Airway Inflammation
Conditions
Brief summary
Deployment of military personnel has been associated with increased respiratory illness likely due, in part, to inhalation of unusual particulate matter (PM), such as from burn pits. Inflammation is a key initial response to inhaled particulates. The researchers have developed a protocol using inhaled wood smoke particles (WSP) as a way to study PM-induced airway inflammation. Exposure to wood smoke particles causes symptoms, even in healthy people, such as eye irritation, cough, shortness of breath, and increased mucous production. The purpose of this research study is to see if an oral steroid treatment can reduce the airway inflammation caused by the inhaled WSP. The exposure will be 500 µg/m³ of WSP for 2 hours, with intermittent exercise on a bicycle and rest. The wood is burned in a typical wood stove and piped into the chamber.
Detailed description
Military deployment is associated with exposure to novel particulate matter (PM), such as from burn pits, aeroallergens, and increased cigarette consumption. War fighters exposed to these inhalational exposures exhibit immediate and chronic respiratory morbidity. For example, military service personnel surveyed in both the Republic of Korea (ROK) and Kabul, Afghanistan reported a general increase in respiratory morbidity, including asthma and chronic bronchitis, associated with their deployment. Air contaminants in the ROK were characterized by elevated levels of both PM 0.5-2.5 and PM 2.5-10. Similarly, exposures in Kabul were characterized by multiple airborne PM exposures, including those from burn pits. Burn pit PM includes metals, bioaerosols, organic by-products, and biomass combustion particles. These findings indicate that inhaled PM is a likely cause of respiratory morbidity in the field. Inflammation is a key initial response to inhaled particulates. Wood smoke particles (WSP) serve as a model agent to study PM-induced bronchitis. WSP inhalation generates reactive oxidant (and nitrosative) species which cause local injury of airway epithelial cells and release of damage-associated molecular patterns (DAMPs) that activate toll-like receptors (TLR) and Interleukin (IL)-1-mediated innate immune responses by resident airway macrophages. Contamination of PM with bioaerosols, which contain lipopolysaccharide (LPS), also activates innate immune responses through toll-like receptor 4 (TLR4) activation of resident airway macrophages. These complementary processes result in recruitment of neutrophils (PMN), which mediate luminal airway inflammation with release of toxic mediators such as neutrophil elastase and myeloperoxidase that promote acute and chronic bronchitis. Therefore, mitigation of PM-induced airway neutrophilic inflammation should be a key focus in order to reduce the respiratory morbidity of military personnel. The researchers have studied a number of pro-inflammatory inhaled agents, such as nebulized LPS, ozone (O3), and WSP, as models of acute neutrophilic bronchitis against which to test a number of therapeutic agents. To this effect, the researchers have reported that inhaled fluticasone inhibits O3-induced and LPS-induced neutrophilic inflammation, and that parenteral anakinra and oral gamma-tocopherol inhibit neutrophilic responses to inhaled LPS. In this study, the researchers will evaluate the efficacy of oral prednisone, a readily available anti-inflammatory medication commonly used in airway inflammatory diseases, in mitigating WSP-induced airway inflammation.
Interventions
DRUG60 mg Prednisone
Immediately following exit from the wood smoke chamber, subjects will receive 60 mg of prednisone per randomization schema
DRUGPlacebo
Immediately following exit from the wood smoke chamber, subjects will receive a matching placebo to the 60 mg of prednisone per randomization schema
Sponsors
United States Department of Defense
University of North Carolina, Chapel Hill
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Intervention model description
The randomization schedule will be generated by using permuted block randomization with a block size of 4 (2 prednisone, 2 placebo for the first treatment period of the protocol).
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Age 18-45 years, inclusive, of both genders * Negative pregnancy test for females who are not s/p hysterectomy with oophorectomy * No history of episodic wheezing, chest tightness, or shortness of breath consistent with asthma, or physician-diagnosed asthma. * Forced expiratory volume at one second (FEV1) of at least 80% of predicted and FEV1/ forced vital capacity (FVC) ≥0.70. * Oxygen saturation of ≥93% * Ability to provide an induced sputum sample. * Subject must demonstrate a ≥10% increase in sputum %PMNs 6 hours following inhaled WSP exposure, when compared to baseline sputum (to be completed in a separate protocol # 15-1775). * Proof of vaccination to COVID-19.
