title: Inflammatory and Comorbid Features of Patients with Severe Asthma and Frequent Exacerbations.
abstract: Reducing asthma exacerbation frequency is an important criterion for approval of asthma therapies, but the clinical features of exacerbation-prone asthma (EPA) remain incompletely defined.
  
  
  
  To describe the clinical, physiologic, inflammatory, and comorbidity factors associated with EPA.
  
  
  
  Baseline data from the NHLBI Severe Asthma Research Program (SARP)-3 were analyzed. An exacerbation was defined as a burst of systemic corticosteroids lasting 3 days or more. Patients were classified by their number of exacerbations in the past year: none, few (one to two), or exacerbation prone (≥3). Replication of a multivariable model was performed with data from the SARP-1 + 2 cohort.
  
  
  
  Of 709 subjects in the SARP-3 cohort, 294 (41%) had no exacerbations and 173 (24%) were exacerbation prone in the prior year. Several factors normally associated with severity (asthma duration, age, sex, race, and socioeconomic status) did not associate with exacerbation frequency in SARP-3; bronchodilator responsiveness also discriminated exacerbation proneness from asthma severity. In the SARP-3 multivariable model, blood eosinophils, body mass index, and bronchodilator responsiveness were positively associated with exacerbation frequency (rate ratios [95% confidence interval], 1.6 [1.2-2.1] for every log unit of eosinophils, 1.3 [1.1-1.4] for every 10 body mass index units, and 1.2 [1.1-1.4] for every 10% increase in bronchodilatory responsiveness). Chronic sinusitis and gastroesophageal reflux were also associated with exacerbation frequency (1.7 [1.4-2.1] and 1.6 [1.3-2.0]), even after adjustment for multiple factors. These effects were replicated in the SARP-1 + 2 multivariable model.
  
  
  
