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The Therapeutic Index as Indicated by Efficacy/Safety Ratio May Be Primarily Assessed by Meta-Analysis of the Efficacy of ICS Combination Therapy for COPD [Letter]

Authors Teramoto S

Received 9 May 2022

Accepted for publication 1 June 2022

Published 22 June 2022 Volume 2022:17 Pages 1453—1454


Checked for plagiarism Yes

Editor who approved publication: Professor Min Zhang

Shinji Teramoto

Department of Respiratory Medicine, Tokyo Medical University Hachioji Medical Center, Tokyo, Japan

Correspondence: Shinji Teramoto, Department of Respiratory Medicine, Tokyo Medical University Hachioji Medical Center, 1163 Tate-machi, Hachioji-shi, Tokyo, 193-0998, Japan, Tel +81-42-665-5611, Fax +81-42-665-1796, Email [email protected]

View the original paper by Dr Ding and colleagues

Dear editor

With interest, we read the review article by Ding et al1 published in the recent issue of the International Journal of Chronic Obstructive Pulmonary Disease (COPD). They performed a systematic literature review and meta-analysis of randomized clinical trials (RCTs) comparing the effect of inhaled corticosteroid (ICS)-containing combination therapy and non-ICS regimen in patients with COPD. The authors have found that a wide range of patients with COPD could benefit from dual and triple ICS-containing therapy. In addition to the significant reduction of acute exacerbation by ICS-containing therapy, a significant improvement in lung function was observed for ICS/long-acting β2 agonists (LABA) versus LABA and ICS/LABA/long-acting anti-muscarinic agents (LAMA) versus LAMA regimens. A significant improvement in quality of life (QoL) was also observed with ICS versus non-ICS therapy. However, the treatment-emergent adverse events were not fully demonstrated. The increased risk of pneumonia following inhaled steroids and ICS-containing combination therapy for COPD is concerning.2 The other recent meta-analysis revealed that ICS-containing triple therapy resulted in 230 fewer AECOPDs but 16 more cases of pneumonia per 1000 patients.3 In Japanese population data, a significant increase in pneumonia events with ICS/LAMA/LABA treatment compared to with LAMA/LABA treatment has also been reported (OR, 3.38; 95% CI, 1.58 to 7.22; P = 0.002; I2 = 0%).4 This safety issue of ICS-containing triple therapy is very important for treatment decisions in COPD and should be summarized in the abstract of the current review paper. Although there are some discussions about the pneumonia risk issue in the body of the text, no data is available in the results section of their abstract.

Importantly, we should consider the inhaled steroids associated pneumonia risk in COPD with caution.5 Although severe pneumonia would result in the significant increase of mortality in COPD, most of the community acquired pneumonia (CAP) and nursing- and healthcare-associated pneumonia (NHCAP) in chronic respiratory diseases could be well treated with appropriate selection of antibiotics and comprehensive therapy including systemic administration of steroids.6 Therefore, we consider the therapeutic merit of the reduced effect on exacerbation in combination with the possible mortality risk of ICS-related pneumonia. The therapeutic index as indicated by efficacy/safety ratio may be primarily assessed by the meta-analysis of the efficacy of ICS combination therapy for COPD. A high therapeutic index is preferable for an ICS combination drug to have a favorable safety and efficacy profile.


The author reports no conflicts of interest in this communication.


1. Ding Y, Sun L, Wang Y, Zhang J, Chen Y. Efficacy of ICS versus non-ICS combination therapy in COPD: a meta-analysis of randomised controlled trials. Int J Chron Obstruct Pulmon Dis. 2022;17:1051–1067. doi:10.2147/COPD.S347588

2. Kew KM, Seniukovich A. Inhaled steroids and risk of pneumonia for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2014;2014(12). doi:10.1002/14651858.CD010115

3. Mammen MJ, Lloyd DR, Kumar S, et al. Triple therapy versus dual or monotherapy with long-acting bronchodilators for chronic obstructive pulmonary disease. A systematic review and meta-analysis. Ann Am Thorac Soc. 2020;17(10):1308–1318. doi:10.1513/AnnalsATS.202001-023OC

4. Koarai A, Yamada M, Ichikawa T, Fujino N, Kawayama T, Sugiura H. Triple versus LAMA/LABA combination therapy for Japanese patients with COPD: a systematic review and meta-analysis. Respir Investig. 2022;60:90–98. doi:10.1016/j.resinv.2021.04.007

5. Stanbrook MB; ACP Journal Club. Review: in COPD, fluticasone or budesonide increases serious pneumonia but not mortality. Ann Intern Med. 2014;161:JC8. doi:10.7326/0003-4819-161-4-201408190-02008

6. Teramoto S. The current definition, epidemiology, animal models and a novel therapeutic strategy for aspiration pneumonia. Respir Investig. 2022;60(1):45–55. doi:10.1016/j.resinv.2021.09.012

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