Exclusion criteria
Clinical contraindications: * Any chronic medical condition considered by the PI as a contraindication to the exposure study including significant cardiovascular disease, diabetes, chronic renal disease, chronic thyroid disease, history of chronic infections/immunodeficiency. * Viral upper respiratory tract infection within 4 weeks of challenge. * Any acute infection requiring antibiotics within 4 weeks of exposure or fever of unknown origin within 4 weeks of challenge. * Abnormal physical findings at the baseline visit, including but not limited to abnormalities on auscultation, temperature of 37.8° C, Systolic BP \> 150mm Hg or \< 85 mm Hg; or Diastolic BP \> 90 mm Hg or \< 50 mm Hg, or pulse oximetry saturation reading less than 93%. * Physician diagnosis of asthma * If there is a history of allergic rhinitis, subjects must be asymptomatic of allergic rhinitis at the time of study enrollment. * Mental illness or history of drug or alcohol abuse that, in the opinion of the investigator, would interfere with the participant's ability to comply with study requirements. * Medications which may impact the results of the WSP exposure, interfere with any other medications potentially used in the study (to include steroids, beta antagonists, non-steroidal anti-inflammatory agents) * Cigarette smoking \> 1 pack per month * Unwillingness to use reliable contraception if sexually active (IUD, birth control pills/patch, condoms). * Use of immunosuppressive or anticoagulant medications including routine use of NSAIDS. Oral contraceptives are acceptable, as are antidepressants and other medications may be permitted if, in the opinion of the investigator, the medication will not interfere with the study procedures or compromise safety and if the dosage has been stable for 1 month. * Orthopedic injuries or impediments that would preclude bicycle or treadmill exercise. * Inability to avoid NSAIDS, Multivitamins, Vitamin C or E or herbal supplements. * Allergy/sensitivity to study drugs or their formulations * Positive COVID-19 test in the past 90 days * Pregnant/lactating women and children (\< 18 years as this is age of majority in North Carolina) will also be excluded since the risks associated with WSP exposure to the fetus or child, respectively, are unknown and cannot be justified for this non-therapeutic protocol. Individuals over 45 years of age will not be included due to the increased possibility of co-morbidities and need for prohibited medications. * Inability or unwillingness of a participant to give written informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to 24 Hours in Sputum Percent Neutrophils | Baseline, 24 hours post WSP exposure | Change in sputum percent neutrophils from baseline to 24 hours post WSP exposure |
| Change From Baseline to 4 Hours in Sputum Percent Neutrophils | Baseline, 4 hours post WSP exposure | Change in sputum percent neutrophils from baseline to 4 hours post WSP exposure |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Number of Sputum Eosinophils | Baseline, 4 and 24 hours post WSP exposure | Eosinophil numbers/mg measured at 4 and 24 hours post WSP exposure. Comparisons at 4 and 24 hours are each made with respect to Baseline. |
| Change in Percent Sputum Eosinophils | Baseline, 4 and 24 hours post WSP exposure | Percent eosinophil measured at 4 and 24 hours post WSP exposure. Comparisons at 4 and 24 hours are each made with respect to Baseline. |
| Change in IL-1b | Baseline, 4 and 24 hours post WSP exposure | Interleukin beta (IL-1b) via Mesoscale platform (pg/mL) at 4 and 24 hours post WSP exposure. Comparisons at 4 and 24 hours are each made with respect to Baseline. |
| Change in IL-8 | Baseline, 4 and 24 hours post WSP exposure | Interleukin-8 (IL-8) via Mesoscale platform (pg/mL) at 4 and 24 hours post WSP exposure. Comparisons at 4 and 24 hours are each made with respect to Baseline. |
| Change in TNFa | Baseline, 4 and 24 hours post WSP exposure | Tumor necrosis factor alpha (TNFa) via Mesoscale platform (pg/mL) at 4 and 24 hours post WSP exposure. Comparisons at 4 and 24 hours are each made with respect to Baseline. |
