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. 2015 Jan 15;191(2):141–148. doi: 10.1164/rccm.201409-1654PP

Incident Pneumonia and Mortality in Patients with Chronic Obstructive Pulmonary Disease. A Double Effect of Inhaled Corticosteroids?

Emir Festic 1,✉, Paul D Scanlon 2
PMCID: PMC4347438  PMID: 25409118

Abstract

Inhaled corticosteroids are commonly prescribed for patients with severe chronic obstructive pulmonary disease. Although their use improves quality of life and reduces exacerbations, it is associated with increased risk of pneumonia. Curiously, their use has not been associated with increased risk of pneumonia-related or overall mortality. We review pertinent literature to further explore the effects of inhaled corticosteroids on incident pneumonia and mortality in patients with chronic obstructive pulmonary disease. The association of use of inhaled corticosteroids and incident pneumonia is substantial and has been present in the majority of the studies on the topic. This includes both randomized controlled trials and observational studies. However, all of the studies have substantial risk of bias. Most randomized trials are limited by lack of systematic ascertainment of pneumonia; they depended on adverse event reporting. Many observational studies included proper radiographic assessment of pneumonia, but they are limited by their retrospective, observational design. The unadjusted higher risk of pneumonia is associated with longer duration of use, more potent ICS compounds, and higher doses. That implies a dose–effect relationship. Unlike pneumonia, mortality is a precise outcome. Despite the robust association of inhaled corticosteroid use with increased risk of pneumonia, all studies find either no difference or a reduction in pulmonary-related and overall mortality associated with the use of inhaled corticosteroids. These observations suggest a double effect of inhaled corticosteroids (i.e., an adverse effect plus an unexplained mitigating effect).

Keywords: pneumonia, mortality, corticosteroids, chronic obstructive pulmonary disease

Inhaled corticosteroids (ICS) are antiinflammatory medications that have been shown to improve symptoms and health status and reduce the incidence of exacerbations in patients with chronic obstructive pulmonary disease (COPD). They are recommended for use by patients with severe COPD or frequent exacerbations (1). Since Toward a Revolution in COPD Health (TORCH) investigators reported increased incidence of pneumonia among patients using ICS in 2007 (2), several well-designed randomized controlled trials (RCTs) have demonstrated a similar risk (3–7). Although these trials relied on unadjusted adverse event reports of pneumonia, frequently without systematic ascertainment or radiographic confirmation, the bulk of evidence supports increased risk of pneumonia associated with use of ICS. We recently demonstrated that this risk is slightly attenuated but not eliminated by adjusting for demographic characteristics, comorbidities, and concurrent medications (8). Other risk factors included higher potency of the ICS compounds, higher doses, and longer duration of use (9), which suggests a dose–effect relationship. The risk is also increased for elderly patients with more severe COPD (10).

Several recent observational studies reported either similar or lesser mortality among ICS users, despite increased risk of pneumonia (11–13). Some of these studies also reported an improvement in other pertinent outcomes among patients using ICS, such as decreased risk of parapneumonic effusion and less frequent need for mechanical ventilation and vasopressors (10, 11, 14). Pneumonia ascertainment was better and more systematic in these observational studies than in the RCTs analyzed in a previous systematic review (15). The recent observational studies mostly focused on more severe pneumonia, requiring hospitalization, whereas the RCTs were performed in the outpatient setting and included a large proportion of pneumonias occurring among ambulatory patients. A much larger number of pneumonia events have been reported and analyzed in studies with observational design.

Even casual reading of the literature raises the possibility of a disconnect between reports of increased risk of pneumonia with ICS use and yet similar or improved mortality outcomes. Consequently, we performed comprehensive review of all studies on the topic to clarify this. We included RCTs and observational studies of patients with COPD using inhaled corticosteroid medications published since the late 1990s, when the first trials of inhaled fluticasone (16) and budesonide (17, 18) reported incident pneumonia events.

