Annals of the American Thoracic Society

Rationale: Radiographically confirmed pneumonia risk with inhaled corticosteroid use in chronic obstructive pulmonary disease (COPD) has not been assessed to date.

Objectives: To determine the incidence of pneumonia, risk factors, and clinical attributes with inhaled fluticasone furoate (FF) in patients with COPD with an exacerbation history.

Methods: Two replicate, 1-year, double-blind clinical trials enrolled subjects with COPD with moderate to very severe airflow limitation and at least one exacerbation within the prior year. Subjects were randomized 1:1:1:1 to receive inhaled once-daily vilanterol (VI) 25 μg or VI 25 μg combined with 50, 100, or 200 μg FF. Subjects were required to have a chest radiograph at screening and within 48 hours of any suspected pneumonia or exacerbation.

Measurements and Main Results: Among 3,255 randomized subjects, 205 pneumonia events occurred in 181 subjects. Chest imaging was available for 195 (95%) of these events. Chest radiographs were also obtained for 1,793 (70%) of the 2,545 moderate and severe exacerbations. For VI alone and the combination with 50, 100, or 200 μg FF, reported pneumonia incidence was 3, 6, 6, and 7%, respectively. However, for events with compatible parenchymal infiltrates, the respective incidences were 2, 4, 4, and 5%. Factors associated with at least a twofold increase in the risk of pneumonia with FF/VI treatment were being a current smoker, having prior pneumonia, body mass index <25 kg/m2, and severe airflow limitation.

Conclusions: Radiographically confirmed pneumonia risk is increased with inhaled FF/VI, although at less than investigator-defined rates. Modifiable pneumonia risk factors should be considered when attempting to optimize COPD management.

Clinical trial registered with (NCT01009463 [HZC102871]; NCT01017952 [HZC102970]).

Pneumonia causes significant morbidity and mortality, and chronic obstructive pulmonary disease (COPD) is a known risk factor (1). Risk factors for pneumonia in patients with COPD include age >65 years, prior COPD exacerbation requiring hospitalization, dyspnea, low FEV1, and low body mass index (BMI) (2, 3). Moreover, COPD exacerbations associated with pneumonia have greater morbidity (worse hypoxemia, intensive care unit admissions, need for mechanical ventilation, longer hospital stays) and mortality than nonpneumonic exacerbations (4), and data from the Copenhagen City Heart study also identified age and low FEV1 as risk factors for serious and fatal pneumonia (5).

Inhaled corticosteroids (ICSs) reduce the risk of COPD exacerbations but increase the probability of having a clinically defined pneumonia, although this association has not been universally reported (6, 7). A nested case–control analysis of managed care databases in the United States found no increased pneumonia risk among patients with COPD using ICSs or combination of an ICS with a long-acting β2-agonist (LABA) (8). However, we and other investigators have reported that use of ICS in patients with COPD is associated with increased risk for pneumonia and pneumonia requiring hospitalization (3, 911). In the TOwards a Revolution in COPD Health (TORCH) trial, the largest of the prospective studies thus far that included an ICS-containing regimen, only 72% of subjects hospitalized with presumptive pneumonia underwent chest radiography (3). Although parenchymal pathology was present in 81% of these chest radiographs, other nonpneumonic disorders were present, including lung neoplasia and congestive heart failure. A recent Cochrane review reported an increase in serious (i.e., hospitalized) pneumonia events in patients with COPD for the inhaled corticosteroids fluticasone and budesonide compared with placebo (12).

However, both retrospective and prospective studies of patients with COPD have reported that, compared with non-ICS users, ICS users had no increase in morbidity or mortality (13, 14). Recently, we reported the results from two replicate studies of a new once-daily ICS/LABA combination product, fluticasone furoate and vilanterol trifenatate (FF/VI), confirming its efficacy in reducing COPD exacerbations compared with VI alone (15). In that study, we reported a doubling in the incidence of pneumonia with FF/VI compared with VI. Unlike TORCH, these studies required chest imaging in all cases of clinical pneumonia, as well as in all moderate and severe exacerbations. The objectives of the current study were to determine the incidence of radiographically confirmed pneumonia and risk factors from the previously reported trials with FF/VI in patients with COPD with an exacerbation history (15). We hypothesized that the incidence of radiographically confirmed pneumonia would be lower than that previously reported.

