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

2018 ◽  
Vol 64 (6) ◽  
pp. 898-908 ◽  
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.

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

2018 ◽  
Vol 27 (148) ◽  
pp. 170124 ◽  
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.

scholarly journals Hyponatremic dehydration and metabolic alkalosis as dominant manifestation in cystic fibrosis infants with mild phenotype - a case series

2018 ◽  
Vol 146 (9-10) ◽  
pp. 581-583 ◽  
Author(s):  
Stojka Fustik ◽  
Tatjana Jakovska ◽  
Dijana Plaseska-Karanfilska
Keyword(s):  
Cystic Fibrosis ◽  
Metabolic Alkalosis ◽  
Clinical Symptoms ◽  
Gastrointestinal Symptoms ◽  
Case Series ◽  
Mild Phenotype ◽  
Mean Values ◽  
Sweat Chloride ◽  
Cf Transmembrane Conductance Regulator ◽  
Compound Heterozygotes

Introduction. Due to increased losses of chloride and sodium in the sweat, children with cystic fibrosis (CF) are predisposed to develop episodes of hyponatremic/hypochloremic dehydration with hypokalemia and metabolic alkalosis when they sweat excessively. Even the patients with mild phenotype may have such episodes of dehydration and salt depletion. Outline of cases. Six cases of pancreatic sufficient (PS) CF patients complicated with episodes of severe hyponatremic dehydration with metabolic alkalosis in infancy are presented. The mean age was 6.3 ? 2.16 months at admission. All the cases had no symptoms suggestive of CF before admission. The most common clinical symptoms at the time of hospitalization were vomiting, anorexia, weight loss, dehydration, irritation, or lethargy. Mean values of blood pH, serum bicarbonate, sodium, chloride, and potassium (mmol/l) were as follows: 7.59 ? 0.06, 41.73 ? 5.78, 117.52 ? 2.88, 66.0 ? 11.58 and 2.62 ? 0.37, respectively. Sweat chloride test was pathological and ranged 69?120 mmol/L. The determination of fecal elastase-1 proved that they were PS (values > 200 ?g/g stool). CF transmembrane conductance regulator gene analyses in six cases confirmed the diagnosis of CF; namely, patients were compound heterozygotes for F508del and other rare mutation or compound heterozygotes for two rare mutations. Conclusion. Distinctive about these cases is that they were PS and had very mild presentation of CF. Without these episodes of dehydration, these patients would have remained undiagnosed until later age. CF should be considered in infants and children presenting with hypoelectrolytemia and metabolic alkalosis even in the absence of respiratory or gastrointestinal symptoms.

scholarly journals Intranasal micro-optical coherence tomography imaging for cystic fibrosis studies

2019 ◽  
Vol 11 (504) ◽  
pp. eaav3505 ◽  
Author(s):  
Hui Min Leung ◽  
Susan E. Birket ◽  
Chulho Hyun ◽  
Timothy N. Ford ◽  
Dongyao Cui ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Optical Coherence Tomography ◽  
Imaging Techniques ◽  
Disease Status ◽  
Cellular Level ◽  
Clear Understanding ◽  
Mucociliary Transport ◽  
Optical Coherence ◽  
Upper Airways ◽  
Cf Transmembrane Conductance Regulator

Cystic fibrosis (CF) is a genetic disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Although impairment of mucociliary clearance contributes to severe morbidity and mortality in people with CF, a clear understanding of the pathophysiology is lacking. This is, in part, due to the absence of clinical imaging techniques capable of capturing CFTR-dependent functional metrics at the cellular level. Here, we report the clinical translation of a 1-μm resolution micro-optical coherence tomography (μOCT) technology to quantitatively characterize the functional microanatomy of human upper airways. Using a minimally invasive intranasal imaging approach, we performed a clinical study on age- and sex-matched CF and control groups. We observed delayed mucociliary transport rate at the cellular level, depletion of periciliary liquid layer, and prevalent loss of ciliation in subjects with CF. Distinctive morphological differences in mucus and various forms of epithelial injury were also revealed by μOCT imaging and had prominent effects on the mucociliary transport apparatus. Elevated mucus reflectance intensity in CF, a proxy for viscosity in situ, had a dominant effect. These results demonstrate the utility of μOCT to determine epithelial function and monitor disease status of CF airways on a per-patient basis, with applicability for other diseases of mucus clearance.

