Inhaled corticosteroid dose-response in asthma: Should we measure inflammation?

William J. Anderson, Philip Short, Sunny Jabbal, Brian Lipworth (Lead / Corresponding author)

Research output: Contribution to journalArticle

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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.ObjectiveTo 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.
Conclusion: 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.
Original languageEnglish
Pages (from-to)179-185
Number of pages6
JournalAnnals of Allergy, Asthma & Immunology
Volume118
Issue number2
Early online date3 Jan 2017
DOIs
Publication statusPublished - Feb 2017

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Architectural Accessibility
Adrenal Cortex Hormones
Asthma
Confidence Intervals
Inflammation
Spirometry
Nitric Oxide
Eosinophil Cationic Protein
Beclomethasone
Forced Expiratory Volume
Eosinophils
Pneumonia
Randomized Controlled Trials
Outcome Assessment (Health Care)
Lung
Serum
Proteins

Keywords

  • Asthma
  • inhaled corticosteroid
  • dose-response
  • inflammation
  • symptoms
  • spirometry
  • FeNO
  • airway hyper-responsiveness
  • ECP
  • blood eosinophils

Cite this

@article{959d2ad5a2044546aaea200252ad5ce9,
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.ObjectiveTo 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.Conclusion: 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.",
keywords = "Asthma, inhaled corticosteroid, dose-response, inflammation, symptoms, spirometry, FeNO, airway hyper-responsiveness, ECP, blood eosinophils",
author = "Anderson, {William J.} and Philip Short and Sunny Jabbal and Brian Lipworth",
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Inhaled corticosteroid dose-response in asthma : Should we measure inflammation? / Anderson, William J.; Short, Philip; Jabbal, Sunny; Lipworth, Brian (Lead / Corresponding author).

In: Annals of Allergy, Asthma & Immunology, Vol. 118, No. 2, 02.2017, p. 179-185.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Inhaled corticosteroid dose-response in asthma

T2 - Should we measure inflammation?

AU - Anderson, William J.

AU - Short, Philip

AU - Jabbal, Sunny

AU - Lipworth, Brian

N1 - No funding sources

PY - 2017/2

Y1 - 2017/2

N2 - 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.ObjectiveTo 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.Conclusion: 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.

AB - 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.ObjectiveTo 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.Conclusion: 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.

KW - Asthma

KW - inhaled corticosteroid

KW - dose-response

KW - inflammation

KW - symptoms

KW - spirometry

KW - FeNO

KW - airway hyper-responsiveness

KW - ECP

KW - blood eosinophils

U2 - 10.1016/j.anai.2016.11.018

DO - 10.1016/j.anai.2016.11.018

M3 - Article

C2 - 28065396

VL - 118

SP - 179

EP - 185

JO - Annals of Allergy, Asthma & Immunology

JF - Annals of Allergy, Asthma & Immunology

SN - 1081-1206

IS - 2

ER -