  EPA may be a distinct susceptibility phenotype with implications for the targeting of exacerbation prevention strategies. Clinical trial registered with www.clinicaltrials.gov (NCT 01760915).
authors.affiliation: 1 University of Wisconsin, Madison, Wisconsin.
authors.forename: Loren C
authors.initials: LC
authors.lastname: Denlinger
authors.affiliation: 2 The Pennsylvania State University College of Medicine, Hershey, Pennsylvania.
authors.forename: Brenda R
authors.initials: BR
authors.lastname: Phillips
authors.affiliation: 1 University of Wisconsin, Madison, Wisconsin.
authors.forename: Sima
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authors.lastname: Ramratnam
authors.affiliation: 3 Case Western Reserve University, Cleveland, Ohio.
authors.forename: Kristie
authors.initials: K
authors.lastname: Ross
authors.affiliation: 4 University of California San Francisco, San Francisco, California.
authors.forename: Nirav R
authors.initials: NR
authors.lastname: Bhakta
authors.affiliation: 5 Harvard Medical School, Boston, Massachusetts.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Cardet
authors.affiliation: 6 Washington University, St. Louis, Missouri.
authors.forename: Mario
authors.initials: M
authors.lastname: Castro
authors.affiliation: 7 Wake Forest University, Winston-Salem, North Carolina.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Peters
authors.affiliation: 5 Harvard Medical School, Boston, Massachusetts.
authors.forename: Wanda
authors.initials: W
authors.lastname: Phipatanakul
authors.affiliation: 8 University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Shean
authors.initials: S
authors.lastname: Aujla
authors.affiliation: 6 Washington University, St. Louis, Missouri.
authors.forename: Leonard B
authors.initials: LB
authors.lastname: Bacharier
authors.affiliation: 7 Wake Forest University, Winston-Salem, North Carolina.
authors.forename: Eugene R
authors.initials: ER
authors.lastname: Bleecker
authors.affiliation: 9 The Cleveland Clinic, Cleveland, Ohio.
authors.forename: Suzy A A
authors.initials: SA
authors.lastname: Comhair
authors.affiliation: 6 Washington University, St. Louis, Missouri.
authors.forename: Andrea
authors.initials: A
authors.lastname: Coverstone
authors.affiliation: 10 University of Virginia, Charlottesville, Virginia.
authors.forename: Mark
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authors.lastname: DeBoer
authors.affiliation: 9 The Cleveland Clinic, Cleveland, Ohio.
authors.forename: Serpil C
authors.initials: SC
authors.lastname: Erzurum
authors.affiliation: 1 University of Wisconsin, Madison, Wisconsin.
authors.forename: Sean B
authors.initials: SB
authors.lastname: Fain
authors.affiliation: 8 University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Merritt
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authors.lastname: Fajt
authors.affiliation: 11 Emory University, Atlanta, Georgia; and.
authors.forename: Anne M
authors.initials: AM
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authors.affiliation: 5 Harvard Medical School, Boston, Massachusetts.
authors.forename: Jonathan
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authors.lastname: Gaffin
authors.affiliation: 3 Case Western Reserve University, Cleveland, Ohio.
authors.forename: Benjamin
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authors.lastname: Gaston
authors.affiliation: 7 Wake Forest University, Winston-Salem, North Carolina.
authors.forename: Annette T
authors.initials: AT
authors.lastname: Hastie
authors.affiliation: 7 Wake Forest University, Winston-Salem, North Carolina.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Hawkins
authors.affiliation: 8 University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Fernando
authors.initials: F
authors.lastname: Holguin
authors.affiliation: 12 Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Irani
authors.affiliation: 5 Harvard Medical School, Boston, Massachusetts.
authors.forename: Elliot
authors.initials: E
authors.lastname: Israel
authors.affiliation: 5 Harvard Medical School, Boston, Massachusetts.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Levy
authors.affiliation: 4 University of California San Francisco, San Francisco, California.
authors.forename: Ngoc
authors.initials: N
authors.lastname: Ly
authors.affiliation: 7 Wake Forest University, Winston-Salem, North Carolina.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Meyers
authors.affiliation: 7 Wake Forest University, Winston-Salem, North Carolina.
authors.forename: Wendy C
authors.initials: WC
authors.lastname: Moore
authors.affiliation: 3 Case Western Reserve University, Cleveland, Ohio.
authors.forename: Ross
authors.initials: R
authors.lastname: Myers
authors.affiliation: 7 Wake Forest University, Winston-Salem, North Carolina.
authors.forename: Maria Theresa D
authors.initials: MT
authors.lastname: Opina
authors.affiliation: 4 University of California San Francisco, San Francisco, California.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Peters
authors.affiliation: 1 University of Wisconsin, Madison, Wisconsin.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Schiebler
authors.affiliation: 1 University of Wisconsin, Madison, Wisconsin.
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Sorkness
authors.affiliation: 10 University of Virginia, Charlottesville, Virginia.
authors.forename: W Gerald
authors.initials: WG
authors.lastname: Teague
authors.affiliation: 8 University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Sally E
authors.initials: SE
authors.lastname: Wenzel
authors.affiliation: 4 University of California San Francisco, San Francisco, California.
authors.forename: Prescott G
authors.initials: PG
authors.lastname: Woodruff
authors.affiliation: 2 The Pennsylvania State University College of Medicine, Hershey, Pennsylvania.
authors.forename: David T
authors.initials: DT
authors.lastname: Mauger
authors.affiliation: 4 University of California San Francisco, San Francisco, California.
authors.forename: John V
authors.initials: JV
authors.lastname: Fahy
authors.affiliation: 1 University of Wisconsin, Madison, Wisconsin.
authors.forename: Nizar N
authors.initials: NN
authors.lastname: Jarjour
mesh_terms: D000293:Adolescent; D000328:Adult; D000420:Albuterol / Q000008:administration & dosage / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy / Q000453:epidemiology / Q000276:immunology / Q000503:physiopathology*; D015415:Biomarkers / Q000032:analysis; D015992:Body Mass Index; D001944:Breath Tests; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D016009:Chi-Square Distribution; D002648:Child; D015897:Comorbidity; D018450:Disease Progression; D004198:Disease Susceptibility; D004351:Drug Resistance / Q000276:immunology*; D004804:Eosinophils / Q000187:drug effects; D005260:Female; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood; D007249:Inflammation / Q000209:etiology*; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000032:analysis; D012720:Severity of Illness Index; D017678:Sex Distribution; D013183:Sputum / Q000737:chemistry
chemical_list: D015415:Biomarkers; D001993:Bronchodilator Agents; D009569:Nitric Oxide; D007073:Immunoglobulin E; D000420:Albuterol
keywords: bronchodilator reversibility; eosinophils; exacerbation-prone asthma; gastroesophageal reflux; sinusitis