Predictive Markers of Asthma Exacerbation during Stepwise Dose Reduction of Inhaled Corticosteroids

Abstract

To determine predictors for failed reduction of inhaled corticosteroids (ICS), in 50 subjects with well-controlled asthma (age 43.7 [18-69]; 22 males) taking a median dose of 1,000 microg ICS/d (100-3,600 microg/d), ICS were halved every 8 wk. Airway hyperresponsiveness (AHR) to a bronchial provocation test (BPT) with histamine was measured at baseline. AHR to BPT with mannitol, spirometry, exhaled nitric oxide (eNO), and, in 31 subjects, sputum inflammatory cells were measured at baseline and at monthly intervals. Thirty-nine subjects suffered an asthma exacerbation. Seven subjects were successfully weaned off ICS. Using a Kaplan- Meier survival analysis, the significant predictors of a failure of ICS reduction were being hyperresponsive to both histamine and mannitol at baseline (p = 0.039), and being hyperresponsive to mannitol during the dose-reduction phase of the study (p = 0.02). Subjects older than 40 yr of age tended to be at greater risk of ICS reduction failure (p = 0.059). Response to mannitol and percentage sputum eosinophils were significantly greater before a failed ICS reduction than before the last successful ICS reduction, whereas there were no significant differences in symptoms, spirometry, or eNO. These findings suggest that documentation of patient's AHR or sputum eosinophils may be useful in guiding the reduction of ICS doses.

Inhaled corticosteroid dose response in asthma

“…The concept of achieving 'total asthma control' 5 is 6 important for reducing the future risk of exacerbations [6][7][8] . It is therefore 7 imperative that we have robust procedures for accurate diagnosis, measurement 8 of severity, prediction of future risk, along with appropriate personalised 9 treatments to achieve this goal.…”

“…Sputum and blood 39 eosinophilia in asthma have both been separately shown to predict loss of 40 asthma control and increased exacerbation rates 6,19,20 . This is also true of 41 fractional exhaled nitric oxide (FeNO) levels 21 and airway hyper-responsiveness 42 (AHR) 6 , the latter being largely driven by airway inflammation 22 . It is therefore 43 logical that one might wish to control inflammation over and above simply 44 controlling symptoms and lung function -much like controlling asymptomatic 45 hypertension to prevent subsequent cardiovascular sequelae.…”

Biomarkers in asthma and allergic rhinitis

“…These studies also demonstrated that the change in eNO is a better predictor for loss of asthma control than baseline eNO per se. However, Leuppi et al found no increase in eNO during asthma exacerbations as a result of tapering off inhaled corticosteroids (ICS) [126]. This aberrant observation may be due to measuring eNO offline in contrast with online measurements used in other studies.…”

Intérêt de la mesure de l’inflammation en clinique dans l’asthme

“…Jatakanon a montré que le pourcentage d'éosinophiles pré-sents dans l'expectoration est un facteur prédictif d'une perte de contrôle de l'asthme [39] . Dans une autre étude, Leuppi a rapporté qu'un pourcentage d'éosinophiles supérieur au seuil de 6,3 % avait une sensibilité de 90 % et une spécificité de 63 % pour la prédiction d'une perte de contrôle de l'asthme lors du sevrage en corticostéroïdes inhalés [44] . L'inflammation éosinophilique des voies respiratoires qui persiste malgré un traitement antiinflammatoire intensif est associée à un asthme plus sévère [45,46] , des exacerbations plus fréquentes [47] et un déclin de la fonction respiratoire [48] .…”

“…De plus, des études de sevrage des corticostéroides [44,59] ont montré que l'éosinophilie de l'expectoration augmente avant l'apparition de l'exacerbation, suggérant que le traitement ciblé par corticostéroïdes inhalés à visée de normalisation du pourcentage d'éosinophiles présents dans le sputum pourrait conduire à une réduction du nombre d'exacerbation chez l'asthmatique. Dans un essai contrôlé randomisé [47] incluant 74 asthmatiques, les patients bénéficiant du traitement adapté en vue de normaliser l'éosinophilie de l'expectoration ont montré un nombre significativement plus faible d'exacerbations sévères et d'hospitalisations que les patients dont le traitement était adapté en fonction des recommandations standard.…”