Abstract
Rationale: Inhaled corticosteroids are commonly prescribed to patients with chronic obstructive pulmonary disease (COPD).
Objectives: To examine whether these medications might be associated with an excess risk of pneumonia.
Methods: We conducted a nested case-control study within a cohort of patients with COPD from Quebec, Canada, over the period 1988–2003, identified on the basis of administrative databases linking hospitalization and drug-dispensing information. Each subject hospitalized for pneumonia during follow-up (case subjects) was age and time matched to four control subjects. The effect of the use of inhaled corticosteroids was assessed by conditional logistic regression, after adjusting for comorbidity and COPD severity.
Measurements and Main Results: The cohort included 175,906 patients with COPD of whom 23,942 were hospitalized for pneumonia during follow-up, for a rate of 1.9 per 100 per year, and matched to 95,768 control subjects. The adjusted rate ratio of hospitalization for pneumonia associated with current use of inhaled corticosteroids was 1.70 (95% confidence interval [CI], 1.63–1.77) and 1.53 (95% CI, 1.30–1.80) for pneumonia hospitalization followed by death within 30 days. The rate ratio of hospitalization for pneumonia was greatest with the highest doses of inhaled corticosteroids, equivalent to fluticasone at 1,000 μg/day or more (rate ratio, 2.25; 95% CI, 2.07–2.44). All-cause mortality was similar for patients hospitalized for pneumonia, whether or not they had received inhaled corticosteroids in the recent past (7.4 and 8.2%, respectively).
Conclusions: The use of inhaled corticosteroids is associated with an excess risk of pneumonia hospitalization and of pneumonia hospitalization followed by death within 30 days, among elderly patients with COPD.
A clinical trial has suggested that there may be an excess risk of severe pneumonia in patients using inhaled corticosteroids.
An excess of severe pneumonia requiring hospitalization was seen among patients with chronic obstructive pulmonary disease who were dispensed inhaled corticosteroids. The effect was greatest for those prescribed higher doses in the recent past.
Several trials have examined the effect of inhaled corticosteroids (ICS) on various outcomes in patients with COPD with different degrees of airflow obstruction, and found no beneficial effect on disease progression as measured by decline in FEV1 (2–5). A meta-analysis of these and other, smaller trials reported a reduction in exacerbations of COPD with the use of ICS (6), a finding that was questioned because of the inappropriate statistical analysis used in several of these trials (7).
ICS are prescribed to as many as 50% of patients with COPD (8–10). ICS have fewer adverse effects than oral corticosteroids, but can be partially absorbed and cause systemic effects such as skin bruising, accelerated bone loss, and increased risk of subcapsular cataracts. The TORCH (Towards a Revolution in COPD Health) study (11), which examined the potential benefit of ICS and long-acting β-agonists in reducing COPD mortality, reported a 19% 3-year rate of pneumonia in patients receiving fluticasone at 1,000 μg/day, either alone or as part of combination therapy, corresponding to a significant 1.6-fold increase over placebo (11). In addition, a smaller study comparing COPD exacerbation rates between patients receiving either salmeterol or the combination of salmeterol and fluticasone found a greater than threefold excess of pneumonia in the group receiving combination therapy (12). Of note, in neither of these trials was the diagnosis of pneumonia necessarily confirmed radiographically.
Infections are an important public health issue, with the age-adjusted death rates from pneumonia and influenza in the United States increasing from 20.4 to 31.8 deaths per 100,000 between 1979 and 1992 (13). Moreover, pneumonia is the third leading cause of hospitalization in the United States (14). In parallel, the prevalence of inhaled corticosteroid use among patients with COPD increased from 13.2 to 41.4% from 1987 to 1995 (8). In this study we assessed, using a large cohort of patients with COPD, whether the use of ICS is associated with an increased risk of serious pneumonia requiring hospitalization.
We used the health databases of the Régie de l'Assurance Maladie du Québec (RAMQ, Quebec City, PQ, Canada), the agency responsible for administering the universal health insurance program of the province of Quebec, Canada, for all its 7 million residents. The databases contain information on demographics and all medical services rendered, along with the diagnostic code of the service (ICD-9 code), and, for all people aged 65 years or older, all outpatient prescription medications dispensed. Information obtained from the Quebec prescription claims databases has been previously validated (15). Values in key fields such as drug, quantity, date dispensed, and duration are missing or out of range in less than 0.5% of records. These databases have been used previously to study the risks of fractures and cataracts associated with ICS (16, 17).