| Change in IL-6 | Baseline, 4 and 24 hours post WSP exposure | Interleukin-6 (IL-6) via Mesoscale platform (pg/mL) at 4 and 24 hours post WSP exposure. Comparisons at 4 and 24 hours are each made with respect to Baseline. |
| Change in Number of Sputum Neutrophils | Baseline, 4 and 24 hours post WSP exposure | Neutrophil numbers/mg measured at 4 and 24 hours post WSP exposure. Comparisons at 4 and 24 hours are each made with respect to Baseline. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Mucociliary Clearance (MCC) | 4 hours post WSP exposure | 4 hours post WSP exposure, the MCC is done. A whole lung region of interest (ROI) bordering the right lung is used to estimate (by computer analysis) whole lung retention of inhaled radiolabeled particles. Labeled particle counts are measured over a 2 hour period to determine the fraction of initial particle counts remaining. From this data, the investigators will determine the percentage of labeled particles cleared from the lung during the 2 hour observation period. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Prednisone, Then Placebo Participants receive prednisone following WSP exposure. After a 4-week washout period, participants receive placebo following WSP exposure.
60 mg Prednisone: Immediately following exit from the wood smoke chamber, subjects receive 60 mg of prednisone per randomization schema
Placebo: Immediately following exit from the wood smoke chamber, subjects receive a matching placebo to the 60 mg of prednisone per randomization schema | 6 |
| Placebo, Then Prednisone Participants receive placebo following WSP exposure. After a 4-week washout period, participants receive prednisone following WSP exposure.
60 mg Prednisone: Immediately following exit from the wood smoke chamber, subjects receive 60 mg of prednisone per randomization schema
Placebo: Immediately following exit from the wood smoke chamber, subjects receive a matching placebo to the 60 mg of prednisone per randomization schema | 6 |
| Total | 12 |
Baseline characteristics
| Characteristic | Prednisone, Then Placebo | Placebo, Then Prednisone | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 6 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 5 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 4 Participants | 9 Participants |
| Region of Enrollment United States | 6 Participants | 6 Participants | 12 Participants |
| Sex: Female, Male Female | 3 Participants | 4 Participants | 7 Participants |
| Sex: Female, Male Male | 3 Participants | 2 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 12 |
| other Total, other adverse events | 5 / 12 | 4 / 12 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 |
Outcome results
Primary
Change From Baseline to 24 Hours in Sputum Percent Neutrophils
Change in sputum percent neutrophils from baseline to 24 hours post WSP exposure
Time frame: Baseline, 24 hours post WSP exposure
Population: Cell differential slide inadequate for 1 participant in prednisone arm; paired analysis drops this participant from analysis across both arms.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Prednisone | Change From Baseline to 24 Hours in Sputum Percent Neutrophils | 8.07 percent neutrophils |
| Placebo | Change From Baseline to 24 Hours in Sputum Percent Neutrophils | 22.68 percent neutrophils |
p-value: 0.17Wilcoxon (Mann-Whitney)
Primary
Change From Baseline to 4 Hours in Sputum Percent Neutrophils
Change in sputum percent neutrophils from baseline to 4 hours post WSP exposure
Time frame: Baseline, 4 hours post WSP exposure
Population: Cell differential slide inadequate for 1 participant in prednisone arm; paired analysis drops this participant from analysis across both arms.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Prednisone | Change From Baseline to 4 Hours in Sputum Percent Neutrophils | -2.62 percent neutrophils |
| Placebo | Change From Baseline to 4 Hours in Sputum Percent Neutrophils | 5.45 percent neutrophils |
p-value: 0.24Wilcoxon (Mann-Whitney)
Secondary
Change in IL-1b
Interleukin beta (IL-1b) via Mesoscale platform (pg/mL) at 4 and 24 hours post WSP exposure. Comparisons at 4 and 24 hours are each made with respect to Baseline.
