Mucus Properties In Children With Primary Ciliary Dyskinesia: Comparison With Cystic Fibrosis

doi:10.1378/chest.129.1.118

Chest

Volume 129, Issue 1, January 2006, Pages 118-123

https://doi.org/10.1378/chest.129.1.118 Get rights and content

Objective

It has been assumed that cystic fibrosis (CF) lung disease is due in part to abnormal airway mucus. Primary ciliary dyskinesia (PCD) is a form of bronchiectasis that is similar to CF in many ways but is caused by congenital defects in mucociliary clearance. Our objective was to compare the biophysical and transport properties of CF and PCD sputa in subjects matched for age and degree of lung function impairment.

Design, setting, participants

PCD patients (n = 19; mean age, 9.5 ± 3.0 years [± SD]; FEV₁, 65.0 ± 7.8 L) were recruited from the clinic at the Royal Brompton Hospital. Patients with CF (n = 30, mean age, 10.8 ± 2.6 years; FEV₁, 61.8 ± 22.8 L) were identified from the Wake Forest University School of Medicine CF Center. Pulmonary function testing and sputum collection were performed as part of routine, scheduled clinic visits.

Measurements

Pulmonary function was measured by spirometry, and sputum was collected during the pulmonary function test maneuver. Some patients were longitudinally assessed at visits during the course of 3 years. Sputum properties measured were dynamic viscoelasticity, wettability, cohesivity, interfacial (surface) tension, solids composition, DNA and interleukin (IL)-8 concentration, in vitro mucociliary transportability, and cough transportability.

Results

Inflammation as measured by IL-8 concentration was three times greater in the PCD sputa (p < 0.0001). There were no significant differences in the sputum biophysical or transport properties comparing CF with PCD sputum.

Conclusions

It is unlikely that established CF lung disease is principally due to abnormal sputum properties, and it is more likely that the biophysical and transport properties reflect disease severity regardless of whether bronchiectasis is due to CF or PCD.

Section snippets

Patients Studied

We recruited children attending the PCD clinic at the Royal Brompton Hospital. The diagnosis had been established on standard criteria, including nasal nitric oxide, ciliary beat frequency, and electron microscopy.¹¹¹ The comparison group were children with CF diagnosed according to the Consensus statement recommendations¹² who were attending the Wake Forest University CF Center. In both centers, spirometry was performed at each clinic visit according to American Thoracic Society guidelines.¹³

Patients

We recruited 19 PCD children, mean ± SD age, 9.5 ± 3.0 years. Fourteen children were able to perform spirometry; FEV₁ was 65.0 ± 7.8% of predicted and FVC was 78.6 ± 14.5% of predicted. Each subject produced a sputum sample at the same single visit. These subjects were age and pulmonary function matched with 30 children with CF who provided a total of 134 sputum samples at 1 to 11 clinic visits over 38 months. Of these, 39 specimens were large enough in volume for complete biophysical and

Discussion

This is the first study to evaluate the biophysical and transport properties of PCD sputum and one of the most comprehensive analyses conducted of CF sputum properties. The aim of this study was to try to determine whether differences between the properties of sputum from two carefully matched groups of patients with different neutrophilic airway diseases leading to bronchiectasis could account for the generally milder prognosis in PCD. The principal findings of this study are surprising. We

References (39)

RosensteinBJ et al.
The diagnosis of cystic fibrosis: a consensus statement
J Pediatr
(1998)
TomkiewiczRP et al.
Rheologic properties of airway secretions in cystic fibrosis, chronic bronchitis, and fatal asthma
Biorheology
(1995)
FeatherEA et al.
Sputum viscosity in cystic fibrosis of the pancreas and other pulmonary diseases
Br J Dis Chest
(1970)
TomkiewiczRP et al.
Rheologic properties of airway secretions in cystic fibrosis, chronic bronchitis, and fatal asthma
Biorheology
(1995)
LacosteJY et al.
Eosinophilic and neutrophilic inflammation in asthma, chronic bronchitis, and chronic obstructive pulmonary disease
J Allergy Clin Immunol
(1993)
YamamotoC et al.
Airway inflammation in COPD assessed by sputum levels of interleukin-B
Chest
(1997)
BushA et al.
Primary ciliary dyskinesia: diagnosis and standards of care
Eur Respir J
(1998)
CorenME et al.
Primary ciliary dyskinesia (PCD) in children: age at diagnosis and symptom history
Acta Paediatrica
(2002)
EllermanA et al.
Longitudinal study of lung function in a cohort of primary ciliary dyskinesia
Eur Respir J
(1997)
NoonePG et al.
Primary ciliary dyskinesia: diagnostic and phenotypic features
Am J Respir Crit Care Med
(2004)

GrubbBR et al.

Mucociliary transport determined byin vivomicrodialysis in the airways of normal and CF mice

Am J Physiol Lung Cell Mol Physiol

(2004)

McShaneD et al.

Normal mucociliary clearance in CF children: evidence against a CFTR-related defect

Eur Respir J

(2004)

LindstromM et al.