A population-based cohort design with a nested case-control analysis was used. The source population consisted of all subjects who, between January 1, 1988, and December 31, 2001, were 66 years of age or older and were dispensed at least one of the following respiratory medications during this period: any form of β-agonist, theophylline, ipratropium bromide, sodium cromoglycate, nedocromil, or ketotifen. The three latter medications were included, even if usually indicated for asthma, because, in day-to-day practice, they may be prescribed to patients with respiratory symptoms that may represent COPD rather than asthma. The cohort of patients with COPD was formed from this source population by identifying all subjects with three or more prescriptions for these medications in any 1-year period and on at least two different dates. Subjects with mention of asthma, either as the primary or a secondary diagnosis during a hospitalization, were excluded. Cohort entry was taken as the date of the third prescription. These subjects were monitored until the first hospitalization for pneumonia after cohort entry, death, or until December 31, 2003.
Case subjects were defined by the first hospitalization with a primary diagnosis of pneumonia of any cause including influenza identified in the RAMQ hospitalization database (ICD-9 codes 480 to 487 inclusive) during cohort follow-up. The date of the case-defining hospitalization was called the index date. We also identified the subset of pneumonia case subjects who died of any cause within 30 days of being hospitalized for pneumonia.
For each case subject, four control subjects matched for age (within 1 yr) were selected at random from all subjects who entered the cohort in the same month as the case subject. Control subjects also had to be at risk on the date of their corresponding case event. This date was taken as the index date for the control subjects.
ICS included orally inhaled beclomethasone, budesonide, triamcinolone, fluticasone, and flunisolide, whether dispensed alone or in a combination inhaler with an inhaled β-agonist. The estimation of equivalencies was chosen on the basis of relative topical potency and what experts consider to be comparable doses according to the National Asthma Education and Prevention Program Expert Panel report 2 (see Figures 3–5b and 3–5c in that report [18]) and the Canadian asthma consensus statement (see Table 8 in that statement [19]). Accordingly, the equivalent doses for inhaled corticosteroids are beclomethasone 100 μg, budesonide 80 μg, triamcinolone 200 μg, fluticasone 50 μg, and flunisolide 200 μg. All doses were converted to fluticasone equivalents and categorized according to defined daily doses (20) of the most recent prescription in the 60 days before the index date as high (fluticasone, 1,000 μg/d or more), moderate (fluticasone, 500–999 μg/d), and low (fluticasone, less than 500 μg/d).
Covariates included age (matched for in the design), sex, and the severity of respiratory disease, as well as other conditions associated with a risk of pneumonia. We quantified the severity of respiratory disease, independently of inhaled corticosteroid use, by the number of dispensed prescriptions of respiratory medications (β-agonists, ipratropium bromide, theophylline, and cromolyns), the number of prescriptions for oral corticosteroids, the presence of a hospitalization with a primary diagnosis of COPD, all measured in the year before the index date. Another covariate was the number of antibiotic prescriptions in the past year, but excluding the last 30 days because such recent antibiotic prescriptions might represent initial therapy for the pneumonia that resulted in hospitalization, the primary outcome of interest. Comorbidity possibly related to the risk of pneumonia was measured on the basis of prescriptions for various classes of medications associated with the treatment of disorders of interest, dispensed in the past year. Diabetes was defined on the basis of dispensed insulin or an oral hypoglycemic agent; cardiac disease on the basis of a prescription for cardiotropes or antihypertensives or diuretics or vasodilators; central nervous system drugs included benzodiazepines, major tranquillizers, anticonvulsants, and drugs for parkinsonism; osteoporosis drugs included calcium, vitamin D, and biphosphonates; rheumatic drugs included gold salts, methotrexate, azathioprine, hydroxychloroquine, and chloroquine. Use of the newer antitumor necrosis factor medications was minimal in this cohort. Nonsteroidal antiinflammatory drugs, antidepressive agents, and narcotics were considered as separate categories. All other prescriptions were grouped.
