Asthma, Atopy
Conditions
Brief summary
There are new, very sensitive methods for detecting bacteria. These methods show that hundreds of millions of microbes (organisms that can only be seen with microscopes), especially bacteria, live in healthy people. The collection of different microbes found in a site is called a microbiome. The investigators know that microbiomes of the skin, sinuses, mouth, gastro-intestinal tract, etc. differ from each other. The make-up of the microbiome - which bacteria are found in a site - may be necessary for good health. For example, the microbiome of the mouth is different in people with inflammation of the gums (periodontitis), and the microbiome of the bowel is different in people with inflammation of the intestinal tract (inflammatory bowel disease). The purpose of this research study is to find out if the microbiome in the lungs is different in healthy people without asthma compared to people with asthma. This study will also find out if the microbiome of the lungs changes when people with asthma take a daily controller medication called an inhaled corticosteroid.
Detailed description
Two broad specific aims of this study are: 1)To evaluate whether the microbiota of the bronchial airways in atopic asthmatics and atopic healthy controls differ in microbial diversity, richness, evenness, or composition of specific bacterial taxa. 2) To determine whether inhaled corticosteroid treatment alters bronchial microbial community composition in asthmatics.
Interventions
DRUGfluticasone
Dry Powder Inhaler: 250 mcg/puff, one puff, twice a day
DRUGPlacebo
Dry Powder Inhaler: Placebo
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Milton S. Hershey Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
Yes
Inclusion criteria
Asthmatic: * History of physician-diagnosed asthma. * Methacholine PC20 \< 8mg/ml and/or FEV1 improvement ≥ 12% in response to 180 mcg albuterol. * FEV1 ≥ 70% of predicted after 180 mcg albuterol. * Stable asthma for ≥ 3 months prior to enrollment (no urgent care visits, no systemic corticosteroid treatment). * Asthma Control Questionnaire 6 Score \< 1.5. * Able to provide informed consent. * Able to perform spirometry as per ATS criteria. * Evidence by allergen skin test of sensitivity to an aeroallergen. * Willingness, if female and able to conceive, to utilize one medically-acceptable form of contraception. Healthy Control: * Evidence by allergen skin test of sensitivity to an aeroallergen. * Able to provide informed consent. * Able to perform spirometry as per ATS criteria.
Exclusion criteria
Asthmatic: * Presence of lung disease other than asthma. * Use of \> 10 doses of nasal corticosteroids in the previous 3 months. * Presence of significant medical illness or other chronic diseases whose treatment could affect the clinical features measured, responses to the therapies to be given in this study, or risks of participating in the study. * History of atrial or ventricular tachyarrhythmia. * Changes suggestive of cardiac ischemia on ECG at baseline. * History of upper respiratory infection, sinusitis, bronchitis, or antibiotic use in the previous 3 months. * History of chronic sinus disease. * Smoking \> 5 pack-years, or within the past year * History of long-term controller medication use for asthma (inhaled or oral corticosteroid, leukotriene pathway antagonist, cromolyn, or theophylline within the preceding 6 months. * History of bleeding disorder. * Reduced creatinine clearance. * Inability, in the opinion of the Study Investigator, to coordinate use of inhaler or otherwise comply with medication regimens. * Contraindication to bronchoscopy on history or examination. Healthy Control: * History of chronic respiratory disease including asthma. * Presence of significant medical illness or other chronic diseases whose treatment could affect the clinical features measured, responses to the therapies to be given in this study, or risks of participating in the study. * History of atrial or ventricular tachyarrhythmia. * Changes suggestive of cardiac ischemia on ECG at baseline. * History of upper respiratory infection, sinusitis, bronchitis, or antibiotic use in the previous 3 months. * Methacholine PC20 \< 16 mg/ml or FEV1 improvement ≥ 12% in response to albuterol. * History of chronic sinus disease * Smoking \> 5 pack-years, or within the past year * Use of \> 10 doses of a nasal corticosteroid preparation in the previous 3 months * FEV1 or FVC \< 80% predicted. * History of bleeding disorder. * Reduced creatinine clearance. * Contraindication to bronchoscopy on history or examination.