TABLE 1

Outcomes from cohort studies (not suitable for meta-analysis)

First author [ref.]ResultsConclusions
Infectious complications: pneumonia
Cohort studies with no ICS use in control group
Wu [71]Pneumonia event rate with ICS use: 703/8813 (8.0%)The aim of the study was to explore the association between post-ICS pulmonary infections (pneumonia and TB) and lung cancer. The incidence observed in those exposed to ICSs was substantially higher than in those not exposed.
Pneumonia event rate with no ICS use: 1654/35 252 (4.7%)
Cohort studies with ICS use in both study arms
Yang [72]Pneumonia:
 Event rate for fluticasone/salmeterol: 12.11 per 100   person-years
  Event rate for budesonide/formoterol: 10.65 per 100   person-years
 aHR 1.13 (95% CI 1.08–1.20)
Patients receiving fluticasone/salmeterol had a higher incidence rate and a higher risk of pneumonia than patients receiving budesonide/formoterol (13% increase of risk).
Pneumonia requiring mechanical ventilation:
 Event rate for fluticasone/salmeterol: 3.94 per 100   person-years
 Event rate for budesonide/formoterol: 3.47 per 100   person-years
 aHR 1.14 (95% CI 1.05–1.24)
Patients receiving fluticasone/salmeterol had a higher incidence rate and a higher risk of pneumonia requiring mechanical ventilation than patients receiving budesonide/formoterol (14% increase of risk).
Janson [52]Pneumonia event rate for fluticasone/salmeterol: 11.0 per 100 patient-years
Pneumonia event rate for budesonide/formoterol: 6.4 per 100 patient-years
RR 1.73 (95% CI 1.57–1.90; p<0.001)
The observed risk with fluticasone/salmeterol was greater than with budesonide/formoterol (73% increase of risk).
Kern [55]Pneumonia event rate for fluticasone/salmeterol: 702/3697 (19.0%)The proportion of patients diagnosed with pneumonia was similar in each group. No evidence of an association was observed.
Pneumonia event rate for budesonide/formoterol: 634/3697 (17.2%)
OR 0.92 (95% CI 0.81–1.04)
Janson [53]The highest risk of pneumonia was associated with a high- vs low-dose of ICSs (HR 1.41, 95% CI 1.23–1.62)ICS use increased the risk of pneumonia in patients with COPD. Asthma was an independent risk factor for pneumonia in the COPD population. Multivariate analysis identified independent predictors of pneumonia in the overall population. The highest risk of pneumonia was associated with high-dose ICS.
The risk of pneumonia was significantly increased with ICSs in patients with FEV1 ≥50% but not in those with FEV1 <50%, with both low- and high-dose ICS use:
 Low-dose ICS vs no ICS: if FEV1 <50%, HR 1.06 (95% CI   0.91–1.25), and if FEV1 ≥50%, HR 1.20 (95% CI 1.05–1.38)
 High-dose ICS vs no use: if FEV1 <50%, HR 0.98 (95% CI   0.81–1.17), and if FEV1 ≥50, HR 1.31 (95% CI 1.10–1.56)
Infectious complications: TB and NTM lung disease
Kim [56]The study assessed the risk of TB in patients with COPD depending on ICS use and the presence of a TB scar at baseline:
 ICS use with TB scar: HR 26.9 (95% CI 3.36–215.75; p=0.002)
 ICS use without TB scar: HR 9.88 (95% CI 1.11–87.93;   p=0.04)
 No ICSs with TB scar: HR 3.85 (95% CI 0.35–42.55; p=0.272)
 No ICSs without TB scar: reference group
The use of ICSs was strongly associated with the risk of developing TB. The highest risk was observed in patients who were ICS users and had previous TB lesions.
Shu [65]This prospective cohort study assessed the risk of developing active TB during follow-up according to the use and dose of ICS:
 High-dose ICS: 5/50
 Medium-dose ICS: 2/72
 No ICS: 3/238 (p=0.010)
The use of high-dose ICSs and prior pulmonary TB were associated with an increased risk of pulmonary TB in patients with COPD.
