Clinical trial NCT02025829: IL-17 Neutrophils in CF Lung Inflammation
Official title: The Role of IL-17 Neutrophils in CF Lung Inflammation
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Cystic Fibrosis
Keywords: cystic fibrosis
IL-17 neutrophils
Lead sponsor: University Hospitals Cleveland Medical Center
Sponsor class: OTHER
Collaborators: name: Case Western Reserve University
First posted: 2014-01-01
Enrollment: 14
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients seen in the cystic fibrosis outpatient clinic (Clinically Stable Cohort) and inpatient unit (Exacerbation/IV Antibiotics Cohort) of Cystic Fibrosis Center in Cleveland, OH (Rainbow Babies and Children's Hospital/University Hospitals Case Medical Center)

Brief summary: The purpose of this study is to determine whether IL-17 polymorphonuclear leukocytes (PMNs) are central to the disease pathology in CF. This will be determined by demonstrating that IL-17 PMNs are present in the CF airway, correlate with lung function measures, and decrease in patients being treated with IV antibiotics for a pulmonary exacerbation.

Detailed description: This study consists of two parts which will be conducted in parallel. In the first part of the study, 14 subjects will be recruited for the Clinically Stable Cohort. Subjects will be asked to provide 1 gm of expectorated sputum and 40-ml of blood. A cell count and differential will be performed on the sputum followed by analysis for IL-17 PMNs by fluorescence-activated cell sorter (FACS). IL-17 PMNs also will be isolated by running the remainder of the cell pellet through a column of magnetic beads designed for this purpose. These neutrophils will be lysed and intracellular cytokines determined. Sputum supernatants will be stored frozen until analyzed for the presence of IL-1β, IL-6, IL-8, IL-17A, TGF-β, TNF-α, and neutrophil elastase. Clinical data will be captured from the subject's clinical outpatient visit including lung function measures and clinical culture results. IL-17 PMNs will be correlated with lung function measures and inflammatory mediators at baseline.

In the second part of this study, 10 subjects will be recruited for the Exacerbation Cohort. Subjects will provide at least 1 gram of expectorated sputum and 40-ml of blood within 72 hours of hospital admission. Sputum and blood will be processed and analyzed as described above. Sputum and blood also will be obtained at the end of treatment (within 72 hours of completion of IV antibiotics) when the subject is at his or her baseline as determined by the managing physician. Clinical data will be captured from the subject's hospitalization records including lung function measures and clinical culture results.

Eligibility criteria: Inclusion Criteria:

* For Both Cohorts: ≥ 18 \< 50 years of age
* For Both Cohorts: Must have a documented diagnosis of CF (positive sweat chloride ≥60 milliequivalents (mEq)/liter, by pilocarpine iontophoresis) and/or a genotype with two identifiable mutations consistent with CF accompanied by one or more clinical features with the CF) phenotype
* For Both Cohorts: Chronically infected with P. aeruginosa defined by 2 positive cultures in the past year or 3 in the last two years
* For Both Cohorts: Ability to expectorate mucus
* For Both Cohorts: Ability to provide written informed consent
* For Clinically Stable Cohort: 4 subjects with one copy of G551D
* For Clinically Stable Cohort: 10 subjects who do not have G551D, they must have one copy of F508del
* For Clinically Stable Cohort: CF subjects must have a baseline FEV1 percent predicted \> 50% (in the last year, obtained from medical record)
* For Clinically Stable Cohort: Clinically stable: free of any acute illness for \>14 days
* For Clinically Stable Cohort: Must have performed spirometry for clinical purposes at that clinical visit
* For Clinically Stable Cohort: Must have a sputum culture sent to the clinical lab for clinical purposes at the time of the study visit
* For Clinically Stable Cohort: Have not been prescribed any new systemic antibiotics for the 14 days prior to enrollment
* For Exacerbation/IV Antibiotics Cohort: One copy of F508del
* For Exacerbation/IV Antibiotics Cohort: Must have a doctor defined pulmonary exacerbation requiring treatment with IV antibiotics
* For Exacerbation/IV Antibiotics Cohort: Must have performed spirometry for clinical purposes within 72 hours of initiating IV antibiotics and within 72 hours of completing IV antibiotics
* For Exacerbation/IV Antibiotics Cohort: Must have a sputum culture sent to the clinical lab for clinical purposes within 72 hours of admission