Pneumonia

In all identified RCTs, pneumonia was measured as a safety or adverse effect (Table 1). These trials studied more than 30,000 patients, more than half of whom were assigned to use ICS. All randomized trials were done with outpatient COPD populations. The majority of RCTs reported increased risk of pneumonia. The most studied medication has been fluticasone, followed by budesonide and mometasone. TORCH was the largest RCT; it included more than 6,000 patients and was the first trial to show significantly increased risk of pneumonia (hazard ratio [HR], 1.64; 95% confidence interval [CI], 1.33–2.02) (19). Several other trials demonstrated increased risk of pneumonia among ICS users (3–7, 17, 20, 21), with HRs from ∼1.90 (95% CI, 1.04–3.49) (3) to 3.09 (95% CI, 1.34–7.12) (20). Some trials showed risk to be increased, but not significantly so, because CIs included relative risk of 1. No RCT showed significantly decreased risk of pneumonia, although in two trials (18, 22) the estimated risks were in the protective range but with CI crossing relative risk of 1. Vestbo and colleagues investigated long-term effects of inhaled budesonide in mild and moderate COPD. The relative risk of pneumonia was 0.67 (95% CI, 0.37–1.20) (18). A decade later, Rennard and colleagues investigated efficacy and tolerability of budesonide/formoterol in patients with COPD, and the relative risk was 0.74 (95% CI, 0.47–1.18) (22). Of note, both studies investigated budesonide, which is associated with less risk of pneumonia compared with fluticasone in other studies (23–25). This could be related to the difference between fluticasone and budesonide in potency or clearance rates from airways (26, 27).

Table 1.

