Bronchial tree-shaped mucous plug in cystic fibrosis: imaging-guided management

Many physicians do not accept the hypothesis put forward in Dr. Chadwick's letter but rather they still accept the statement by the Committee on Therapy regarding the treatment of cystic fibrosis. This document states, "the aim of nebulization therapy in cystic fibrosis is to deposit particles of water or water-containing medication in the bronchial tree at the site of the disease process" and further goes on to state "nebulization or aerosol therapy must not be confused with humidification."

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Novel molecular approaches to cystic fibrosis gene therapy

Biochemical Journal ◽

10.1042/bj20041923 ◽

2005 ◽

Vol 387 (1) ◽

pp. 1-15 ◽

Cited By ~ 47

Author(s):

Tim W. R. LEE ◽

David A. MATTHEWS ◽

G. Eric BLAIR

Keyword(s):

Cystic Fibrosis ◽

Gene Therapy ◽

Gene Delivery ◽

Viral Vectors ◽

Bronchial Tree ◽

Endosomal Escape ◽

Host Cells ◽

Cystic Fibrosis Gene ◽

Viral Gene ◽

Molecular Approaches

Gene therapy holds promise for the treatment of a range of inherited diseases, such as cystic fibrosis. However, efficient delivery and expression of the therapeutic transgene at levels sufficient to result in phenotypic correction of cystic fibrosis pulmonary disease has proved elusive. There are many reasons for this lack of progress, both macroscopically in terms of airway defence mechanisms and at the molecular level with regard to effective cDNA delivery. This review of approaches to cystic fibrosis gene therapy covers these areas in detail and highlights recent progress in the field. For gene therapy to be effective in patients with cystic fibrosis, the cDNA encoding the cystic fibrosis transmembrane conductance regulator protein must be delivered effectively to the nucleus of the epithelial cells lining the bronchial tree within the lungs. Expression of the transgene must be maintained at adequate levels for the lifetime of the patient, either by repeat dosage of the vector or by targeting airway stem cells. Clinical trials of gene therapy for cystic fibrosis have demonstrated proof of principle, but gene expression has been limited to 30 days at best. Results suggest that viral vectors such as adenovirus and adeno-associated virus are unsuited to repeat dosing, as the immune response reduces the effectiveness of each subsequent dose. Nonviral approaches, such as cationic liposomes, appear more suited to repeat dosing, but have been less effective. Current work regarding non-viral gene delivery is now focused on understanding the mechanisms involved in cell entry, endosomal escape and nuclear import of the transgene. There is now increasing evidence to suggest that additional ligands that facilitate endosomal escape or contain a nuclear localization signal may enhance liposome-mediated gene delivery. Much progress in this area has been informed by advances in our understanding of the mechanisms by which viruses deliver their genomes to the nuclei of host cells.

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Repeatability of the 6-min walk test in non-cystic fibrosis bronchiectasis

Scientific Reports ◽

10.1038/s41598-020-75093-7 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Paula Maria Eidt Rovedder ◽

Rafael Oliveira Fernandes ◽

Patrícia Santos Jacques ◽

Bruna Ziegler ◽

Francini Porcher Andrade ◽

...

Keyword(s):

Cystic Fibrosis ◽

Intraclass Correlation ◽

Severity Index ◽

Bronchial Tree ◽

Test Reliability ◽

Walk Test ◽

Altman Plot ◽

Cross Sectional ◽

Minute Walk ◽

High Intraclass Correlation Coefficient

Abstract Non-cystic fibrosis bronchiectasis (NCFB) is a chronic lung disease characterized by progressive and irreversible changes of the bronchial tree. The evaluation of exercise capacity is essential to manage this disease. This study aims to determine the within-subject repeatability of two Six Minute Walk Test (6MWT) in adults with NCFB. NCFB. This cross-sectional observational study included 66 NCFB subjects above 18 years-old (mean of 55 ± 17 years old, 68% women). 73% of the participants presented moderate to severe clinical condition classified by Bronchiectasis Severity Index. It showed that these participants walked 16.6 m less (95%CI 3.8 to 29.4; p < 0.01) in the second 6MWT when compared to the first test, with a within-subject coefficient variation of 9.4% (95%CI 7.2–11.2%) and an intra-test reliability with a high intraclass correlation coefficient of 0.88 (95%CI 0.80–0.93). Bland–Altman plot showed an agreement regarding test repeatability, besides presented a large limit of agreement (− 85 to 116 m). Respiratory rate and systolic blood pressure were significantly higher before starting the second test. In conclusion, 6MWT seems to be reproducible in NCFB subjects and vital sign verification should be attentively checked to assess if the patient is fully recovered to perform a second test, as well as the disease severity score. Other studies on this matter should be conducted with a larger number of participants to confirm the findings of the present study.