Lee [75]Univariate time-dependent Cox regression analysis in 23 594 patients with COPD revealed that ICS dose-dependently increased the risk of pulmonary TB (HR 1.01, 95% CI 1.00–1.02); in multivariate analysis, the effect of ICSs became obscured; adding ICSs into the multivariate model produced a minimal effect on the other co-variables (HR 1.01, 95% CI 0.99–1.03)Although ICS therapy has been shown to predispose patients with COPD to pneumonia in large RCTs, it does not increase the risk of TB in real-world practice.
Wu [71]TB event rate for ICS use: 182/8813 (2.1%)The aim of the study was to explore the association between post-ICS pulmonary infections (pneumonia and TB) and lung cancer. The incidence of TB observed in those exposed to ICSs was similar to that in those not exposed.
TB event rate for no ICS use: 678/35 252 (1.9%)
Huang [76]Fluticasone/salmeterol cohort: incidence rate 0.15/100 person-years
Budesonide/formoterol cohort: incidence rate 0.17/100 person-years
aHR 0.900 (95% CI 0.565–1.435)
Long-term treatment with budesonide/formoterol was associated with rates of TB similar to those of fluticasone/salmeterol in patients with COPD.
Metabolic complications: fractures
Cho [46]In patients with severe COPD:
 ICSs alone: 22/169 (13%); rate 53.8 per 1000 patient-years
 ICS/LABAs: 28/638 (4.4%); rate 24.1 per 1000 patient-years
In patients with non-severe COPD:
 ICSs alone: 38/277 (13.7%); rate 25.1 per 1000 patient-years
 ICS/LABAs: 70/911 (7.7%); rate 12.4 per 1000 patient-years
Cumulative hazards during study period and 5-year cumulative hazards of fracture:
 New ICS users: 0.150 and 0.084
 New ICS/LABA users: 0.120 and 0.045 (p<0.001)
Among newly diagnosed patients with COPD and new users of ICSs or ICS/LABA, use of ICS/LABA in a single inhaler was associated with delayed first hospitalisation for fracture, as compared with use of ICSs alone.
Gonnelli [51]Prevalence of vertebral fractures (radiology):
 No treatment (n=509): 32.3%
 ICS (n=1664): 42.6%
 Other treatments (n=449): 41.8%
Prevalence of vertebral fractures (radiology) in patients with ICSs (n=1664) by dose:
 ICS ≤750 g: 39.9%
 ICS 750–1500 μg: 41.9%
 ICS >1500 μg: 46%
Fractures vs no fractures:
 ICS >1500 μg·day–1: OR 1.40 (95% CI 1.04–1.89; p 0.03)
 ICS 750–1500 μg·day–1: OR 1.36 (95% CI 0.93–1.72; ns)
 ICS <750 μg·day–1: OR 1.26 (95% CI 0.98–1.89; ns)
 No treatment: OR 1.00 (reference group)
The prevalence rates of vertebral fractures increased in patients taking higher daily doses of ICS.
The risk of vertebral fractures was significantly increased in patients taking the highest dose (>1500 ug) of ICS. The use of ICSs at doses ranging from 751–1500 ug was associated with a positive, but not significant, increase in vertebral fracture risk.
Metabolic complications: diabetes
Caughey [45]Diabetes-related hospitalisations:
 After 5 years, 19.8% of ICS users had a diabetes-related   hospitalisation vs 16.2% in non-users (p=0.18)
 When stratified by ICS dose, patients who received a total   DDD of ICSs ≥0.83/day had a 94% increased likelihood of   diabetes-related hospitalisation (HR 1.94, 95% CI   1.14–3.28; p=0.014) compared with patients not receiving   ICS; lower ICS doses (<0.83 DDD/day) not associated with   increased risks of diabetes-related hospitalisations
In patients with diabetes and COPD, an increased risk of diabetes-related hospitalisations was only evident with the use of high doses of ICS. A dose-dependent increase in risk associated with ICS use was observed.