Reviewed Randomized Controlled Trials

Study Interventions Patients Enrolled Estimable Outcomes
Aaron et al. (41) Tiotropium 18 μg + placebo 156 Pneumonia
Tiotropium 18 μg + salmeterol 25 μg 148 Overall mortality
Tiotropium 18 μg + fluticasone/salmeterol 250/25 μg 145  
Anzueto et al. (4) Fluticasone propionate/salmeterol 250/50 μg 394 Pneumonia
Salmeterol 50 μg 403 Overall mortality
Burge et al. (42) Fluticasone propionate 500 μg 376 Pneumonia
Placebo 375 Overall mortality
Calverley et al. (43) Budesonide/formoterol 320/9 μg 254 Pneumonia
Budesonide 400 μg 257
Formoterol 9 μg 255
Placebo 256
Calverley et al. (44) Fluticasone/salmeterol 500/50 μg 358 Pneumonia
Fluticasone propionate 500 μg 374
Salmeterol 50 μg 372
Placebo 361
Calverley et al. (45) Beclomethasone/formoterol MDI 100/6 μg 237 Pneumonia
Budesonide/formoterol DPI 200/6 μg 242 Overall mortality
Formoterol DPI 12 μg 239  
Calverley et al. (5) Salmeterol/fluticasone propionate 50/500 μg 658 Pneumonia
Tiotropium bromide 18 μg 665 Pneumonia mortality
    Overall mortality
Crim et al. (19) Fluticasone 500 μg 1,534 Pneumonia
Salmeterol 50 μg 1,521 Pneumonia mortality
Salmeterol/fluticasone 50/500 μg 1,533 Overall mortality
Placebo 1,524  
Doherty et al. (46) Mometasone/formoterol 400/10 μg 225 Pneumonia
Mometasone/formoterol 200/10 μg 239 Overall mortality
Mometasone 400 μg 253  
Formoterol 10 μg 243  
Placebo 236  
Dransfield et al. (7) Vilanterol 25 μg 409 Pneumonia
Fluticasone furoate 50 μg + vilanterol 25 μg 408 Pneumonia mortality
Fluticasone furoate 100 + vilanterol 25 μg 403 Overall mortality
Fluticasone 200 μg + vilanterol 25 μg 402  
Ferguson et al. (3) Fluticasone propionate/salmeterol 250/50 μg 394 Pneumonia
Salmeterol 50 μg 388 Overall mortality
Kardos et al. (20) Fluticasone propionate/salmeterol 500/50 μg 507 Pneumonia
Salmeterol 50 μg 487 Pneumonia mortality
    Overall mortality
Kerwin et al. (47) Fluticasone/vilanterol 100/25 μg 206 Pneumonia
Fluticasone/vilanterol 50/25 μg 206 Overall mortality
Fluticasone 100 μg 206  
Vilanterol 25 μg 205  
Placebo 207  
Mahler et al. (48) Fluticasone 500 μg 168 Pneumonia
Salmeterol 50 μg 160 Pneumonia mortality
Fluticasone/salmeterol 500/50 μg 165 Overall mortality
Placebo 181  
Martinez et al. (49) Fluticasone furoate 100 μg 204 Pneumonia
Fluticasone furoate 200 μg 203 Overall mortality
Vilanterol 25 μg 203  
Fluticasone furoate/vilanterol 100/25 μg 204  
Fluticasone furoate/vilanterol 200/25 μg 205  
Placebo 205  
Paggiaro et al. (16) Fluticasone propionate 500 μg 142 Pneumonia
Placebo 139 Overall mortality
Pauwels et al. (17) Budesonide 400 μg 634 Pneumonia
Placebo 643 Overall mortality
Rennard et al. (22) Budesonide/formoterol pMDI 320/9 μg 494 Pneumonia
Budesonide/formoterol pMDI 160/9 μg 494 Overall mortalit
Formoterol DPI 9 μg 495  
Placebo 481  
Sharafkhaneh et al. (6) Budesonide/formoterol pMDI 320/9 μg 407 Pneumonia
Budesonide/formoterol pMDI 160/9 μg 408 Pneumonia mortality
Formoterol DPI 9 μg 404 Overall mortality
Szafranski et al. (50) Budesonide/formoterol 320/9 μg 208 Pneumonia
Budesonide 200 μg 198 Overall mortality
Formoterol 4.5 μg 201  
Placebo 205  
Tashkin et al. (51) Budesonide/formoterol pMDI 320/9 μg 277 Pneumonia
Budesonide/formoterol pMDI 160/9 μg 281 Overall mortality
Budesonide pMDI 320 μg + formoterol DPI 9 μg 287  
Budesonide pMDI 320 μg 275  
Formoterol DPI 9 μg 284  
Placebo 300  
Tashkin et al. (52) Mometasone/formoterol 400/10 μg 217 Pneumonia
Mometasone/formoterol 200/10 μg 207 Overall mortality
Mometasone 400 μg 210  
Formoterol 10 μg 209  
Placebo 212  
Van der valk et al. (53) Fluticasone 500 μg 123 Pneumonia
Placebo 121 Overall Mortality
Vestbo et al. (54) Budesonide 145 Pneumonia
Placebo 145 Overall Mortality
Vogelmeier et al. (55) QVA 149 (LABA indacaterol and the LAMA glycopyrronium in fixed combination 110/50 μg) 259 Pneumonia
Salmeterol/fluticasone 50 μg/500 μg 264 Overall mortality
Welte et al. (56) Tiotropium 18 μg + budesonide/formoterol 320/9 μg 329 Pneumonia
Tiotropium 18 μg + placebo 331 Overall mortality
Wouters et al. (21) Salmeterol/fluticasone 50 μg/500 μg 189 Pneumonia
Salmeterol 50 μg 184 Overall mortality
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Definition of abbreviations: DPI = dry powder inhaler; LABA = long-acting β-agonist; LAMA = long-acting muscarinic agent; MDI = metered dose inhaler; pMDI = pressurized metered dose inhaler.

Observational studies included more systematic assessment for pneumonia, including radiographic confirmation (Table 2). They assessed more than 250,000 patients, approximately 50,000 of whom used ICS, for risk of pneumonia requiring an emergency room evaluation or hospital admission. All observational studies showed increased risk of pneumonia, with HRs ranging from 1.10 (95% CI, 1.08–1.13) (11) to 2.65 (95% CI, 1.25–5.61) (28).

