Genetic Disorders of Mucociliary Clearance in Nontuberculous Mycobacterial Lung Disease

Cystic Fibrosis Clinical Trial

Official title: Genetic Disorders of Mucociliary Clearance

Status Completed

Clinical Trial 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.)

Clinical Trial 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. ;

Related Conditions & MeSH terms

• Chronic Granulomatous Disease
• Ciliary Motility Disorders
• Cystic Fibrosis
• Dyskinesias
• Fibrosis
• Genetic Diseases, Inborn
• Granulomatous Disease, Chronic
• Infections
• Mycobacterium Infections
• Nontuberculous Mycobacterial Infection
• Primary Ciliary Dyskinesia
• Pseudohypoaldosteronism

• NCT number: NCT00368446
• Study type: Observational
• Source: National Institutes of Health Clinical Center (CC)
• Status: Completed
• Start date: October 17, 2006