Study Design and Subjects

We performed a predefined analysis within the replicate FF/VI COPD exacerbation studies described previously (15). In brief, identical, replicate, multicenter, double-blind, parallel-group trials compared three strengths of FF/VI (50, 100, or 200 μg of FF combined with 25 μg of VI) (corresponding to emitted FF doses of 44, 92, and 184 μg, respectively, and an emitted VI dose of 22 μg) with VI 25 μg administered once daily in the morning via the ELLIPTA dry powder inhaler (GSK, UK; ELLIPTA is a trademark of the GSK group of companies). Participants were ≥40 years old, had a history of COPD as defined by the American Thoracic Society and the European Respiratory Society (16), a smoking history of ≥10 pack-years, a post-bronchodilator FEV1/FVC ratio of ≤0.70, a post-bronchodilator FEV1 ≤70% predicted value (17), and a documented history of ≥1 COPD exacerbation treated with systemic or oral corticosteroids, antibiotics, and/or hospitalization within the year before screening.

At screening, eligible subjects were required to have a posteroanterior and lateral chest radiograph that was overread by an independent radiologist (BioClinica, Newtown, PA) as being without abnormalities that would preclude identification of a pneumonic infiltrate were one to develop during the study. Following a 4-week run-in, during which they received open-label fluticasone propionate (FP)/salmeterol (SAL) 250 μg/50 μg twice daily, eligible subjects were randomized (1:1:1:1) to one of the four treatment regimens for 52 weeks with the primary efficacy parameter being the annual rate of moderate (requiring treatment with systemic corticosteroids and/or antibiotics) and severe (necessitating hospitalization) exacerbations.

Identification of Adverse Events

Pneumonia as an adverse event (AE) or serious AE (SAE) was defined as described previously (3) and coded using the Medical Dictionary for Regulatory Activities (MedDRA Version 14.1; International Federation of Pharmaceutical Manufacturers and Associations, Geneva, Switzerland). All MedDRA preferred terms that could relate to pneumonia (see Table E1 in the online supplement) were counted to provide a more complete assessment of all physician-reported pneumonias. For fatal pneumonia-related events, the hospital records were obtained; summaries of the hospital course are included as File E2.

Collection of Pneumonia Events

There was no a priori definition of pneumonia. Investigators were given guidance on criteria to consider when identifying an AE of pneumonia (File E3). Nonetheless, the final determination of the AE as pneumonia or exacerbation was made at the investigators’ discretion.

After randomization, the protocol required chest radiographs to be performed within 48 hours of any suspected pneumonia or a moderate/severe COPD exacerbation. During the conduct of the trials, we recognized that many pneumonia events were reported to, or identified by, the investigator after the 48-hour window. Therefore, to minimize missing pneumonia cases, we prespecified in our analysis plan, prior to unblinding, the inclusion of all chest radiographs that were performed within −7 to +14 days from initial diagnosis of the pneumonia event, as older patients (as is typical with COPD) can have delayed radiographic resolution following pneumonia (18). For events initially diagnosed as exacerbations, chest radiographs performed within the window of 0 to +14 days were used to identify an exacerbation with an infiltrate. The radiographs were overread by a blinded, independent radiologist and compared with the screening chest radiograph to confirm the presence of new findings compatible with pneumonia (see File E4 for the template report form). The interpretation from this independent review was provided directly to the investigator. For subjects hospitalized at institutions unaffiliated with the investigator, where the chest radiographs were not available or provided for central overread, the SAE narratives and/or medical records were reviewed to obtain chest imaging results, if performed. In addition, for any AE characterized as pneumonia, the investigator was to collect information regarding the clinical presentation of the subject at the time of the event (File E5).

Statistical Methods

Analyses were performed on the intent-to-treat population using integrated data from the replicate studies. The a priori analysis plans for each study provided for detailed summaries of pneumonia, exacerbations, and chest radiograph outcomes; for the integrated data, the analyses included all pneumonia AE reports, irrespective of the chest radiograph results. In addition, we analyzed post hoc all pneumonia AE reports with a compatible chest radiograph using the same predefined analysis methods. These analyses included time to first pneumonia, time to first serious pneumonia, and time to first pneumonia with a compatible chest radiograph using a stratified (by study) Cox proportional hazards model that allowed for smoking status and treatment to obtain hazard ratios for FF/VI compared with VI alone.