Table 2.

Reviewed Observational Studies

Study ICS Patients; Non-ICS Patients Estimable Outcomes
Ernst et al. (9) 12,354; 83,413 Pneumonia
Overall mortality
Joo et al. (57) 21,054; 110,537 Pneumonia
Pneumonia mortality
Chen et al. (11) 8,271; 7,497 Pneumonia
Pneumonia mortality
Overall mortality
Cheng et al. (28) 125; 149 Pneumonia
Pneumonia mortality
Festic et al. (58) 226; 363 Pneumonia
Pneumonia mortality
Overall mortality
Ko et al. (30) 42; 36 Pneumonia mortality
Overall mortality
Malo de Molina et al. (12) 2,420; 3,933 Pneumonia mortality
Overall mortality
Sellares et al. (14) 340; 394 Pneumonia mortality
Overall mortality
Singanayagam et al. (13) 376; 114 Pneumonia mortality
Overall mortality
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Definition of abbreviations: ICS = inhaled corticosteroids.

Pneumonia-related Mortality

Five RCTs of ICS in COPD have reported unadjusted risk of pneumonia-related mortality; none found a difference between ICS and non-ICS arms (5–7, 19, 20). The TORCH trial had the largest number of participants and hence the greatest weight in estimating the risk (19). Four other trials had wide CIs; thus, there is a lack of precision in estimating pneumonia-related mortality from RCTs. Indeed, it is often impossible to determine whether a patient dies due to pneumonia or merely with pneumonia. For the purpose of this review, we considered short-term (30-d) mortality after hospitalization for pneumonia as pneumonia-related mortality in observational studies.

We identified seven observational studies of ICS in patients with COPD that evaluated pneumonia-related mortality after hospitalization for pneumonia. Three studies included more than three-fourths of all patients. They showed decreased 30-day mortality on hospitalization for pneumonia using national administrative databases (11, 12, 29). A study of Veterans Affairs (VA) hospitals assessed the association of ICS exposure with mortality for more than 6,000 hospitalized subjects with COPD with pneumonia in a covariate-adjusted regression model (12). The unadjusted relative risk was 0.50 (95% CI, 0.41–0.60) for 30-day mortality. Joo and colleagues analyzed a dataset of more than 14,000 patients from the VA and Centers for Medicare and Medicaid Services, and the results showed decreased risk of 30-day mortality followed admission for pneumonia (odds ratio [OR], 0.74 [95% CI, 0.66–0.83]) (29). More recently, Chen and colleagues reported outcomes of more than 15,000 patients with COPD with pneumonia through the use of the VA database (11). The short-term mortality after hospitalization for pneumonia was again decreased (relative risk, 0.75 [95% CI, 0.69–0.82]). Four other studies, encompassing only one-fourth of patients, demonstrated no increased risk of pneumonia-related death with the wide CIs (8, 13, 14, 30). Retrospective, observational design adds to the above-mentioned imprecision of assessment of pneumonia-related mortality. However, it is evident that the decreased short-term mortality after hospitalization for pneumonia is in the direction opposite to the increased risk of pneumonia in the same studies. Although Ernst and colleagues in restricted subgroup analysis reported that more patients with COPD hospitalized with pneumonia who died within 30 days used ICS than not, this subgroup of patients was confounded by more severe respiratory disease, greater frequency of COPD hospitalization, and thus the greater number of prescriptions for all respiratory drugs, including systemic corticosteroids and antibiotics (9). Analysis of all patients in this cohort showed lower all-cause 30-day mortality among patients hospitalized for pneumonia who were dispensed versus those not dispensed ICS (7.4 vs. 8.2%, P = 0.05).

