Primary Ciliary Dyskinesia in Adult Bronchiectasis

Official title

Novel Use of Combined High-Speed Video Microscopy and Nasal Nitric Oxide Screening for Identification of Primary Ciliary Dyskinesia in Adult Bronchiectasis

Overview

The purpose of this study is to help determine how often primary ciliary dyskinesia (PCD) is present but undiagnosed in adults with bronchiectasis.

Detailed description

Bronchiectasis is a chronic respiratory disease characterized by irreversible bronchial dilatation, impaired mucociliary clearance, and recurrent infection. Despite comprehensive evaluation, 40-80% of adults with non-cystic fibrosis (CF) bronchiectasis have no identifiable cause. This diagnostic absence limits opportunities for targeted therapy, individualized prognostication, and potential genetic counseling.

Primary ciliary dyskinesia (PCD) is an inherited disorder of motile cilia that leads to chronic otosinopulmonary disease. Nearly 100% of affected individuals develop bronchiectasis by adulthood (4). Diagnosis is complex with no 'gold standard' test and requires multiple specialized diagnostics-most available only at large referral centers. In current North American practice, evaluation of suspected PCD frequently begins with measurement of nasal nitric oxide (nNO), an accurate screening tool when performed correctly. However, testing errors occur due to discrepancies in technique, and false negatives are well-described in a growing list of PCD genotypes harboring preserved ciliary ultrastructure, as well as in select primary immunodeficiencies.

High-speed video microscopy analysis (HSVA) is a key PCD diagnostic tool that directly visualizes ciliary beating ex vivo, providing detailed assessment of ciliary beat frequency, waveform, and pattern. As a functional assay, HSVA has substantial diagnostic value in cases where PCD would otherwise remain unrecognized (e.g., patients with normal nNO, normal/nondiagnostic transmission electron microscopy (TEM), or incomplete genetic testing). When performed using standardized protocols and blinded review, multicenter studies demonstrate excellent diagnostic performance, with sensitivities and specificities of of 96-100% and 91-96% respectively. Air-liquid interface (ALI) culture further refines accuracy by differentiating inherent ciliary defects from secondary, inflammation-induced abnormalities.

Growing evidence suggests that PCD remains significantly underrecognized worldwide. Large-scale genomic analyses now estimate a global prevalence as high as 1 in 7,500-two to four times higher than previous estimates. These findings are amplified in adults with bronchiectasis: a recent genomic sequencing study of patients with idiopathic bronchiectasis revealed that more than 10% carried pathogenic variants in motile ciliopathy genes, yet the vast majority had never undergone targeted testing for PCD.

Collectively, these data indicate that a substantial proportion of adults with bronchiectasis may have undiagnosed PCD. Identifying this population has meaningful clinical implications. Confirmation of PCD enables precise airway clearance and infection-control strategies, recognition and treatment of potential cardiac and multi-organ manifestations, and appropriate genetic counseling. Moreover, as disease-modifying and gene-targeted therapies advance toward clinical use, timely and accurate diagnosis will be essential to ensuring equitable access to emerging treatments.

Hypothesis: Unrecognized PCD is prevalent within a significant and measurable proportion of adults with non-CF bronchiectasis. The combined use of upfront nNO and HSVA of ALI-cultured ciliated nasal epithelia represents a unique, highly sensitive, and potentially diagnostic method to help identify this patient population.

Interventions

• Procedure Nasal Nitric Oxide Measurement
  Subjects will have their nasal nitric oxide measured using commercially available chemiluminescence analyzer in accordance with American Thoracic Society/European Respiratory Society guidelines
• Procedure Nasopharyngeal (Nasal) Samples
  Human nasal epithelial cells will be collected via nasal swab, nasal curettage or nasal brush from each nostril.

Primary outcome measures

• Percentage of participants with a screen positive result [Time frame: From Baseline through study completion, approximately two years.]