The impact of predefined subgroup factors on the risk of a pneumonia adverse event was assessed by fitting a separate Cox proportional hazards model for each of the following factors: age (<64, ≥65 yr), sex, cardiovascular history/risk factors (File E6), BMI (<25, ≥25 kg/m2), post-bronchodilator % predicted FEV1 (<30%, 30% to <60%, ≥60%), history of pneumonia within year prior to screening, geographic region, and the relationship of each factor to treatment. Each model included the subgroup factor and the interaction of the subgroup factor and treatment. Hazard ratios were obtained for each level of the subgroup factor for FF/VI compared with VI, irrespective of whether the interaction was statistically significant. A similar post hoc analysis was performed with BMI categories of ≤21 or >21 kg/m2 (19). The rate of moderate/severe exacerbations was analyzed as described previously (15). In a post hoc analysis, clinical characteristics and chest X-ray assessments were summarized (irrespective of treatment group) for the subgroups of subjects who experienced pneumonia nonserious AEs and those who experienced pneumonia SAEs. Chi-square tests were used to compare proportions, and one-way ANOVA was used to compare mean values to aid in describing differences between these two subgroups.


Of the 5,266 subjects screened in the two studies, 3,255 were randomized (Table 1). Subjects were mostly male with a mean (SD) age of 63.7 (9.2) years and BMI of 26.9 (5.9) kg/m2. Forty-four percent of the subjects were current smokers with a mean smoking history of 46.2 (27.7) pack-years. The subjects demonstrated on average severe airflow limitation with a mean (SD) % predicted post-bronchodilator FEV1 of 45.4% (13.4).

Table 1. Patient demographics and baseline characteristics (combined studies, ITT population)

 VI 25 μg (n= 818)FF/VI 50 μg/25 μg (n = 820)FF/VI 100 μg/25 μg (n = 806)FF/VI 200 μg/25 μg (n = 811)
Age, yr    
 Mean (SD)63.6 (9.4)63.6 (9.3)63.8 (9.2)63.6 (9.1)
Female sex, n (%)344 (42)344 (42)353 (44)344 (42)
Smoking status, n (%)    
 Former364 (44)364 (44)359 (45)352 (43)
 Current454 (56)456 (56)447 (55)459 (57)
Total pack-years    
 Mean (SD)45.7 (27.2)46.2 (26.7)46.6 (27.5)46.3 (29.5)
 FEV1% predicted post-bronchodilator45.2 (13.0)45.4 (13.6)46.0 (13.4)45.2 (13.4)
Reversibility FEV1 (%)    
 Mean (SD)14.5 (16.6)14.4 (15.4)14.7 (15.5)14.6 (18.5)

Definition of abbreviations: FF = fluticasone furoate; ITT = intent-to-treat; VI = vilanterol.

Values are mean (SD) unless otherwise stated.

Investigator-diagnosed events

Among the 3,255 randomized subjects, 205 events of pneumonia were reported in 181 subjects during the double-blind treatment period (Table 2); 98% of these cases of pneumonia were community-acquired. For 176 pneumonia events, the chest radiograph was blindly read by the independent radiologist. For 19 serious pneumonia events initially diagnosed at an institution with which the investigator was not associated, chest imaging was performed and interpreted only by the radiologist at the institution where the subject was evaluated. With the inclusion of these cases, chest imaging data was available for 195 (95%) of the total 205 pneumonia events (Table 3). Pneumonia led to study withdrawal of 22 subjects, of whom 16 had radiographic evidence of new infiltrates.