Overall Mortality

We reviewed all published RCTs to estimate unadjusted risk of overall or long-term (90-d) mortality with ICS use in patients with COPD. In all studies but one, the risk was not different from the comparison arm. The only study that showed significant difference in risk was reported by Calverley and colleagues, with the estimated relative risk in the protective range: 0.56 (95% CI, 0.33–0.94) (5). This trial, Investigating New Standards for Prophylaxis in Reduction of Exacerbations (INSPIRE), was a 2-year study of 1,323 patients randomized to salmeterol/fluticasone propionate twice daily versus once-daily tiotropium. It showed a twofold increase in the risk of pneumonia among patients using fluticasone. However, one-half of all pneumonia events in the fluticasone arm were associated with an ongoing or unresolved COPD exacerbation. The data interpretation from this study’s daily record cards suggested identical numbers of de novo pneumonias in both ICS (fluticasone) and non-ICS arms but more unresolved exacerbations preceding pneumonia events in the patients treated with ICS (5).

Six observational studies estimated risk of overall mortality. In addition to two above-mentioned studies that showed lower risk of both short-term and longer-term mortality after hospitalization for pneumonia (11, 12), a case-control study by Ernst and colleagues showed a small decrease in risk of all-cause mortality (OR, 0.89; 95% CI, 0.80–1.00) (9). This was despite more than twice the risk of pneumonia observed in this nested case-control study (OR, 2.14; 95% CI, 2.02–2.28). These three studies encompassed 80% of all patients and showed significantly decreased all-cause or longer-term (90-d) mortality. Three other studies, including 20% of all reported patients, demonstrated no increased risk of overall mortality relative to ICS use (8, 13, 30).

A very recently published observational population-based study from Ontario analyzed health administration data for patients with newly prescribed combination of ICS/long-acting β-agonists (LABA) compared with LABA alone within an 8-year period (31). It showed no difference in incidence of pneumonia requiring hospitalization between the two arms after propensity-score–matched regression analysis (HR, 1.01; 95% CI, 0.93–1.08). However, patients with new prescriptions for ICS/LABA compared with those using LABA alone had decreased risk of overall mortality (HR, 0.92; 95% CI, 0.88–0.96). It is not known which ICS medications were predominantly used (budesonide vs. fluticasone) or in which doses. Unlike other studies on the topic, this study included patients with previous diagnosis of asthma. It is possible that inclusion of patients with asthma affected the estimated risk of incident pneumonia, as most previous studies demonstrated no increased risk of pneumonia in patients with asthma (32–34). An updated metaanalysis of observational studies including this one would be informative.

The Double Effect of Inhaled Corticosteroids?

Our literature review affirms the increase in unadjusted risk of pneumonia among ICS users, as demonstrated by both RCTs and observational studies of patients with COPD. Despite this risk, pneumonia-related and overall mortality were not different in RCTs and were decreased in the majority of patients enrolled into observational studies.

The evidence for an unadjusted increase in risk of pneumonia among users of ICS is strong. The risk of incident pneumonia is not the same for all patients, varying with potency, dose, and duration of ICS use (9). We recently found that the unadjusted increase in risk of pneumonia is attenuated after adjusting for baseline characteristics, comorbidities, and concurrent medications (8). Therefore, host characteristics, as well as differences in medication properties, are important in determining the additional risk for pneumonia. However, regardless of the effect of confounding factors on the true risk of pneumonia, these same factors would affect the mortality outcomes as well.

The rationale for the increased risk of pneumonia among patients with COPD using ICS may include a combination of immunosuppressive effect plus the effect of obstruction of airways that are colonized with bacteria (35). It has been shown that ICS can achieve locally high concentrations in the lung (36) and that their potency was directly proportional with the increased risk of pneumonia (9). The established immunosuppressive effects could then decrease the innate ability to battle primary or secondary (postviral) bacterial infections resulting in pneumonia.

