Is it Time to “Step Up” Rescue Treatment for Asthma to Prevent Exacerbations?

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McKeever T, Mortimer K, Wilson A, et al. Quadrupling Inhaled Glucocorticoid Dose to Abort Asthma Exacerbations. N Engl J Med. 2018; 378: 902-910. <b>AND</b> Jackson DJ, Bacharier LB, Mauger DT, et al. Quintupling Inhaled Glucocorticoids to Prevent Childhood Asthma Exacerbations. N Engl J Med. 2018; 378: 891-901.

We’ve been managing asthma, for the most part, the same way for quite some time now … short acting beta agonist (SABA) for quick relief, inhaled corticosteroids (ICS) as first line maintenance treatment, step up if needed, step down if possible … plus self-management education and a written asthma action plan.  Despite many treatment options, numerous adults, adolescents, and children still suffer from asthma exacerbations, leading to reduced quality of life, missed work and school, higher costs, and increased asthma-related morbidity and mortality. Exacerbations can be triggered by acute respiratory infections, exposure to allergens and other environmental conditions, and poor medication use behaviors. Regardless of cause, finding ways to reduce or prevent exacerbations should be a priority.1,2


Doubling the ICS dose to prevent exacerbations for patients in the yellow zone of an action plan has been recommended in the past.3-5 But a 2016 Cochrane review concluded that there was no benefit in doubling the ICS dose to prevent asthma exacerbations.6 Obviously, we haven’t gotten to the bottom of this yet. The recent publication of two studies in NEJM evaluating the effect of increasing inhaled glucocorticoids to prevent asthma exacerbations provide some new insights. One of the studies was done in school-aged children (5-11 years old) and the other in adults and adolescents.7,8


The adult and adolescent study was a pragmatic, unblinded, randomized controlled trial that enrolled 1922 patients with asthma.7  Participants were at least 16 years of age, receiving an inhaled glucocorticoid (with or without add on medication), and had at least one asthma exacerbation requiring systemic glucocorticoids in the previous year. Patients were randomized to one of two self-management groups.  One group quadrupled the ICS dose group and the other continued the same ICS dose. The self-management plans for each group were based on Asthma UK guidelines and only differed in what the patients were instructed to do in “zone 2” (essentially the U.S. equivalent of the “yellow zone”). At the onset of worsening asthma control (zone 2 or yellow zone), patients in the quadrupling group were instructed to increase their bronchodilator (rescue) medication for symptom relief, as well as to increase the dose of their inhaled glucocorticoid medication by a factor of 4.  They continued the increased dose until there was improvement in either symptoms or peak flow for a maximum of 14 days.  Patients in the control group were instructed to increase only their bronchodilator medication when their symptoms worsened. Participants were followed for 12 months and the primary outcome was the time to a severe asthma exacerbation (defined as treatment with systemic glucocorticoids or an unscheduled health care visit for asthma).  A secondary outcome was the number of participants that had a severe exacerbation. Patients in the quadrupling group (45%) were less likely to report a severe asthma exacerbation than patients in the and control group (52%).  The adjusted hazard ratio for the time to first exacerbation of 0.81 (95% CI, 0.71 to 0.92; P=0.002). Adjustment for variables such as age, sex, peak flow, smoking status, and glucocorticoid dose had little effect. Adverse events were reported 2-4 weeks after zone 2 activation (Table 1). Hospitalization, one of the serious adverse events reported, was also included in the primary outcome analysis, and was the most common serious adverse event. There was no difference in incidence of pneumonia between the two groups. Non-serious adverse events related to local effects of inhaled glucocorticoids were more common in the quadrupling group.1



Table 1. Adverse Events – Adults and Adolescents Asthma Study7


Quadrupling group

Control group

Serious adverse events

11 patients (2 %)
11 events

22 patients (4 %)
32 events

Hospitalization for asthma

3 events

18 events

Pneumonia or lower respiratory tract infection

5 events (1 death)

6 events

Non-serious adverse events

41 patients (7%)
56 events

10 patients (2%)
13 events

Oral candidiasis

19 events

7 events


17 events

2 events


When designing the trial, investigators felt that a 30% (or greater) reduction in exacerbations would be clinically meaningful.  So, while a 19% reduction was statistically significant, one could question the clinical impact. None-the-less, the number of patients needed to be treated (NNT) in order to prevent one additional exacerbation was 15. Strengths of this study include increased external validity due to its pragmatic design with 80% of participants recruited from primary care clinics and broad inclusion criteria. However, the unblinded nature of the study increases the risk of bias and could have influenced patients’ decisions to seek medical care or physicians’ treatment decisions.1


