Chronic airway disease in primary ciliary dyskinesia-spiced with geno-phenotype associations

Abstract

Primary ciliary dyskinesia (PCD) can be defined as a multiorgan ciliopathy with a dominant element of chronic airway disease affecting the nose, sinuses, middle ear, and in particular, the lower airways. Although most patients with PCD are diagnosed during preschool years, it is obvious that the chronic lung disease starts its course already from birth. The many faces of the clinical picture change, as does lung function, structural lung damage, the burden of infection, and of treatment throughout life. A markedly severe neutrophil inflammation in the respiratory tract seems pervasive and is only to a minimal extent ameliorated by a treatment strategy, which is predominantly aimed at bacterial infections. An ever-increasing understanding of the different aspects, their interrelationships, and possible different age courses conditioned by the underlying genotype is the focus of much attention. The future is likely to offer personalized medicine in the form of mRNA therapy, but to that end, it is of utmost importance that all patients with PCD be carefully characterized and given a genetic diagnosis. In this narrative review, we have concentrated on lower airways and summarized the current understanding of the chronic airway disease in this motile ciliopathy. In addition, we highlight the challenges, gaps, and opportunities in PCD lung disease research.

Keywords: Primary; airway disease; chronic; ciliary; dyskinesia.

FIGURE 1

The vicious cycle of primary ciliary dyskinesia lung disease including current treatments with and without evidence and future possibilities for treatments. Abnormal ciliary function impairs mucociliary clearance and constitute along with abnormal mucus properties the initial link in the cycle predisposing individuals to microbial infections. Airway clearance techniques, hydrator therapies, and rhDNase may potentially increase the clearance, while gene/mRNA therapy could potentially restore ciliary function. Antibiotics are the primary treatment to prevent persistent colonization, while macrolides and inhaled corticosteroids (ICS) may reduce inflammation and and exacerbations, and β2‐agonists ameliorate bronchial obstruction. Neutrophil serine protease (NSP) inhibitors are potential treatments for reduction of inflammation and exacerbations in patients with bronchiectasis

FIGURE 2

Lung function and structural damage in two patients with primary cilia dyskinesia (PCD) at opposite ends of the age spectrum. Upper parts show flow‐volume curves from forced expiratory maneuvers with airway flow on the Y‐axis in liters per seconds (L/s) and volume on x‐axis in liters (L). Blue loops are the patients' actual performances, while the black line is the predicted/expected ideal flow‐volume loop (gray zone the reference interval). Tables in the middle displays predicted and best performance values of forced expired volume in first second (FEV1), forced expired vital capacity (FVC), FEV1/FVC%, peak expired flow (PEF), maximal (mid‐)expiratory flow at 50% of expired FVC, and maximal mid‐expiratory flow between 25 and 75% of expired FVC (MMEF 75/25). Z‐scores are displayed as green dots when values are within normal range etc. HRCT scans in the bottom show mucus plugging and “tree in bud” appearance to the left, while the right image demonstrates bilateral severe and multiple bronchiectasis at multiple locations but as typically seen in PCD preferentially at the bottom of the lungs. Notice also emphysematic appearance. A is a 9‐year‐old boy recently diagnosed demonstrating He demonstrates extreme difficulty in performing a smooth flow‐volume curve—note the jagged appearance. This is due to his mucus‐filled airways appearing on HRCT as white lines with budding—tree in bud. Later on, his lung function and HRCT improved significantly by treatment. B panel is a 72‐year‐old female with PCD just keeping an FEV1 above 40% of predicted