Table 2. Investigator-reported pneumonia* adverse events (combined studies)

 VI 25 μg (n = 818)FF/VI 50 μg/25 μg (n = 820)FF/VI 100 μg/25 μg (n = 806)FF/VI 200 μg/25 μg (n = 811)
Subjects with pneumonia,* n (%)27 (3)48 (6)51 (6)55 (7)
 Event rate/1,000 treatment-years42.378.685.794.9
 HR (95% CI) 1.7 (1.1, 2.8)1.8 (1.2, 3.0)2.0 (1.3, 3.2)
 P value 0.0250.0100.008
Subjects with serious pneumonia,* n (%)8 (0.98)24 (3)25 (3)23 (3)
 Event rate/1,000 treatment-years12.137.842.935.1
 HR (95% CI) 2.8 (1.3, 6.5)3.0 (1.4, 6.8)2.7 (1.3, 6.3)
 P value 0.0110.0070.014
Fatal pneumonia,* n (%)1 (0.12)01 (0.12)7§ (0.86)
Event rate/1,000 treatment-years1.501.510.2

Definition of abbreviations: CI = confidence interval; FF = fluticasone furoate; HR = hazard ratio; VI = vilanterol.

*A composite of many Medical Dictionary for Regulatory Activities (MedDRA Version 14.1) preferred terms was included under “pneumonia” (see the online supplement).

Analysis was performed using a Cox proportional hazards model, stratified by study, and with terms for treatment and smoking status.

This represented one case of posttreatment fatal pneumonia on VI 25 μg (see Case 9 in the online supplement).

§Although pneumonia was not reported as the fatal adverse event for one subject on FF/VI 200 μg/25 μg (recorded as a chronic obstructive pulmonary disease exacerbation) in one of the two studies, the investigator reported a nonserious pneumonia event and completed the pneumonia page on the case report form (see Case 1 in the online supplement).

Table 3. Radiographic imaging of pneumonia* adverse events (combined studies)

 VI 25 μg (n = 818)FF/VI 50 μg/25 μg (n = 820)FF/VI 100 μg/25 μg (n = 806)FF/VI 200 μg/25 μg (n = 811)
Total number of on-treatment pneumonia* events28545865
Pneumonia* events for which chest imaging was performed, n (%)26 (93)51 (94)57 (98)61 (94)
 Infiltrates present, n (%)15 (58)33 (65)36 (63)44 (72)
 Infiltrates absent, n (%)11 (42)17 (33)21 (37)17 (28)
No chest imaging performed, n (%)2 (7)3 (6)1 (2)4 (6)
Number (%) subjects with at least one chest X-ray with infiltrates present15 (2)32 (4)32 (4)37 (5)
 HR (95% CI) 2.04 (1.13, 3.83)2.07 (1.15, 3.89)2.39 (1.35, 4.45)
 P value 0.0220.0200.004

Definition of abbreviations: CI = confidence interval; FF = fluticasone furoate; HR = hazard ratio; VI = vilanterol.

*A composite of many Medical Dictionary for Regulatory Activities (MedDRA Version 14.1) preferred terms was included under “pneumonia” (see the online supplement).

In a further one subject, radiographic presence or absence of infiltrates was not indicated.

Analysis was performed using a Cox proportional hazards model, stratified by study, and with terms for treatment and smoking status.

Hazard ratios from the analysis of time to first on-treatment, investigator-defined pneumonia indicated that risk for pneumonia was significantly higher in all FF/VI treatment groups compared with the VI 25 μg group (Table 2). Overall, 13% of the subjects at risk in the FF/VI 50 μg/25 μg group, 15% of the subjects at risk in the FF/VI 100 μg/25 μg group and 18% of the subjects at risk in the FF 200 μg/VI 25 μg group experienced a second pneumonia event during the treatment period, compared with 5% of subjects randomized to VI 25 μg. The relative magnitude of the increase in pneumonia events in relation to exacerbation reduction is presented in Figures E1–E4.

Radiographically confirmed events

Chest imaging confirmed that most cases of investigator-defined pneumonia had infiltrates compatible with the diagnosis (Table 3). Pneumonia cases with radiographic infiltrates also demonstrated an approximate doubling of the incidence in the FF-containing arms compared with VI (Table 3, Figure 1). Detailed information was not provided on the clinical course for pneumonia events managed on an outpatient basis, and chest imaging was not performed for 10 of these events (Table 3). However, for those events with chest imaging, parenchymal infiltrates were confirmed in 12 of 18, 14 of 25, 17 of 28, and 27 of 37 of the VI 25 μg or FF/VI 50 μg/25 μg, 100 μg/25 μg, and 200 μg/25 μg groups, respectively.

