Outcomes from nested case–control studies

First author [ref.]ResultsConclusions
Infectious complications: pneumonia
Cascini [80]Incidence rate for current ICS use: 87/1000 patient-yearsICS use was associated with an excess risk of pneumonia. The effect was greatest for higher doses and elderly patients.
Incidence rate for past ICS use: 32/1000 patient-years
aRR (current ICS use vs no use): 2.29 (95% CI 1.99–2.63)
aRR (past ICS use vs no use): 1.23 (95% CI 1.07–1.42)
In current ICS users, a dose-related trend was tested
Ernst [81]aRR of hospitalisation for pneumonia (current ICS use vs no use): 1.70 (95% CI 1.63–1.77)The use of ICSs is associated with an excess risk of pneumonia hospitalisation and of pneumonia hospitalisation followed by death within 30 days among elderly patients with COPD.
aRR of pneumonia hospitalisation followed by death within 30 days (current ICS use vs no use): 1.53 (95% CI 1.30–1.80)
RR of hospitalisation for pneumonia (highest doses of ICSs vs non-users): 2.25 (95% CI 2.07–2.44)
The risk of pneumonia increased with higher ICS doses
Joo [88]aOR of pneumonia hospitalisation (current ICS users vs non-users): 1.38 (95% CI 1.31–1.45)The use of ICSs among patients with newly diagnosed COPD is associated with an increased risk of hospitalisation for pneumonia.
Mapel [92]Relative to patients using SABDs, the control group, the only treatment associated with a nonsignificant increased risk of pneumonia was ICSs used alone (OR 1.29, 95% CI 0.96–1.73; p=0.09)Patients with COPD using ICSs alone had a slightly increased risk of pneumonia that did not reach statistical significance (adjusted risk 26–29%). Those who used FSC or other combinations of ICSs with LABA did not have an increased risk for pneumonia.
Users of FSC had no increased risk for pneumonia relative to SABDs (OR 1.03, 95% CI 0.74–1.42)
Suissa [96]RR of serious pneumonia (current ICS use vs no use): 1.69 (95% CI 1.63–1.75)ICS use by patients with COPD increases the risk of serious pneumonia. The risk is particularly elevated and dose-related to fluticasone.
RR of serious pneumonia with fluticasone: 2.01 (95% CI 1.93–2.10)
RR of serious pneumonia with budesonide: 1.17 (95% CI 1.09–1.26)
The risk of serious pneumonia was sustained with long-term ICS use and declined gradually after stopping ICS use, disappearing after 6 months
The rate of serious pneumonia was higher with fluticasone (RR 2.01, 95% CI 1.93–2.10), but was much lower with budesonide (RR 1.17, 95% CI 1.09–1.26)
Suissa [97]Incidence rate of serious pneumonia: 2.8/100 person-yearsThe study assessed the effect of ICSs discontinuation in COPD on the incidence of serious pneumonia. Discontinuation of ICS use in COPD is associated with a reduction in the elevated risk of serious pneumonia, particularly with fluticasone.
aRR of serious pneumonia (discontinued use vs current use): 0.63 (0.60–0.66)
Discontinuation of ICSs was associated with a decrease in the rate of serious pneumonia; the risk reduction was rapidly evident, increasing from 20% in the first month to 50% by the fourth month after discontinuation
Thornton Snider [99]Pneumonia (current ICS users vs non-users): OR 1.26 (95% CI 1.16–1.36)ICS use, particularly current use and high-dose use, is associated with increased pneumonia risk.
Pneumonia (current high-dose users vs non-users): OR 1.55 (95% CI 1.25–1.92)
The risk increased with higher ICS doses
Wang [100]Pneumonia (current use of ICSs vs no use): aOR 1.25 (95% CI 1.20–1.30)ICSs are significantly associated with an increased risk of pneumonia in patients with COPD. The effect is prominent for fluticasone-containing ICSs but not for budesonide-containing ICSs.
Pneumonia (past use of ICSs vs no use): aOR 1.21 (95% CI 1.16–1.26)
There was an increase in the OR with an increase in the average daily dosage
Fluticasone users were more likely to be at a higher risk of pneumonia; in contrast, there were no statistically significant associations between the risk of pneumonia and the use of budesonide
Infectious complications: TB and NTM lung disease
Andréjak [77]NTM:
Patients with COPD vs no COPD: aOR 13.1 (95% CI 7.4– 23.3)
COPD on current ICS therapy vs no COPD: aOR 29.1 (95% CI 13.3–63.8)
COPD and former ICS use (> 6 months) vs no COPD: aOR 3.8 (95% CI 0.9–16.8)
Chronic respiratory disease, particularly COPD treated with ICS therapy, is a strong risk factor for NTM-PD. The risk is highly reduced when ICSs are withdrawn. The risk of NTM disease is higher with higher doses of ICS.
Brode [79]NTM-PD:
Current ICS use vs non-ICS use: aOR 1.86 (95% CI 1.60– 2.15)
aOR for current fluticasone use: 2.09 (95% CI 1.80–2.43)
aOR for current budesonide use: 1.19 (95% CI 0.97–1.45)
There was a strong dose–response relationship between incident NTM-PD and cumulative ICS dose over 1 year
This study suggests that ICS use is associated with an increased risk of NTM-PD but was not significant for TB.
Current ICS use vs non-ICS use: aOR 1.43 (95% CI 0.95–2.16)
Brassard [78]TB:
Any ICS use: RR 1.27 (95% CI 1.05–1.53)
Current ICS use: RR 1.33 (95% CI 1.04–1.71)
Exposure to ICSs is not associated with risk of TB in the presence of OCSs but is associated with increased TB risk in non-users of OCSs.
