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

University of North Carolina, Chapel Hill436 enrolled

Overview

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).

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

436

Conditions

Primary Ciliary Dyskinesia Primary Immune Deficiency Kartagener Syndrome

Interventions

Genetic Testing for PCD or PIDDIAGNOSTIC_TEST

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 Member Genetic TestingOTHER

Unaffected family members will undergo genetic testing if genetic findings are identified in their affected family member.

Eligibility

Sex: ALLMin age: 5 YearsMax age: 45 Years

Medical Language ↔ Plain English

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.

Locations (8)

Stanford University

Palo Alto, California, United States

Children's Hospital Colorado

Aurora, Colorado, United States

National Heart, Lung and Blood Institute

Bethesda, Maryland, United States

Washington University in St. Louis

St Louis, Missouri, United States

Outcomes

Primary Outcomes

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.

Time frame: 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).