Diagnosis and management of primary ciliary dyskinesia

Abstract

Primary ciliary dyskinesia (PCD) is a rare autosomal recessive disorder with defective structure and/or function of motile cilia/flagella, causing chronic upper and lower respiratory tract infections, fertility problems, and disorders of organ laterality. Diagnosing PCD requires a combined approach utilizing characteristic phenotypes and complementary methods for detection of defects of ciliary function and ultrastructure, measurement of nasal nitric oxide and genetic testing. Currently, biallelic mutations in 31 different genes have been linked to PCD allowing a genetic diagnosis in approximately ~ 60% of cases. Management includes surveillance of pulmonary function, imaging, and microbiology of upper and lower airways in addition to daily airway clearance and prompt antibiotic treatment of infections. Early referral to specialized centers that use a multidisciplinary approach is likely to improve outcomes. Currently, evidence-based knowledge on PCD care is missing let alone management guidelines. Research and clinical investigators, supported by European and North American patient support groups, have joined forces under the name of BESTCILIA, a European Commission funded consortium dedicated to improve PCD care and knowledge. Core programs of this network include the establishment of an international PCD registry, the generation of disease specific PCD quality of life questionnaires, and the first randomized controlled trial in PCD.

Figure 1

Methods used for PCD diagnosis. (A, B) Immunofluorescence co-staining of human respiratory epithelial cells with DNAH5-specific antibodies (red) and antibodies against acetylated α-tubulin (green). Nuclei were stained with Hoechst 33342 (blue). Overlays and bright-field images are shown on the right. Whereas in healthy human respiratory epithelial cells (wt, A) both DNAH5 and acetylated α-tubulin antibodies co-localize along the entire length of the ciliary axonemes, in an individual with an outer dynein arm defect (B), the ODA heavy chain DNAH5 is absent from the axonemes. (C) Transmission electron tomography of healthy respiratory epithelial cells (wt) showing no ultrastructural abnormality. Outer dynein arms (ODAs) are highlighted with red arrows. In an individual with DNAH5 mutations, ODAs are missing. (D) Diagram of ciliary beat patterns as deduced from high-speed videomicroscopy. A normal ciliary beat pattern (wt) is characterized by a strong beating stroke (symbolized in grey) followed by a recovery stroke (symbolized in green). In DNAH5 mutant cilia, only a minimal residual ciliary activity is present.

Figure 2

Clinical features of primary ciliary dyskinesia. (A) Coronal computed tomography (CT) scan of a 17-year-old PCD individual showing diffuse pansinusitis with mucosal thickening and polyposis. (B) Endoscopic view showing nasal polyp (same patient). (C) Chest X-ray of a 6-year-old PCD individual with middle lobe atelectasis. Silhouetting of the right heart border is present. (D) Chest CT of a 6-year-old individual with situs inversus totalis. The left-sided middle lobe shows extensive bronchiectasis with volume loss (white arrow). In addition, consolidations and mucous impaction are present in the right upper lobe.