Airway Inflammation in Children with Primary Ciliary Dyskinesia

Understanding the role of airway inflammation in children with primary ciliary dyskinesia 

Primary ciliary dyskinesia (PCD) is a rare genetic condition that affects the cilia (hair-like structures) that line the airways. PCD leads to impaired mucociliary clearance and can result in chronic ear, sinus and lung infections. 

Clinical features of lung disease often appear in childhood and include:

• Chronic respiratory symptoms of cough, wheezing and shortness of breath
• Impaired lung function
• Bronchiectasis (damaged airways of the lung)

Lung disease severity and progression is related to genotype and ultrastructural defects of the cilia. 

Airway inflammation is the most common key indicator of lung disease in people with cystic fibrosis (CF) and non-CF bronchiectasis. Prior to this study, the relationship between airway inflammation and lung disease in PCD was not well understood. Study authors sought to better understand the role that airway inflammation plays in PCD lung disease. 

Using a multicenter cohort of children with PCD, researchers:

• Investigated if measurements of airway inflammation are linked to lung function, bronchiectasis and airway infections
• Assessed for differences in inflammatory measurements between different ciliary ultrastructural defect categories
• Compared sputum inflammatory measurements in children with PCD and an age-matched cohort of children with CF

Study design and sputum (mucus) analysis

The prospective, longitudinal, observational study was conducted at multiple clinical research sites of the National Institute of Health-funded Genetic Disorders of Mucociliary Clearance Consortium (GDMCC). 

Scott Sagel, MD, PhD, a pediatric pulmonologist and researcher in The Breathing Institute at Children’s Hospital Colorado, was the lead study author. He is lead site investigator for the GDMCC and medical director of the Clinical Translational Research Centers (CTRC) Core Laboratory at Children's Colorado, where study specimens were analyzed. 

Participants were clinically stable at the time of study visits.

Collected data:

• Demographic and clinical information
• Spirometry (lung function)
• Chest computed tomography (CT) scans (from biennial longitudinal study visits) scored to compute percent of and total structural lung disease of:
• Atelectasis
• Bronchiectasis
• Airway wall thickening
• Mucus plugging
• Spontaneously expectorated sputum samples tested for
• Staphylococcus aureus
• Haemophilus influenzae
• Streptococcus pneumoniae
• Moraxella catarrhalis
• Pseudomonas aeruginosa 
• Inflammation measurements

Sputum specimens were frozen on site after collection and shipped to the CTRC Laboratory in Colorado. Then they were thawed, processed and analyzed for markers of inflammation.

Relationships between sputum inflammation measurements and clinical outcomes 

Study participants were:

• 4.3 years mean age, initial diagnosis 
• 13.9 years mean age, specimen collection
• 51% female
• 80.8% FEV1 percent predicted mean

Baseline clinical features:

• 82% neonatal respiratory distress 
• 49% situs inversus/laterality defect 
• 95% chronic otitis media 
• 97% chronic nasal congestion 
• 97% chronic cough

Respiratory culture results:

• 18% Haemophilus influenzae
• 29% Staphylococcus aureus
• 12% Streptococcus pneumoniae
• 3% Moraxella catarrhalis
• 51% no pathogenic bacteria detected
• 35% one pathogenic bacterium detected
• 14% two or more pathogenic bacterium detected

Medications:

Ciliary ultrastructural defects and PCD-causing genes with two pathogenic or likely pathogenic variants identified in participants included:

• 36 with outer dynein arm (ODA) defects
• 6 with combined outer and inner dynein arm (ODA/IDA) defects
• 26 with absent IDA and microtubular disorganization (MTD) (IDA/MTD) defects
• 4 with normal ciliary ultrastructure
• 5 with other ciliary defects (1 oligocilia; 4 central apparatus (CA) defects)

Elevated concentrations of sputum proteases and cytokines were associated with impaired lung function and structural damage as determined by chest computed tomography.

In comparisons of sputum inflammation measures between groups:

• No differences in sputum inflammatory measurement concentrations found between the IDA/MTD and the ODA cohorts
• No differences in sputum inflammatory measures found between those routinely treated with azithromycin, hypertonic saline, dornase alfa or inhaled corticosteroids and those not treated
• Sputum IL-8 and TNF-a concentrations found to be significantly higher in PCD cohort compared with CF subject measurements; NE, IL-1b and IL-6 concentrations similar between both groups

Airway inflammation links and therapeutic interventions

Additional findings:

• H. influenzae and S. aureus were the most common bacteria isolated in the study cohort. 
• Individuals with detectable bacterial pathogens in sputa had greater inflammation compared to those without. 
• P. aeruginosa, associated with greater airway inflammation in CF, was not a common finding in the study cohort.
• There was a correlation between inflammation and CT-derived measures of bronchiectasis, mucus plugging and total structural lung disease.
• Higher NE concentrations were linked to impaired lung function and structural lung injury.
• IL-1b, IL-8 and TNF-a were associated with worse lung function and structural injury.

Significant findings:

• Sputum NE, IL-1b, IL-8 and TNF-a measurements can be used as biomarkers for PCD lung disease severity and activity.
• The justification was found for therapeutic interventions to reduce or neutralize free NE activity and proinflammatory cytokines to prevent their harmful effects on diseased PCD airways.
• Increased inflammation is not an exclusive feature of CF, despite longstanding debates.
• Inflammatory biomarkers could be useful outcome measures for clinical studies of the efficacy of mucoactive and anti-inflammatory drugs for PCD.

Conclusion: Sputum inflammatory measures are PCD biomarkers 

This study provides more knowledge into the role of lower airway inflammation in the development of PCD lung disease. Study findings demonstrated elevated concentrations of sputum proteases and cytokines were associated with impaired lung function and structural damage. The findings suggest sputum inflammatory measurements could serve as biomarkers in PCD for monitoring disease activity and provide measurable outcomes for clinical drug trials.