Nasal Nitric Oxide Across Mutations in Primary Ciliary Dyskinesia (nNO_PCD)

High or Low. Nasal Nitric Oxide Across Mutations in Primary Ciliary Dyskinesia. A Genotype/Phenotype Analysis of Nasal NO in Patients With PCD Within the European Reference Network (ERN)

Primary Ciliary Dyskinesia (PCD) is a rare genetic disorder characterized by dysfunction of motile cilia associated with recurrent infections of the airways, laterality defects (Situs inversus totalis in about 50% of cases) and fertility problems. At present, mutations in > 45 genes associated with PCD and mucociliary clearance disorders have been identified, representing most likely two thirds of all human cases.

The aims of this study are:

1. Correlation between nasal NO levels and distinct PCD genotypes

2. Determination of further parameters potentially associated with nasal NO levels in genotyped PCD individuals

   1. course of clinical manifestations (e.g. neonatal distress, infections, bronchiectasis)
   2. diagnostic results (HVMA, TEM, IF)
   3. lung function outcome (FVC, FEV1)

Study Overview

• Status: Recruiting
• Conditions: Primary Ciliary Dyskinesia; Ciliary Motility Disorders

Detailed Description

Nasal Nitric Oxide (nNO) concentration is usually low or very low in patients with Primary Ciliary Dyskinesia (PCD) for yet unknown reasons (1).

Measured nNO holds a strong ability to separate healthy subjects from patients with PCD in both childhood and adulthood and across several different nNO sampling modalities (2) (3-5) and nNO is widely used as an important supplementary diagnostic test for PCD work up in both Europe (6) and North America (7). Low nNO in PCD was first reported 26 years ago (8). Nasal NO has been associated with host paranasal sinus defense as sufficient nNO production in non-PCD subjects is thought to play a role in maintaining paranasal sinus sterility (9). Furhermore, ciliary beating seems to be upregulated by a NO dependent pathway in bovine airway epithelium (10), influencing mucociliary clearance. However, human in vitro studies of ciliated airway cells in air-liquid-interface (ALI) culture have been ambiguous as to whether the biosynthesis of NO in PCD is impaired (11) (12) or not (13; 14) and the etiology of low nNO in PCD and presumed link to ciliary beating remains unclear. So far, attempts to link PCD phenotype and genotype has indicated that patients with PCD harboring CCDC39 and CCDC40 mutations may have a poorer lung function development (15).

In rare cases of PCD (<5%) (16) nNO concentration is within normal range. More than 14 different PCD-causing genes (e.g RSPH1, GAS8, RPGR, CCNO, CCDC103, CFAP221, DNAH9, FOXJ1, GAS2L2, LRRC56, NEK10, SPEF2, STK36, TTC12) has been associated with nNO values above the agreed cut off for nNO-production rate of 77 nL/min in a few patients with PCD (16). However, individuals with NEK10 or FOXJ1 mutations, for example, display a very severe respiratory phenotype (17), but making a diagnosis is challenging because of normal nNO values as well as apparently normal ciliary beating.

Since nNO also holds potential as an outcome parameter in future clinical trials of PCD, better understanding of nNO in PCD is warranted.

Demand of large number of patients with PCD is crucial, keeping the rareness of nearnormal and normal nNO levels in PCD in mind. Motivated by the analysis of lung function in a large cohort of genotyped PCD-patients, this multicenter Involvement across international PCD centers is an obvious opportunity for gaining such further knowledge with the focus on nasal NO.

