The purpose of this protocol is to perform a prospective, randomized, double-blinded, pacebo-controlled clinical trial to determine the influence of a non-invasive positive pressure ventilation device on exercise capacity and symptoms in adult patients with ECAC. Primary outcome will include the total distance traversed by the study subject during a standard 6-minute walk test, and secondary outcomes will include peak flow measurement and symptom reporting before and after the exercise testing. The study will focus on the use of continuous positive airway pressure (CPAP) device. CPAP is FDA-approved for the treatment of various medical conditions, including obstructive sleep apnea and heart failure, but is not FDA-approved for the treatment of ECAC. The study will enroll 32 ambulatory study subjects with confirmed ECAC at the BIDMC, and each study subject will be monitored for up to 3 months.

Basal 6MWT performed as a standard of care in these patients will be compared to intervention ones to see if there is an improvement of at least 24 meters in their 6MWT distance, then both groups will be compared to see if there is a statistically significant difference between groups. Subjects, treating physicians and the research fellow performing the 6MWT will be blinded to the intervention; the only un-blinded personnel to the intervention will be the study coordinator who will be in charge of setting the CPAP before every intervention.

As part of the standard of care of our institution, patients that are referred due to suspicion of ECAC undergo initial PFTs, 6MWT and dynamic CT scan. With this information, patients are evaluated in clinic by the interventional pulmonary and thoracic surgery team who decide if the patient has the mentioned disease based on the previous testing. To corroborate the findings patients with moderate so severe disease are taken into a bronchoscopy with dynamic maneuvers as part of the standard of care. Initial bronchoscopic examination will be performed as described in the following section "I-Dynamic Bronchoscopy Protocol" as part of the standard of care of patients. After initial evaluation, during the same intervention, all patients that agree to participate in our study will go through a CPAP calibration procedure; in order to determine the adequate pressure to achieve airway patency of at least 70% during end exhalation in each individual case. After regular bronchoscopic examination, a full face F&P SimplusTM CPAP mask (Fisher & Paykel, Irvine, CA, USA) will be placed in all patients to prevent un-blinding the treating physician. The mask will be connected to a dual axis swivel adapter (T-adapter) and the bronchoscope will be advanced to the nares through the swivel adaptor; air leak will be prevented by the tight disposable cap of the swivel adaptor as described by Murgu et al.20

The calibration process will be performed following the technique first described by Ferguson et al10, bronchoscope will be positioned to assess the area with ECAC previously identified during regular examination; bronchoscope will be placed in the center of the lumen while assuring a constant 1-cm distance between the tip of the bronchoscope and the target area being measured, images will be taken during end inspiration and end expiration, gradual increases of 1 cmH2O in the CPAP pressure will be made until a 70% or less collapse is seen during end expiration by the bronchoscopist. At any given pressure increase the assessment of airway collapse will be made in 3 different respiratory cycles, the whole procedure will be recorded and posteriorly analyzed using morphometric bronchoscopy (Image J analysis program) as described in the "Morphometric Bronchoscopy" section.

Patient Population Subjects (>18 years of age) with previous diagnosis of ECAC confirmed by dynamic CT scan and/or bronchoscopy, who are currently receiving adequate medical therapy (Optimal medication doses and interventions defined by Interventional Pulmonary team) for comorbidities such as COPD, GERD, asthma, etc and are able to perform a 6 MWT.

Tracheobronchomalacia Evaluation CT Central Airway Protocol: All patients will be imaged according to our standard low dose CT central airway protocol21, which includes imaging during end-inspiratory and continuous dynamic expiratory phases. A multidetector row, helical CT scanner (LightSpeed; GE Medical Systems; Milwaukee, WI; or Aquilion; Toshiba America Medical Systems; Tustin, CA) which includes 4, 8, 16, and 64 detector-row systems will be used. Helical scanning will be performed in the cranio-caudal dimension during both respiratory phases. An experienced thoracic radiologist will review the CT images on a picture archiving and communication system (PACS) [Path-Speed, General Electric Medical Systems]. Using a computerized tracing tool in our PACS system, the inner wall of the airway will be hand traced at the level of maximal collapse in dynamic expiratory images to calculate the cross-sectional area of the airway (mm2). At the same level on end-inspiration images, the cross-sectional area of the airway lumen will be determined by using the same method. The percentage of luminal collapse between both respiratory phases will be calculated using the following formula= [1 - (Aee/Aei)],) X100, where Aee is luminal area at end expiration and Aei is luminal area at end inspiration. Mild ECAC is diagnosed if the percent of luminal collapse during dynamic expiration is 70-80%, moderate from 80-90% and severe >90%.

I-Dynamic Bronchoscopy Protocol All patients who are enrolled for the study will undergo bronchoscopy under minimal sedation using intravenous midazolam and fentanyl to allow spontaneous respiration. Lidocaine (1%, 20 ml), will be delivered by atomizer to the posterior oropharynx until the gag reflex is suppressed. The larynx, vocal cords, aryepiglottic folds and entire tracheobronchial tree will be irrigated with 1% lidocaine in 2-ml aliquots delivered through the bronchoscope during the procedure. An Olympus BF P180 video bronchoscope (Olympus America, Melville, NY) with a 4.9-mm outer diameter and 2.0-mm working channel will be used to minimize any stenting effect. The bronchoscope will be introduced into the proximal trachea at the level of the cricoid. At that point, patients will be instructed to take a deep breath, hold it and then blow it out (forced expiratory maneuver). Maneuver will be done at the following six sites: proximal trachea at the level of the cricoid; mid-trachea 5 cm proximal to the carina; distal trachea 2 cm proximal to the carina; right main stem bronchus at the right tracheobronchial angle; bronchus intermedius and left main bronchus at the left tracheobronchial angle. The maneuver will be repeated three times to ensure maximal airway narrowing during exhalation. All bronchoscopies will be video recorded and reviewed after the procedure to assess the degree of airway collapse. Mild ECAC is defined as a collapse 70-80%, moderate 80-90% and severe >90% of the airway during exhalation. This is standard of care for patients with EDAC.

