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Genetic Disorders of Mucociliary Clearance in Nontuberculous Mycobacterial Lung Disease

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00368446
Recruitment Status : Completed
First Posted : August 24, 2006
Last Update Posted : May 20, 2020
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )

Brief Summary:

Healthy volunteers and patients with diseases that involve problems clearing mucus from the lungs will be examined and tested to better understand the reasons for recurring lung infections in these patients and to try to develop better ways to diagnose and treat them. The study will also try to identify the genes responsible for these diseases.

Healthy volunteers 18 years of age and older and patients 2 years of age or older with suspected primary ciliary dyskinesia (PCD), variant cystic fibrosis (CF) or pseudohypoaldosteronism (PHA) may be eligible for this study. Patients enrolled in the Natural History Study of Nontuberculous Mycobacteria at NIH or other NIH natural history protocols may also be enrolled. Participants undergo the following tests and procedures during a 1-day visit at the NIH Clinical Center, as follows:

All patients and normal volunteers have the following procedures:

  • Physical examination and review of medical and genetic history and family genetic history.
  • Lung function test and measurement of oxygen saturation level.
  • Nitric oxide measurement to measure the amount of nitric oxide production in the nose: A small tube is placed in the nose while the subject breathes through the mouth into a cardboard tube.

All patients have the following additional procedures:

  • Blood tests for liver and kidney function, blood count, immunoglobulins and pregnancy test (where appropriate).
  • Blood test or buccal scrape (brushing the inside of the cheek) to obtain DNA to look for gene mutations that cause PCD, CF or PHA.
  • Scrape biopsy of cell lining the inside of the nose: A small toothpick-sized plastic stick with a tiny cup on the end is used to get nasal lining cells to look at the cilia (hair-like structures that move mucus).
  • Semen analysis (in some men) to test sperm tail function or structure.

Patients suspected of having a variant of CF or PHA, including nontuberculous mycobacterial lung disease, have the following additional procedures:

  • Sweat chloride test: A medicine is placed on the arm to produce sweat; then, a very low level of electric current is applied for 5 to 12 minutes. Sweat is collected in a plastic tube and tested for salt content.
  • Blood draw for CF genetic testing, if necessary, and to measure levels of the enzyme trypsin.
  • Saliva collection to measure sodium and chloride content.
  • Nasal potential difference to measure the electrical activity of the cells lining the inside of the nose: A soft plastic tube filled with a salt solution is passed into the nasal passage and a sterile needle is placed under the skin of the arm. This test provides information about how the lining of the nose is able to get used to changes in temperature and humidity. (Normal volunteers also have this test.)

Condition or disease
Cystic Fibrosis Pseudohypoaldosteronism Nontuberculosis Mycobacterial Infection Chronic Granulomatous Disease Primary Ciliary Dyskinesia

Detailed Description:

Background: Nontuberculous mycobacteria (NTM) are ubiquitous environmental organisms that have been increasingly associated with human disease, commonly involving the lung. Post menopausal Caucasian women seem particularly predisposed to the development of peripheral nodules and dilated airways (bronchiectasis) associated with these organisms. These women have distinguishing body characteristics of being taller and thinner than age and gender matched controls yet have no identifiable systemic immune defects. There is, however, considerable overlap with genetic disorders of mucociliary clearance such as cystic fibrosis (CF) and primary ciliary dyskinesia (PCD). The Genetic Diseases of Mucociliary Clearance Consortium (GDMCC) is one of 10 consortia in the Rare Diseases Clinical Research Network formed under the Office of Rare Diseases in collaboration with NCRR, NICHD, NINDS, NIAMS, NIDDK, NHLBI in response to the Rare Diseases Act of 2002. The GDMCC is comprised of 5 geographically-dispersed clinical research sites that are designed to study rare diseases which involve defects in clearance of mucus secretions from the airways (defective "mucociliary clearance"). These sites will collaborate in diagnostic, genetic, and other studies in patients with impairments of mucociliary clearance, including primary ciliary dyskinesia (PCD), variant cystic fibrosis (CF), and pseudohypoaldosteronism (PHA). These studies are also applicable to diseases where altered airways clearance may play a primary or contributory role such as nontuberculous mycobacterial lung disease, chronic granulomatous disease, and the hyper-IgE syndromes. Disorders such as PCD, CF, and PHA reflect genetic defects in airway host-defense, and typically result in chronic infection of the airways. Patients with these disorders of the conducting airways and sinuses have delayed (or incorrect) diagnoses, because diagnostic tests are not readily available. These patients may also have sub-optimal management of their clinical disease, because the cause of these disorders is not well-defined, and treatment regimens are usually not driven by evidence-based medicine.

