Inhaled corticosteroid dose response using domiciliary exhaled nitric oxide in persistent asthma: the FENOtype trial.
BACKGROUND
International guidelines advocate a standard approach to asthma management for all, despite its heterogeneity. "Personalized" treatment of inflammatory asthma phenotypes confers superior benefits. We wished to evaluate dose response to inhaled corticosteroids (ICSs) in patients with asthma with an elevated fractional exhaled nitric oxide (Feno) phenotype using domiciliary measurements.


METHODS
We performed a randomized, crossover trial in 21 patients with mild to moderate persistent asthma receiving ICSs with elevated Feno (>30 parts per billion [ppb]) that increased further (>10 ppb) after ICS washout. Patients were randomized to 2 weeks of either fluticasone propionate 50 μg bid (FP100) or 250 μg bid (FP500). The primary outcome was response in diurnal domiciliary Feno levels. Secondary outcomes included mannitol challenge, serum eosinophilic cationic protein (ECP), blood eosinophil count, and asthma control questionnaire.


RESULTS
We found significant dose-related reductions of diurnal Feno compared with baseline - morning Feno: baseline = 71 ppb (95% CI, 61-83 ppb); FP100 = 34 ppb (95% CI, 29-40 ppb), P < .001; FP500 = 27 ppb (95% CI, 22-33 ppb), P < .001; and significant dose separation for morning, P < .05, and evening, P < .001. Time-series Feno displayed exponential decay: FP100 R² = 0.913, half-life = 69 h (95% CI, 50-114 h); FP500 R² = 0.966, half-life = 55 h (95% CI, 45-69 h), as well as diurnal variation. The Asthma Control Questionnaire showed significant improvements exceeding the minimal important difference (>0.5) with values in keeping with controlled asthma (<0.75) after each dose: FP100 = 0.48 (95% CI, 0.24-0.71), P = .004; FP500 = 0.37 (95% CI, 0.18-0.57), P = .001. All other secondary inflammatory related outcomes (mannitol, ECP, and eosinophils) showed significant improvements from baseline but no dose separation.


CONCLUSIONS
There is a significant dose response of diurnal Feno to ICS in patients with asthma with an elevated Feno phenotype, which translates into well-controlled asthma. Further interventional studies are warranted using domiciliary Feno in this specific phenotype.


BACKGROUND
ClinicalTrials.gov; No.: NCT00995657; URL: clinicaltrials.gov.
Asthma and Allergy Research Group, Division of Cardiovascular and Diabetes Medicine, Ninewells Hospital and Medical School, The University of Dundee, Dundee, Scotland.
William J
WJ
Anderson
Asthma and Allergy Research Group, Division of Cardiovascular and Diabetes Medicine, Ninewells Hospital and Medical School, The University of Dundee, Dundee, Scotland.
Philip M
PM
Short
Asthma and Allergy Research Group, Division of Cardiovascular and Diabetes Medicine, Ninewells Hospital and Medical School, The University of Dundee, Dundee, Scotland.
Peter A
PA
Williamson
Asthma and Allergy Research Group, Division of Cardiovascular and Diabetes Medicine, Ninewells Hospital and Medical School, The University of Dundee, Dundee, Scotland. Electronic address: brianlipworth@gmail.com.
Brian J
BJ
Lipworth
D000280:Administration, Inhalation; D000293:Adolescent; D000305:Adrenal Cortex Hormones / Q000008:administration & dosage* / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D000730:Androstadienes / Q000008:administration & dosage / Q000627:therapeutic use; D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism*; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000627:therapeutic use; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D045853:Exhalation; D005260:Female; D000068298:Fluticasone; D006699:Home Care Services; D006801:Humans; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism*; D010641:Phenotype; D011795:Surveys and Questionnaires; D016896:Treatment Outcome; D055815:Young Adult
D000305:Adrenal Cortex Hormones; D000730:Androstadienes; D001993:Bronchodilator Agents; D009569:Nitric Oxide; D000068298:Fluticasone