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

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ClinicalTrials.gov Identifier: NCT04702243
Recruitment Status : Recruiting
First Posted : January 8, 2021
Last Update Posted : April 13, 2023
Sponsor:
Collaborators:
Washington University School of Medicine
National Heart, Lung, and Blood Institute (NHLBI)
Children's Hospital Colorado
Stanford University
Seattle Children's Hospital
The Hospital for Sick Children
McGill University
Children's Hospital Medical Center, Cincinnati
Information provided by (Responsible Party):
University of North Carolina, Chapel Hill

Study Description
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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).

Condition or disease Intervention/treatment
Primary Ciliary Dyskinesia Primary Immune Deficiency Kartagener Syndrome 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 Design
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Study Type : Observational
Estimated Enrollment : 1500 participants
Observational Model: Cohort
Time Perspective: Cross-Sectional
Official Title: Defining the Genetic Etiology of Suppurative Lung Disease in Children and Adults
Actual Study Start Date : December 1, 2020
Estimated Primary Completion Date : July 31, 2024
Estimated Study Completion Date : July 31, 2024

Resource links provided by the National Library of Medicine


Groups and Cohorts
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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.


Outcome Measures
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Primary Outcome Measures :
  1. Number of Participants with a Confirmed Diagnosis of PCD or PID [ Time Frame: 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.

  2. Prevalence of Neonatal Respiratory Distress Seen in PCD and PID [ Time Frame: During a single 6-hour visit ]
    Medical records will be reviewed to denote presence or absence of neonatal respiratory distress (occurs at birth).

  3. Prevalence of the Onset of Chronic Nasal Congestion Before Six Months of Age Seen in PCD and PID [ Time Frame: 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.

  4. Prevalence of the Onset of Daily Wet Cough Before Six Months of Age Seen in PCD and PID [ Time Frame: 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.

  5. Prevalence of Laterality Defects Seen in PCD and PID [ Time Frame: During a single 6-hour visit ]
    Medical records will be reviewed to denote presence or absence of laterality defects (situs inversus/heterotaxy).

  6. Prevalence of Chronic/Recurrent Sinus Disease Seen in PCD and PID [ Time Frame: During a single 6-hour visit ]
    Medical records will be reviewed to denote presence or absence of chronic/recurrent sinus disease.

  7. Prevalence of Chronic/Recurrent Middle Ear Disease Seen in PCD and PID [ Time Frame: During a single 6-hour visit ]
    Medical records will be reviewed to denote presence or absence of chronic/recurrent middle ear disease.

  8. Prevalence of Recurrent Pneumonia/Sepsis Seen in PCD and PID [ Time Frame: 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).

  9. Prevalence of Skin Infections/Abscesses Seen in PCD and PID [ Time Frame: During a single 6-hour visit ]
    Medical records will be reviewed to denote to denote presence or absence of skin infections/abscesses.

  10. Prevalence of Abnormal Nasal Nitric Oxide Values Seen in PCD and PID [ Time Frame: 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.

  11. Prevalence of Abnormal Immunoglobulin G Values Seen in PCD and PID [ Time Frame: 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).

  12. Prevalence of Abnormal Lymphocyte Markers Seen in PCD and PID (Laboratory Tests) [ Time Frame: 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).

  13. Mean FEV1 Percent Predicted Values in PCD and PID [ Time Frame: During a single 6-hour visit ]
    Forced expired volume in 1 second (FEV1) will be assessed by percentage of the predicted value (0-100%).


Biospecimen Retention:   Samples With DNA
blood draw or buccal swab

Eligibility Criteria
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Ages Eligible for Study:   5 Years to 45 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Subjects who have suppurative lung disease but without a defined genetic diagnosis.
Criteria

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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04702243


Contacts
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Contact: Kelli Sullivan, MPH 919-962-9786 kelli_sullivan@med.unc.edu
Contact: Joseph Hatch, MSPH 919-962-4383 hatchjo@email.unc.edu

Locations
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United States, California
Stanford University Recruiting
Palo Alto, California, United States, 94304
Contact: Jackie Spano, DNP    650-721-1132    jmzirbes@stanford.edu   
United States, Colorado
Children's Hospital Colorado Recruiting
Aurora, Colorado, United States, 80045
Contact: Anna Duong    720-777-0946    anna.duong@childrenscolorado.org   
Contact: Mary Cross    720-777-4645    mary.cross@childrenscolorado.org   
United States, Maryland
National Heart, Lung and Blood Institute Recruiting
Bethesda, Maryland, United States, 20814
Contact: Kelly Kumar    301-435-2783    kelly.kumar@nih.gov   
United States, Missouri
Washington University in St. Louis Recruiting
Saint Louis, Missouri, United States, 63130
Contact: Jane Quante, RN    314-454-2353    quante_j@wustl.edu   
United States, North Carolina
University of North Carolina at Chapel Hill Recruiting
Chapel Hill, North Carolina, United States, 27599
Contact: Nicole Capps, DNP    919-962-9948    nicole_capps@med.unc.edu   
Contact: Kelli Sullivan, MPH    919-962-9786    kelli_sullivan@med.unc.edu   
United States, Washington
Seattle Children's Hospital Recruiting
Seattle, Washington, United States, 98105
Contact: Cisco Pascual    206-884-2648    cisco.pascual@seattlechildrens.org   
Contact: Sharon McNamara    206-987-3921    sharon.mcnamara@seattlechildrens.org   
Canada, Ontario
The Hospital for Sick Children Recruiting
Toronto, Ontario, Canada, M5G 0A4
Contact: Fatima Adil       fatima.adil@sickkids.ca   
Canada, Quebec
McGill University Recruiting
Montréal, Quebec, Canada, H4A 3J1
Contact: Sandra Pepin    514-934-1934 ext 23737    sandra.pepin@muhc.mcgill.ca   
Contact: Mylene Roy    514-934-1934 ext 36382    mylene.roy@muhc.mcgill.ca   
Sponsors and Collaborators
University of North Carolina, Chapel Hill
Washington University School of Medicine
National Heart, Lung, and Blood Institute (NHLBI)
Children's Hospital Colorado
Stanford University
Seattle Children's Hospital
The Hospital for Sick Children
McGill University
Children's Hospital Medical Center, Cincinnati
Investigators
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Principal Investigator: Kenneth Olivier, MD, MPH University of North Carolina, Chapel Hill
More Information
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Responsible Party: University of North Carolina, Chapel Hill
ClinicalTrials.gov Identifier: NCT04702243    
Other Study ID Numbers: 20-0508
5U54HL096458-17 ( U.S. NIH Grant/Contract )
First Posted: January 8, 2021    Key Record Dates
Last Update Posted: April 13, 2023
Last Verified: April 2023

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Lung Diseases
Ciliary Motility Disorders
Kartagener Syndrome
Dyskinesias
Primary Immunodeficiency Diseases
Immunologic Deficiency Syndromes
Respiratory Tract Diseases
Movement Disorders
Central Nervous System Diseases
Nervous System Diseases
Neurologic Manifestations
Immune System Diseases
Otorhinolaryngologic Diseases
 Ciliopathies
Abnormalities, Multiple
Congenital Abnormalities
Genetic Diseases, Inborn
Bronchiectasis
Bronchial Diseases
Respiratory System Abnormalities
Dextrocardia
Heart Defects, Congenital
Cardiovascular Abnormalities
Cardiovascular Diseases
Heart Diseases
Situs Inversus