On the other hand, ICS are potent antiinflammatory medications. They have been shown to up-regulate production of antiinflammatory proteins and to inhibit the transcription of proinflammatory cytokines and chemokines (37). It is plausible that these antiinflammatory effects may reduce the severity of incident pneumonia and then explain the observed change in the risk direction between pneumonia and mortality. Previous observational studies suggested a protective effect of ICS for selected groups of patients. In a study of patients at risk for pulmonary toxicity from chemotherapy, inhaled fluticasone reduced the incidence of delayed pulmonary toxicity (38). In a retrospective cohort of patients from Olmsted County, Minnesota and a large multicenter prospective Lung Injury Prediction Score (LIPS) cohort of patients at risk for acute lung injury, the use of ICS was associated with decreased risk of acute lung injury for patients with pneumonia and those at risk of direct lung injury, respectively (39, 40).

In this review, we find no difference in pneumonia-related or overall mortality despite significantly increased unadjusted risk for pneumonia in RCTs. This may not be surprising, given that all RCTs evaluated outpatient populations, and a good proportion of pneumonias were likely not severe. Simply said, relatively few incident pneumonias were fatal, so perhaps this could alternatively explain why no difference was found in pneumonia-related or overall mortality in RCTs. On the contrary, observational studies enrolled only patients with COPD with pneumonia requiring emergency room evaluation and hospitalization. Both COPD and pneumonia are among the most frequent causes of death, and as such the overall mortality might be expected to be increased in a group of patients with higher rates of serious pneumonia. However, our review suggests that the majority of these patients using ICS had actually decreased mortality risk. It is possible that if ICS were to possess protective effects, these would have been observed mostly in the cases of severe or potentially fatal pneumonia. Although observational studies typically have greater risk of bias compared with RCTs, there are several factors to be considered. The majority of RCTs reported have high risk of bias in ascertainment of pneumonia because of lack of radiographic confirmation of suspected pneumonia and low incidence of pneumonia events. On the contrary, the majority of observational studies included in our review systematically tracked and abstracted pneumonia events and used radiographic confirmation. Observational design allowed for including a much larger number of patients and assessing much larger number of pneumonia events. Finally, despite all the inherent limitations, both RCTs and observational studies showed remarkably similarly increased risk estimates for pneumonia, while paradoxically showing equivalent or lower pneumonia-related and overall mortality associated with use of ICS in COPD. These observations support a double effect of ICS: ICS predispose patients with COPD to the increased risk of pneumonia but conversely have a counterbalancing beneficial effect on mortality resulting in no net change, or possibly a slight improvement in mortality. In the absence of mechanistics trials, we can only postulate that either ICS decrease the severity of incident pneumonia or there is another mitigating effect of ICS that reduces total risk of death to counterbalance mortality associated with increased risk of pneumonia.

There are other noteworthy limitations of the studies we reviewed. Although the risks of outcomes we considered were mostly unadjusted, the large number of patients included in the studies partially alleviates this concern. Some studies used multivariate adjustments; however, the differing methodology and covariates used in the adjustment analyses preclude the accurate synthesis and interpretation of the adjusted results. Other confounding factors, particularly COPD severity and presence of comorbidities, would need to be addressed prospectively. We considered all patients on ICS as ICS users, regardless of adherence or whether ICS were used alone or in combination with other agents. Similarly, subjects who did not use ICS were all those not using ICS regardless of use of other agents. Our main intention was to assess for the possible double effect of ICS, and further analyses of ICS alone or in combination were not practical at this stage. Only future prospective trials of ICS, which would systematically assess and monitor pneumonia as a prespecified outcome using objective pneumonia definitions, could clarify this and other above-mentioned concerns.

Footnotes

Supported in part by NIH grant UL1 TR000135 and the Mayo Clinic Foundation (E.F.).

Author Contributions: E.F. and P.D.S.: substantial contributions to the conception or design of the work or the acquisition, analysis, or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Originally Published in Press as DOI: 10.1164/rccm.201409-1654PP on November 19, 2014

Author disclosures are available with the text of this article at www.atsjournals.org.

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