All analyses were based on techniques for matched data. Crude and adjusted rate ratios of pneumonia and of pneumonia followed by death within 30 days, with inhaled corticosteroid use were estimated with 95% confidence intervals by conditional logistic regression. Subjects were considered as current users if the last prescription was dispensed within 60 days of the index date, and nonuse during the prior year was used as the reference category. Subjects whose last prescription was dispensed between 61 and 365 days before the index date were classified as past users. Age and calendar time were inherently accounted for by the matching. Further adjustment factors included sex and the severity of respiratory disease, as well as all other covariates measuring conditions associated with the risk of pneumonia. The rate ratio for inhaled corticosteroid use was stratified by concurrent use of oral corticosteroids and by whether subjects had been hospitalized for COPD in the prior year. All analyses were conducted with SAS version 9.1 (SAS Institute, Cary, NC).
We identified a cohort of 175,906 patients with COPD, aged 72 (± 4.4) years at cohort entry. Of these patients 50.1% were men, and the duration of follow-up was 7.1 (± 4.04) years. During 1,241,741 person-years of follow-up, 23,942 patients were hospitalized for pneumonia (case subjects), for a rate of 1.9 per 100 per year. Case subjects and control subjects were elderly (77 ± 4.5 yr) and the time to hospitalization was 5.2 years on average (Table 1). There were more men among the case subjects hospitalized for pneumonia than among the control subjects. The case subjects had more severe respiratory disease as reflected by the greater frequency of COPD hospitalization, as well as by the greater number of prescriptions for respiratory drugs, antibiotics (excluding those prescribed in the month before hospitalization or the matching index date for the control subjects), and systemic corticosteroids. Comorbidity was also more prevalent in the case subjects.
Case Subjects | Control Subjects | |
|---|---|---|
| Number | 23,942 | 95,768 |
| Age (yr), mean ± SD | 77 ± 4.5 | 77 ± 4.5 |
| Follow-up (yr), mean ± SD | 5.2 ± 3.5 | 5.2 ± 3.5 |
| Sex, % men | 60.4 | 46.5 |
| Hospitalization for COPD in the prior year, % | 14.5 | 3.6 |
| Medication use in the year before index date | ||
| Antibiotics (no. of prescriptions) , mean ± SD | 0.9 ± 1.5 | 0.6 ± 1.2 |
| Respiratory drugs (no. of prescriptions), mean ± SD | 17.5 ± 22.7 | 9.0 ± 16.0 |
| Oral corticosteroids (no. of prescriptions), mean ± SD | 1.2 ± 3.5 | 0.5 ± 2.2 |
| Cardiac drugs, % | 66.7 | 61.1 |
| Diabetes drugs, % | 14.0 | 11.9 |
| Antidepression drugs, % | 17.2 | 13.7 |
| Central nervous system drugs, % | 9.1 | 5.2 |
| Osteoporosis drugs, % | 9.4 | 8.9 |
| NSAIDs, % | 35.5 | 37.8 |
| Narcotics, % | 6.6 | 3.7 |
| Antirheumatic, % | 1.4 | 0.8 |
| Others, % | 13.8 | 14.5 |
As shown in Table 2, the prevalence of inhaled corticosteroid use in the past year was 48.2% for the case subjects and 30.1% for the control subjects. After adjustment for differences in the covariates, current use of inhaled corticosteroids was associated with an increase of 70% in the rate of a hospitalization for pneumonia (rate ratio [RR], 1.70; 95% confidence interval [CI], 1.63–1.77). There was a dose–response relationship, with the rate of pneumonia greatest with the highest doses of inhaled corticosteroids, equivalent to fluticasone at 1,000 μg/day or more (RR, 2.25; 95% CI, 2.07–2.44). Past use of inhaled corticosteroids was associated with a small increase in risk (RR, 1.31), which decreased to 1.20 for use of these medications last dispensed from 9 to 12 months before the index date. When restricting the analysis to patients with pneumonia who died within 30 days of hospitalization, an increase of 53% (RR, 1.53; 95% CI, 1.30–1.80) was seen with current use of ICS, whereas use of higher doses, equivalent to fluticasone at 1,000 μg/day or more, was associated with a 78% increase (RR, 1.78; 95% CI, 1.33–2.37) in the risk for pneumonia hospitalization followed by death within 30 days.