Eligibility criteria

Inclusion criteria

• Adults (≥18) with CT-confirmed bronchiectasis

Exclusion criteria

• Pre-existing diagnosis of cystic fibrosis
• Pre-existing diagnosis of primary ciliary dyskinesia
• Inability to perform testing
• Refusal of consent

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Diagnostic

Study locations

Center list to be confirmed — check the primary protocol.

Publications

• Chalmers JD, Aliberti S, Polverino E, Vendrell M, Crichton M, Loebinger M, Dimakou K, Clifton I, van der Eerden M, Rohde G, Murris-Espin M, Masefield S, Gerada E, Shteinberg M, Ringshausen F, Haworth C, Boersma W, Rademacher J, Hill AT, Aksamit T, O'Donnell A, Morgan L, Milenkovic B, Tramma L, Neves J, Menendez R, Paggiaro P, Botnaru V, Skrgat S, Wilson R, Goeminne P, De Soyza A, Welte T, Torres A PMID 27730179
• Ringshausen FC, de Roux A, Diel R, Hohmann D, Welte T, Rademacher J. Bronchiectasis in Germany: a population-based estimation of disease prevalence. Eur Respir J. 2015 Dec;46(6):1805-7. doi: 10.1183/13993003.00954-2015. Epub 2015 Aug 20. No abstract available. PMID 26293498
• Lucas JS, Barbato A, Collins SA, Goutaki M, Behan L, Caudri D, Dell S, Eber E, Escudier E, Hirst RA, Hogg C, Jorissen M, Latzin P, Legendre M, Leigh MW, Midulla F, Nielsen KG, Omran H, Papon JF, Pohunek P, Redfern B, Rigau D, Rindlisbacher B, Santamaria F, Shoemark A, Snijders D, Tonia T, Titieni A, Walker WT, Werner C, Bush A, Kuehni CE. European Respiratory Society guidelines for the diagnosis o PMID 27836958
• Leigh MW, Pittman JE, Carson JL, Ferkol TW, Dell SD, Davis SD, Knowles MR, Zariwala MA. Clinical and genetic aspects of primary ciliary dyskinesia/Kartagener syndrome. Genet Med. 2009 Jul;11(7):473-87. doi: 10.1097/GIM.0b013e3181a53562. PMID 19606528
• Raidt J, Krenz H, Tebbe J, Grosse-Onnebrink J, Olbrich H, Loges NT, Biebach L, Schmalstieg C, Kessler C, Wallmeier J, Dworniczak B, Pennekamp P, Dugas M, Werner C, Omran H. Limitations of Nasal Nitric Oxide Measurement for Diagnosis of Primary Ciliary Dyskinesia with Normal Ultrastructure. Ann Am Thorac Soc. 2022 Aug;19(8):1275-1284. doi: 10.1513/AnnalsATS.202106-728OC. PMID 35202559
• Hannah WB, Seifert BA, Truty R, Zariwala MA, Ameel K, Zhao Y, Nykamp K, Gaston B. The global prevalence and ethnic heterogeneity of primary ciliary dyskinesia gene variants: a genetic database analysis. Lancet Respir Med. 2022 May;10(5):459-468. doi: 10.1016/S2213-2600(21)00453-7. Epub 2022 Jan 17. PMID 35051411
• Barber AT, Davis SD, Boutros H, Zariwala M, Knowles MR, Leigh MW. Use caution interpreting nasal nitric oxide: Overlap in primary ciliary dyskinesia and primary immunodeficiency. Pediatr Pulmonol. 2021 Dec;56(12):4045-4047. doi: 10.1002/ppul.25636. Epub 2021 Sep 2. No abstract available. PMID 34473915
• Popatia R, Haver K, Casey A. Primary Ciliary Dyskinesia: An Update on New Diagnostic Modalities and Review of the Literature. Pediatr Allergy Immunol Pulmonol. 2014 Jun 1;27(2):51-59. doi: 10.1089/ped.2013.0314. PMID 24963453

Identifiers

NCT: NCT07566611 · 29887

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