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Targeted therapy for cystic fibrosis

Russian Pulmonology ◽

10.18093/0869-0189-2021-31-2-226-236 ◽

2021 ◽

Vol 31 (2) ◽

pp. 226-236

Author(s):

S. I. Kutsev ◽

V. L. Izhevskaya ◽

E. I. Kondratyeva

Keyword(s):

Cystic Fibrosis ◽

Pancreatic Insufficiency ◽

Mutant Gene ◽

Bronchial Tree ◽

Cftr Gene ◽

Protein Activity ◽

Enzyme Preparations ◽

Calorie Diet ◽

Cftr Protein ◽

Cftr Modulators

The basic therapy of cystic fibrosis is currently aimed at slowing down the pathological processes associated with a decrease in the CFTR protein activity (cystic fibrosis transmembrane conductance regulator) in the gastrointestinal tract and the respiratory system. The pancreatic insufficiency is well compensated by replacement therapy with microsphere enzyme preparations and a high-calorie diet rich in proteins and fat. Chronic treatment of cystic fibrosis-related lung disease aims to improve the clearance of the bronchial tree, suppressing chronic bacterial infection and local chronic inflammation. However, no therapy was available to correct the defect in the gene or its product until 2012.The aim was to analyze literature on CFTR modulators, including their efficacy and safety, and assess the potential for developing new modulators to treat cystic fibrosis.Materials. The review included literature data (45 publications) on the use of CFTR modulators and international websites’ data.Results. Since the discovery of the CFTR gene in 1989, more than 2000 mutations or variants of the CFTR gene (hereinafter referred to as genetic variants) have been described. They interfere with the synthesis of the CFTR protein, its transport to the apical membrane of the cell, or disrupt its function as a channel for chloride anions. Although it is currently not possible to completely replace the mutant gene with a normal copy, small molecules have been identified that can modify the mutant CFTR protein and amend its function. The potential therapeutic measures are determined by class of the mutation. In clinical practice, pharmacological modeling of ion transport is currently possible only with the use of CFTR modulators: correctors and potentiators. The review defines these groups of drugs and describes 4 licensed CFTR modulators, including molecules of ivacaftor, lumacaftor, tezacaftor, elexacaftor. The data on the promising emerging next generation modulators and the prospects for the personalized selection of drugs using the assays on intestinal organoids are presented.

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RADIOLOGIC DIAGNOSTIC'S CAPABILITIES OF LUNG INJURY IN ADULT PATIENTS WITH CYSTIC FIBROSIS

Medical Science of Ukraine (MSU) ◽

10.32345/2664-4738.1-2.2019.07 ◽

2019 ◽

Vol 15 (1-2) ◽

pp. 51-58

Author(s):

N.L. Morozova ◽

M.M. Tkachenko ◽

A.A. Romanenko

Keyword(s):

Cystic Fibrosis ◽

Lung Injury ◽

Structural Changes ◽

Diagnostic Value ◽

Bronchial Tree ◽

Adult Patients ◽

Lung Damage ◽

Ct Scans ◽

Diagnostic Process ◽

Adequate Treatment

Relevance. The viability of patients is determined by the degree of lung injury despite the fact that cystic fibrosis (CF) is a multiple organ disease. Early diagnosis and adequate treatment complex of cystic fibrosis prolong the lives of patients and improves its quality. Therefore, timely and detailed diagnosis of cystic fibrosis lung is particularly important problem. The central role for its solution belongs to radiological studies. Objective. To refine the radiology’s capabilities in detecting lung changes in case of cystic fibrosis in adult patients and to determine the role of the computed tomography (CT) in the diagnostic process. Materials and methods. The results of radiography and CT scans of 15 patients, for whom the diagnosis of CF was established in adulthood, were analyzed. Results. The most typical radiographic and CT signs of lung damage were determined in adult CF patients. It has been shown that the radiographic changes in the lungs are non-specific for CF patients and are determined by the secondary inflammatory process. The diagnostic capabilities of CT scans in detecting subtle structural changes in the lung tissue and bronchial tree are underlined, which allows to diagnose light and atypical forms of CF in adults, determinate the stage and activity of the pathological process and the effectiveness of the treatment. Findings. The radiation studies were able to define the CF’s specific symptoms of lung lesions. Radiography of the thoracic cavity’s organs is a necessary step in the preliminary diagnosis for adult patients with CF or in the medical emergency's cases. The CT has the greatest diagnostic value in detecting subtle structural and functional specific changes of CF. The regular monitoring using CT scans is necessary for improving the control of the respiratory organs’ state and determine the further tactics for the particular patient.

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Imaging in non-cystic fibrosis bronchiectasis and current limitations

BJR|Open ◽

10.1259/bjro.20210026 ◽

2021 ◽

Vol 3 (1) ◽

pp. 20210026

Author(s):

Roberta Eufrasia Ledda ◽

Maurizio Balbi ◽

Francesca Milone ◽

Andrea Ciuni ◽

Mario Silva ◽

...