Aims: The major aim of this study is to employ a systematic approach to the diagnostic and functional evaluation of these patients with chronic airways disease in individual patients, better define host susceptibility to infections from environmental organisms such as the nontuberculous mycobacteria, and potentially lead to the development of better diagnostic techniques, including genetic testing. In addition, we will compare/contrast clinical features (phenotype) across these disorders. A rigorous cross-sectional comparison of the clinical features will provide better understanding of the clinical disease of these disorders; in turn this will lead not only to a better standard of clinical care, but will also assist in the identification of novel therapeutic approaches.

Methods: This is a cross-sectional diagnostic / mechanistic protocol to investigate airway host-defenses. The patient populations for these studies include individuals with recurring airway infections such as those with nontuberculous mycobacteria lung disease who may have defective airway host defenses as a predisposing factor, individuals carrying a tentative diagnosis of the three known genetic disorders of mucociliary clearance (PCD, variant CF, or PHA), and individuals suspected to have one of these disorders but with inadequate or inconclusive diagnostic tests. Individuals in this latter category must have a preliminary clinical evaluation to evaluate for other more common disorders that may have similar manifestations including classical CF, immunodeficiency, asthma, and severe gastroesophageal reflux. The evaluation will include a detailed assessment of clinical features; specialized laboratory measurements such as nasal potential difference to evaluate the function of chloride and sodium channels associated with CF and PHA, nasal biopsy specimens and nasal nitric oxide measurements to assess cilia structure and function which are abnormal in PCD; and genetic studies to identify disease - causing mutations in genes associated with CF, PCD, and PHA.

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Study Type : Observational
Actual Enrollment : 87 participants
Observational Model: Case-Control
Time Perspective: Cross-Sectional
Official Title: Genetic Disorders of Mucociliary Clearance
Actual Study Start Date : October 17, 2006

Patients with Genetic Disorders of Mucociliary Clearance

Primary Outcome Measures :
  1. PCD compatible clinical phenotype or sibling with PCD,plus defect in ciliary ultrastructure [ Time Frame: 6 years ]
    compatible clinical phenotype (sinopulmonary disease and/orneonatal respiratory disorder plus or minus situs inversus) or siblingwith PCD, plus defect in ciliary ultrastructure (inner or outer dynein arm; radial spoke; central complex)

Information from the National Library of Medicine

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Ages Eligible for Study:   2 Years to 99 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
There are approximately 100 patients who have been referred to the Clinical Center at NIH, or who have contacted us directly for evaluation of nontuberculous mycobacterial lung disease. Most of these are post- menopausal Caucasian women. Some had known diagnoses of CF or PCD at the time of referral and others have been subsequently diagnosed with these disorders after evaluation here. This population likely reflects a concentrated source population of potential cases of PCD and @@@variant CF to feed into the Consortium. Additionally, the Clinical Center will serve as a referral site for cases of suspected PCD, variant CF, and PHA who don't necessarily have nontuberculous mycobacterial infections. These referrals will likely be concentrated in the National Capital Area and constitute a minority of the patients evaluated on the protocol.

Overview: Inclusion criteria reflect the two-fold purpose of this protocol. It is primarily intended to evaluate the cohort of patients followed at the NIH Clinical Center under Protocol 01-I-0202, Natural History, Genetics, Phenotype, and Treatment of Mycobacterial Infections, and in this regard, the inclusion criteria mirror those of that protocol. Secondly it is part of the multicenter collaborative protocol as a participating site in the Genetic Disorders of Mucociliary Clearance Consortium, one of the Rare Disease Clinical Consortia sponsored by the Office of Rare Diseases. There is a clear-cut need for geographically dispersed centers to have expertise in the diagnostic evaluation and treatment of patients with rare diseases of the airways, including patients with suspected PCD, non-classical or variant CF, and PHA. The 5 sites will perform rigorous diagnostic evaluations utilizing innovative, but standardized methods (SOPs contained in Manual of Operations). As a participating site in the Consortium, we will cast a broad net to include as many participants as feasible. This will include a multi-center standardized diagnostic evaluation and clinical evaluation, giving us a better chance to define the clinical spectrum of disease.

