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

Recruiting

• Conditions: Primary Ciliary Dyskinesia; Primary Immune Deficiency; Kartagener Syndrome
• Interventions: Diagnostic Test: Genetic Testing for PCD or PID; Other: Unaffected Family Member Genetic Testing

• Registration Number: NCT04702243
• Lead Sponsor: University of North Carolina, Chapel Hill

Brief 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).

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 Timeline

• Study Start: 2020-12-01
• Study First Submitted: 2020-12-16
• Study First Submitted QC: 2021-01-06
• Study First Posted: 2021-01-08
• Status Verified: 2024-10
• Last Update Submitted: 2024-10-07
• Last Update Posted: 2024-10-08
• Primary Completion: 2025-07-31
• Study Completion: 2025-07-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 1500

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

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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.

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Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Affected Participants	Genetic Testing for PCD or PID	Subjects who have suppurative lung disease without a known genetic diagnosis
Unaffected Family Members	Unaffected Family Member Genetic Testing	Unaffected family members may be enrolled in the study for collection of DNA only

Primary Outcome Measures

Name	Time	Method
Prevalence of Laterality Defects Seen in PCD and PID	During a single 6-hour visit	Medical records will be reviewed to denote presence or absence of laterality defects (situs inversus/heterotaxy).
Prevalence of Chronic/Recurrent Sinus Disease Seen in PCD and PID	During a single 6-hour visit	Medical records will be reviewed to denote presence or absence of chronic/recurrent sinus disease.
Number of Participants with a Confirmed Diagnosis of PCD or PID	Up to approximately 4 years	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.
Prevalence of Recurrent Pneumonia/Sepsis Seen in PCD and PID	During a single 6-hour visit	Medical records will be reviewed to denote to denote presence or absence of recurrent pneumonia/sepsis (that is not bronchiectasis).
Prevalence of Neonatal Respiratory Distress Seen in PCD and PID	During a single 6-hour visit	Medical records will be reviewed to denote presence or absence of neonatal respiratory distress (occurs at birth).
Prevalence of the Onset of Daily Wet Cough Before Six Months of Age Seen in PCD and PID	During a single 6-hour visit	Medical records will be reviewed to denote presence or absence of the onset of daily wet cough before age 6 months.
Prevalence of Chronic/Recurrent Middle Ear Disease Seen in PCD and PID	During a single 6-hour visit	Medical records will be reviewed to denote presence or absence of chronic/recurrent middle ear disease.
Mean FEV1 Percent Predicted Values in PCD and PID	During a single 6-hour visit	Forced expired volume in 1 second (FEV1) will be assessed by percentage of the predicted value (0-100%).
Prevalence of Skin Infections/Abscesses Seen in PCD and PID	During a single 6-hour visit	Medical records will be reviewed to denote to denote presence or absence of skin infections/abscesses.
Prevalence of the Onset of Chronic Nasal Congestion Before Six Months of Age Seen in PCD and PID	During a single 6-hour visit	Medical records will be reviewed to denote presence or absence of the onset of chronic nasal congestion before age 6 months.
Prevalence of Abnormal Nasal Nitric Oxide Values Seen in PCD and PID	During a single 6-hour visit	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.
Prevalence of Abnormal Immunoglobulin G Values Seen in PCD and PID	During a single 6-hour visit	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).
Prevalence of Abnormal Lymphocyte Markers Seen in PCD and PID (Laboratory Tests)	During a single 6-hour visit	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).

Trial Locations

Locations (8)

Children's Hospital Colorado; 🇺🇸 Aurora, Colorado, United States

Stanford University; 🇺🇸 Palo Alto, California, United States

National Heart, Lung and Blood Institute; 🇺🇸 Bethesda, Maryland, United States

McGill University; 🇨🇦 Montréal, Quebec, Canada

Washington University in St. Louis; 🇺🇸 Saint Louis, Missouri, United States

Seattle Children's Hospital; 🇺🇸 Seattle, Washington, United States

University of North Carolina at Chapel Hill; 🇺🇸 Chapel Hill, North Carolina, United States

The Hospital for Sick Children; 🇨🇦 Toronto, Ontario, Canada