Keyword(s):

Cystic Fibrosis ◽

Respiratory Symptoms ◽

Quantitative Imaging ◽

Scoring Systems ◽

Bronchial Tree ◽

Research Setting ◽

Radiological Criteria ◽

Prognostic Data ◽

Ct Features

Non-cystic fibrosis bronchiectasis represents a heterogenous spectrum of disorders characterised by an abnormal and permanent dilatation of the bronchial tree associated with respiratory symptoms. To date, diagnosis relies on computed tomography (CT) evidence of dilated airways. Nevertheless, definite radiological criteria and standardised CT protocols are still to be defined. Although largely used, current radiological scoring systems have shown substantial drawbacks, mostly failing to correlate morphological abnormalities with clinical and prognostic data. In limited cases, bronchiectasis morphology and distribution, along with associated CT features, enable radiologists to confidently suggest an underlying cause. Quantitative imaging analyses have shown a potential to overcome the limitations of the current radiological criteria, but their application is still limited to a research setting. In the present review, we discuss the role of imaging and its current limitations in non-cystic fibrosis bronchiectasis. The potential of automatic quantitative approaches and artificial intelligence in such a context will be also mentioned.

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Upper respiratory tract diseases in patients with cystic fibrosis

Consilium Medicum ◽

10.26442/20751753.2021.9.201024 ◽

2021 ◽

Vol 23 (9) ◽

pp. 441-444

Author(s):

Eduard V. Sinkov ◽

Keyword(s):

Cystic Fibrosis ◽

Respiratory Tract ◽

Chronic Rhinosinusitis ◽

Lower Respiratory Tract ◽

Inflammatory Process ◽

Bronchial Tree ◽

Respiratory Epithelium ◽

Upper Respiratory Tract ◽

Respiratory Pathology ◽

Upper Respiratory

Among ENT organ diseases in patients with cystic fibrosis, chronic rhinosinusitis is leading. The respiratory epithelium lining the surface of the upper and lower respiratory tract has the same structure. And as a result, in patients with cystic fibrosis, along with the bronchial tree, the upper respiratory tract is involved in the inflammatory process, while chronic rhinosinusitis develops. Impaired drainage leads to stagnation of infected thick mucus. Timely examination and treatment of upper respiratory pathology in patients with cystic fibrosis is needed. In surgical treatment, the method of choice is extended FESS. Observation by an ENT physician and conservative treatment of polypose rhinosinusitis should be carried out throughout the life of a patient with cystic fibrosis.

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Pregnancy in cystic fibrosis of the pancreas

JAMA ◽

10.1001/jama.195.12.993 ◽

1966 ◽

Vol 195 (12) ◽

pp. 993-1000 ◽

Cited By ~ 9

Author(s):

R. J. Grand

Keyword(s):

Cystic Fibrosis

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Freeze-Fracture Examination of Tight Junctions of Human Eccrine Sweat Glands

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s1431927600002786 ◽

1980 ◽

Vol 38 ◽

pp. 634-635

Author(s):

J. V. Briggman ◽

J. Bigelow ◽

H. Bank ◽

S. S. Spicer

Keyword(s):

Cystic Fibrosis ◽

Freeze Fracture ◽

Sweat Glands ◽

Hypertonic Solution ◽

Dark Cells ◽

Clear Cells ◽

Junctional Complexes ◽

Secretory Coil ◽

Eccrine Sweat Glands ◽

Eccrine Sweat

The prevalence of strands shown by freeze-fracture in the zonula occludens of junctional complexes is thought to correspond closely with the transepi-thelial electrical resistance and with the tightness of the junction and its obstruction to paracellular flow.1 The complexity of the network of junc¬tional complex strands does not appear invariably related to the degree of tightness of the junction, however, as rabbit ileal junctions have a complex network of strands and are permeable to lanthanum. In human eccrine sweat glands the extent of paracellular relative to transcellular flow remains unknown, both for secretion of the isotonic precursor fluid by the coil and for resorption of a hypertonic solution by the duct. The studies reported here undertook, therefore, to determine with the freeze-fracture technique the complexity of the network of ridges in the junctional complexes between cells in the secretory coil and the sweat ducts. Glands from a patient with cystic fibrosis were also examined because an alteration in junctional strands could underlie the decreased Na+ resorption by sweat ducts in this disease. Freeze-fracture replicas were prepared by standard procedures on isolated coil and duct segments of human sweat glands. Junctional complexes between clear cells, between dark cells and between clear and dark cells on the main lumen, and between clear cells on intercellular canaliculi of the coil con¬tained abundant anastomosing closely spaced strands averaging 6.4 + 0.7 (mean + SE) and 9.0 +0.5 (Fig. 1) per complex, respectively. Thus, the junctions in the intercellular canaliculi of the coil appeared comparable in complexity to those of tight epithlia. Occasional junctions exhibited, in addition, 2 to 5 widely spaced anastomosing strands in a very close network basal to the compact network. The fewer junctional complexes observed thus far between the superficial duct cells consisted on the average of 6 strands arranged in a close network and 1 to 4 underlying strands that lay widely separated from one another (Fig. 2). The duct epitelium would, thus, be judged slightly more "leaky" than the coil. Infrequent junctional complexes observed to date in the secretory coil segment of a cystic fibrosis specimen disclosed rela¬tively few closely crowded strands.

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