Pneumonia as a Serious Adverse Event

Although the results for pneumonia as an AE suggest a possible dose–harm relationship, this was less obvious for pneumonia SAEs (i.e., events resulting in or prolonging hospitalization), expressed either as an event rate or for subjects with an event (Table 2). Chest imaging was obtained for all SAE pneumonia events. Infiltrates compatible with pneumonia were present in three (38%), 19 (73%), 19 (66%), and 17 (71%) of the serious events for the VI 25 μg and the FF/VI 50 μg/25 μg, 100 μg/25 μg, and 200 μg/25 μg treatment arms, respectively. There were seven on-treatment fatal pneumonia events in the FF/VI 200 μg/25 μg group and one in the FF/VI 100 μg/25 μg group, and one additional fatal pneumonia event occurred in the post-treatment period in the VI 25 μg treatment arm. The clinical course and chest imaging pattern related to these fatal events are described in File E2.


Of the 2,545 moderate and severe exacerbations, 1,793 (70%) chest radiographs were obtained and blindly reviewed by the independent radiologist for the presence of new infiltrates. In the 752 cases where chest imaging was not performed, 672 (89%) were associated with moderate exacerbations. The most common reasons that chest radiographs were not obtained for exacerbations included the investigator becoming aware of the event only at a subsequent scheduled visit or after the 48-hour window and therefore electing not to obtain the film. However, in 93% of these events where a chest X-ray was obtained, there were no infiltrates suggestive of pneumonia. Of the 120 events where an infiltrate was detected (i.e., 7% of those with chest radiographs), the investigator also reported pneumonia as an adverse event in 72 cases (60%). For exacerbations with infiltrates but not concurrently diagnosed pneumonia, 13, 8, 13, and 14 of these events occurred in the VI 25 μg group and in the FF/VI 50 μg/25 μg, 100 μg/25 μg, and 200 μg/25 μg groups, respectively.

Risk Factors for Pneumonia with FF

Compared with VI as monotherapy, for FF/VI 100 μg/25 μg, the factors associated with at least a twofold increased risk were being a current smoker, having a prior history of pneumonia, low BMI (<25 kg/m2), and severe airflow limitation (Figure 2). These risk factors persisted even when the analysis was restricted to those subjects with compatible infiltrates (data not shown). A similar analysis for FF/VI 50 μg/25 μg and 200 μg/25 μg strengths is shown as Figure E5.

Vaccination Status

Approximately 23% of subjects reported having received a vaccination for influenza at any time during the course of the study, and even fewer received one for pneumococcal pneumonia (7%). There was no significant difference in the incidence of serious versus nonserious pneumonias and fatal versus nonfatal pneumonias in the influenza- or pneumonia-vaccinated and unvaccinated subgroups of subjects.

Clinical Characteristics of Nonserious versus Serious Pneumonia Events

Investigators were required to collect specific clinical information regarding pneumonia events. We conducted a post hoc analysis of these data to describe clinical findings that distinguished nonserious from serious pneumonia events. There were no differences in screening lung function between subjects who experienced only a nonserious pneumonia (n = 101) versus those who had at least one serious event (n = 80) (FEV1 = 43.1% vs. 39.8% predicted). However, subjects with a serious pneumonia reported a higher incidence of exacerbations requiring hospitalization within the year prior to study enrollment compared with those with a nonserious pneumonia (30% vs. 22%; P = 0.046). Few subjects in either group had sputum cultures performed (7% in the AE group and 28% in the SAE group). Culture results and other clinical, radiographic, and laboratory findings are presented in File E7.

This detailed analysis of pneumonia data from replicate yearlong exacerbation studies confirm the near-doubling in both investigator-defined and radiographically confirmed pneumonia risk for patients with COPD receiving an ICS-containing regimen. The data also suggest considerable overlap with the diagnosis of pneumonia and exacerbation. The TORCH trial was the first large, prospective study to identify an increased pneumonia risk in subjects with COPD receiving ICS-containing regimens (20). However, that study was hampered in its ability to quantify the risk, as chest imaging studies were not required. In fact, chest radiographs were available in only 72% of hospitalized cases of pneumonia and in none of the nonhospitalized cases; in many instances, concomitant intrathoracic disorders, which could have confounded the diagnosis, were also present (3). Also, only the fatal events adjudicated as pneumonia-related required the presence of an infiltrate on the chest radiograph (21).

