Defining the Genetic Etiology of Suppurative Lung Disease in Children and Adults

Primary Ciliary Dyskinesia Clinical Trial

Official title:

Defining the Genetic Etiology of Suppurative Lung Disease in Children and Adults

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04702243
• Other study ID #: 20-0508
• Secondary ID: 5U54HL096458-17
• Status: Recruiting
• Start date: December 1, 2020
• Est. completion date: July 31, 2024

Study information

• Verified date: April 2024
• Source: University of North Carolina, Chapel Hill
• Contact: Kelli Sullivan, MPH
• Phone: 919-962-9786
• Email: kelli_sullivan[@]med.unc.edu
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

The investigators will utilize a systematic approach for the diagnostic evaluation of patients to identify characteristics which may distinguish between Primary Immunodeficiency (PID) disorders versus Primary Ciliary Dyskinesia (PCD).

Description:

This protocol utilizes a cross-sectional study design. Over a 5-year period, the investigators will enroll patients who have clinical and lab features characteristic of a PID disorder or PCD, but do not have a confirmed genetic diagnosis. Innovative, standardized methods (SOPs) will be utilized, including ciliary ultrastructural analyses by transmission electron microscopy (TEM), as pertinent. Measures of nasal nitric oxide (nNO) will be performed in all subjects to allow comparisons of nNO values in PID vs. PCD. Patients with high likelihood of a PID disorder or a high likelihood of PCD will initially undergo research genetic testing on a commercial approved panel for PID disorders or a panel of at least 37 PCD genes. All subjects who do not have a genetic diagnosis from the test panels will undergo whole exome sequencing (WES) to search for novel genetic etiologies for PID or PCD.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 1500
• Est. completion date: July 31, 2024
• Est. primary completion date: July 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 5 Years to 45 Years

Eligibility

Pediatric subjects (aged 5-17 years): Inclusion criteria include the major criterion (bronchiectasis in > 1 lobe on current or chest CT in previous 24 months, if available for review), plus one minor criterion, or two minor criteria, if bronchiectasis is not present, (including at least 1 "lung" minor criteria).

Adult subjects (aged 18-45 years): Inclusion criteria include the major criteria (bronchiectasis in > 1 lobe on current or chest CT in previous 36 months, if available for review), plus one minor criterion, or three minor criteria, if bronchiectasis is not present, (including at least 1 "lung" minor criteria).

Inclusion Criteria:

General Criteria

• Age 5-45 years

• Male and Female Subjects

• All races and ethnicities

Major Clinical Criteria

• Bronchiectasis in > 1 lobe

Minor Clinical Criteria, Lung

• Neonatal respiratory distress (in term neonates with O2 requirement)

• Chronic wet cough (year-round for at least 12 months)

• Recurrent episodes of bacterial bronchitis

• Recurrent pneumonia (confirmed on chest x-ray)

• Respiratory non-tuberculous mycobacteria (NTM) (documented respiratory NTM culture)

Minor Clinical Criteria, Other

• Chronic nasal congestion

• Recurrent/chronic paranasal sinusitis

• Ongoing middle-ear disease and/or tympanostomy tube placement at age = 4 years

• Organ laterality defect

• Low nasal nitric oxide (< 77 nL/min) (by plateau measurement)

• Confirmed family history of PID or PCD

Exclusion Criteria:

• Anyone who has a confirmed genetic diagnosis of PCD or PID

• Cystic Fibrosis

• Alpha-antitrypsin deficiency in adults (18 years and older)

• Congenital upper or lower airway anomalies

• Post-lung or heart transplant, or other conditions requiring immunosuppression therapy

• Other confounding features, such as lung disease due to prematurity (born < 28 weeks gestation) or HIV

• Neurological compromise and evidence of recurrent aspiration

• Conditions known to be commonly associated with bronchiectasis, such as prior mycobacterium tuberculosis

• Have not had standard clinical evaluation to address other potential causes of chronic oto-sino- pulmonary disease, particularly cystic fibrosis, aspiration or airway anatomic abnormalities.

Related Conditions & MeSH terms

• Ciliary Motility Disorders
• Dyskinesias
• Immunologic Deficiency Syndromes
• Kartagener Syndrome
• Lung Diseases
• Primary Ciliary Dyskinesia
• Primary Immune Deficiency
• Primary Immunodeficiency Diseases

Intervention

Diagnostic Test:
• Genetic Testing for PCD or PID
Patients with high likelihood of a PID disorder or a high likelihood of PCD will initially undergo research genetic testing on a commercial approved panel for PID disorders or a panel of at least 37 PCD genes.

