Airway Disease in Children with Primary Ciliary Dyskinesia: Impact of Ciliary Ultrastructure Defect and Genotype

Abstract

Rationale: Primary ciliary dyskinesia (PCD) is characterized by impaired mucociliary clearance, recurrent respiratory infections, progressive airway damage, and obstructive lung disease. Although the association of ciliary ultrastructure defect/genotype with the severity of airflow obstruction has been well characterized, their association with airway abnormalities on chest computed tomography (CT) has been minimally evaluated. Objectives: We sought to delineate the association of ciliary defect class/genotype with chest CT scores in children with PCD. Methods: Cross-sectional analysis of children with PCD (N = 146) enrolled in a prospective multicenter observational study, stratified by defect type: outer dynein arm (ODA), ODA/inner dynein arm (IDA), IDA/microtubular disorganization (MTD), and normal/near normal ultrastructure with associated genotypes. CTs were scored using the MERAGMA-PCD (Melbourne-Rotterdam Annotated Grid Morphometric Analysis for PCD), evaluating airway abnormalities in a hierarchical order: atelectasis, bronchiectasis, bronchial wall thickening, and mucus plugging/tree-in-bud opacities. The volume fraction of each component was expressed as the percentage of total lung volume. The percentage of disease was computed as the sum of all components. Regression analyses were used to describe the association between clinical predictors and CT scores. Results: Acceptable chest CTs were obtained in 141 children (71 male): 57 ODA, 20 ODA/IDA, 40 IDA/MTD, and 24 normal/near normal. The mean (standard deviation) age was 8.5 (4.6) years, forced expiratory volume in 1 second (FEV₁) percent predicted was 82.4 (19.5), and %Disease was 4.6 (3.5). Children with IDA/MTD defects had a higher %Disease compared with children with ODA defects (2.71% higher [95% confidence interval (CI), 1.37-4.06; P < 0.001]), driven by higher %Mucus plugging (2.35% higher [1.43-3.26; P < 0.001]). Increasing age, lower body mass index, and lower FEV₁ were associated with a higher %Disease (0.23%; 95% CI, 0.11-0.35; P < 0.001 and 0.03%; 95% CI, 0.01-0.04; P = 0.008 and 0.05%; 95% CI, 0.01-0.08; P = 0.011, respectively). Conclusions: Children with IDA/MTD defects had significantly greater airway disease on CT, primarily mucus plugging, compared with children with ODA defects.

Keywords: PCD; bronchiectasis; computed tomography; lung function; pediatric lung disease.

Figure 1.

Flow chart outlining the enrolled participants. *Definite primary ciliary dyskinesia (PCD) is defined as abnormal ciliary ultrastructure by transmission electron microscopy and/or identification of two pathogenic variants in a PCD-associated gene together with compatible clinical features (Davis and colleagues [5]). CT = computed tomography.

Figure 2.

Spectrum of disease scores in 141 children with primary ciliary dyskinesia (PCD) using the (A) Melbourne-Rotterdam annotated grid morphometric analysis (MERAGMA)-PCD CT scoring system and (B) stratified by ciliary ultrastructural defect inner dynein arm/microtubular disorganization (IDA/MTD) versus (C) other. Stacked bar plots showing the wide spectrum of disease scores found by the MERAGMA-PCD scoring system. Participants are sorted on the basis of the total score percentage. %Disease for each patient is subdivided by the subscores %Bronchiectasis, %Mucus plugging, %Airway wall thickening, and %Atelectasis. (A) All children enrolled. (B) Children with PCD and IDA/MTD ciliary ultrastructural defects. (C) Children with PCD and all other ciliary ultrastructural defects. CT = computed tomography.

Figure 3.

Forest plots demonstrating the association between airway abnormalities on the basis of Melbourne-Rotterdam annotated grid morphometric analysis for primary ciliary dyskinesia (PCD) CT scores and ciliary ultrastructural defect* in 141 children with PCD. *Ciliary ultrastructural defect reference group ODA. Adjusted for age and sex. CI = confidence interval; CT = computed tomography; IDA = inner dynein arm; MTD = microtubular disorganization; ODA = outer dynein arm; US = ultrastructure.