Clinical trial NCT04949308: Nasal Nitric Oxide Across Mutations in Primary Ciliary Dyskinesia
Official title: 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)
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Ciliary Motility Disorders
Primary Ciliary Dyskinesia
Lead sponsor: University Hospital Muenster
Sponsor class: OTHER
Collaborators: name: Rigshospitalet, Denmark
name: Hospital Vall d'Hebron
name: KU Leuven
name: Amsterdam UMC, location VUmc
name: University of Valencia
name: NOVA Medical School
name: University of Geneva, Switzerland
name: University of Bern
name: Ruhr University of Bochum
name: Charite University, Berlin, Germany
name: Hannover Medical School
name: Medical University of Vienna
name: Royal Brompton & Harefield NHS Foundation Trust
name: University College, London
name: University of Dundee
name: University of Southampton
name: University of Leicester
name: University of Pisa
name: Federico II University
name: Bambino Gesù Hospital and Research Institute
name: University of Nicosia
name: Oslo University Hospital
name: Hospital de Niños R. Gutierrez de Buenos Aires
name: Hacettepe University
name: Marmara University
name: University Hospital, Motol
name: University Children's Hospital, Zurich
name: The Leeds Teaching Hospitals NHS Trust
name: Hadassah Medical Organization
name: Göteborg University
name: Schneider Children's Medical Center, Israel
name: University of Sao Paulo
name: University Hospital of Cologne
name: University of Belgrade
name: University Hospital, Martin
name: Abderrahmane Mami Hospital
First posted: 2021-07-02
Enrollment: 2000
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_CONTROL
Time perspective: RETROSPECTIVE
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

Brief summary: 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)

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

Eligibility criteria: 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:

-

Primary outcomes:
measure: Genotype-nasal Nitric Oxide Corelation
timeFrame: up to 20 years retrospective
Secondary outcomes:
Other outcomes:
Locations:
city: Münster
country: Germany
facility: University Hospital Münster
state: NRW
Study officials:
affiliation: University Hospital Muenster
name: Heymut Omran, Prof,Dr,MD
role: STUDY_CHAIR
References: