title: Inhaled corticosteroid dose response in asthma: Should we measure inflammation?
abstract: BACKGROUND
  Inhaled corticosteroid (ICS) titration in asthma is primarily based on symptoms and pulmonary function. ICSs may not be increased on this basis despite residual airway inflammation.
  
  
  OBJECTIVE
  To compare the dose-response relationships of ICSs on measures of pulmonary function, symptoms, and inflammation in patients with persistent asthma.
  
  
  METHODS
  We performed a pooled post hoc analysis of 121 patients with mild to moderate asthma from 4 randomized clinical trials that incorporated an ICS dose ramp. Dose ramps were 0 to 200, 0 to 800, and 200 to 800 μg/d (beclomethasone equivalents). Outcome measures included spirometry, fractional exhaled nitric oxide, airway hyperresponsiveness (AHR), symptoms, serum eosinophilic cationic protein, and blood eosinophils.
  
  
  RESULTS
  We found a plateau beyond a small improvement at 0 to 200 μg for forced expiratory volume in 1 second: 3.3% (95% confidence interval [CI], 2.0%-4.7%) at 0 to 200 μg vs 0.3% (95% CI, -0.8% to 1.4%) 200 to 800 μg (P = .001). A similar plateau was seen for symptom improvement beyond 0 to 200 μg. Inflammatory and AHR outcomes revealed further room for improvement beyond low-dose ICSs. There was dose-related suppression (P < .001) for fractional exhaled nitric oxide: 40.4 ppb (95% CI, 34.7-46.9 ppb) for ICS free, 26.8 ppb (95% CI, 23.4-30.2 ppb) for 200 μg, and 20.8 ppb (95% CI, 18.8-23.1 ppb) for 800 μg. Eosinophilic cationic protein concentration was significantly reduced with both higher dose ramps. Eosinophil counts also improved across all 3 dose ramps, with dose separation of 370/μL (95% CI, 280-450/μL) for ICS free vs 250/μL (95% CI, 200-300/μL) 800 μg (P = .03). AHR improved with all 3 dose ramps, with greater improvement at lower doses for indirect vs direct challenges.
  
  
  CONCLUSIONS
  ICS dose response may extend beyond low dose for inflammation and AHR but not symptoms or spirometry. Further study is required to identify whether this correlates with suboptimal longitudinal asthma control.
  
  
  BACKGROUND
  ClinicalTrials.gov Identifiers: NCT00667992, NCT00995657, NCT01216579, NCT01544634.
authors.affiliation: Scottish Centre for Respiratory Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, Scotland.
authors.forename: William J
authors.initials: WJ
authors.lastname: Anderson
authors.affiliation: Scottish Centre for Respiratory Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, Scotland.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Short
authors.affiliation: Scottish Centre for Respiratory Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, Scotland.
authors.forename: Sunny
authors.initials: S
authors.lastname: Jabbal
authors.affiliation: Scottish Centre for Respiratory Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee, Scotland. Electronic address: b.j.lipworth@dundee.ac.uk.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Lipworth
mesh_terms: D000280:Administration, Inhalation; D000293:Adolescent; D000305:Adrenal Cortex Hormones / Q000008:administration & dosage*; D000328:Adult; D000368:Aged; D000485:Allergens / Q000276:immunology; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage*; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D015415:Biomarkers; D005260:Female; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D012129:Respiratory Function Tests; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000305:Adrenal Cortex Hormones; D000485:Allergens; D018927:Anti-Asthmatic Agents; D015415:Biomarkers; D009569:Nitric Oxide