Time frame: Baseline, 4 and 24 hours post WSP exposure
Population: An attempt was made to analyze samples for 12 participants; although some samples had insufficient quantity remaining. Data are reported for all samples that yielded data for each endpoint and at each time.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Prednisone | Change in IL-1b | 4 hours post WSP exposure | 39.60 pg/mL |
| Prednisone | Change in IL-1b | 24 hours post WSP exposure | 357.00 pg/mL |
| Placebo | Change in IL-1b | 4 hours post WSP exposure | -41.80 pg/mL |
| Placebo | Change in IL-1b | 24 hours post WSP exposure | 128.00 pg/mL |
Comparison: 4 hours post WSP exposurep-value: 0.46Wilcoxon (Mann-Whitney)
Comparison: 24 hours post WSP exposurep-value: 0.46Wilcoxon (Mann-Whitney)
Secondary
Change in IL-6
Interleukin-6 (IL-6) via Mesoscale platform (pg/mL) at 4 and 24 hours post WSP exposure. Comparisons at 4 and 24 hours are each made with respect to Baseline.
Time frame: Baseline, 4 and 24 hours post WSP exposure
Population: An attempt was made to analyze samples for 12 participants; although some samples had insufficient quantity remaining. Data are reported for all samples that yielded data for each endpoint and at each time.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Prednisone | Change in IL-6 | 4 hours post WSP exposure | 52.78 pg/mL |
| Prednisone | Change in IL-6 | 24 hours post WSP exposure | 37.69 pg/mL |
| Placebo | Change in IL-6 | 4 hours post WSP exposure | 80.35 pg/mL |
| Placebo | Change in IL-6 | 24 hours post WSP exposure | 0.00 pg/mL |
Comparison: 4 hours post WSP exposurep-value: 0.82Wilcoxon (Mann-Whitney)
Comparison: 24 hours post WSP exposurep-value: 0.99Wilcoxon (Mann-Whitney)
Secondary
Change in IL-8
Interleukin-8 (IL-8) via Mesoscale platform (pg/mL) at 4 and 24 hours post WSP exposure. Comparisons at 4 and 24 hours are each made with respect to Baseline.
Time frame: Baseline, 4 and 24 hours post WSP exposure
Population: An attempt was made to analyze samples for 12 participants; although some samples had insufficient quantity remaining. Data are reported for all samples that yielded data for each endpoint and at each time.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Prednisone | Change in IL-8 | 4 hours post WSP exposure | 1416.00 pg/mL |
| Prednisone | Change in IL-8 | 24 hours post WSP exposure | 4835.00 pg/mL |
| Placebo | Change in IL-8 | 4 hours post WSP exposure | 869.00 pg/mL |
| Placebo | Change in IL-8 | 24 hours post WSP exposure | 627.00 pg/mL |
Comparison: 4 hours post WSP exposurep-value: 0.38Wilcoxon (Mann-Whitney)
Comparison: 24 hours post WSP exposurep-value: 0.84Wilcoxon (Mann-Whitney)
Secondary
Change in Number of Sputum Eosinophils
Eosinophil numbers/mg measured at 4 and 24 hours post WSP exposure. Comparisons at 4 and 24 hours are each made with respect to Baseline.
Time frame: Baseline, 4 and 24 hours post WSP exposure
Population: Cell differential slide inadequate for 1 participant in prednisone arm; paired analysis drops this participant from analysis across both arms.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Prednisone | Change in Number of Sputum Eosinophils | 4 hours post WSP exposure | 0.00 Eosinophils/mg |
| Prednisone | Change in Number of Sputum Eosinophils | 24 hours post WSP exposure | 0.00 Eosinophils/mg |
| Placebo | Change in Number of Sputum Eosinophils | 4 hours post WSP exposure | 0.00 Eosinophils/mg |
| Placebo | Change in Number of Sputum Eosinophils | 24 hours post WSP exposure | 0.00 Eosinophils/mg |
Comparison: 4 hours post WSP exposurep-value: 0.77Wilcoxon (Mann-Whitney)
Comparison: 24 hours post WSP exposurep-value: 0.48Wilcoxon (Mann-Whitney)
Secondary
Change in Number of Sputum Neutrophils
Neutrophil numbers/mg measured at 4 and 24 hours post WSP exposure. Comparisons at 4 and 24 hours are each made with respect to Baseline.