The second study enrolled children with asthma (n=254) aged 5 -11 years old.8  This was a 52-week randomized, double-blind, parallel group trial.  Participants had to have at least one asthma exacerbation treated with systemic glucocorticoids in the previous year. Participants also had to meet one of the criteria listed in Table 2, and were excluded if asthma was “too severe” (> 5 exacerbations treated with systemic glucocorticoids in previous year or a history of life-threatening asthma).2


Table 2. Inclusion criteria – Children Asthma Study:8

Mild-to-moderate persistent asthma treated with step 2 therapy

Current symptoms or an exacerbation history qualifying the child for step 2 therapy

Current treatment with step 3 therapy and a Childhood Asthma Control Test (C-ACT) score > 19, no more than 2 exacerbations treated with prednisolone in the past 6 months, FEV1 before bronchodilator ≥ 80% predicted, and a willingness to step down therapy to step 2


Participants were randomized in a 1:1 ratio to receive blinded inhaled glucocorticoid therapy either at the low dose or at the high dose (quintupling the dose) for 7 days when they had early signs of reduced asthma control (“yellow zone”). All participants received open-label low dose inhaled glucocorticoid maintenance therapy when they were in the “green zone” and discontinued this treatment when they were receiving blinded yellow zone therapy. Participants were given an asthma action plan to identify when yellow zone therapy should be initiated. Daily symptoms, medication use, and peak flow monitoring were recorded in an electronic diary. The primary outcome was the rate of severe asthma exacerbations treated with systemic glucocorticoids. Several secondary outcomes were also evaluated including hospitalizations, total glucocorticoid exposure, and linear growth.2


Participants in the high dose ICS group and the low dose ICS group were similarly likely to experience at least one severe asthma exacerbation requiring systemic glucocorticoids (38 patients vs. 30 patients; p>0.05). The rate in the high dose group was 0.48 exacerbations per year and the rate in the low dose group was 0.37 per year (RR = 1.3; 95% CI, 0.8 to 2.1; P=0.30). There were 4 hospitalizations due to asthma, all occuring in the high dose group, but the between group difference was not significant (P=0.12). Children in the high dose group had greater exposure to inhaled glucocorticoids and greater total exposure to glucocorticoids than children in the low dose group. The growth rate in the high dose group was 0.23 cm less per year compared to the low dose group (P=0.06).  In children aged 5-7 in the high dose group there was a dose-response impact on growth (0.12 cm per year lower growth per yellow zone episode, P=0.02). Other secondary outcomes and adverse events were not significantly different. Investigators concluded that quintupling the dose of inhaled glucocorticoids for 7 days at the first signs of loss of asthma control did not reduce the rate of severe exacerbations or improve other asthma outcomes, but it did increase the exposure to glucocorticoids and reduce linear growth rate.2


It should be noted that fewer yellow zone episodes and severe exacerbations than they anticipated were observed, thus reducing the power of the trial to detect a difference between groups. But the data do not suggest that the high dose group was unlikely to derive any benefits and the authors concluded that enrolling more patients to meet power would not have change the study’s conclusions. The results of this study are limited to a very specific patient group - children age 5-11 with mild-to-moderate persistent asthma on low dose ICS maintenance therapy.8 There is some evidence that the use of high dose inhaled glucocorticoids could be beneficial to prevent exacerbations in patients not using ICS maintenance therapy.


So, what should we do in practice? Is it worth trying? Most practitioners are going to want more evidence before this becomes the standard of care.  These studies do not provide sufficient support for the universal adoption of this strategy. The conflicting results and variable trial designs make it difficult to determine if some patients with asthma might benefit. None-the-less, the Global Initiative for Asthma (GINA) recommends increasing maintenance ICS early for worsening asthma symptoms.9


Perhaps the most important intervention in patients with chronic asthma is self-management education. Managing asthma, including the treatments for maintenance and exacerbations, is not a one size fits all approach. For now, I will continue to focus my efforts on adherence to controller medications, appropriate inhaler technique, and the use of asthma action plans when needed. These results do make me wonder about the potential benefit and utility of increasing the ICS dose when asthma symptoms worsen but I’m not yet convinced. What about you?  What do you do in your practice?