scholarly journals Two years of newborn screening for cystic fibrosis in North Macedonia: First experience

2021 ◽  
Vol 24 (1) ◽  
pp. 41-46
Author(s):  
S Fustik ◽  
V Anastasovska ◽  
D Plaseska-Karanfilska ◽  
A Stamatova ◽  
L Spirevska ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pilot Study ◽  
Newborn Screening ◽  
Chloride Concentration ◽  
Sweat Test ◽  
Sweat Chloride ◽  
Frequent Mutations ◽  
Cftr Mutations ◽  
The Republic ◽  
Cf Transmembrane Conductance Regulator

Abstract There is a widely accepted consensus on the benefits of newborn screening (NBS) for cystic fibrosis (CF) in terms of reduced disease severity, improved quality of life, lower treatment burden, and reduced costs. More and more countries in the world are introducing NBS for CF as a national preventive health program. Newborn screening for CF was introduced in the Republic of North Macedonia (RNM) in April, 2019, after a pilot study of 6 months in 2018. A two-step immunoreactive trysinogen (IRT-IRT) algorithm is performed, and then a sweat test for confirmation/exclusion of the CF diagnosis when the IRT values were both over the cutoff (70.0 and 45.0 ng/mL, respectively). In cases with confirmed diagnosis of CF (a sweat chloride concentration >60.0 mmol/L) or with intermediate sweat test results (a sweat chloride concentration of between 30.0 and 59.0 mmol/L), CF transmembrane conductance regulator (CFTR) mutation analysis is performed. By the end of 2020, over a period of 27 months, including the pilot study period, a total number of 43,139 newborns were screened for CF. Seventeen (0.039%) newborns were diagnosed with CF. In all newly discovered CF cases by screening, the diagnosis was confirmed by determination of the CFTR mutations. The most common CFTR mutation, F508del, was found with an overall incidence of 70.6%. Other more frequent mutations were G542X (11.8%) and N1303K (5.9%). Four mutations were found in one CFTR allele each: G1349D, G126D, 457TAT>G and CFTRdupexon22, with the last one being newly discovered with unknown consequences. An incredibly large difference was found in the incidence of the disease between the Macedonian and Albanian neonatal population, with almost four time higher prevalence among Albanians (1:4530 vs. 1:1284).

scholarly journals Cystic fibrosis

2019 ◽  
Vol 13 (1) ◽  
pp. 39-46
Author(s):  
Jen Standen
Keyword(s):  
Cystic Fibrosis ◽  
Genetic Testing ◽  
Neonatal Screening ◽  
Tertiary Care ◽  
Multidisciplinary Care ◽  
Shared Care ◽  
The Uk

In the UK over 10 000 people live with cystic fibrosis (CF), with 1-in-25 people being carriers of the disease. Multidisciplinary care is provided by tertiary care CF centres, with or without local secondary service shared care agreements. There are still, however, several reasons why CF sufferers or their families present to their GPs. This article aims to provide a brief overview of CF and its management. It also gives the information needed to guide patients about genetic testing and neonatal screening for the disease.

ΔF508 Genotype Does Not Predict Disease Severity in an Ethnically Diverse Cystic Fibrosis Population

PEDIATRICS ◽  
1994 ◽  
Vol 93 (1) ◽  
pp. 114-118
Author(s):  
Lucille A. Lester ◽  
Jerome Kraut ◽  
John Lloyd-Still ◽  
Theodore Karrison ◽  
Carol Mott ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Disease Severity ◽  
Ethnically Diverse ◽  
Clinical Parameter ◽  
Population Based ◽  
Age At Diagnosis ◽  
Chest Roentgenogram ◽  
Sweat Chloride ◽  
Cystic Fibrosis Population ◽  
Cftr Mutations

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.

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

Thorax ◽  
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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