The criteria for participants to enter this study mandates that each patient either be enrolled in the 01-I-0202, Natural History, Genetics, Phenotype, and Treatment of Mycobacterial Infections or related NIH Natural History Protocol, or if referred as part of the Consortium, have received a standard (current clinical practice) diagnostic evaluation that includes testing for asthma, severe gastroesophageal reflux and/or classic CF, prior to enrolling in the Consortium study. Healthy adult control participants will be enrolled for comparison assessment of noninvasive nasal nitric oxide and nasal potential difference measurements only. The health status of these control participants will be assessed with the standardized clinical history, family history, physical exam including height and weight, vital signs, oximetry, and spirometry measurements.

To enter the study, individuals with a suspected mucociliary clearance defect (n=100) must be age 2 years or older and meet one of the 4 following profiles:

  1. Have known or suspected nontuberculous mycobacterial lung disease and enrolled in Protocol 01-I-0202, Natural History, Genetics, Phenotype, and Treatment of Mycobacterial Infections.
  2. Have high suspicion for the diagnosis of PCD, based on ciliary ultrastructural changes on EM (if performed elsewhere prior to referral) or clinical features (chronic sinopulmonary disease, chronic otitis media, history of neonatal respiratory distress or situs inversus), or PCD in a sibling and one of the clinical features of PCD.
  3. Have chronic sino-pulmonary disease with clinical features that overlap with variant CF and PCD, but with diagnostic tests to rule out classical CF (sweat Cl- testing and CF gene mutation screening). This may include patients with other known immune deficiencies such as chronic granulomatous disease followed on NIH natural history protocols.
  4. Known or suspected PHA (or variant PHA), which might include elevated (or borderline) sweat Cl- values.

To enter the study as a healthy control (n=25), individuals must be age 18 or older and free of any known disease, chronic medical conditions, family history of cystic fibrosis or primary ciliary dyskinesia, or any cognitive impairment or significant disability that might preclude voluntary consent or the ability to safely comply with the instructions or sit through the testing.


Persons who cannot be evaluated at the Clinical Center or who have severe cognitive impairment or other severe disability that precludes the ability to understand instructions or sit/lie still for the evaluation will be excluded. Certain conditions may preclude specific procedures included in the protocol, but may still allow pertinent parts of this diagnostic evaluation. These conditions/procedures may include: pregnancy/Chest PA/Lat x-ray; allergy to pilocarpine /sweat testing. For reversible conditions such as acute upper airway infection, significant epistaxis within the prior week (not related to #2 below), or lower airway infection with uncontrollable coughing, the participant may need to be rescheduled upon resolution.

For nasal nitric oxide and nasal potential difference measurements or nasal mucosal scrape biopsies:

  1. Anatomic abnormality of the nose or sinuses (e.g. complete sinus blockage or turbinatectomy) that precludes either the measurement of nasal nitric oxide or nasal potential difference.
  2. A severe bleeding diathesis or condition such as hereditary hemorrhagic telangiectasia syndrome that may predispose to significant nasal bleeding or result in severely excoriated nasal mucosa.
  3. Inability to sit still for up to 15 minutes while the nasal catheters are held on the mucosal surface for transepithelial potential difference measurements. This would include the presence of acute or chronic lower respiratory tract infection that results in uncontrollable coughing.
  4. Diffuse skin condition that would preclude placement of the subcutaneous reference electrode (butterfly needle) for nasal PD measurement.

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 identifier (NCT number): NCT00368446

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United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
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Principal Investigator: Kenneth N Olivier, M.D. National Heart, Lung, and Blood Institute (NHLBI)

Additional Information:
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Responsible Party: National Heart, Lung, and Blood Institute (NHLBI) Identifier: NCT00368446    
Other Study ID Numbers: 060217
First Posted: August 24, 2006    Key Record Dates
Last Update Posted: May 20, 2020
Last Verified: March 17, 2020
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) ):
Nontuberculous Mycobacterial Infection
Primary Ciliary Dyskinesia
Cystic Fibrosis
Chronic Granulomatous Disease
Mycobacterial Infection
Healthy Volunteer
Additional relevant MeSH terms:
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Mycobacterium Infections
Cystic Fibrosis
Ciliary Motility Disorders
Kartagener Syndrome
Granulomatous Disease, Chronic
Genetic Diseases, Inborn
Pathologic Processes
Pancreatic Diseases
Digestive System Diseases
Lung Diseases
Respiratory Tract Diseases
Infant, Newborn, Diseases
Movement Disorders
Central Nervous System Diseases
Nervous System Diseases
Neurologic Manifestations
Signs and Symptoms
Phagocyte Bactericidal Dysfunction
Leukocyte Disorders
Hematologic Diseases
Genetic Diseases, X-Linked
Immunologic Deficiency Syndromes
Immune System Diseases
Otorhinolaryngologic Diseases
Abnormalities, Multiple