Flynn [49]Worsening of existing diabetes:
 ICS use: 326.1 per 1000 person-years
 No ICS use: 318.4 per 1000 person-years
 HR 0.57 (95% CI 0.25–1.30)
ICS use was not associated with new-onset diabetes nor worsening of existing diabetes.
Price [63]Change in HbA1c:
 ICS use: median 0.18% (IQR −0.23–0.6%)
 No ICS use: median 0.03% (IQR −0.33–0.5%)
 Adjusted difference 0.16% (95% CI 0.05–0.27%)
Increase in rate of hospitalisation for diabetes mellitus:
 ICS use: 41 (6.0%)
 No ICS use: 31 (4.5%)
Progression to insulin:
 ICS use: 28 (4.7%)
 No ICS use: 12 (2%)
For patients with COPD and comorbid type 2 diabetes mellitus, ICS therapy may have a negative impact on diabetes control. Patients prescribed higher cumulative doses of ICSs may be at greater risk of diabetes progression.
Price [62]Diabetes progression:
 Patients initiating ICS: mean rate 33.3 per 100 patient-years
 Control (LABD): mean rate 37.2 per 100 patient-years
 HR 1.04 (95% CI 0.87–1.25)
Diabetes onset:
 Patients initiating ICS: mean rate 1.25 diagnoses per 100   patient-years
 Control (LABD): mean rate 1.05 diagnoses per 100   patient-years
 aHR 1.27 (95% CI 1.07–1.50; p=0.006)
For patients prescribed ICS, compared with LABD, the risk of diabetes onset was significantly increased with overall no increase in risk of diabetes progression. The risk of diabetes progression also showed a clear dose–response relationship with mean daily ICS exposure for all patients and for the GOLD A/B and GOLD C/D subgroups.
Ajmera [44]New-onset diabetes:
 ICS use: 7.4%
 No ICS use: 1.39%
 aOR 1.23 (95% CI 1.07–1.47)
ICS use was associated with an increased risk of new-onset diabetes.
Local complications: eye disorders
Flynn [49]Cataract-related outcomes: cumulative exposure univariate analysis HR 1.43 (95% CI 1.11–1.83); multivariate analysis HR 1.42 (95% CI 1.07–1.88)There was a significant association between ICS use and increased cataract-related admissions.
Kendzerska [54]Cataract surgery: adjusted association, HR 0.93 (95% CI 0.88–0.98)No association between ICS use and cataract surgery.
Local complications: oral candidiasis
Dekhuijzen [48]Oral candidiasis:
 ICS/LABA: 5.5%
 No ICS: 2.7%
 aOR 2.18 (95% CI 1.84–2.59)
Comparison between type of ICS:
 Budesonide: 5.7%
 Fluticasone: 7.0%
 aOR 0.77 (95% CI 0.63–0.94)
After adjusting for intended ICS daily dose: fully aOR 1.04 (95% CI 0.54–2.00)
ICS use increases the incidence of oral thrush in COPD, and this effect is dose-dependent for fluticasone/salmeterol therapies.
Significantly fewer patients prescribed budesonide developed oral thrush compared with patients prescribed fluticasone. However, after adjusting for intended ICS daily dose, no significant differences were found in the incidence of oral thrush between budesonide and fluticasone study arms.
A pattern of increasing odds for oral thrush with increasing ICS dose was observed.

ICS: inhaled corticosteroid; TB: tuberculosis; aHR: adjusted hazard ratio; RR: risk ratio; OR: odds ratio; HR: hazard ratio; FEV1: forced expiratory volume in 1 s; NTM: nontuberculous mycobacteria; RCT: randomised clinical trial; LABA: long-acting β2-agonist; ns: nonsignificant; DDD: defined daily dose; GOLD: Global Initiative for Chronic Obstructive Lung Disease; aOR: adjusted odds ratio; IQR: interquartile range; LABD: long-acting bronchodilators.