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

Disclosures

BMC Pulm Med. 2020;20(282) 

In This Article

Results

Study Selection and Study Characteristics

Figure 1 shows the study selection process. A total of 3011 references were identified after an initial search, and 17 RCTs[11–17,22–31] including 20,478 patients were finally included in the meta-analysis. Of the 17 RCTs, 16 were multicenter, double-blind, randomized trials. These studies were published from 2002 to 2019, with population sizes ranging from 149 to 6184 participants. Duration of the trials ranged from 1 month to 36 months, with 10 trials[11,12,15,16,24–27,29,30] longer than or equal to 6 months, and 7 trials[13,14,17,22,23,28,31] shorter than 6 months. Eleven trials[11,13,15–17,23,25,26,28–30] investigated a high-dose ICSs treatment, 8 trials[12,16,22,24,27,29–31] investigated a medium-dose ICSs treatment, and 5 trials[12,14,17,27,28] investigated a low-dose ICSs treatment. Fluticasone was evaluated in 10 trials,[11,13–15,17,22–24,26,28] mometasone in 4 trials,[16,25,29,30] budesonide in 3 trials,[12,27,31] and beclomethasone in 1 trial.[27] Table 1 shows the main characteristics of the included studies.

Figure 1.

Study selection process

Risk of Bias and Quality of Evidence

All trials were assessed using the Cochrane Collaboration risk of bias assessment tool. RCTs with four or more features were considered to be of high quality. Seventeen RCTs were regarded as high quality according to the risk of bias assessment tool and were included in the meta-analysis. All studies had low risk of selective reporting bias. One study had high risk of blinding of participants and personnel bias, 1 study had high risk of blinding of outcome assessment bias, and 1 study had high risk of incomplete outcome data. One study had unclear risk of random sequence generation bias, 2 studies had unclear risk of allocation concealment bias, 1 study had unclear risk of incomplete outcome data bias and 7 studies had other bias (Figure 2).

Figure 2.

Risk of bias of the included studies

Risk of URTI Associated With ICSs

All 17 RCTs with 20,478 patients reported URTI as an adverse event. The risk of URTI was 8.6% (991 of 11,587 patients) in the ICSs treatment groups, 7.7% (686 of 8891 patients) in the control groups, and 8.2% in all patients (1677 of 20,478 patients). Compared with non-ICSs treatment, ICSs was associated with a significantly increased the risk of URTI in patients with COPD (RR, 1.13; 95% CI 1.03–1.24; P = 0.01; heterogeneity: I2 = 7%) (Figure 3).

Figure 3.

Risk of URTI associated with ICSs. URTI, upper respiratory tract infection; ICSs, inhaled corticosteroids

Risk of URTI Associated With ICSs for Different Durations

Long-term use of ICSs[11,12,15,16,24–27,29,30] (10 RCTs, 15,634 patients) did not increase the risk of URTI (RR, 1.08; 95% CI 0.97–1.2; P = 0.14; heterogeneity: I2 = 0%), whereas short- term use of ICSs[13,14,17,22,23,28,31] (7 RCTs, 4844 patients) was associated with a significantly increased the risk of URTI (RR, 1.29; 95% CI 1.06–1.56; P = 0.01; heterogeneity: I2 = 14%) (Figure 4).

Figure 4.

Risk of URTI associated with ICSs for different duration. URTI, upper respiratory tract infection; ICSs, inhaled corticosteroids

Risk of URTI Associated With Different Doses of ICSs

High-dose ICSs[11,13,15–17,23,25,26,28–30] treatment (11 RCTs, 12,930 patients) was associated with a significantly increased the risk of URTI (RR, 1.14; 95% CI 1.02–1.27; P = 0.02; heterogeneity: I2 = 0%), but neither medium-dose ICSs (8 RCTs, 4849 patients)[12,16,22,24,27,29–31] (RR, 1.02; 95% CI 0.82–1.27; P = 0.86; heterogeneity: I2 = 0%) nor low-dose ICSs (5 RCTs, 2699 patients)[12,14,17,27,28] (RR, 1.25; 95% CI 0.9–1.74; P = 0.18; heterogeneity: I2 = 1%) increased the risk of URTI (Figure 5).