Other:
• Unaffected Family Member Genetic Testing
Unaffected family members will undergo genetic testing if genetic findings are identified in their affected family member.

Locations

Country	Name	City	State
Canada	McGill University	Montréal	Quebec
Canada	The Hospital for Sick Children	Toronto	Ontario
United States	Children's Hospital Colorado	Aurora	Colorado
United States	National Heart, Lung and Blood Institute	Bethesda	Maryland
United States	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina
United States	Stanford University	Palo Alto	California
United States	Washington University in St. Louis	Saint Louis	Missouri
United States	Seattle Children's Hospital	Seattle	Washington

Sponsors (9)

Lead Sponsor	Collaborator
University of North Carolina, Chapel Hill	Children's Hospital Colorado, Children's Hospital Medical Center, Cincinnati, McGill University, National Heart, Lung, and Blood Institute (NHLBI), Seattle Children's Hospital, Stanford University, The Hospital for Sick Children, Washington University School of Medicine

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants with a Confirmed Diagnosis of PCD or PID	A commercial genetic panel will be used to test for disease causing mutation in PCD or PID. If the commercial panel does not yield positive results, WES research testing will be used to identify disease causing mutations in PCD and PID in order to confirm the diagnosis.	Up to approximately 4 years
Primary	Prevalence of Neonatal Respiratory Distress Seen in PCD and PID	Medical records will be reviewed to denote presence or absence of neonatal respiratory distress (occurs at birth).	During a single 6-hour visit
Primary	Prevalence of the Onset of Chronic Nasal Congestion Before Six Months of Age Seen in PCD and PID	Medical records will be reviewed to denote presence or absence of the onset of chronic nasal congestion before age 6 months.	During a single 6-hour visit
Primary	Prevalence of the Onset of Daily Wet Cough Before Six Months of Age Seen in PCD and PID	Medical records will be reviewed to denote presence or absence of the onset of daily wet cough before age 6 months.	During a single 6-hour visit
Primary	Prevalence of Laterality Defects Seen in PCD and PID	Medical records will be reviewed to denote presence or absence of laterality defects (situs inversus/heterotaxy).	During a single 6-hour visit
Primary	Prevalence of Chronic/Recurrent Sinus Disease Seen in PCD and PID	Medical records will be reviewed to denote presence or absence of chronic/recurrent sinus disease.	During a single 6-hour visit
Primary	Prevalence of Chronic/Recurrent Middle Ear Disease Seen in PCD and PID	Medical records will be reviewed to denote presence or absence of chronic/recurrent middle ear disease.	During a single 6-hour visit
Primary	Prevalence of Recurrent Pneumonia/Sepsis Seen in PCD and PID	Medical records will be reviewed to denote to denote presence or absence of recurrent pneumonia/sepsis (that is not bronchiectasis).	During a single 6-hour visit
Primary	Prevalence of Skin Infections/Abscesses Seen in PCD and PID	Medical records will be reviewed to denote to denote presence or absence of skin infections/abscesses.	During a single 6-hour visit
Primary	Prevalence of Abnormal Nasal Nitric Oxide Values Seen in PCD and PID	Nasal nitric oxide will be measured to determine the number of subjects who have an abnormal value, utilizing a cut-off of 77 nl/min.	During a single 6-hour visit
Primary	Prevalence of Abnormal Immunoglobulin G Values Seen in PCD and PID	Immunoglobulin G will be measured to determine the number of subjects who have an abnormal value, utilizing the local laboratory age-defined cut-off ranges (United States: mg/dL; Canada: g/L).	During a single 6-hour visit
Primary	Prevalence of Abnormal Lymphocyte Markers Seen in PCD and PID (Laboratory Tests)	Lymphocyte Markers will be measured to determine the number of subjects who have an abnormal value, utilizing the local laboratory age-defined cut-off ranges (% of lymphocytes).	During a single 6-hour visit
Primary	Mean FEV1 Percent Predicted Values in PCD and PID	Forced expired volume in 1 second (FEV1) will be assessed by percentage of the predicted value (0-100%).	During a single 6-hour visit