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

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).

Study Overview

• Status: Recruiting
• Conditions: Primary Ciliary Dyskinesia; Kartagener Syndrome; Primary Immune Deficiency
• Intervention / Treatment: Diagnostic test: Genetic Testing for PCD or PID; Other: Unaffected Family Member Genetic Testing

Detailed 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.

• Study Type: Observational
• Enrollment (Anticipated): 1500

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 0A4
      • Recruiting
      • The Hospital for Sick Children
      • Contact: Fatima Adil; Email: fatima.adil@sickkids.ca
  • Quebec
    • Montréal, Quebec, Canada, H4A 3J1
      • Recruiting
      • McGill University
• United States
  • California
    • Palo Alto, California, United States, 94304
      • Recruiting
      • Stanford University
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Recruiting
      • Children's Hospital Colorado
      • Contact: Anna Duong; Phone Number: 720-777-0946; Email: Anna.Duong@childrenscolorado.org
  • Maryland
    • Bethesda, Maryland, United States, 20814
      • Recruiting
      • National Heart, Lung and Blood Institute
      • Contact: Kelly Kumar; Phone Number: 301-435-2783; Email: kelly.kumar@nih.gov
  • Missouri
    • Saint Louis, Missouri, United States, 63130
      • Recruiting
      • Washington University in St. Louis
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • Recruiting
      • University Of North Carolina At Chapel Hill
  • Washington
    • Seattle, Washington, United States, 98105
      • Recruiting
      • Seattle Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years to 45 years (Child, Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Subjects who have suppurative lung disease but without a defined genetic diagnosis.

Description

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.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Cross-Sectional

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Affected Participants; Subjects who have suppurative lung disease without a known genetic diagnosis	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.
Unaffected Family Members; Unaffected family members may be enrolled in the study for collection of DNA only	Other: Unaffected Family Member Genetic Testing; Unaffected family members will undergo genetic testing if genetic findings are identified in their affected family member.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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
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
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
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
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
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
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
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
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
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

Collaborators and Investigators

• Sponsor: University of North Carolina, Chapel Hill
• Collaborators: The Hospital for Sick Children; Washington University School of Medicine; McGill University; National Heart, Lung, and Blood Institute (NHLBI); Children's Hospital Colorado; Seattle Children's Hospital; Stanford University; Children's Hospital Medical Center, Cincinnati
• Investigators: Principal Investigator: Kenneth Olivier, MD, MPH, University of North Carolina, Chapel Hill

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2020
• Primary Completion (Anticipated): July 31, 2024
• Study Completion (Anticipated): July 31, 2024

Study Registration Dates

• First Submitted: December 16, 2020
• First Submitted That Met QC Criteria: January 6, 2021
• First Posted (Actual): January 8, 2021

Study Record Updates

• Last Update Posted (Actual): April 13, 2023
• Last Update Submitted That Met QC Criteria: April 12, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Central Nervous System Diseases; Nervous System Diseases; Respiratory Tract Diseases; Immune System Diseases; Neurologic Manifestations; Congenital Abnormalities; Bronchial Diseases; Genetic Diseases, Inborn; Otorhinolaryngologic Diseases; Movement Disorders; Heart Defects, Congenital; Cardiovascular Abnormalities; Abnormalities, Multiple; Ciliopathies; Bronchiectasis; Respiratory System Abnormalities; Dextrocardia; Situs Inversus; Lung Diseases; Immunologic Deficiency Syndromes; Primary Immunodeficiency Diseases; Dyskinesias; Ciliary Motility Disorders; Kartagener Syndrome
• Other Study ID Numbers: 20-0508; 5U54HL096458-17 (U.S. NIH Grant/Contract)

Drug and device information, study documents

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