Lee [90]TB:
aOR for ICS use: 1.20 (95% CI 1.08–1.34)
The association was dose-dependent (p for trend <0.001)
ICS use increases the risk of TB. A subgroup analysis revealed that ICS use increased the risk of TB development among non-users of OCSs but not among OCS users.
Metabolic complications: fractures
Gonzalez [84]Fracture RR (any use of ICSs vs no use): 1.00 (95% CI 0.97–1.03)Long-term ICS use at high doses is associated with a modest increase in the risk of hip and upper extremity fractures in patients with COPD. This dose-duration risk increase does not appear to be higher for women.
The fracture rate was increased with >4 years of ICS use at daily doses ≥1000 μg in fluticasone equivalents (RR 1.10, 95% CI 1.02–1.19)
Johannes [87]ORs for exposure in the preceding 30 days were 1.05 (95% CI 0.89–1.24), 1.13 (95% CI 0.90–1.40), and 0.97 (95% CI 0.78–1.21) for all ICS, fluticasone propionate and other ICS, respectively
No dose–response effect was present
No increased nonvertebral fracture risk with ICS exposure as a class or with fluticasone propionate alone was detected. This study could not evaluate very high-dose ICS, long-term ICS exposure or vertebral fracture risk.
Lee [89]Exposure to ICSs at any time during follow-up was not associated with an increased fracture risk (aOR 0.97, 95% CI 0.84–1.11); however, current high-dose ICS users (≥700 µg per day) had an increased risk of fractures compared with patients with no exposure (aOR 1.68, 95% CI 1.10–2.57)In patients with COPD, current use of high-dose ICS was associated with an increased risk of nonvertebral fractures.
Miller [93]Use of FSC in the year prior to the index date was associated with a statistically significant increase in the odds of nonvertebral fractures (aOR 1.25, 95% CI 1.07–1.47)Use of FSC was associated with an elevation in the risk of nonvertebral fractures. No increased risk was observed for other ICS use.
Pujades-Rodríguez [95]Risk of fracture increased with increasing mean daily doses of inhaled corticosteroid (p for trend 0.007) and was most marked in those whose daily dose was >1600 µg (OR 1.80, 95% CI 1.04–3.11)Use of ICSs is associated with a significant increase in fracture risk, particularly at higher doses.
Metabolic complications: diabetes
Gayle [83]Type 2 diabetes mellitus:
The aOR for patients receiving ICSs (higher doses) significantly increased compared with patients receiving no ICS therapy (OR 1.73, 95% CI 1.65–1.82)
Patients with a high number of ICS prescriptions were more likely to develop diabetes (OR 1.83, 95% CI 1.48–2.26) for 16–20 prescriptions and 1.61 (95% CI 1.53–1.69) for 1–5 prescriptions
Incidence of type 2 diabetes mellitus among patients with COPD is high and exposure to ICSs and frequent exacerbations are associated with a higher risk of type 2 diabetes mellitus among patients with COPD.
Suissa [98]Current use of ICSs vs no ICS use was associated with a 34% increase in the rate of new-onset diabetes (RR 1.34, 95% CI 1.29–1.39) and diabetes progression (RR 1.34, 95% CI 1.17–1.53)In patients with respiratory disease, ICS use is associated with modest increases in the risks of diabetes onset and diabetes progression. The risks are more pronounced at the higher doses currently prescribed in the treatment of COPD.
The risk increases were greatest with the highest ICSs doses, equivalent to fluticasone 1000 g per day or more (RR 1.64, 95% CI 1.52–1.76 and RR 1.54, 95% CI 1.18–2.02, respectively)
Local complications: eye disorders
Jick [86]After adjusting for age and gender, incidence rates of cataract development in the ICS subjects were slightly higher than in the nonexposed cohort (RR 1.3, 95% CI 1.1–1.5)Age appears to modify the association between use of ICSs and the risk of cataract development with an increased effect among the oldest patients at the highest dosages of ICS. This finding may be owing to a differential effect of the drug at different ages or to the influence of diagnostic bias and uncontrolled confounding among older patients.
Among individuals ≥40 years of age, the RR increased with use of increasing numbers of ICS prescriptions; this trend was not evident in those under age 40
Gonzalez [85]The aRR for glaucoma was 1.05 (95% CI 0.91–1.20) with ICS use in the preceding 30 daysCurrent use and continuous use of high-dose ICSs did not result in an increased risk of glaucoma or raised intra-ocular pressure requiring treatment.
There was no dose-related effect of ICSs on the risk of glaucoma or raised intra-ocular pressure requiring treatment; continuous use of high-dose ICSs for ≥3 months was not associated with an increased risk of glaucoma
Miller [94]2941 incident cataract cases and 327 incident glaucoma cases were identified in the COPD cohort (n=53 191)FSC or other ICS exposure was not associated with an increased odds of cataracts or glaucoma, nor was a dose–response relationship observed.
Fluticasone (as fixed-dose combination) or ICS prescriptions were not associated with risk of incident cataracts or glaucoma for any exposure (dose) category, after adjusting for confounders
A trend was observed according to the duration and the number of prescriptions in the last year for cataracts, but not for glaucoma

ICS: inhaled corticosteroid; aRR: adjusted risk ratio; RR: risk ratio; aOR: adjusted odds ratio; SABD: short-acting bronchodilator; OR: odds ratio; FSC: fluticasone propionate/salmeterol fixed-dose combination; LABA: long-acting β2-agonist; TB: tuberculosis: NTM: nontuberculous mycobacteria; NTM-PD: nontuberculous mycobacteria pulmonary disease; OCS: oral corticosteroid.