-points or biomarkers (e.g. forced expiratory volume in 1 s and sweat chloride) for all mutations has not yet been achieved. In this respect, the use of alternative end-points and innovative nonclinical models could be helpful for the understanding of those translational discrepancies. Collaborative endeavours to promote further research and development in these areas as well as early dialogue with the regulatory bodies available at the European competent authorities are recommended.

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Advances in the Diagnosis and Management of Cystic Fibrosis in the Genomic Era

Clinical Chemistry ◽

10.1373/clinchem.2017.274670 ◽

2018 ◽

Vol 64 (6) ◽

pp. 898-908 ◽

Cited By ~ 7

Author(s):

Joesph R Wiencek ◽

Stanley F Lo

Keyword(s):

Cystic Fibrosis ◽

Multidisciplinary Care ◽

Disease Status ◽

Reference Intervals ◽

Patient Registries ◽

Screening Programs ◽

Sweat Chloride ◽

Clinical Databases ◽

Standard Of Practice ◽

Cf Transmembrane Conductance Regulator

Abstract BACKGROUND Cystic fibrosis (CF) is a complex autosomal recessive disease that continues to present unique diagnostic challenges. Because CF was first described in 1938, there has been a substantial growth of genetic and phenotypic information about the disorder. During the past few years, as more evidence has become available, a consortium of international experts determined that the 2008 guidelines from the CF Foundation needed to be reviewed and updated. CONTENT The goal of this review is to highlight the latest advances in CF multidisciplinary care, together with the recent updates to the 2017 CF Foundation diagnostic guidelines. SUMMARY Data from newborn screening programs, patient registries, clinical databases, and functional research have led to a better understanding of the CF transmembrane conductance regulator (CFTR) gene. Recent consensus guidelines have provided recommendations for clinicians and laboratorians to better assist with interpretation of disease status and related CF mutations. The highly recommended Clinical and Functional Translation of CFTR project should be the first resource in the evaluation of disease severity for CF mutations. Screen-positive newborns and patients with high clinical suspicion for CF are always recommended to undergo confirmatory sweat chloride testing with interpretations based on updated reference intervals. Every patient diagnosed with CF should receive genotyping, as novel molecular therapies are becoming standard of practice. The future of CF management must consider healthcare system disparities as CF transitions from a historically childhood disease to a predominantly adult epidemic.

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Sputum Neutrophil Elastase in pediatric cystic fibrosis and non-cystic fibrosis bronchiectasis

QJM ◽

10.1093/qjmed/hcab113.027 ◽

2021 ◽

Vol 114 (Supplement_1) ◽

Author(s):

Eman M Fouda ◽

Heba A Ali ◽

Mona A. A Salem ◽

Heba H Radwan

Keyword(s):

Cystic Fibrosis ◽

Neutrophil Elastase ◽

Severity Index ◽

Cross Sectional Study ◽

University Hospital ◽

Cross Sectional ◽

Sweat Chloride ◽

Chronic Lung Diseases ◽

Severe Group ◽

Group B

Abstract Objective To assess the value of sputum neutrophil elastase as a biomarker of severity in cases of non-cystic fibrosis bronchectasis & cystic fibrosis. Methods This cross-sectional study was conducted on 50 bronchiectasis patients aged from 1 to 13 years presented to pediatric chest clinic and department of Ain shams university hospital., there were classified into 2 groups; Group A cystic fibrosis patients(30) and group B non-cystic fibrosis bronchiectasis patients(20). Inclusion criteria :children aged from 1 to 16 years, patients were diagnosed with bronchiectasis clinically and with HRCT chest and cystic Fibrosis patients were diagnosed by positive sweat chloride test and genetic study. Exclusion Criteria includes no other known chronic lung diseases. All patients were evaluated by full medical history and full clinical examination, the following lab investigations were done :sweat chloride test, CFTR mutation study, sputum sampling and culture. Quantitative sputum neutrophil elastase assay was done, and the severity of disease was assessed using clinical scores as SK score ,FACED score and bronchiectasis severity index and by using radiological scores as Bhalla and modified Reiff score. Results Steatorrhea was more prevalent among cystic fibrosis patients (80%) than non-CF bronchiectasis patients (0%).(P = 0.00). Clubbing was more prevalent among non -cystic fibrosis bronchectasis (10) (50 %), than cystic fibrosis (2 patients) (6.7 %).(P = 0.00). In cystic fibrosis, neutrophil elastase was significantly higher among severe group (126 ng/mL) than among the moderate (30 ng/mL) and mild (16 ng/mL) groups.(P = 0.00). While in non-CF bronchiectasis patients, neutrophil elastase was significantly higher among severe group (67 ng/mL) than among the moderate (24 ng/mL) and mild (11 ng/mL) groups.(P = 0.00) Conclusion There was a significant correlation between sputum neutrophil elastase and disease severity in bronchiectasis (both cystic fibrosis and non-CF).

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