Which patients benefit from ICS as an add-on?

The eosinophil count in the blood (EOS) is considered a suitable biomarker for deciding whether COPD patients are likely to derive additional clinical benefit from inhaled steroids (ICS) as an add-on. A secondary analysis by Dalin et al. supports the recommendation that from an EOS of 150 cells/μL the addition of an ICS makes therapeutic sense. Above this threshold, a relevant reduction in the risk of exacerbation was demonstrated.

Current treatment recommendations, based on GOLD 2023, indicate that patients who have at least two further exacerbations or one exacerbation-related hospitalization despite treatment with LABA/LAMA or LABA/ICS benefit from the use of a triple combination of ICS/LABA/LAMA [1,2]. This appears to be particularly true in patients with a blood eosinophilia (EOS) of ≥150 cells/ μL [2–4]. Various studies have contributed to the fact that the value of inhaled steroids (ICS) in COPD has increased over time.
has changed over time. Positive effects of ICS in COPD with regard to exacerbations and other parameters were first reported in the
This was demonstrated in 2000 in the ISOLDE study [5]. Surprisingly, the TORCH study conducted in 2007 was unable to demonstrate a reduction in overall mortality, but did show significant benefits in all other endpoints [6]. In 2016, a long-acting beta-2 mimetic plus a long-acting anticholinergic agent (LABA/LAMA) proved to be superior to a LABA/ICS combination in the prevention of exacerbations in the FLAME study [7]. This questioned the role of ICS in patients with COPD. However, several recent studies show that certain COPD subgroups benefit from ICS as an add-on [10]. An additional benefit of the triple combination ICS/LABA/LAMA was recently demonstrated in the IMPACT and ETHOS studies [8,9].

Why blood eosinophilia is suitable as a biomarker

ICS have anti-inflammatory effects and the eosinophil count in sputum correlates with the degree of inflammation in the lungs [10–12]. Therefore, the eosinophil count in the blood acts as a relevant biomarker for deciding whether ICS treatment is appropriate in patients with COPD. Previous studies have shown that COPD patients with blood eosinophils above 2% respond better to treatment with systemic steroids compared to those with lower levels [13,14]. According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD), blood eosinophils should be measured in absolute numbers (cells/μL), which is how this has been done in recent studies [15,16]. The cut-off value regarding EOS for an ICS indication in COPD is the subject of controversial debate. From a meta-analysis published in 2022 by Dalin et al. shows that COPD patients with an EOS of ≥150 cells/μL have an additional benefit from the use of an ICS. The PROSPERO study, funded by the Danish Health Authority, included 11 RCTs with a total of 29,654 patients, with ICS used in double and triple combinations [10]. From an EOS of 150 cells/μl, there was a clear correlation between continued ICS treatment in terms of the number of exacerbations, lung function and quality of life. The RCTs with an ICS/LABA/LAMA study arm are shown in Table 1 [10].

The higher the blood eosinophilia, the greater the additional benefit

In the meta-analysis by Dalin et al. the relative reduction in the risk of a moderate to severe exacerbation with an EOS <150 cells/μl was 12% (ratio: 0.88; 95% CI: 0.83-0.94). [10]. With an EOS in the range of 150-300 cells/μL, a relative reduction of 20% was observed (ratio: 0.80; 95% CI: 0.69-0.94). And in patients with an EOS >300 cells/μL, there was a clinically relevant reduction of 43% (ratio: 0.57; 95% CI: 0.49-0.66). The differences in risk reduction between the three EOS subgroups proved to be significant (p<0.00001). In patients with an EOS in the range of 150-300 cells/μL and >300 cells/μL, continued treatment with ICS improved lung function by 0.05 L (mean _FEV1 difference; 95% CI: 0.03-0.07 L) and 0.06 L (mean _FEV1 difference; 95% CI: 0.04-0.09 L), respectively. A test for differences in the subgroups showed that continued ICS treatment had a different effect on lung function in the subgroups (p=0.04), with patients with an EOS ≥150 cells/μL showing a greater improvement than patients with lower EOS values. In patients with EOS <150 cells/μL, continued ICS treatment probably had no effect on lung function (mean _FEV1 difference: 0.02 L; 95% CI: 0.00-0.05 L). Regardless of the EOS subgroups, continued treatment with ICS increased the risk of pneumonia (risk ratio: 1.39; 95% CI: 1.19-1.63).

