American Journal of Respiratory and Critical Care Medicine

To the Editor:

We read with interest the concise review by Beasley and colleagues on inhaled corticosteroids (ICS) in adult asthma (1). We agree that the definition of low, moderate, and high doses of ICS is arbitrary, as stated in the Global Initiative for Asthma report, although the Global Initiative for Asthma makes clear that it is simply an assessment of estimated clinical comparability based on available studies and product information, and that a large number of patients with asthma need only a low dose of ICS (www.ginasthma.org).

However, with regard to the statement that the maximum obtainable patient benefit is with low-dose ICS, we would like to emphasize that the evidence provided to support this statement is from studies on nonphenotyped asthma, a significant proportion of which probably have no or low levels of airway eosinophilia. The main therapeutic target of ICS is the eosinophil, and the degree of airway eosinophilia varies significantly from one patient to another, so that the dose of ICS needed to reduce such eosinophilia significantly varies greatly. It is likely that the “classical” benefit/systemic effects curve differs significantly in eosinophilic asthma, and that the observed plateau is shifted to the right in this population. The reason for the reported lack of efficacy of doubling and quadrupling of doses of ICS is likely that the nature of airway inflammation was not considered in those clinical trials. Furthermore, studies that have looked at sputum eosinophils have demonstrated that high doses of corticosteroids are as effective as prednisone in moderate to severe exacerbations (2, 3). Another study showed that high-dose ICS is also effective in treating exacerbations of asthma (4).

The best way to show an ICS dose response and compare ICS products is therefore not to use unselected patients but, rather, to choose patients with either high sputum eosinophils or high FeNO and then perform dose escalation studies (5). Furthermore, ICS dose response also depends on the outcome measured, with airway hyperresponsiveness showing the best dose-dependent improvement over time (6).

As stated in all guidelines, we should always consider using the lowest possible dose of ICS (or oral corticosteroids [OCS], and ideally no OCS) to control asthma while avoiding the risks for adverse effects. Doses of ICS may be minimized by various measures, including environmental control, use of adjunct therapies such as long-acting inhaled bronchodilators, and in the more severe patient, by the early introduction of biologics. However, prevention of OCS use and related exacerbations should be a priority, which could be avoided in some patients by using high doses of ICS. In this regard, in a study over a median period of 10 years (maximum, 30 yr), we showed that when the dose of ICS/prednisone was adjusted to keep sputum eosinophils under control, exacerbations and the rate of decline of lung function were significantly reduced, although at a price of adverse effects, mainly when OCS was needed (7). Adverse effects of high doses of ICS have been confounded by methodologic issues and intercurrent OCS use, and there is probably also a variation in susceptibility to those effects from one patient to another.

We therefore agree with Beasley and colleagues that we should prevent overdosing with ICS when not necessary, and that in this regard, there is a significant care gap in asthma management with an underutilization of noninvasive measurements of airway inflammation, particularly in moderate to severe asthma. We endorse the need for rigorous dose–response studies of ICS to be conducted in patients who are well characterized on the basis of their inflammatory endotypes.

1. Beasley R, Harper J, Bird G, Maijers I, Weatherall M, Pavord ID. Inhaled corticosteroid therapy in adult asthma: time for a new therapeutic dose terminology. Am J Respir Crit Care Med 2019;199:14711477.
2. Belda J, Margarit G, Martínez C, Bellido-Casado J, Casan P, Torrejón M, et al. Anti-inflammatory effects of high-dose inhaled fluticasone versus oral prednisone in asthma exacerbations. Eur Respir J 2007;30:11431149.
3. Di Franco A, Bacci E, Bartoli ML, Cianchetti S, Dente FL, Taccola M, et al. Inhaled fluticasone propionate is effective as well as oral prednisone in reducing sputum eosinophilia during exacerbations of asthma which do not require hospitalization. Pulm Pharmacol Ther 2006;19:353360.
4. Gibson PG, Saltos N, Fakes K. Acute anti-inflammatory effects of inhaled budesonide in asthma: a randomized controlled trial. Am J Respir Crit Care Med 2001;163:3236.
5. Heatlh Canada. Guidance document: data requirements for safety and effectiveness of subsequent entry inhaled corticosteroid products used for the treatment of asthma [updated 2018 Oct 31; accessed 2019 Nov 4]. Available from: https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/applications-submissions/guidance-documents/inhaled-corticosteroid-profile/inhaled-corticosteroid-guidance.html.
6. Kelly MM, Leigh R, Jayaram L, Goldsmith CH, Parameswaran K, Hargreave FE. Eosinophilic bronchitis in asthma: a model for establishing dose-response and relative potency of inhaled corticosteroids. J Allergy Clin Immunol 2006;117:989994.
7. Aziz-Ur-Rehman A, Dasgupta A, Kjarsgaard M, Hargreave FE, Nair P. Sputum cell counts to manage prednisone-dependent asthma: effects on FEV1 and eosinophilic exacerbations. Allergy Asthma Clin Immunol 2017;13:17.
*Corresponding author (e-mail: ).

Originally Published in Press as DOI: 10.1164/rccm.201907-1301LE on July 24, 2019

Author disclosures are available with the text of this letter at www.atsjournals.org.

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