Our replicate studies were of similar design to those of Ferguson and colleagues (6) and Anzueto and colleagues (22), which compared a twice-daily FP/SAL 250/50 μg combination product with salmeterol. For these pooled FP/SAL exacerbation studies, the exposure-adjusted pneumonia rate was 91.9 events per 1,000 treatment-years, which is comparable to the 85.7 event rate we report with FF/VI 100 μg/25 μg. The exposure-adjusted rate for VI and salmeterol was also comparable at 42.3 and 48.8 events per 1,000 treatment-years, respectively. Furthermore, the event rates for serious pneumonia were comparable between the ICS/LABA products (42.9 vs. 53.0 events/1,000 treatment-years for FF/VI 100 μg/25 μg and FP/SAL 250 μg/50 μg, respectively). The serious pneumonia event rate was lower with VI compared with salmeterol (12.1 vs. 33.1 events per 1,000 treatment-years). The exposure-adjusted pneumonia rates we observed are higher than a previously reported value of 35.9 per 1,000 treatment-years in patients with severe COPD (2). It is likely that our higher incidence is in part related to differences in the definition of severity, i.e., the degree of airflow limitation in our study versus the use of oxygen or nebulized therapy (2) and our requirement of a prior history of exacerbations.

Interestingly, a diagnosis of pneumonia was often made despite the absence of radiographic infiltrates. For example, 27–62% of the events resulting in or prolonging hospitalization revealed no new parenchymal infiltrates; yet, a diagnosis of pneumonia was rendered. The reasons for this discrepancy are unclear, however, it is recognized that, in certain circumstances (e.g., dehydration), the radiographic appearance of an infiltrate may lag the clinical presentation, and it is possible that a subsequent film was obtained that was unavailable for the independent radiologist to interpret. Conversely, a much smaller percentage of events with centrally overread chest radiographs that were felt to be solely exacerbations contained new infiltrates (2.7%). Although it is unclear why this was deemed the diagnosis despite the chest radiographic appearance, we speculate that the investigator felt the clinical presentation did not warrant a diagnosis of pneumonia.

An approximate doubling in the risk with FF/VI was still observed, even after restricting the diagnosis of pneumonia to cases with compatible infiltrates visualized on chest imaging. Factors associated with at least a twofold increase in risk of pneumonia with FF/VI 100 μg/25 μg compared with VI alone were low BMI, 30% ≤ FEV1 <50% predicted, age >65 years, a prior exacerbation history, being a current smoker, and having a prior pneumonia event. These risk factors are nearly identical to those we previously described for patients with COPD, irrespective of treatment regimen (3). It is unclear why this increased risk was not seen in the subgroup with very severe airflow limitation. This may be a reflection of the smaller number of subjects recruited in this group. We also could not confirm a dose-related increase in the pneumonia risk associated with FF/VI, which was also not evident in a recently reported prospective study with FP (23). There were seven fatal pneumonia-related events reported with FF/VI 200 μg/25 μg. It was unclear from the hospital records whether in each circumstance the fatal event was temporally related to FF/VI 200 μg/25 μg administration, was precipitated by pneumonia, or whether pneumonia was itself the fatal event (File E2). However, it should be emphasized that FF/VI 200 μg/25 μg is not approved for use in patients with COPD.

Vaccination was left to the discretion of the subjects’ personal health-care provider, and most subjects had no documentation of either prior pneumococcal or current influenza vaccination. A prior study from Spain suggested that the 23-valent pneumococcal polysaccharide vaccine is effective in preventing community-acquired pneumonia (CAP) in patients with COPD <65 years of age with an FEV1 <40% of predicted value (24). Therefore, it is unclear to what extent the incidence could have been reduced with adequate vaccination.