Literature:

Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease report; 2023, https://goldcopd.org/2023-gold-report-2,(last accessed 19.03.2024)
COPD, Guideline short version: www.medix-guidelines.ch/lungenkrankheiten/copd, last update: 08/2023, (last accessed 19.03.2024)
Wegewitz U, et al: Resuming the discussion of AMSTAR: what can (should) be made better? BMC Med Res Methodol 2016; 16.
Scherer RW, Saldanha IJ: How should systematic reviewers handle conference abstracts? A view from the trenches. Syst Rev 2019; 8: 264.
Burge PS, et al: Randomized, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ. 2000; 320: 1297-1303.
Calverley PMA, et al: TORCH investigators, Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. NEJM 2007; 356: 775-789.
Wedzicha JA, et al: FLAME investigators, indacaterol-glycopyrronium versus salmeterol-fluticasone for COPD. NEJM 2016; 374: 2222-2234.
Pascoe S, et al: Blood eosinophils and treatment response with triple and dual combination therapy in chronic obstructive pulmonary disease: analysis of the IMPACT trial. Lancet Respir Med 2019; 7: 745-756.
Rabe KF, et al: ETHOS investigators, triple inhaled therapy at two glucocorticoid doses in moderate-to-very-severe COPD. NEJM 2020; 383: 35-48.
Dalin DA, et al: A systematic review of blood eosinophils and continued treatment with inhaled corticosteroids in patients with COPD. Respir Med 2022 Jul; 198: 106880.
Brightling CE, et al: Sputum eosinophilia and the short term response to inhaled mometasone in chronic obstructive pulmonary disease. Thorax 2005; 60: 193-198.
Tashkin DP, Wechsler ME: Role of eosinophils in airway inflammation of chronic obstructive pulmonary disease. Int J Chronic Obstr Pulm Dis 2018; 13: 335-349.
Bafadhel M, et al: Blood eosinophils to direct corticosteroid treatment of exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012; 186: 48-55.
Bafadhel M, et al: Blood eosinophil guided prednisolone therapy for exacerbations of COPD: a further analysis. Eur Respir J 2014; 44: 789-791.
Global Initiative for Chronic Obstructive Lung Disease GOLD Global Strategy for Prevention, Diagnosis and Management of COPD (2019 Report).
Global Initiative for Chronic Obstructive Lung Disease GOLD Global Strategy for Prevention, Diagnosis and Management of COPD, 2021 Report.
Bafadhel M, et al: Predictors of exacerbation risk and response to budesonide in patients with chronic obstructive pulmonary disease: a post-hoc analysis of three randomized trials. Lancet Respir. Med. 2018; 6: 117-126.
Goyal P, et al: Comparison of effect of indacaterol with salmeterol/fluticasone fixed dose combination on COPD exacerbations based on baseline blood eosinophil counts: post-hoc analysis from the instead study. Respirology 2015; 20 (n.d.): 43.
Ferguson GT, et al: Triple therapy with budesonide/glycopyrrolate/formoterol fumarate with co-suspension delivery technology versus dual therapies in chronic obstructive pulmonary disease (KRONOS): a double-blind, parallel-group, multicentre, phase 3 randomized controlled trial. Lancet Respir Med 2018; 6: 747-758.
Pascoe S, et al: Blood eosinophil counts, exacerbations, and response to the addition of inhaled fluticasone furoate to vilanterol in patients with chronic obstructive pulmonary disease: a secondary analysis of data from two parallel randomised controlled trials. Lancet Respir Med 2015; 3: 435-442.
Hanania NA, et al: Efficacy and safety of two doses of budesonide/formoterol fumarate metered dose inhaler in COPD. ERJ Open Res 2020; 6.
Chapman KR, et al: Long-Term triple therapy de-escalation to indacaterol/glycopyrronium in patients with chronic obstructive pulmonary disease (SUNSET): a randomized, double-blind, triple-dummy clinical trial. Am J Respir Crit Care Med 2018; 198: 329-339.
Papi A, et al: Extrafine inhaled triple therapy versus dual bronchodilator therapy in chronic obstructive pulmonary disease (TRIBUTE): a double-blind, parallel group, randomized controlled trial. Lancet Lond Engl 2018; 391: 1076-1108.
Watz H, et al: Blood eosinophil count and exacerbations in severe chronic obstructive pulmonary disease after withdrawal of inhaled corticosteroids: a post-hoc analysis of the WISDOM trial. Lancet Respir Med 2016; 4: 390-398.
Siddiqui SH, et al: Blood eosinophils: a biomarker of response to extrafine beclomethasone/formoterol in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2015; 192: 523-552.