Case Subjects | Control Subjects | Crude Rate Ratio | Adjusted* | |||
|---|---|---|---|---|---|---|
| Rate Ratio | 95% CI | |||||
| Number of subjects | 23,942 | 95,768 | ||||
| Inhaled corticosteroid use, % | ||||||
| No use in the past year | 51.8 | 69.9 | 1.00 | 1.00 | Reference | |
| Current use (last 60 d) | 24.8 | 12.9 | 2.74 | 1.70 | 1.63–1.77 | |
| High dose | 5.7 | 2.1 | 4.05 | 2.25 | 2.07–2.44 | |
| Medium dose | 14.8 | 8.0 | 2.64 | 1.63 | 1.55–1.71 | |
| Low dose | 4.3 | 2.8 | 2.11 | 1.50 | 1.38–1.62 | |
| Past use, % | 23.4 | 17.2 | 1.91 | 1.31 | 1.26–1.36 | |
| 61 to 180 d | 12.7 | 8.6 | 2.08 | 1.41 | 1.34–1.48 | |
| 181 to 270 d | 5.8 | 4.5 | 1.81 | 1.25 | 1.16–1.34 | |
| 270 to 365 d | 4.9 | 4.0 | 1.68 | 1.20 | 1.11–1.29 | |
The rate ratio of pneumonia for current use of ICS (RR, 1.70) remained similar when stratified by markers of COPD severity (Table 3), the concurrent use of oral corticosteroids (RR, 1.63) and nonconcurrent use (RR, 1.61), and COPD hospitalization in the past year (RR, 1.54) or not (RR, 1.69). The duration of pneumonia hospitalization was similar whether subjects were current users of ICS (mean, 11.7 d; SD, 14.7) or not (mean, 11.8 d; SD, 19.9). All-cause mortality within 30 days of being hospitalized for pneumonia was also similar: 1,475 deaths among 18,005 subjects (8.2%) not dispensed ICS in the prior 2 months and 439 deaths among 5,937 subjects (7.4%) dispensed ICS.
Case Subjects | Control Subjects | Crude Rate Ratio | Adjusted* | |||
|---|---|---|---|---|---|---|
| Rate Ratio | 95% CI | |||||
| Use of oral corticosteroids in prior year | ||||||
| Number of subjects | 7,060 | 13,075 | ||||
| No use of ICS in past year | 25.7 | 40.1 | 1.00 | 1.00 | Reference | |
| Current use (last 60 d) | 38.3 | 27.3 | 2.40 | 1.63 | 1.41–1.88 | |
| No use of oral corticosteroids in prior year | ||||||
| Number of subjects | 16,882 | 82,693 | ||||
| No use of ICS in past year | 62.7 | 74.7 | 1.00 | 1.00 | Reference | |
| Current use (last 60 d) | 19.1 | 10.6 | 2.32 | 1.61 | 1.53–1.70 | |
| Hospitalized for COPD in prior year | ||||||
| Number of subjects | 3,466 | 3,400 | ||||
| No use of ICS in past year | 19.9 | 27.1 | 1.00 | 1.00 | Reference | |
| Current use (last 60 d) | 40.6 | 34.1 | 1.77 | 1.54 | 1.07–2.20 | |
| Not hospitalized for COPD in prior year | ||||||
| Number of subjects | 20,476 | 92,368 | ||||
| No use of ICS in past year | 57.2 | 71.5 | 1.00 | 1.00 | Reference | |
| Current use (last 60 d) | 22.1 | 12.1 | 2.43 | 1.69 | 1.61–1.77 | |
In a large cohort of patients with COPD, we found that current inhaled corticosteroid use was associated with a significant 70% increase in the risk of being hospitalized for pneumonia. This risk increased with higher doses of ICS, such that the dispensing of 1,000 μg of fluticasone per day or the equivalent was associated with a greater than twofold increase in the risk of a hospitalization for pneumonia. Furthermore, for the severest pneumonias leading to death within 30 days of hospitalization, the risk with current inhaled corticosteroid use was also significantly increased.
COPD itself is associated with an increased risk of pneumonia (21, 22) and the risk of a pneumonia hospitalization is greater for patients with severe underlying disease (23). Meanwhile, higher doses of ICS are more likely to be prescribed to patients with more severe disease. To avoid confounding by severity of the underlying disease, which would create an artificial association between use of inhaled corticosteroids and the risk of pneumonia, it is important to adjust for the severity of COPD. In the present analysis, differences in severity of COPD between the case patients and the control subjects were accounted for by adjusting for symptoms as reflected by the number of prescriptions for respiratory medications other than inhaled corticosteroids, and for exacerbations as reflected by prescriptions for oral corticosteroids, antibiotics, as well as hospitalization for a COPD exacerbation. Furthermore, in analyses stratified by whether or not patients received oral steroids or were hospitalized for COPD in the past year, the risk associated with use of ICS was similar. Although we have no measures of lung function, it seems unlikely that FEV1 would be associated with both the likelihood of pneumonia and the taking of ICS independently of the other markers of disease severity that we were able to adjust for. Furthermore, the similarities in the duration of hospitalization for pneumonia, and in all-cause mortality in the 30 days after such a hospital admission, argue strongly that COPD severity at the time of hospitalization was similar in subjects recently dispensed ICS or not.