Long-term clearance from small airways in patients with cystic fibrosis

Eur Respir J

(2005)

TirouvanziamR et al.

Inflammation and infection in naive human cystic fibrosis airway grafts

Am J Respir Cell Mol Biol

(2000)

EllermanA et al.

Longitudinal study of lung function in a cohort of primary ciliary dyskinesia

Eur Respir J

(1997)

NoonePG et al.

Primary ciliary dyskinesia: diagnostic and phenotypic features

Am J Respir Crit Care Med

(2004)

NarangI et al.

Nitric oxide in chronic airway inflammation in children: diagnostic use and pathophysiological significance

Thorax

(2002)

Standardization of spirometry, 1994 update

Am J Respir Crit Care Med

(1995)

KingM et al.

Mucus rheology: relationship with transport

(1994)

Cited by (95)

Safety and efficacy of the epithelial sodium channel blocker idrevloride in people with primary ciliary dyskinesia (CLEAN-PCD): a multinational, phase 2, randomised, double-blind, placebo-controlled crossover trial
2024, The Lancet Respiratory Medicine
Mucociliary clearance is dysfunctional in people with primary ciliary dyskinesia, resulting in the accumulation of dehydrated mucus in the airways that is difficult to clear. We undertook a study to assess the benefit on lung function of treatment with a nebulised epithelial sodium channel (ENaC) blocker, idrevloride, with or without hypertonic saline, in people with primary ciliary dyskinesia.
The CLEAN-PCD trial was a phase 2, randomised, double-blind, placebo-controlled crossover trial conducted at 32 tertiary adult and paediatric care centres and university hospitals in Canada, Denmark, Germany, Italy, the Netherlands, Poland, the UK, and the USA. People with a confirmed diagnosis of primary ciliary dyskinesia, aged 12 years or older, with a percentage of predicted FEV₁ (ppFEV₁) in the range of 40% to <90%, were randomly assigned in a 2:2:1:1 ratio (block size=6), stratified by ppFEV₁ at screening, to one of four sequences: (1) idrevloride in hypertonic saline in treatment period 1 then hypertonic saline in treatment period 2; (2) hypertonic saline in treatment period 1 then idrevloride in hypertonic saline in treatment period 2; (3) idrevloride in treatment period 1 then placebo in treatment period 2; and (4) placebo in treatment period 1 then idrevloride in treatment period 2. The idrevloride dose was 85 μg and hypertonic saline was 4·2% NaCl. 3 mL of each study treatment was nebulised twice daily for 28 days in treatment periods 1 and 2; the two 28-day treatment periods were separated by a 28-day washout period. The primary endpoint was absolute change from baseline in ppFEV₁ after 28 days. Safety assessments and reports of adverse events were made at clinic visits during each treatment period and by a follow-up telephone call 28 days after the last dose of study drug. Additionally, adverse events could be reported at a follow-up telephone call 3 days after the start of dosing and as they arose. Participants who received at least one dose of study drug were included in the safety analyses (safety set), and those who also had spirometry data were included in the efficacy analyses (full analysis set). The completed study is registered (EudraCT 2015-004917-26; ClinicalTrials.gov NCT02871778).
Between Sep 14, 2016, and May 31, 2018, 216 patients were screened and 123 were randomly assigned to one of four crossover sequences. Across the two treatment periods, treatment with idrevloride in hypertonic saline was initiated in 80 patients and completed in 78 patients (all 78 had data available and were included in the analysis); hypertonic saline initiated in 81 patients and completed in 76 patients (75 had data available and were included in the analysis); idrevloride initiated in 37 patients and completed in 35 patients (34 had data available and were included in the analysis); and placebo initiated in 36 patients and completed in 34 patients (all 34 had data available and were included in the analysis). Greater absolute increases in ppFEV₁ from baseline to 28 days of treatment were seen with idrevloride in hypertonic saline (least-squares mean absolute change from baseline 1·0 percentage points, 95% CI –0·4 to 2·4) than with hypertonic saline alone (least-squares mean absolute change from baseline of –0·5 percentage points, –2·0 to 0·9; difference 1·5 percentage points, 95% CI <0·1 to 3·0; p=0·044). There was no significant difference in ppFEV₁ for the parallel comparison of idrevloride in hypertonic saline compared with placebo or the crossover comparison of idrevloride with placebo. Adverse events were similar across treatments (57 to 65% of patients). Cough occurred in a greater proportion of participants during treatments that contained idrevloride or hypertonic saline compared with placebo, and oropharyngeal pain occurred in a greater proportion of participants during idrevloride treatments than during treatment with hypertonic saline alone or placebo, whereas chest discomfort was more common during treatments that included hypertonic saline.
In this phase 2 crossover study, idrevloride in hypertonic saline was safe and associated with improved lung function over a 28-day period in people with primary ciliary dyskinesia compared with hypertonic saline alone. Larger, longer clinical studies are warranted to explore the potential benefits of idrevloride in combination with hypertonic saline in people with primary ciliary dyskinesia.
Parion Sciences, under agreement with Vertex Pharmaceuticals.
Association Between Viscoelastic Characteristics and Sputum Colour in Patients With Bronchiectasis
2023, Archivos de Bronconeumologia
A review of upper airway physiology relevant to the delivery and deposition of inhalation aerosols
2022, Advanced Drug Delivery Reviews
Developing effective oral inhaled drug delivery treatment strategies for respiratory diseases necessitates a thorough knowledge of the respiratory system physiology, such as the differences in the airway channel's structure and geometry in health and diseases, their surface properties, and mechanisms that maintain their patency. While respiratory diseases, such as chronic obstructive pulmonary disease (COPD) and asthma and their implications on the lower airways have been the core focus of most of the current research, the role of the upper airway in these diseases is less known, especially in the context of inhaled drug delivery. This is despite the fact that the upper airway is the passageway for inhaled drugs to be delivered to the lower airways, and their replicas are indispensable in current standards, such as the cascade impactor experiments for testing inhaled drug delivery technology. This review provides an overview of upper airway collapsibility and their mechanical properties, the effects of age and gender on upper airway geometry, and surface properties. The review also discusses how COPD and asthma affect the upper airway and the typical inhalation flow characteristics exhibited by the patients with these diseases.
Primary Ciliary Dyskinesia
2021, Encyclopedia of Respiratory Medicine, Second Edition
Primary ciliary dyskinesia (PCD) is a genetically and clinically heterogeneous lung disease. Dysfunction of motile cilia causes impaired mucociliary function. Patients typically present with neonatal respiratory distress of unknown cause, persistent daily wet cough, perennial rhinosinusitis, otitis media and bronchiectasis; 50% of patients have situs inversus. In this article we review the underlying genetics of PCD, and how this leads to progressive disease. We discuss what is known about the prevalence, natural history and risk factors for less favorable outcomes. We review current diagnostic and management strategies. Finally, we discuss future directions to maintain the trajectory of evidence.
Primary ciliary dyskinesia in the genomics age
2020, The Lancet Respiratory Medicine
Primary ciliary dyskinesia is a genetically and clinically heterogeneous syndrome. Impaired function of motile cilia causes failure of mucociliary clearance. Patients typically present with neonatal respiratory distress of unknown cause and then continue to have a daily wet cough, recurrent chest infections, perennial rhinosinusitis, otitis media with effusion, and bronchiectasis. Approximately 50% of patients have situs inversus, and infertility is common. While understanding of the underlying genetics and disease mechanisms have substantially advanced in recent years, there remains a paucity of evidence for treatment. Next-generation sequencing has increased gene discovery, and mutations in more than 40 genes have been reported to cause primary ciliary dyskinesia, with many other genes likely to be discovered. Increased knowledge of cilia genes is challenging perceptions of the clinical phenotype, as some genes reported in the last 5 years are associated with mild respiratory disease. Developments in genomics and molecular medicine are rapidly improving diagnosis, and a genetic cause can be identified in approximately 70% of patients known to have primary ciliary dyskinesia. Groups are now investigating novel and personalised treatments, although gene therapies are unlikely to be available in the near future.
Azithromycin promotes proliferation, and inhibits inflammation in nasal epithelial cells in primary ciliary dyskinesia
2023, Scientific Reports