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Microbial Community Richness | baseline and after 6 weeks of treatment | Richness is the total number of different bacterial taxa detected in the sample. |
| Microbial Community Diversity | baseline and after 6 weeks of treatment | The Shannon diversity index is a type of entropy measure and is a function of the distribution of the total number of organisms across all of the species. If S is the total number of species in the sample and p\_i is the number of organisms in the i-th species divided by the total number of organisms, then Diversity = -Σ p\_i log(p\_i). |
| Microbial Community Evenness | baseline and after 6 weeks of treatment | Pielou's evenness index is a scaled measure of biodiversity and is equal to the observed Shannon diversity index divided by the maximum possible Shannon diversity index, which would occur if all of the species in the sample were equally abundant. Evenness = D/log(S), where D is the Shannon Diversity index and log(S) is the maximum diversity of the sample. |
Countries
United States
Participant flow
Pre-assignment details
Healthy controls and non-atopic asthmatics assessed only at baseline.
Participants by arm
| Arm | Count |
|---|---|
| Atopic Asthmatics Treated With Inhaled Corticosteroid Fluticasone (250 mcg/puff, one puff, twice a day) | 28 |
| Atopic Asthmatics Treated With Placebo Placebo fluticasone (one puff, twice a day) | 14 |
| Atopic Non-asthmatics | 21 |
| Healthy Control | 21 |
| Total | 84 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Atopic Asthmatics Treated With Placebo | Total | Healthy Control | Atopic Non-asthmatics | Atopic Asthmatics Treated With Inhaled Corticosteroid |
|---|---|---|---|---|---|
| Age, Continuous | 37 years | 30 years | 28 years | 28 years | 30 years |
| Blood Eosinophils | 3.6 percent of cells in blood sample | 2.0 percent of cells in blood sample | 1.4 percent of cells in blood sample | 2.0 percent of cells in blood sample | 3.3 percent of cells in blood sample |
| Forced Expiratory Volume in 1 second | 84 percent of predicted | 96 percent of predicted | 100 percent of predicted | 98 percent of predicted | 94 percent of predicted |
| Gender Female | 7 Participants | 46 Participants | 12 Participants | 11 Participants | 16 Participants |
| Gender Male | 7 Participants | 38 Participants | 9 Participants | 10 Participants | 12 Participants |
| Race/Ethnicity, Customized Black | 3 participants | 19 participants | 3 participants | 6 participants | 7 participants |
| Race/Ethnicity, Customized Hispanic or Latio | 0 participants | 5 participants | 2 participants | 0 participants | 3 participants |
| Race/Ethnicity, Customized Other | 2 participants | 9 participants | 1 participants | 4 participants | 2 participants |
| Race/Ethnicity, Customized White | 9 participants | 51 participants | 15 participants | 11 participants | 16 participants |
| Sputum eosinophils | 0.7 percent of cells in sputum sample | 0.2 percent of cells in sputum sample | 0 percent of cells in sputum sample | 0 percent of cells in sputum sample | 0.3 percent of cells in sputum sample |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 2 / 28 | 2 / 14 |
| serious Total, serious adverse events | 0 / 28 | 0 / 14 |
Outcome results
Primary
Microbial Community Diversity
The Shannon diversity index is a type of entropy measure and is a function of the distribution of the total number of organisms across all of the species. If S is the total number of species in the sample and p\_i is the number of organisms in the i-th species divided by the total number of organisms, then Diversity = -Σ p\_i log(p\_i).
