The Severe Asthma Research Program III-Boston Clinical Site
Condition: Asthma
MeSH terms: Asthma
Study type: Observational

Summary: 
      Asthma is a disease characterized by inflammation in the airways. The body naturally makes
      compounds that reduce inflammation. Unfortunately, for patients with severe asthma, the
      pathway these compounds use to reduce inflammation seems to be perturbed. Investigators have
      chosen to focus on the anti-inflammatory compounds called lipoxins and how they work through
      the "ALX Axis", a name given to the ALX receptor pathway and its ligands. Work from the
      Brigham and Women's Hospital has suggested that in patients with severe asthma, the ALX axis
      may not work properly and therefore may not shut off inflammation as expected. Also, there is
      information to suggest that in some cases, steroids (prednisone and similar drugs), which are
      commonly used to treat asthma, may affect the ALX axis in a negative way, paradoxically
      making the inflammation worse instead of better.

      As part of the NIH Severe Asthma Research Program the Asthma Research Center's goal is to
      identify what causes the problems in the ALX axis in severe asthma. To do so, participants
      with severe asthma will be compared to participants with milder forms of asthma.
      Investigators will use samples taken directly from the lungs of people with asthma, as well
      as blood, urine and CT scans of the lungs to better understand how the ALX axis changes both
      before and after corticosteroid treatment and throughout a three year span. Participants will
      come into the Asthma Research Center to have the procedures done.

      Investigators expect participants will perform breathing tests and complete questionnaires
      and diaries. To better understand if corticosteroids negatively affect the ALX axis in severe
      asthma, researchers will take samples before and after a one time steroid injection
      equivalent to a prednisone treatment for asthma. Participants will perform two bronchoscopy
      procedures, before and after corticosteroid treatment, where biopsies and cells will be
      obtained from the participant's lungs. Investigators will use these samples to observe any
      changes that the corticosteroid may have on the ALX axis. At the end of the study,
      researchers at the Brigham and Women's Hospital expect to understand the ALX axis in such a
      way that will allow them to formulate new therapies and drug targets to treat people with
      asthma, especially severe asthma, more effectively.

      In Boston, this study will be run together by the Asthma Research Center at the Brigham and
      Women's Hospital (adults) and Boston Children's Hospital (children).
    

Detailed description: 
      Severe asthma accounts for the majority of the morbidity and mortality related to asthma. It
      is characterized by persistent airway inflammation despite anti-inflammatory therapy,
      persistent airway hyperresponsiveness, and "remodeling" of the airways that includes
      fibrosis. Lipoxin A4 (LXA4) and 15-epimer-LXA4 are lipid-derived mediators that have been
      shown to promote anti-inflammatory and pro-resolving cellular responses through their effects
      at ALX/FPR2 receptors. They promote resolution of inflammation, inhibit airway
      hyperresponsiveness, and counteract pro-fibrotic processes. Investigators at the Brigham and
      Women's Hospital and others have shown that the ALX effector pathway and its constituent
      ligands (ALX axis) is perturbed in severe asthma (SA) compared with non-severe asthma (NSA).
      Specifically, in SA LXA4 production is decreased and ALX/FPR2 receptor expression is reduced.
      Further, investigators at the Brigham and Women's Hospital have shown that low levels of
      lipoxins, relative to pro phlogistic leukotrienes, are associated with reduced airway
      function (FEV1). Considering these data and the function of the ALX axis, it appears that
      perturbations of constituents of this axis could identify, and perhaps underlie, several of
      the processes that characterize severe, progressive asthma. Further to this point, work in
      progress being done at the Brigham and Women's Hospital indicates that corticosteroids (CS)
      interactions with the ALX axis may underlie some of these perturbations. CS can decrease the
      production of LXA4. More importantly, while CS increase production of pro-resolving annexin
      A1, they also appear to promote pro-inflammatory signaling through ALX/FPR2 via upregulation
      of serum amyloid A (SAA). SAA is expressed in the lung and is associated with exacerbations
      of COPD.

      Hypotheses:

      Peripheral blood leukocytes and bronchoalveolar lavage fluids will be obtained from SA and
      NSA subjects before and after intramuscular triamcinolone at baseline to test the hypothesis
      that in vivo corticosteroids will reduce pro-inflammatory cellular responses and enhance
      LXA4-mediated anti-inflammatory responses in the majority of asthmatic subjects. There is a
      sub-group of individuals with severe asthma in which in vivo corticosteroids will
      paradoxically increase pro-inflammatory responses. Investigators will also test the
      hypothesis that such paradoxical signaling can be overcome by lipoxins. In addition,
      investigators will test the hypothesis that basal p anti-inflammatory responses are dampened
      in severe asthma.

      Investigators at the Brigham and Women's Hospital hypothesize that a cohort of severe
      asthmatic subjects with impaired counter-regulatory signaling will have a specific ALX axis
      phenotype that will predispose them to increased inflammation, asthma exacerbations and
      disease progression.

      Investigators will test the hypothesis that in vivo corticosteroids will not increase (and
      may decrease) LXA4 or 15-epi-LXA4 but will increase annexin A1 and serum amyloid A and that
      the levels of these compounds post-CS will differ by disease severity, remaining stable over
      a 3 year interval.

      Samples will be obtained at study entry before and after intramuscular triamcinolone to test
      the hypothesis that in vivo corticosteroids increase ALX/FPR2 expression in leukocytes and
      airway cells.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        The target recruitment goal for our center is 75% adults (age 18 to 60) and 25% children
        age 6-17 years. Within the pediatric age group, an attempt will be made to enroll equal
        numbers of children 6-11 and 12-17 years of age. Similarly, an attempt will be made to
        enroll at least 50% females and 30% minorities.

        Given the mission of SARP, a diverse sample of subjects with asthma is needed to gain
        better understanding of asthma and its endotypes. Because there are a number of respiratory
        disorders that may be confused with asthma or confound asthma assessment, SARP enrollees
        must meet the all of the eligibility criteria described.
      
Biospecimen description: 
      CBC/Diff, Total IgE, Serum, Plasma, DNA, RNA Urine EBC Sputum: Supernatant, Cell Pellet
      Bronch: BAl, Bronchial Brushings, Bronchial Biopsy
    
Keywords: Asthma; Severe Asthma; SARP