After collapse degree is assessed trough forced expiratory maneuver, a nasal CPAP device (Define model) will be used in the patient, forced expiratory maneuvers will be repeated with different CPAP configurations until a 70% or less airway collapse is achieved. Calibration at which 70% airway collapse is achieved will be recorded and posteriorly used as the CPAP volume for the second 6MWT.

Morphometric bronchoscopy Cross-sectional area (CSA) of the airway will be calculated after the procedure by using the Image J analysis program (available free of charge at http://rsb.info.nih.gov/ij/) using two different measurement techniques as it was described by Murgu et al.22 The graphical measurement method uses color levels within the image to identify an appropriate region to be measured. Images are imported into Image J and a color balance window is opened (Image > Adjust > Color Balance). The histogram is then set to RGB color. The minimum and maximum bars are adjusted so that the resulting line corresponds to the highest point of the histogram. Only red, yellow, white, and black colors then remain. The black area, which represents the region to be measured for CSA, is selected using a wand tool. Using the region of interest (ROI) Manager (Analyze > Tools > ROI Manager) the selected area is then calculated in pixels. The manual measurement method requires that the operator selects the area to be measured by first opening the image using Image J. Using the polygon selections tool, the area of interest is then selected, and the ROI manager is used as in the graphical method.

Finally to provide an objective measurement in our patients, a collapsibility index (CI) will be calculated: difference in airway lumen size between end inspiration and end expiration: CI = (CSAinspir - CSAexpir)/(CSAinspire x 100%). Then measurements obtained for each patient during 3 respiratory cycles will be compared to discard that there is any significant statistical difference between them.

Six Minute Walk Test The 6MWT is a test that requires a 100-ft hallway but no exercise equipment or advanced training for technicians. It evaluates the global and integrated responses of all the systems involved during exercise, including the pulmonary and cardiovascular systems, systemic circulation, peripheral circulation, blood, neuromuscular units, and muscle metabolism. Testing will be performed by the study personnel in a controlled environment. Supplies such as oxygen, sublingual nitroglycerine, aspirin, and albuterol (metered dose inhaler or nebulizer) will be available. The distance walked will be reported in meters. Data from both groups will be compared in order to verify if CPAP has a positive impact on exercise capacity in these patients. Since subjects have never used CPAP before and are not used to the device a 10 minute Run-in period will be allowed in which the CPAP will be placed while the patient is seating to allow he/she to get used to the sensation generated by the machine, at this time the study personnel will also look for air leaks that could compromise the results of the study. Either a regular CPAP or a sham-CPAP will be used for the Run-in period depending on the result of the randomization; this will be done to avoid the patient noticing the difference between this period and the 6 MWT which could happen if only regular CPAP was used.

Sham-CPAP The Sham-CPAP will be created following the methods of Farre et al23 And Rodway et al.24 An enlarged air leak incorporated into the exhalation valve will be positioned between the mask and the CPAP tubing, allowing airflow resistance of the exhalation port to be almost eliminated by increasing its area, thereby virtually cancelling positive pressure. Also an orifice restrictor in the CPAP circuit will be connected between the CPAP unit and the tubing in order to load the blower with the same airflow resistance as in true CPAP. These changes allow the ventilator operating noise and the airflow through the exhalation port remain unchanged, which are crucial to a CPAP placebo.

Enrollment CPAP naïve patients with a diagnosis of ECAC will be informed about the trial and if interested will be recruited for our randomized controlled study. Patients who meet the inclusion criteria by the principle investigator or co-investigators will be approached during an office visit to our Chest Disease Clinic at BIDMC

Inclusion Criteria:

• Patient with a diagnosis of ECAC either via bronchoscopy or CT Scan
• Age > 18 years
• Patients that will undergo a diagnostic or therapeutic bronchoscopy as part of their standard of care
• Patients with a baseline 6 MWT
• Patients that have never used CPAP devices in the past

Exclusion Criteria:

• Patients with poorly-controlled respiratory comorbidities (asthma, COPD, obstructed sleep apnea, GERD, relapsing polychondritis)
• No evidence for acute respiratory tract infection, or respiratory tract infection within the prior 3 weeks
• Resting bradycardia (<50 beats/min), frequent multifocal PVCs, complex ventricular arrhythmia, sustained SVT
• Dysrhythmia that might pose a risk during exercise or training
• Any disease or condition that interferes with completion of initial or follow-up assessments
• Subject has co-morbidities that may significantly reduce subject's ability to improve exercise capacity (e.g., severe arthritis, planned knee surgery) or baseline limitation on 6MWT is not due to dyspnea.
• Subject has an inability to walk >140m (150 yd) in 6 minutes
• Subject has an inability to tolerate bronchoscopy under moderate sedation or general anesthesia.
• Subject has a known sensitivity to drugs required to perform bronchoscopy.

Randomization will be stratified using the variables sex (Female and male) and age (<60 and >60). Additionally a block 2-4 pattern will be used to assure a random and evenly distributed patient population in the different strata. Randomization will be carried out by the research coordinator; the rest of the personnel will be blinded to the allocation of the patients to the different groups.