Time frame: Baseline, 4 and 24 hours post WSP exposure
Population: Cell differential slide inadequate for 1 participant in prednisone arm; paired analysis drops this participant from analysis across both arms.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Prednisone | Change in Number of Sputum Neutrophils | 4 hours post WSP exposure | 52.00 Neutrophils/mg |
| Prednisone | Change in Number of Sputum Neutrophils | 24 hours post WSP exposure | -17.00 Neutrophils/mg |
| Placebo | Change in Number of Sputum Neutrophils | 4 hours post WSP exposure | 36.00 Neutrophils/mg |
| Placebo | Change in Number of Sputum Neutrophils | 24 hours post WSP exposure | 37.00 Neutrophils/mg |
Comparison: 4 hours post WSP exposurep-value: 0.7Wilcoxon (Mann-Whitney)
Comparison: 24 hours post WSP exposurep-value: 0.37Wilcoxon (Mann-Whitney)
Secondary
Change in Percent Sputum Eosinophils
Percent eosinophil measured at 4 and 24 hours post WSP exposure. Comparisons at 4 and 24 hours are each made with respect to Baseline.
Time frame: Baseline, 4 and 24 hours post WSP exposure
Population: Cell differential slide inadequate for 1 participant in prednisone arm; paired analysis drops this participant from analysis across both arms.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Prednisone | Change in Percent Sputum Eosinophils | 4 hours post WSP exposure | 0.00 percent eosinophils |
| Prednisone | Change in Percent Sputum Eosinophils | 24 hours post WSP exposure | 0.00 percent eosinophils |
| Placebo | Change in Percent Sputum Eosinophils | 4 hours post WSP exposure | 0.00 percent eosinophils |
| Placebo | Change in Percent Sputum Eosinophils | 24 hours post WSP exposure | 0.00 percent eosinophils |
Comparison: 4 hours post WSP exposurep-value: 0.96Wilcoxon (Mann-Whitney)
Comparison: 24 hours post WSP exposurep-value: 0.91Wilcoxon (Mann-Whitney)
Secondary
Change in TNFa
Tumor necrosis factor alpha (TNFa) via Mesoscale platform (pg/mL) at 4 and 24 hours post WSP exposure. Comparisons at 4 and 24 hours are each made with respect to Baseline.
Time frame: Baseline, 4 and 24 hours post WSP exposure
Population: An attempt was made to analyze samples for 12 participants; although some samples had insufficient quantity remaining. Data are reported for all samples that yielded data for each endpoint and at each time.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Prednisone | Change in TNFa | 4 hours post WSP exposure | -3.63 pg/mL |
| Prednisone | Change in TNFa | 24 hours post WSP exposure | 17.70 pg/mL |
| Placebo | Change in TNFa | 4 hours post WSP exposure | 0.00 pg/mL |
| Placebo | Change in TNFa | 24 hours post WSP exposure | 0.00 pg/mL |
Comparison: 4 hours post WSP exposurep-value: 0.49Wilcoxon (Mann-Whitney)
Comparison: 24 hours post WSP exposurep-value: 0.52Wilcoxon (Mann-Whitney)
Other Pre-specified
Mucociliary Clearance (MCC)
4 hours post WSP exposure, the MCC is done. A whole lung region of interest (ROI) bordering the right lung is used to estimate (by computer analysis) whole lung retention of inhaled radiolabeled particles. Labeled particle counts are measured over a 2 hour period to determine the fraction of initial particle counts remaining. From this data, the investigators will determine the percentage of labeled particles cleared from the lung during the 2 hour observation period.
Time frame: 4 hours post WSP exposure