Time frame: baseline and after 6 weeks of treatment
Population: Only baseline samples were collected from atopic non-asthmatics and healthy controls. Data was not available for all participants due to insufficient amplification in some samples.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Atopic Asthmatics Treated With Inhaled Corticosteroids | Microbial Community Diversity | baseline | 5.4 Shannon Diversity Index |
| Atopic Asthmatics Treated With Inhaled Corticosteroids | Microbial Community Diversity | after 6 weeks of treatment | 5.0 Shannon Diversity Index |
| Atopic Asthmatics Treated With Placebo | Microbial Community Diversity | after 6 weeks of treatment | 5.1 Shannon Diversity Index |
| Atopic Asthmatics Treated With Placebo | Microbial Community Diversity | baseline | 5.7 Shannon Diversity Index |
| Atopic Non-asthmatics | Microbial Community Diversity | baseline | 5.6 Shannon Diversity Index |
| Atopic Non-asthmatics | Microbial Community Diversity | after 6 weeks of treatment | NA Shannon Diversity Index |
| Healthy Control | Microbial Community Diversity | baseline | 5.3 Shannon Diversity Index |
| Healthy Control | Microbial Community Diversity | after 6 weeks of treatment | NA Shannon Diversity Index |
Primary
Microbial Community Evenness
Pielou's evenness index is a scaled measure of biodiversity and is equal to the observed Shannon diversity index divided by the maximum possible Shannon diversity index, which would occur if all of the species in the sample were equally abundant. Evenness = D/log(S), where D is the Shannon Diversity index and log(S) is the maximum diversity of the sample.
Time frame: baseline and after 6 weeks of treatment
Population: Only baseline samples were collected from atopic non-asthmatics and healthy controls. Data was not available for all participants due to insufficient amplification in some samples.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Atopic Asthmatics Treated With Inhaled Corticosteroids | Microbial Community Evenness | after 6 weeks of treatment | 0.85 Pielou's evenness index |
| Atopic Asthmatics Treated With Inhaled Corticosteroids | Microbial Community Evenness | baseline | 0.88 Pielou's evenness index |
| Atopic Asthmatics Treated With Placebo | Microbial Community Evenness | after 6 weeks of treatment | 0.86 Pielou's evenness index |
| Atopic Asthmatics Treated With Placebo | Microbial Community Evenness | baseline | 0.88 Pielou's evenness index |
| Atopic Non-asthmatics | Microbial Community Evenness | baseline | 0.90 Pielou's evenness index |
| Atopic Non-asthmatics | Microbial Community Evenness | after 6 weeks of treatment | NA Pielou's evenness index |
| Healthy Control | Microbial Community Evenness | after 6 weeks of treatment | NA Pielou's evenness index |
| Healthy Control | Microbial Community Evenness | baseline | 0.86 Pielou's evenness index |
Primary
Microbial Community Richness
Richness is the total number of different bacterial taxa detected in the sample.
Time frame: baseline and after 6 weeks of treatment
Population: Only baseline samples were collected from atopic non-asthmatics and healthy controls. Data was not available for all participants due to insufficient amplification in some samples.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Atopic Asthmatics Treated With Inhaled Corticosteroids | Microbial Community Richness | baseline | 449 number of bacterial taxa |
| Atopic Asthmatics Treated With Inhaled Corticosteroids | Microbial Community Richness | after 6 weeks of treatment | 456 number of bacterial taxa |
| Atopic Asthmatics Treated With Placebo | Microbial Community Richness | after 6 weeks of treatment | 405 number of bacterial taxa |
| Atopic Asthmatics Treated With Placebo | Microbial Community Richness | baseline | 543 number of bacterial taxa |
| Atopic Non-asthmatics | Microbial Community Richness | baseline | 483 number of bacterial taxa |
| Atopic Non-asthmatics | Microbial Community Richness | after 6 weeks of treatment | NA number of bacterial taxa |
| Healthy Control | Microbial Community Richness | after 6 weeks of treatment | NA number of bacterial taxa |
| Healthy Control | Microbial Community Richness | baseline | 444 number of bacterial taxa |