A Proposed Revision of the Stepwise Treatment Algorithm in Asthma

To the Editor:

The stepwise approach to the pharmacologic treatment of asthma is a core foundation of asthma guidelines (1). Through this approach, treatment intensity is increased in discrete steps to obtain symptom control and reduce exacerbation risk and is decreased after a period of prolonged control. The stepwise approach is usually shown by an algorithm, as illustrated in the 2020 Global Initiative for Asthma (GINA) strategy update (Figure 1). Here, we review the 2020 GINA stepwise algorithm and suggest alternative evidence-based algorithms that address potential problems with the currently recommended approach.

Figure 1.

Personalized management for adults and adolescents to control symptoms and minimize future risk. The 2020 Global Initiative for Asthma algorithm. Reprinted by permission from Reference 1. BDP = beclomethasone dipropionate; HDM = house dust mite; ICS = inhaled corticosteroid; LABA = long-acting β₂-agonist; LTRA = leukotriene receptor antagonist; OCS = oral corticosteroids; SABA = short-acting β₂-agonist; SLIT = sublingual immunotherapy.

Currently at each step, the GINA algorithm aligns treatment recommendations based on inhaled corticosteroid (ICS)/formoterol reliever therapy with those of the traditional short-acting β₂-agonist (SABA) reliever therapy. This assumes that the efficacy of treatment incorporating ICS/formoterol reliever therapy at each step aligns more closely with the corresponding alternative treatment incorporating a SABA reliever at the same step, rather than at adjacent higher or lower steps, which is not the case (2–4). This is illustrated by the recent systematic review and network meta-analysis that reported that the relative risk of a severe exacerbation with low-dose ICS/formoterol maintenance and reliever therapy at GINA step 3 compared with low-dose ICS/long-acting β₂-agonist (LABA) plus SABA therapy (GINA step 3), medium-dose ICS/LABA plus SABA (GINA step 4), and high-dose ICS/LABA plus SABA (GINA step 5) was 0.55 (95% confidence interval [CI], 0.47–0.64), 0.71 (95% CI, 0.56–0.91), and 0.78 (95% CI, 0.51–1.21) respectively (3). Thus, low-dose ICS/formoterol maintenance and reliever therapy at GINA step 3 aligns most closely in terms of efficacy with high-dose ICS/LABA plus SABA therapy at GINA step 5 and then progressively aligns to a lesser extent with medium-dose ICS/LABA plus SABA therapy at GINA step 4 and then with low-dose ICS/LABA plus SABA therapy at GINA step 3. This ranking of efficacy is thus discordant with the current algorithm. This structural problem could be resolved by separating the instructions for the stepwise approach incorporating ICS/formoterol reliever therapy from those incorporating SABA reliever therapy by using two separate algorithms, as was undertaken in the New Zealand asthma guidelines in 2020 (5). This avoids the problem of step misalignment and the potential inadvertent mixing of the two approaches. It is possible to simplify the algorithms further by not including other less effective “second-line” alternative treatments.

The antiinflammatory reliever–based algorithm using ICS/formoterol can be based on four steps, the first step being use of ICS/formoterol as the sole reliever therapy (Figure 2A), which is currently proposed at GINA steps 1 and 2 (Figure 1). Steps 2 and 3/4 are use of “standard”-dose (low-dose) and “higher”-dose (medium-dose) ICS/formoterol maintenance and reliever therapy, corresponding to the current GINA steps 3 and 4/5; the add-on therapies in severe asthma are introduced at step 4 (currently GINA step 5) (Figures 1 and 2A). The antiinflammatory reliever–based algorithm can be considered the preferred strategy, as it outperforms the traditional SABA reliever–based algorithm at each step in reducing the risk of severe exacerbations (2–4).

Figure 2.

The prototypic algorithms based on (A) antiinflammatory reliever therapy and (B) SABA reliever therapy. *Or standard-dose ICS taken whenever SABA is taken. AIR = antiinflammatory reliever therapy; ICS = inhaled corticosteroid; LABA = long-acting β₂-agonist; SABA = short-acting β₂-agonist.

The traditional SABA reliever–based algorithm can also comprise four steps (Figure 2B). With the recommendation that a SABA should no longer be used as the sole reliever therapy without an ICS (1), regularly scheduled maintenance ICS therapy together with SABA reliever therapy (currently one of the preferred treatment options at GINA step 2) is recommended for step 1. At steps 2 and 3/4, “standard”-dose (low-dose) and “higher”-dose (medium- or high-dose) maintenance ICS/LABA and SABA reliever therapies are recommended, corresponding to the current GINA steps 3 and 4/5: the add-on therapies in severe asthma are introduced at step 4 (previously GINA step 5). Although the option to prescribe either medium- or high-dose ICS/LABA therapy is provided, including them at the same step is based on the similar efficacy yet greater risk of adverse systemic effects with the high-dose ICS regimen (6) and the known reluctance to step down from high doses of ICS/LABA therapy (7), which may contribute to the common prescription of inappropriately excessive doses of ICSs (6).

One of the main uncertainties with both algorithms is the paucity of evidence on which to base the thresholds for changing treatment steps, a limitation that is shared with the current GINA algorithm (8). Current evidence suggests that the presence of biomarkers of type 2 airway inflammation is the most effective way to identify patients likely to respond to higher-intensity ICS treatment (9). In their absence, a reasonable approach is to base changes in treatment on two key factors, namely whether there has been a recent severe exacerbation and the frequency of reliever use. A severe exacerbation could prompt medical review for consideration of an increase in the treatment step, as such an event is associated with an increased risk of future severe exacerbations (10). Transition points based on high SABA use could be used for the traditional SABA reliever–based algorithm, as increasing use is a marker of poor asthma control and exacerbation risk (10, 11). However, there is a different relationship with increasing ICS/formoterol use, in which higher use reduces the level of risk of an exacerbation, compared with SABA use (11). This could be addressed by guiding the patient to assign the higher reliever use to a higher regularly scheduled maintenance dose for the period of increased use. For both algorithms, “treatable traits” would be identified and managed in their own right (9).

In conclusion, the scientific evidence that ICS/formoterol reliever therapy is more effective at reducing severe exacerbation risk than SABA reliever therapy, either alone or when received together with maintenance ICS/formoterol therapy, has led to a paradigm shift in asthma management, which has the potential to cause confusion, as it replaces the long-established clinical practice that all patients should receive SABA reliever therapy. The potential confusion is evident from the current stepwise treatment algorithm’s complexity, due to the attempt to represent all treatment options, and the inclusion of two reliever therapy regimens with differing efficacy in a single figure (Figure 1). These structural problems can be addressed by separating the current algorithm into two separate algorithms based on antiinflammatory ICS/formoterol and SABA reliever therapy strategies. The priority now is to investigate the practical implementation of the algorithms to better inform their use in clinical practice.