Figure 5.

Risk of URTI associated with different doses of ICSs. URTI, upper respiratory tract infection; ICSs, inhaled corticosteroids

Risk of URTI Associated With High-dose ICSs for Different Durations

Long-term use of high-dose ICSs[11,15,16,25,26,29,30] (7 RCTs, 12,916 patients) did not increase the risk of URTI (RR, 1.09; 95% CI 0.98–1.22; P = 0.13; heterogeneity: I2 = 0%), whereas short- term use of high-dose ICSs[13,17,23,28] (4 RCTs, 2509 patients) was associated with a significantly increased the risk of URTI (RR, 1.31; 95% CI 1.02–1.67; P = 0.03; heterogeneity: I2 = 7%) (Figure 6).

Figure 6.

Risk of URTI associated with high-dose ICSs for different durations. URTI, upper respiratory tract infection; ICSs, inhaled corticosteroids

Risk of URTI Associated With Fluticasone

Fluticasone[11,13–15,17,22–24,26,28] (10 RCTs, 12,547 patients) was associated with a significantly increased the risk of URTI for all dose groups (RR, 1.16; 95% CI 1.04–1.3; P = 0.01; heterogeneity: I2 = 27%). Subgroup analyses suggested that high-dose fluticasone[11,13,15,17,23,26,28] (7 RCTs, 9537patients) was associated with a significantly increased the risk of URTI (RR, 1.17; 95% CI 1.03–1.32; P = 0.02; heterogeneity: I2 = 27%), but neither medium-dose fluticasone (2 RCTs, 1505patients)[22,24] (RR, 0.97; 95% CI 0.71–1.32; P = 0.84; heterogeneity: I2 = 0%) nor low- dose fluticasone (3 RCTs, 1964 patients)[14,17,28] (RR, 1.39; 95% CI 0.92–2.1; P = 0.12; heterogeneity: I2 = 30%) increased the risk of URTI. Moreover, long-term use of high-dose fluticasone (3 RCTs, 7503 patients)[11,15,26] did not increase the risk of URTI (RR, 1.12; 95% CI 0.97–1.29; P = 0.13; heterogeneity: I2 = 50%), whereas short-term use of high-dose fluticasone (4 RCTs, 2034 patients) was associated with a significantly increased the risk of URTI (RR, 1.33; 95% CI 1.03–1.71; P = 0.03; heterogeneity: I2 = 0%) (Figure 7).

Figure 7.

Risk of URTI associated with fluticasone. URTI, upper respiratory tract infection

Risk of URTI Associated With Mometasone

Mometasone[16,25,29,30] (4 RCTs, 5413 patients) did not increase the risk of URTI for all dose groups (RR, 1.05; 95% CI 0.87–1.26; P = 0.61; heterogeneity: I2 = 0%). Subgroup analyses suggested that neither high-dose mometasone (4 RCTs, 4521 patients)[16,25,29,30] (RR, 1.06; 95% CI 0.87–1.28; P = 0.57; heterogeneity: I2 = 0%) nor medium-dose mometasone (3 RCTs, 2692 patients)[16,29,30] (RR, 0.98; 95% CI 0.67–1.43; P = 0.93; heterogeneity: I2 = 0%) increased the risk of URTI (Figure 8).

Figure 8.

Risk of URTI associated with mometasone. URTI, upper respiratory tract infection

Risk of URTI Associated With Budesonide

Budesonide[12,27,31] (3 RCTs, 2518 patients) did not increase the risk of URTI (RR, 1.08; 95% CI 0.77–1.5; P = 0.67; heterogeneity: I2 = 46%) (Figure 9).

Figure 9.

Risk of URTI associated with budesonide. URTI, upper respiratory tract infection

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