Primary Ciliary Dyskinesia: Longitudinal Study of Lung Disease by Ultrastructure Defect and Genotype.

TitlePrimary Ciliary Dyskinesia: Longitudinal Study of Lung Disease by Ultrastructure Defect and Genotype.
Publication TypeJournal Article
Year of Publication2019
AuthorsDavis, SD, Rosenfeld, M, Lee, H-S, Ferkol, TW, Sagel, SD, Dell, SD, Milla, C, Pittman, JE, Shapiro, AJ, Sullivan, KM, Nykamp, KR, Krischer, JP, Zariwala, MA, Knowles, MR, Leigh, MW
JournalAm J Respir Crit Care Med
Volume199
Issue2
Pagination190-198
Date Published2019 Jan 15
ISSN1535-4970
Abstract

RATIONALE: In primary ciliary dyskinesia, factors leading to disease heterogeneity are poorly understood.

OBJECTIVES: To describe early lung disease progression in primary ciliary dyskinesia and identify associations between ultrastructural defects and genotypes with clinical phenotype.

METHODS: This was a prospective, longitudinal (5 yr), multicenter, observational study. Inclusion criteria were less than 19 years at enrollment and greater than or equal to two annual study visits. Linear mixed effects models including random slope and random intercept were used to evaluate longitudinal associations between the ciliary defect group (or genotype group) and clinical features (percent predicted FEV and weight and height z-scores).

MEASUREMENTS AND MAIN RESULTS: A total of 137 participants completed 732 visits. The group with absent inner dynein arm, central apparatus defects, and microtubular disorganization (IDA/CA/MTD) (n = 41) were significantly younger at diagnosis and in mixed effects models had significantly lower percent predicted FEV and weight and height z-scores than the isolated outer dynein arm defect (n = 55) group. Participants with CCDC39 or CCDC40 mutations (n = 34) had lower percent predicted FEV and weight and height z-scores than those with DNAH5 mutations (n = 36). For the entire cohort, percent predicted FEV decline was heterogeneous with a mean (SE) decline of 0.57 (0.25) percent predicted/yr. Rate of decline was different from zero only in the IDA/MTD/CA group (mean [SE], -1.11 [0.48] percent predicted/yr; P = 0.02).

CONCLUSIONS: Participants with IDA/MTD/CA defects, which included individuals with CCDC39 or CCDC40 mutations, had worse lung function and growth indices compared with those with outer dynein arm defects and DNAH5 mutations, respectively. The only group with a significant lung function decline over time were participants with IDA/MTD/CA defects.

DOI10.1164/rccm.201803-0548OC
Alternate JournalAm. J. Respir. Crit. Care Med.
PubMed ID30067075
PubMed Central IDPMC6353004
Grant ListU54 HG006493 / HG / NHGRI NIH HHS / United States
UC2 HL102926 / HL / NHLBI NIH HHS / United States
UM1 HG006504 / HG / NHGRI NIH HHS / United States
RC2 HL102926 / HL / NHLBI NIH HHS / United States
UL1 TR001863 / TR / NCATS NIH HHS / United States
U54 HL096458 / HL / NHLBI NIH HHS / United States
R01 HL071798 / HL / NHLBI NIH HHS / United States
UL1 TR001082 / TR / NCATS NIH HHS / United States