Exclusion Criteria:

* For Both Cohorts: Pregnancy (based on self-report)
* For Both Cohorts: Co-infection with Burkholderia cepacia complex organisms
* For Both Cohorts: Any condition that in the opinion of the subject or the subject's managing physician that would compromise that individuals ability to participate in these studies
* For Both Cohorts: Inability to tolerate the study procedures

Primary outcomes:
measure: Change in Sputum IL-17 Neutrophils
timeFrame: End of Treatment, two weeks. Samples will be obtained from each study volunteer at the beginning of IV antibiotic treatment and at the completion of antibiotic treatment for a pulmonary exacerbation
Secondary outcomes:
measure: Sputum Inflammatory Mediators: IL-1β, IL-6, IL-8, IL-17A, TGF-β, TNF-α, and Neutrophil Elastase
timeFrame: Samples will be obtained at one outpatient clinic visit during the next calendar year
measure: Sputum Inflammatory Mediators: IL-1β, IL-6, IL-8, IL-17A, and Neutrophil Elastase
timeFrame: End of Treatment, two weeks. Samples will be obtained from each study volunteer at the beginning of IV antibiotic treatment and at the completion of antibiotic treatment for a pulmonary exacerbation
Other outcomes:
Locations:
city: Cleveland
country: United States
facility: Rainbow Babies and Children's Hospital
state: Ohio
Study officials:
affiliation: Rainbow Babies and Children's Hospital
name: James F. Chmiel, MD, MPH
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Lands LC, Stanojevic S. Oral non-steroidal anti-inflammatory drug therapy for lung disease in cystic fibrosis. Cochrane Database Syst Rev. 2013 Jun 13;(6):CD001505. doi: 10.1002/14651858.CD001505.pub3.
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citation: Oermann CM, Sockrider MM, Konstan MW. The use of anti-inflammatory medications in cystic fibrosis: trends and physician attitudes. Chest. 1999 Apr;115(4):1053-8. doi: 10.1378/chest.115.4.1053.
citation: Konstan MW. Ibuprofen therapy for cystic fibrosis lung disease: revisited. Curr Opin Pulm Med. 2008 Nov;14(6):567-73. doi: 10.1097/MCP.0b013e32831311e8.
citation: Konstan MW, Byard PJ, Hoppel CL, Davis PB. Effect of high-dose ibuprofen in patients with cystic fibrosis. N Engl J Med. 1995 Mar 30;332(13):848-54. doi: 10.1056/NEJM199503303321303.
citation: Konstan MW, Schluchter MD, Xue W, Davis PB. Clinical use of Ibuprofen is associated with slower FEV1 decline in children with cystic fibrosis. Am J Respir Crit Care Med. 2007 Dec 1;176(11):1084-9. doi: 10.1164/rccm.200702-181OC. Epub 2007 Sep 13.
citation: Chmiel JF, Konstan MW. Inflammation and anti-inflammatory therapies for cystic fibrosis. Clin Chest Med. 2007 Jun;28(2):331-46. doi: 10.1016/j.ccm.2007.02.002.
citation: Taylor PR, Roy S, Leal SM Jr, Sun Y, Howell SJ, Cobb BA, Li X, Pearlman E. Activation of neutrophils by autocrine IL-17A-IL-17RC interactions during fungal infection is regulated by IL-6, IL-23, RORgammat and dectin-2. Nat Immunol. 2014 Feb;15(2):143-51. doi: 10.1038/ni.2797. Epub 2013 Dec 22.