Pulmonary exacerbations in primary ciliary dyskinesia

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Primary ciliary dyskinesia (PCD) is a rare inherited disorder of motile ciliary dysfunction characterized by impaired mucociliary clearance, chronic sino-pulmonary disease, and progressive bronchiectasis. Pulmonary exacerbations (PEx) are a major contributor to morbidity, lung function decline, and healthcare utilization in PCD, yet historically have been poorly defined and understudied. This review summarizes current evidence regarding the definition, epidemiology, pathophysiology, clinical impact, and management of PEx in PCD, with emphasis on recent advances that are beginning to establish a disease-specific evidence base. Recent international consensus efforts have proposed standardized definitions for PEx, although significant heterogeneity remains across clinical studies. Prospective cohort data demonstrate that PEx occur frequently across all age groups, including infancy, and are associated with impaired lung function recovery, structural lung damage, and increased disease severity, particularly in patients with chronic Pseudomonas aeruginosa infection. Emerging biomarkers such as lung clearance index and exhaled breath analysis using volatile organic compounds may improve prediction and monitoring of exacerbations. Management strategies currently rely largely on extrapolation from cystic fibrosis and non-cystic fibrosis bronchiectasis and include prompt antibiotic therapy, intensified airway clearance, and supportive care. However, recent randomized controlled trials, including BESTCILIA and CLEAN-PCD, have provided the first high-quality evidence supporting maintenance azithromycin therapy and airway hydration strategies in PCD. Despite these advances, important gaps remain regarding optimal exacerbation definitions, treatment duration, predictors of incomplete recovery, and the role of anti-inflammatory and targeted therapies. CONCLUSION: Continued international collaboration, validated outcome measures, and development of mechanism-based therapies will be essential to improve long-term outcomes for patients with PCD. WHAT IS KNOWN: • Primary ciliary dyskinesia (PCD) is a rare inherited disorder of motile ciliary dysfunction causing chronic sino-pulmonary disease, recurrent respiratory infections, and progressive bronchiectasis from early childhood. • Pulmonary exacerbations (PEx) are a major driver of morbidity and lung function decline in PCD, but have historically been inconsistently defined and understudied, with management largely extrapolated from cystic fibrosis and non-CF bronchiectasis. Recent international consensus efforts have proposed standardized definitions for PEx, although significant heterogeneity remains across clinical studies. WHAT IS NEW: • Prospective international cohort data (Schreck et al. 2026) establish a PEx incidence of approximately 3.1 per person per year across all age groups, with higher risk in adult females and Pseudomonas aeruginosa-colonized patients. PEx are frequent even in the first 2 years of life. Pulmonary exacerbations cause substantial acute loss in forced expiratory volume in 1 s (FEV1), and approximately 20-25% of events do not recover to baseline lung function. • The BESTCILIA trial provides the first high-quality evidence that maintenance azithromycin reduces PEx frequency by 55% in PCD, and the CLEAN-PCD trial provides proof-of-concept for airway rehydration (ENaC blockade + hypertonic saline) as a PCD-specific therapeutic strategy.Novel anti-inflammatory therapies (DPP1 inhibitors, neutrophil elastase inhibitors), inhaled biologics, and gene-directed strategies are entering the PCD therapeutic pipeline and may transform future PEx prevention.

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