The aims of this study are:

1. Correlation between nasal NO levels and distinct PCD genotypes

2. Determination of further parameters potentially associated with nasal NO levels in genotyped PCD individuals

   1. course of clinical manifestations (e.g. neonatal distress, infections, bronchiectasis)
   2. diagnostic results (HVMA, TEM, IF)
   3. lung function outcome (FVC, FEV1)

Inclusion criteria:

1. Patients with a genetically confirmed diagnosis of PCD (bi-allelic mutations in a gene, known to cause PCD) with typical clinical symptoms of PCD
2. PCD individuals of all age groups with at least one nNO measurement performed according to diagnostic guidelines. Serial nNO measurements should be included if available (e.g. yearly), at least for infants and young children

• Study Type: Observational
• Enrollment (Anticipated): 2000

Contacts and Locations

• Study Contact: Name: Johanna Raidt, MD; Phone Number: +49 251 83 40003; Email: Johanna.Raidt@ukmuenster.de
• Study Contact Backup: Name: Simone Helms; Phone Number: + 49 251 83 48358; Email: Simone.Helms@ukmuenster.de

Study Locations

• Germany
  • NRW
    • Münster, NRW, Germany, 48149
      • Recruiting
      • University Hospital Münster
      • Contact: Heymut Omran, Prof, Dr, MD; Phone Number: 41097 +4925183; Email: PCDregistry.eu@ukmuenster.de
      • Contact: Simone Helms; Phone Number: 48358 +4925183; Email: Simone.Helms@ukmuenster.de
      • Principal Investigator: Heymut Omran, Prof, Dr, MD
      • Sub-Investigator: Johanna Raidt, MD, Dr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients with a genetically confirmed diagnosis of PCD (bi-allelic mutations in a gene, known to cause PCD) with typical clinical symptoms of PCD

Description

Inclusion Criteria:

1. Patients with a genetically confirmed diagnosis of PCD (bi-allelic mutations in a gene, known to cause PCD) with typical clinical symptoms of PCD
2. PCD individuals of all age groups with at least one nNO measurement performed according to diagnostic guidelines. Serial nNO measurements should be included if available (e.g. yearly), at least for infants and young children

Exclusion Criteria:

-

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Retrospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Genetic diagnosis; Genetic: Genetic diagnosis No Intervention foreseen, but genetically confirmed diagnosis of PCD (bi-allelic mutations in a gene, known to cause PCD) with typical clinical symptoms of PCD and at least one other method confirming PCD-diagnosis is needed

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Genotype-nasal Nitric Oxide Corelation	nNO in correlation to the genetic make-up	up to 20 years retrospective

Collaborators and Investigators

• Sponsor: University Hospital Muenster
• Collaborators: University of Pisa; Medical University of Vienna; Hacettepe University; Charite University, Berlin, Germany; Oslo University Hospital; Göteborg University; Hannover Medical School; Federico II University; Rigshospitalet, Denmark; KU Leuven; Hadassah Medical Organization; University College, London; The Leeds Teaching Hospitals NHS Trust; University of Sao Paulo; Bambino Gesù Hospital and Research Institute; Marmara University; University of Southampton; Amsterdam UMC, location VUmc; University of Bern; Ruhr University of Bochum; University of Valencia; University Children's Hospital, Zurich; Royal Brompton & Harefield NHS Foundation Trust; University of Leicester; University of Belgrade; University of Dundee; University Hospital of Cologne; University of Geneva, Switzerland; Schneider Children's Medical Center, Israel; Hospital de Niños R. Gutierrez de Buenos Aires; Hospital Vall d'Hebron; NOVA Medical School; University of Nicosia; University Hospital, Motol; University Hospital, Martin; Abderrahmane Mami Hospital
• Investigators: Study Chair: Heymut Omran, Prof,Dr,MD, University Hospital Muenster

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2021
• Primary Completion (Anticipated): June 30, 2022
• Study Completion (Anticipated): December 31, 2022

Study Registration Dates

• First Submitted: June 24, 2021
• First Submitted That Met QC Criteria: June 24, 2021
• First Posted (Actual): July 2, 2021

Study Record Updates

• Last Update Posted (Actual): July 2, 2021
• Last Update Submitted That Met QC Criteria: June 24, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Respiratory Tract Diseases; Neurologic Manifestations; Congenital Abnormalities; Genetic Diseases, Inborn; Otorhinolaryngologic Diseases; Movement Disorders; Abnormalities, Multiple; Ciliopathies; Dyskinesias; Ciliary Motility Disorders
• Other Study ID Numbers: JR_nNO_PCD_09_2020

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No