The utility of fractional exhaled nitric oxide suppression in the identification of nonadherence in difficult asthma

Am J Respir Crit Care Med. 2012 Dec 1;186(11):1102-8. doi: 10.1164/rccm.201204-0587OC. Epub 2012 Sep 28.


Rationale: Nonadherence to inhaled corticosteroid therapy (ICS) is a major contributor to poor control in difficult asthma, yet it is challenging to ascertain.

Objectives: Identify a test for nonadherence using fractional exhaled nitric oxide (Fe(NO)) suppression after directly observed inhaled corticosteroid (DOICS) treatment.

Methods: Difficult asthma patients with an elevated Fe(NO) (>45 ppb) were recruited as adherent (ICS prescription filling >80%) or nonadherent (filling <50%). They received 7 days of DOICS (budesonide 1,600 μg) and a test for nonadherence based on changes in Fe(NO) was developed. Using this test, clinic patients were prospectively classified as adherent or nonadherent and this was then validated against prescription filling records, prednisolone assay, and concordance interview.

Measurements and main results: After 7 days of DOICS nonadherent (n = 9) compared with adherent subjects (n = 13) had a greater reduction in Fe(NO) to 47 ± 21% versus 79 ± 26% of baseline measurement (P = 0.003), which was also evident after 5 days (P = 0.02) and a Fe(NO) test for nonadherence (area under the curve = 0.86; 95% confidence interval, 0.68-1.00) was defined. Prospective validation in 40 subjects found the test identified 13 as nonadherent; eight confirmed nonadherence during interview (three of whom had excellent prescription filling but did not take medication), five denied nonadherence, two had poor inhaler technique (unintentional nonadherence), and one also denied nonadherence to prednisolone despite nonadherent blood level. Twenty-seven participants were adherent on testing, which was confirmed in 21. Five admitted poor ICS adherence but of these, four were adherent with oral steroids and one with omalizumab.

Conclusions: Fe(NO) suppression after DOICS provides an objective test to distinguish adherent from nonadherent patients with difficult asthma. Clinical trial registered with (NCT 01219036).

Trial registration: NCT01219036.

Publication types

  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Inhalation
  • Adrenal Cortex Hormones / administration & dosage*
  • Adult
  • Asthma / diagnosis
  • Asthma / drug therapy*
  • Breath Tests
  • Bronchodilator Agents / administration & dosage
  • Drug Administration Schedule
  • Exhalation / drug effects
  • Female
  • Forced Expiratory Volume
  • Humans
  • Male
  • Medication Adherence / statistics & numerical data*
  • Middle Aged
  • Nitric Oxide / analysis*
  • Patient Compliance
  • Prednisolone / administration & dosage
  • Prospective Studies
  • Reference Values
  • Reproducibility of Results
  • Respiratory Function Tests
  • Severity of Illness Index
  • Young Adult


  • Adrenal Cortex Hormones
  • Bronchodilator Agents
  • Nitric Oxide
  • Prednisolone

Associated data