Association Between Inhaled Corticosteroids and Upper Respiratory Tract Infection in Patients With Chronic Obstructive Pulmonary Disease

A Meta-Analysis of Randomized Controlled Trials

Hong Chen; Yulin Feng; Ke Wang; Jing Yang; Yuejun Du


BMC Pulm Med. 2020;20(282) 

In This Article

Abstract and Introduction


Background: We aimed to assess the association between inhaled corticosteroids (ICSs) and the risk of upper respiratory tract infection (URTI) in patients with chronic obstructive pulmonary disease (COPD).

Methods: PubMed, Embase, Cochrane Library and Clinical were searched from inception to October 2019. Randomized controlled trials (RCTs) of any ICSs vs control for COPD with reporting of URTI as an adverse event were included. The study was registered with PROSPERO prospectively (#CRD42020153134).

Results: Seventeen RCTs (20,478 patients) were included. ICSs significantly increased the risk of URTI in COPD patients (RR, 1.13; 95% CI 1.03–1.24; P = 0.01; heterogeneity: I2 = 7%). Futher subgroup analyses suggested that short-term use of ICSs increased the risk of URTI (RR, 1.29; 95% CI 1.06–1.56; P = 0.01; heterogeneity: I2 = 14%) but not for long-term use (RR, 1.08; 95% CI 0.97–1.2; P = 0.14; heterogeneity: I2 = 0%). Short-term use of high-dose fluticasone increased the risk of URTI (RR, 1.33; 95% CI 1.03–1.71; P = 0.03; heterogeneity: I2 = 0%) but not for long-term use (RR, 1.12; 95% CI 0.97–1.29; P = 0.13; heterogeneity: I2 = 50%). Medium-dose (RR, 0.97; 95% CI 0.71–1.32; P = 0.84; heterogeneity: I2 = 0%) and low-dose (RR, 1.39; 95% CI 0.92–2.1; P = 0.12; heterogeneity: I2 = 30%) fluticasone did not increase the risk of URTI regardless of duration. Neither mometasone (RR, 1.05; 95% CI 0.87–1.26; P = 0.61; heterogeneity: I2 = 0%) nor budesonide (RR, 1.08; 95% CI 0.77–1.5; P = 0.67; heterogeneity: I2 = 46%) increased the risk of URTI, regardless of dosage or duration.

Conclusions: Long-term use of ICSs does not increase the risk of URTI in patients with COPD. Short-term use of high-dose fluticasone increases the risk of URTI in patients with COPD, but not mometasone or budesonide.


Chronic obstructive pulmonary disease (COPD) is currently the third leading cause of death and disability worldwide.[1–3] Exacerbation is the major reason for hospital admission of patients with COPD and related to a significantly worse survival outcome.[4–6] Inhaled corticosteroids (ICSs) or combined with long-acting bronchodilators have been recommended to treat COPD patients with repeated exacerbations.[1]

Although ICSs are generally considered to be relatively safe and well tolerated in patients, some adverse effects associated with ICSs have also been observed, such as the development of oropharyngeal candidiasis,[6] adrenal suppression,[7] diabetes,[8] and pneumonia.[9] However, the association between ICSs and risk of upper respiratory tract infection (URTI) remains unclear, though URTI is the most common respiratory infection and also an important cause of exacerbation of COPD.[10] The large prospective study Toward a Revolution in COPD Health (TORCH) trial reported ICSs might increase the morbidity of URTI in COPD patients.[11] Moreover, other randomized controlled trials (RCTs) reported different or even contrary outcomes, and most of these studies were inadequate to detect significant difference between ICSs treatment groups and control groups.[12–17]

Whether ICSs increase the risk of URTI in COPD patients may depend on duration, dosage and type of ICSs. Lack of safety evidence may result in insufficient use or over use of ICSs. Therefore, we conducted this meta-analysis of RCTs to assess the association between ICSs use and the risk of URTI in patients with COPD. We also aimed to clarify the contributions of medication details for the association, including duration, dosage level and type of ICSs.