TGF-(Beta) and Susceptibility to RSV
TGF-(Beta) and Susceptibility to RSV
Background:

 -  Human respiratory syncytial virus (RSV) is a virus that causes respiratory tract
 infections, and is frequently responsible for hospital visits in infants and children.
 It can also trigger severe breathing problems for individuals who have asthma, but these
 infections are generally better tolerated in non-asthmatics. Some research suggests that
 lack of an efficient immune system response in people with asthma may make it difficult
 for the body to fight the effects of RSV.

 -  Transforming Growth Factor-beta (TGF-[beta]) is a chemical in the body that is more
 prevalent in the lungs of people with asthma and related respiratory disorders. More
 information is needed about the effects of TGF-[beta] and whether it makes individuals
 with asthma more prone to developing RSV. Researchers hope to use this information to
 determine possible treatments and therapies for individuals with asthma who contract
 RSV.

 Objectives:

 - To determine the possible role of TGF-[beta] in increased asthmatic susceptibility to RSV
 infection.

 Eligibility:

 - Individuals between 18 and 60 years of age who are either healthy nonsmokers or mild
 asthmatics.

 Design:

 -  This study involves a screening visit and a study visit.

 -  Participants will be screened with a medical history and physical examination, as well
 as blood samples and a pulmonary function test.

 -  At the study visit, participants will receive mild anesthetic and have a bronchoscopy,
 in which researchers insert a bronchoscope through the participant s nose or mouth and
 into the lungs to examine the lungs and collect lung cells.

 -  Participants will be contacted by a research team member 24 36 hours after the
 bronchoscopy to ask about any side effects from the procedure.
This is a cross-sectional, controlled study designed to investigate whether Transforming
 Growth Factor-beta (TGF-beta) mediates increased asthmatic epithelial susceptibility to
 respiratory syncytial virus (RSV) infection by examining responses to RSV infection in
 epithelial cells cultured from asthmatic and non-asthmatic participants. Non-smoking healthy
 adults and mild asthmatics, aged 18-60 years old, will be recruited to participate. Potential
 participants will be prescreened and scheduled for a final eligibility visit that will
 include medical history review, vital signs, physical examination, blood draw, and pulmonary
 function tests (PFTs). After eligibility is confirmed, the participant will be scheduled for
 bronchoscopy. During the bronchoscopy, bronchial epithelia and alveolar macrophages will be
 obtained from the participant for analysis. Alveolar macrophages will be evaluated ex-vivo
 for inflammatory activity at baseline and after stimulation.

 The primary objective of the laboratory analysis is to determine if TGF-beta mediates
 increased asthmatic epithelial susceptibility to RSV infection. The study has three aims
 which are interrelated: 1) To determine if asthmatic bronchial epithelia express more
 TGF-beta than normal epithelia; 2) to determine if RSV replication is greater in asthmatic
 epithelia than normal epithelia; and 3) to determine if TGF-beta mediates asthmatic bronchial
 epithelial susceptibility to RSV infections.
-INCLUSION CRITERIA:

 1. Male or female between 18 and 60 years of age

 2. Non-asthmatics and mild asthmatics as defined below:

 -  Non-asthmatic must have no prior diagnosis of asthma, no history of health care
 utilization or medication use for asthma, no current symptoms, and Forced
 Expiratory Volume in 1 Second (FEV1) greater than or equal to 80% predicted.

 -  Asthmatics must have physician-diagnosed asthma for at least one year and
 evidence of mild, persistent disease during the month prior to Visit 1 (based on
 2008 GINA guidelines).

 a) Participants who are currently taking a controller medication must:

 i. use the equivalent to GINA Step 1 or 2 therapy; and

 ii. have controlled disease, as defined by:

 -  daytime symptoms less than or equal to 2 times week, such as wheezing, tightness
 in the chest, shortness of breath, and cough,

 -  no nocturnal symptoms;

 b) Participants who are not currently taking a controller must have:

 i.<TAB>daytime symptoms > 1 time a week but < 1 time a day, such as wheezing,
 tightness in the chest, shortness of breath, and cough;

 ii. nocturnal awakenings > 2 times a month but < 1 time a week;

 c) All asthmatic participants must have either:

 i.<TAB>Pre-bronchdilator FEV1 greater than or equal to 80% predicted and a positive
 methacholine challenge (PC20 less than or equal to 4 mg / ml); or

 ii.<TAB>Pre-bronchodilator FEV1 < 80% and post-bronchodilator FEV1 greater than or
 equal to 80% with significant bronchodilator reversibility (at least 12% or 200ml
 change in FEV1)

 3. Participants must be able to understand and provide written informed consent

 4. Participants must be able to travel to the CRU and the EPA

 EXCLUSION CRITERIA:

 1. Use of oral steroid treatment(s) within 30 days of Visit 1

 2. Acute asthma-related healthcare utilization within 30 days of Visit 1, such as ED
 visits, systemic corticosteroids, and nebulizer treatment for asthma exacerbation

 3. Known or suspected respiratory infections within 30 days of Visit 1, such as flu,
 pneumonia, severe cold, tuberculosis, or bronchitis

 4. Known or suspected viral infection within 30 days of Visit 1

 5. History of chronic obstructive pulmonary disease other than asthma

 6. History of immunological disease or current cancer

 7. Uncontrolled cardiovascular disease such as angina, prior myocardial infarction,
 stroke, and high cholesterol

 8. Cardiac malformations

 9. Pulmonary hypertension

 10. Bleeding disorders

 11. Facial deformity, major facial surgery

 12. Currently pregnant or breast feeding

 13. Current smoker, significant second-hand smoke exposure (defined by urine cotinine >
 100 ng/ml at Visit 1 or Visit 2) or former smokers (defined by a history of smoking >
 100 cigarettes)

 14. Insulin dependent diabetes

 15. Used any of the following medications within 30 days of Visit 1: oral corticosteroids,
 systemic immunosuppressants or other immune-modifying drugs [e.g., Rituxan, Humira,
 Enbrel, Azathioprine (Imuran), Cyclosporine (Neoral, Sandimmune, and SangCya),
 cyclophosphamide, TNF antagonists], anticoagulants (clopidogrel, heparin, enoxaparin
 and related drugs, coumadin), and sustained use (i.e. more than one dose per day for
 more than two days) of non-steroidal anti-inflammatory drugs (aspirin, ibuprofen,
 indomethacin) within seven days of bronchoscopy

 16. Allergy or history of adverse reactions to methacholine or lidocaine

 17. Severe asthma as defined by a history of intubation for unstable asthma

 18. Any condition that, in the investigator's opinion, places the participant at undue
 risk for complications (e.g. from PFTs, fiberoptic bronchoscopy, bronchalveolar lavage
 and/or bronchial brushings)

 19. Temperature > 37.6 C; blood pressure < 90/50 mm Hg or blood pressure >170/95 mm Hg;
 pulse rate < 50 or > 100 beats/minute

 20. Body weight < 50 kg (<110 lbs)

 21. The following abnormal lab values (values obtained during clinical assessment):

 -  Platelet count < 100,000 per 10(9)/L

 -  White blood cells count < 3000 per 10(9)/L

 -  Hematocrit < 35% for both female and male

 -  Prothrombin Time (PT) / Abnormal International Normalized Ratio (INR) and partial
 prothromboplastin time (PTT) based on reference laboratory established reference
 ranges

 -  Serum creatinine > 1.4 mg/dL