Genetic Disorders of Mucociliary Clearance in Nontuberculous Mycobacterial Lung Disease

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.

- INCLUSION CRITERIA:

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.

EXCLUSION CRITERIA:

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.