The prescription databases used for the present study provide information about dispensed medications and one cannot be assured that study subjects were actually taking the dispensed drugs. If patients were not taking these medications, this would tend to attenuate the actual risk increase.
Our results suggest that the excess risk of pneumonia is associated with current use of ICS and that this adverse effect largely dissipates once treatment is stopped for 6 months or more. The risk observed with use of inhaled corticosteroids in the period from 2 to 6 months and from 6 to 12 months before the event likely also represents continued use at lower than the usual defined daily doses as well as intermittent use. Alternatively, such a residual effect many months before the event may be the result of not being able to take into account differences in severity of COPD linked to being prescribed inhaled corticosteroids more than 6 months before the event.
The risk of pneumonia with ICS has not received much attention in previous studies of the benefits or adverse effects of these medications. This is likely due in part to the relatively small numbers of subjects in most clinical trials of ICS in COPD, as well as the lower doses used in those trials. In this respect, it is noteworthy that two trials (11, 12) found an excess of pneumonia among patients receiving high doses of ICS for COPD. Neither of these trials required that the diagnosis of pneumonia be confirmed radiographically; thus the accuracy of the diagnosis of pneumonia can be questioned. In the current study we also cannot be sure that the diagnosis was based on radiographic findings. It seems highly likely, however, that for patients with a hospitalization with a primary diagnosis of pneumonia, the diagnosis was in fact supported by a compatible radiographic finding.
Wolfe and coworkers (24) reported a dose-related increase in the risk of pneumonia with oral corticosteroids in patients with rheumatoid arthritis; prednisone not exceeding 5 mg/day was associated with a hazard ratio of 1.4 (95% CI, 1.1–1.6), 5–10 mg/day with a hazard ratio 2.1 (95% CI, 1.7–2.7) and more than 10 mg/day with a hazard ratio of 2.3 (95% CI, 1.6–3.2). High doses of ICS are known to be associated with systemic effects and 1,000 μg of inhaled fluticasone, the most commonly used inhaled corticosteroid in Canada, is estimated to be equivalent to approximately 10 mg of prednisone per day when the systemic effect is evaluated by suppression of serum cortisol (25). Thus our findings in patients with COPD receiving high doses of ICS are compatible with the increased risk of pneumonia seen with low doses of oral corticosteroids in patients with rheumatoid arthritis.
A major strength of the current analysis is the large number of pneumonia hospitalizations that occurred in this elderly group, thus allowing precise estimates of the risk associated with various doses of inhaled corticosteroids. Of note, even relatively low doses of ICS were associated with an excess risk of pneumonia. Whereas the risks observed at the higher doses appear consistent with the risks observed with low doses of prednisone, the smaller risk associated with lower doses of ICS could represent residual confounding or possibly reflect effects of ICS on local airway defense mechanisms, or again, relate to systemic effects not reflected in measures of adrenal function.
Adverse effects of inhaled corticosteroids in patients with COPD are particularly troublesome given the limited evidence for their efficacy. In the current study, we attempted to eliminate as much as possible patients whose predominant airway disease was asthma rather than COPD, because the risk:benefit ratio of inhaled corticosteroids for asthma will be quite different. Furthermore, because pneumonia leading to hospitalization is the third leading cause of hospitalization in the United States after childbirth and psychosis (14) and use of inhaled corticosteroids in COPD is common, the impact on health care costs of an excess of pneumonia with use of these medications is large. Although we observed both an increase in pneumonia hospitalizations and an increase in pneumonia hospitalizations leading to death with use of inhaled corticosteroids, we did not observe either more prolonged hospitalization or increased all-cause mortality among those hospitalized patients who had been dispensed ICS, suggesting that response to treatment, or the severity of the pneumonia, is not adversely affected by this treatment.
In summary, we found a dose-related increase in the risk of hospitalization for pneumonia, and of hospitalization for pneumonia leading to death, among patients with COPD who were using ICS. This adverse effect of ICS needs to be considered when prescribing these medications to patients with COPD.
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