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      Effect of airway clearance therapies on mucociliary clearance in adults with cystic fibrosis: A randomized controlled trial

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          Abstract

          Background

          Cystic fibrosis (CF) is an inherited disorder causing impaired mucociliary clearance within the respiratory tract, and is associated with bronchiectasis, chronic respiratory infections, and early death. Airway clearance therapies have long been a cornerstone of management of individuals with CF, although evidence supporting their use is lacking. We designed a randomized controlled trial to quantitatively compare the effects of different forms of airway clearance on mucociliary clearance.

          Methods

          Three different physiotherapy methods to augment cough-clearance were studied in addition to cough-clearance alone: high-frequency chest-wall oscillating vest, oscillatory positive expiratory pressure, and whole-body vibration. We used gamma scintigraphy after inhalation of radiolabeled particles to quantify mucus clearance before, during, and after physiotherapy. As secondary endpoints, we measured concentrations of small molecules in exhaled breath that may impact mucus clearance.

          Results

          Ten subjects were enrolled and completed study procedures. No differences were identified between any method of airway clearance, including cough clearance alone. We did identify changes in certain small molecule concentrations in exhaled breath following airway clearance.

          Conclusions

          Due to the limitations of this study, we do not believe the negative results suggest a change in clinical practice with regard to airway clearance. Findings pertaining to small molecules in exhaled breath may serve as future opportunities for study.

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          Most cited references33

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          Mucus clearance as a primary innate defense mechanism for mammalian airways.

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            Mucus clearance and lung function in cystic fibrosis with hypertonic saline.

            Abnormal homeostasis of the volume of airway surface liquid in patients with cystic fibrosis is thought to produce defects in mucus clearance and airway defense. Through osmotic forces, hypertonic saline may increase the volume of airway surface liquid, restore mucus clearance, and improve lung function. A total of 24 patients with cystic fibrosis were randomly assigned to receive treatment with inhaled hypertonic saline (5 ml of 7 percent sodium chloride) four times daily with or without pretreatment with amiloride. Mucus clearance and lung function were measured during 14-day baseline and treatment periods. Long-term inhalation of hypertonic saline without pretreatment with amiloride (i.e., with placebo pretreatment) resulted in a sustained (> or =8 hours) increase in 1-hour rates of mucus clearance, as compared with those with amiloride pretreatment (14.0+/-2.0 vs. 7.0+/-1.5 percent, respectively; P=0.02) and increased 24-hour rates of mucus clearance over baseline. Furthermore, inhalation of hypertonic saline with placebo improved the forced expiratory volume in one second (FEV1) between the baseline period and the treatment period (mean difference, 6.62 percent; 95 percent confidence interval, 1.6 to 11.7; P=0.02), whereas hypertonic saline with amiloride did not improve FEV1 (mean difference, 2.9 percent; 95 percent confidence interval, -2.2 to 8.0; P=0.23). Forced vital capacity (FVC), the forced expiratory flow between 25 and 75 percent of FVC (FEF25-75), and respiratory symptoms also significantly improved in patients treated with hypertonic saline and placebo, whereas the residual volume as a proportion of total lung capacity (RV:TLC) did not change in either group. A comparison of the changes in lung function in the two groups showed no significant difference. In vitro data suggested that sustained hydration of airway surfaces was responsible for the sustained improvement in mucus clearance, whereas inhibition of osmotically driven water transport by amiloride accounted for the observed loss of clinical benefit. In patients with cystic fibrosis, inhalation of hypertonic saline produced a sustained acceleration of mucus clearance and improved lung function. This treatment may protect the lung from insults that reduce mucus clearance and produce lung disease. Copyright 2006 Massachusetts Medical Society.
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              Clinical mechanism of the cystic fibrosis transmembrane conductance regulator potentiator ivacaftor in G551D-mediated cystic fibrosis.

              Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator recently approved for patients with CF age 6 and older with the G551D mutation.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SoftwareRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SoftwareRole: ValidationRole: VisualizationRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: InvestigationRole: Project administrationRole: ResourcesRole: SoftwareRole: ValidationRole: VisualizationRole: Writing – review & editing
                Role: Formal analysisRole: MethodologyRole: SoftwareRole: ValidationRole: VisualizationRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SoftwareRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SoftwareRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS One
                plos
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                20 May 2022
                2022
                : 17
                : 5
                : e0268622
                Affiliations
                [1 ] Department of Medicine, Oregon Health and Science University (OHSU), Portland, Oregon, United States of America
                [2 ] Department of Medicine, University of North Carolina (UNC), Chapel Hill, North Carolina, United States of America
                University of Ottawa, CANADA
                Author notes

                Competing Interests: The authors received a PowerPlate® device from the manufacturer (Performance Health Systems LLC, Northbrook, IL, USA). This product was provided for the purposes of conducting this study without stipulation or conditions, and returned following completion of the study. No other goods, services, or any other form of compensation were provided to the authors by this entity. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

                Author information
                https://orcid.org/0000-0003-4290-8044
                Article
                PONE-D-21-05105
                10.1371/journal.pone.0268622
                9122229
                35594286
                763987f3-ec4a-4027-93e6-294b0bc26cb1
                © 2022 Trimble 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.

                History
                : 23 February 2021
                : 4 April 2022
                Page count
                Figures: 3, Tables: 2, Pages: 13
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100000897, Cystic Fibrosis Foundation;
                Award ID: REACT16A0
                Award Recipient :
                This work was supported by a grant to AT and SD from the Cystic Fibrosis Foundation ( http://www.cff.org REACT16A0). The funders of this study were not involved in the study design, execution of the procedures, data analysis, preparation of the manuscript, or decision to publish. Investigators received no financial support from commercial entities for the completion of this study. A PowerPlate® device was provided by the manufacturer, Performance Health Systems LLC, Northbrook, IL, USA.
                Categories
                Research Article
                Biology and Life Sciences
                Bioengineering
                Biotechnology
                Small Molecules
                Engineering and Technology
                Bioengineering
                Biotechnology
                Small Molecules
                Physical Sciences
                Chemistry
                Chemical Compounds
                Organic Compounds
                Small Molecules
                Physical Sciences
                Chemistry
                Organic Chemistry
                Organic Compounds
                Small Molecules
                Biology and Life Sciences
                Physiology
                Physiological Processes
                Coughing
                Medicine and Health Sciences
                Clinical Medicine
                Signs and Symptoms
                Coughing
                Medicine and Health Sciences
                Medical Conditions
                Genetic Diseases
                Autosomal Recessive Diseases
                Cystic Fibrosis
                Medicine and Health Sciences
                Clinical Genetics
                Genetic Diseases
                Autosomal Recessive Diseases
                Cystic Fibrosis
                Biology and Life Sciences
                Developmental Biology
                Fibrosis
                Cystic Fibrosis
                Medicine and Health Sciences
                Pulmonology
                Cystic Fibrosis
                Biology and Life Sciences
                Anatomy
                Body Fluids
                Mucus
                Medicine and Health Sciences
                Anatomy
                Body Fluids
                Mucus
                Biology and Life Sciences
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                Body Fluids
                Mucus
                Physical Sciences
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                Isotopes
                Biology and Life Sciences
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                Mucus
                Sputum
                Medicine and Health Sciences
                Anatomy
                Body Fluids
                Mucus
                Sputum
                Biology and Life Sciences
                Physiology
                Body Fluids
                Mucus
                Sputum
                Biology and Life Sciences
                Biochemistry
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                Purine Metabolism
                Biology and Life Sciences
                Biochemistry
                Glycobiology
                Glycosylamines
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                Adenosine
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