View all citing articles on Scopus

: Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).

View full text

Chest

Original research: Airway SecretionsMucus Properties In Children With Primary Ciliary Dyskinesia: Comparison With Cystic Fibrosis

Objective

Design, setting, participants

Measurements

Results

Conclusions

Section snippets

Patients Studied

Patients

Discussion

J Pediatr

Biorheology

Br J Dis Chest

Biorheology

J Allergy Clin Immunol

Chest

Primary ciliary dyskinesia: diagnosis and standards of care

Eur Respir J

Primary ciliary dyskinesia (PCD) in children: age at diagnosis and symptom history

Acta Paediatrica

Longitudinal study of lung function in a cohort of primary ciliary dyskinesia

Eur Respir J

Primary ciliary dyskinesia: diagnostic and phenotypic features

Am J Respir Crit Care Med

Mucociliary transport determined byin vivomicrodialysis in the airways of normal and CF mice

Am J Physiol Lung Cell Mol Physiol

Normal mucociliary clearance in CF children: evidence against a CFTR-related defect

Eur Respir J

Long-term clearance from small airways in patients with cystic fibrosis

Eur Respir J

Inflammation and infection in naive human cystic fibrosis airway grafts

Am J Respir Cell Mol Biol

Longitudinal study of lung function in a cohort of primary ciliary dyskinesia

Eur Respir J

Primary ciliary dyskinesia: diagnostic and phenotypic features

Am J Respir Crit Care Med

Nitric oxide in chronic airway inflammation in children: diagnostic use and pathophysiological significance

Thorax

Standardization of spirometry, 1994 update

Am J Respir Crit Care Med

Mucus rheology: relationship with transport

Original research: Airway Secretions
Mucus Properties In Children With Primary Ciliary Dyskinesia: Comparison With Cystic Fibrosis