Strengths and Limitations of This Study

It is important to note that these studies were not designed as pneumonia trials. As such, rigor was not placed on identifying specific causative pathogens using serological, culture, or molecular techniques. Recommendations for diagnostic testing in clinical practice remain controversial, and such testing is suggested only if it would significantly alter standard empirical therapy, which is effective in the majority of patients (25, 26). On the other hand, this is the first study confirming pneumonia risk with chest imaging as part of a clinical trial with ICS in patients with COPD. We obtained chest imaging results in 91% of the nonhospitalized and all of the hospitalized pneumonia cases. Although these cases were not independently adjudicated, we believe the information gleaned from these analyses is robust. In addition, most cases where chest radiographs were not obtained were associated with moderate exacerbations, for which choice and duration of antibiotics are similar to those used to manage nonhospitalized CAP.

These studies were also not designed to explore potential mechanisms for the observed increased pneumonia rates. Patterson and colleagues reported in a mouse model that inhaled FP impaired the expression of infection-induced cytokines by alveolar macrophages from animals inoculated with Klebsiella pneumoniae, reduced reactive nitric oxide production and inducible nitric oxide synthase mRNA expression by alveolar macrophages, and decreased bacterial clearance (27). FF has slightly greater potency than FP as assessed in in vitro functional assays (28) and is four times more potent than FP in improving lung function in subjects with asthma (29). However, the ability and magnitude of effect of FF on altering host mechanisms is currently unknown.

In an exacerbation study comparing FP/SAL 500 μg/50 μg with tiotropium, Calverley and colleagues observed that subjects receiving the ICS/LABA combination were more likely to have an ongoing or unresolved exacerbation prior to their pneumonia diagnosis. The authors speculated that possible explanations included a delay in the institution of appropriate antibiotic therapy due to the use of the ICS, as well as inadequate antibiotic treatment (30). In this regard, File and colleagues proposed a descriptive disease model to explain the progression of acute exacerbations to pneumonia (31). Although the severity of airflow obstruction was linked to progression to CAP, the authors also reported that CAP was strongly associated with Streptococcus pneumoniae infection, particularly when the ratio of the area under the concentration-time curve from 0 to 24 hours to minimum inhibitory concentration (AUIC) for the selected antibiotic was <100. Conversely, pathogens other than S. pneumoniae and an AUIC ≥ 100 were less likely to be associated with progression of an exacerbation to pneumonia. We had limited information on recovered pathogens from subjects and antibiotic therapy used, and therefore we cannot comment on whether an appropriate antimicrobial regimen was selected to treat the exacerbation or pneumonia events in this study.


The role of ICSs in reducing exacerbations is well established in the Global Initiative for Chronic Obstructive Lung Diseases COPD treatment paradigm (32). Further investigations are needed to better understand how ICSs alter the microbiome and host defense mechanisms in the respiratory tract of COPD patients. We have demonstrated that the incidence of radiographically confirmed pneumonia is increased with inhaled FF/VI, which is low compared with the incidence of COPD exacerbations, and there is considerable overlap. Pneumonia risk factors that are modifiable (low BMI, current smoking) should be considered when attempting to optimize COPD management.

The authors acknowledge Amanda Emmett (GSK), statistician, and support in the form of graphic services and technical support in the submission of the manuscript provided by Ian Grieve, Ph.D., at Gardiner-Caldwell Communications (Macclesfield, UK) that was funded by GSK.

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Correspondence and requests for reprints should be sent to Courtney Crim, M.D., Respiratory Therapeutic Area Unit, GSK, Five Moore Drive, 5.3317.3A, Research Triangle Park, NC 27709-3398. E-mail:

Supported by GSK.

Author Contributions: C.C., J.B., J.V., F.J.M., F.B., S.L., P.M.A.C.: study conception and design; C.C., M.T.D., J.B., P.W.J., N.A.H., J.V., A.W., F.J.M., F.B., S.L., P.M.A.C.: analysis and interpretation; C.C., M.T.D., J.B., P.W.J., N.A.H., D.A.M., J.V., A.W., F.J.M., F.B., S.L., P.M.A.C.: drafting the manuscript for important intellectual content.

This article has an online supplement, which is available from the issue’s table of contents at

Author disclosures are available with the text of this article at


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