1. Nebulization of Vitamin D for attenuation of lung inflammation
Greg Wallace Bone Marrow transplant
Jason C. Woods Pulmonary Medicine, Radiology, Physics

2. Problem
Chronic Graft vs Host Disease of the lungs (Bronchiolitis Obliterans)
Occurs after lung and bone marrow transplants
Airway fibrosis
Ineffective treatment options (high mortality, 22%)
Late identification of the condition
No early intervention strategy

3. Chronic Obstructive Pulmonary Disease (COPD)
Chronic Obstructive Pulmonary Disease (COPD) and is characterized by
persistent airflow limitation caused by a combination of small airways
disease, alveolar septum destruction and impaired secretions clearance.
Chronic inflammation causes structural changes and narrowing of the small airways.
Destruction of the lung parenchyma, also by inflammatory process, leads :
To loss of alveolar attachments to the walls of the small airways.
Reduction of the outward pulling and tethering of the walls of the
small airways, which normally keeps them open.
Sub-optimal tissue available to conduct gas exchange, leading to
chronic difficulty in breathing
It's caused by long-term exposure to irritating gases or particulate matter,
most often from cigarette smoke.

4. Main Causes for COPD Tobacco smoking Air pollution
Genetics, congenital protein deficiency
Chronic lung disease of childhood
Occupational exposure

5. Common symptoms & complications
Shortness of breath
Caught, expectoration
Dyspnea
Fatigue and tightness in the chest
Main Complications
Wheezing or gasping for air
Increased weight loss
Swelling in the legs and feet
Respiratory infections
Heart problems
Lung cancer
High blood pressure in lung arteries
Depression

6. COPD Pathophysiology
Small airways are damaged, bronchiectasis, early collapse in expiration, failure to expectorate
Extensive tissue damage, loss of elastic recoil lung hyperinflation
Production of excessive secretions (goblet cell hyperplasia) and purulent sputum
Lung damage is in homogenous
COPD
Healthy

7. Common Treatments Smoking cessation Anti- inflammatory Medications:
Aerosolized drugs
Bronchodilators
Inhaled steroids
Combination inhalers (bronchodilators and inhaled steroids)
Oral medication
Antibiotics
Corticosteroids
Physiotherapy/lung therapies (to improve mucus clearance and muscle strength):
Oxygen therapy , Non-invasive ventilation, airway vibration
Pulmonary rehabilitation program
Surgery:
Lung volume reduction surgery
Lung tranplant
Bullectomy

8. Therapeutic devices & Technologies
LungFlute®
Positive Expiratory Pressure
Positive Expiratory Pressure and Oscillations
Vibratory PEP Therapy System
High Frequency Chest Wall Oscillation
Inhalators
Drug delivery device
Positive Expiratory Pressure and Acoustic Oscillations

9. Disadvantages with the current devices and treatment
COPD treatment is suboptimal (lancet 2017)
Aerosolized therapy is paradoxically delivered better to the healthier areas and less to obstructed airways
that need more medication
Ineffective cough – ineffective expectoration – recurrent exacerbations
Current devices do not give a complete solution (for lung therapy and effective drug delivery)
Non personalized therapy and medication device based resulting non effective treatment and drug overdosing
Small airways are not sufficiently been ventilated resulting:
Ischemic changes and necrosis development
Accumulation of mucus
Inefficient medication treatment resulting recurrent hospital readmission

10. Our objective: administration of Vitamin D125 into the lungs
1-25 Vitamin D works wonders in skin GVHD
Why not … in the lung?
Chronic GVHD day 0
Chronic GVHD day 14

11. Problem No nebulized form of Vitamin D at present
Vitamin D is lipid soluble
No human studies in lung
Surfactant, Vit A

12. Drug deposition in the “correct” airways
Adolescent/adult lung
Lower conducting airways
(level 5-12)
Subject in
MRI Scanner
Inhaled 129Xe
Subject in
MRI Scanner
Maps of obstructed areas
Thomen et al. J Cyst Fibros. 2016
Walkup et al. Pediatr Radiol. 2016

13. If we aerosolize vitamin D, need to determine
What particle sizes will deliver maximal drug to level 5-12 airways?
More challenging in pediatrics, since patients of all sizes (6-18 years old, kg)
2. How well can we target individual airways
and/or levels, based upon 129Xe MRI data?
E.g., Level 5-12 airways?
Apical segment,
left lower lobe (bronchoscope)?
Jason I changed the range from kg, our patients usually are off the chart due to chronic illness

14. Need statement
An affordable, portable, non-invasive inhalation/nebulizer device for effective aerosolized (Vitamin D125) drug delivery into the small airway on a daily basis treatment at patient home setting and hospital

15. Conclusions 1,25 Vitamin D would be used in asthma, COPD, ARDS, CF…
Vitamin D 1,25 works very well in skin GVHD
Key was 1,25 formulation
Hyperpolarized gas MRI can depict & quantify lung GVHD early
Very sensitive measure of early lung obstruction
Can nebulize 1,25 form of Vitamin D
Need to optimize delivery: CFD and particle size? Directed lavage?
1,25 Vitamin D would be used in asthma, COPD, ARDS, CF…

16. Molecular Medicine Reports 2017; 16:7432

17. Biology of Blood and Marrow transplantation 2017; epub before print