EDITORIAL February 2014 Volume 89 Number 2
Pneumonia Associated With Inhaled Corticosteroid Use in Chronic Obstructive Pulmonary Disease: Another Perspective
I
nhaled corticosteroids (ICSs) have had a central role in the management of asthma, even before publication of the first Guidelines for the Diagnosis and Management of Asthma in 1991.1 Much evidence has been amassed in support of asthma treatment with ICSs. Their role in the management of chronic obstructive pulmonary disease (COPD) and other pulmonary diseases has developed despite less than robust scientific support. In recent years, alternative medications have been introduced to treat COPD, and the use of ICSs has been challenged, in part because of concerns for both efficacy and safety. In this issue of Mayo Clinic Proceedings, Festic et al2 examine the use of ICSs in the treatment of COPD and use a novel approach to determine if this management choice is associated with new-onset pneumonia. The use of systemic cortisone therapy for asthma was introduced in 1950,3 and adaptation to ICSs with the introduction of beclomethasone followed in the early 1970s.4 Currently, ICSs have become the mainstay of asthma therapy and are considered the most effective form of therapy.5 The use of ICSs followed in patients with COPD, partly by inference based on similarities with asthma pathophysiology and clinical presentations. Despite relatively weak scientific evidence, with time the use of ICSs became a substantial component of COPD treatment. A 1997 Canadian survey of hospitalized patients discovered that COPD was a more common indication for ICS prescriptions than asthma.6 In the 1990s, it was hypothesized that regular use of ICSs by patients with COPD would slow the accelerated rate of decline in lung function, particularly among current smokers.7 However,
validation studies were not supportive; 3 years of therapy with various formulations of ICSs produced no improvement in the accelerated rate of lung function decline in patients with mild to severe COPD.8-11 However, additional analyses from those trials revealed that ICSs reduced the frequency of acute exacerbations of COPD and improved health status and symptoms of COPD. These factors became the main indications for use of ICSs by patients with severe or very severe COPD or with frequent exacerbations.12 The contemporary use of ICSs in COPD may be oversubscribed, in part because of commercial preparations that combine ICSs with other drugs that have independent efficacy in treating COPD. The commonly available combination preparations of ICSs with long-acting b-adrenergic agonist (LABA) bronchodilators are widely prescribed, and it is estimated that up to 50% to 70% of patients with COPD use ICSs, mostly as combination therapy.13 Meanwhile, there are numerous other medications that reduce exacerbations, including freestanding LABAs,14 longacting muscarinic antagonists,15 the macrolide antibiotic azithromycin,16 and the phosphodiesterase type 4 inhibitor roflumilast.17 To varying degrees, these drugs also improve symptoms, quality of life, and exercise tolerance. The Towards a Revolution in COPD Health (TORCH) trial14 was designed to evaluate a possible survival benefit associated with the use of the combination of the LABA salmeterol and the ICS fluticasone propionate in comparison with placebo. The survival benefit fell short of the predetermined requirement for statistical significance. An independent secondary analysis of the data from the TORCH trial discovered a survival benefit associated with salmeterol that
Mayo Clin Proc. n February 2014;89(2):139-141 n http://dx.doi.org/10.1016/j.mayocp.2013.12.009 www.mayoclinicproceedings.org n ª 2014 Mayo Foundation for Medical Education and Research
See also page 154
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MAYO CLINIC PROCEEDINGS
was statistically significant, alone and in combination with fluticasone, in comparison with placebo or fluticasone alone.18 The TORCH trial reported, for the first time, an increased risk of pneumonia associated with the use of the ICS compared with the placebo group. Since completion of the TORCH trial, other studies and subsequent meta-analyses have reported a 50% to 70% increase in risk of pneumonia associated with the use of ICSs in COPD.19-21 This conclusion was validated in a recent large cohort-based study.22 The risk has been mostly associated with fluticasone propionate and not budesonide or ciclesonide, and mostly with high doses of fluticasone propionate. Despite these many observations, lingering questions remain. Is this association between ICS use and pneumonia real or an epiphenomenon (ie, are patients who have more severe COPD and use ICSs more frequently more likely to experience pneumonia simply because of their baseline COPD)? Associations between medications and adverse events in observational cohorts may be confounded by indication: patients who use cardioactive medications die of cardiovascular disease more frequently, usually not because of adverse effects of medications but more often because of underlying disease. In the study by Suissa et al,22 for example, users of ICSs to treat COPD had greater than twice as many hospitalizations in the prior year and more than twice as many prescription respiratory medications, as compared with the non-ICS group. If there is indeed a propensity for ICSs to increase the rate of pneumonia in patients with COPD, what is the magnitude of the ICS effect? And how does it compare to the potential benefits of therapy? Pneumonia can be difficult to diagnose with certainty, particularly in patients with underlying lung disease and chronic symptoms. Adverse event reporting in clinical trials is generally not adjudicated, and studies rarely include critical review of either clinical or radiographic evidence in support of the diagnosis. Most studies are unable to distinguish community-acquired pneumonia from hospitalassociated pneumonia. The increased incidence of pneumonia has not been documented to affect overall mortality in most studies of patients with COPD, despite it being a highly morbid and frequently fatal illness.14,19-21 140
Mayo Clin Proc.
n
Festic et al2 used a novel approach to evaluate the possibility that ICS use predisposes patients with COPD to pneumonia. Using an established database from a lung injury study,23 they performed a secondary analysis of patients admitted to the hospital with at least one risk factor for acute respiratory distress syndrome. The cohort included 5584 patients, of which 1234 (22.1%) had pneumonia, 589 (10.6%) had a diagnosis of COPD, and 495 (8.9%) were using ICSs before admission. Unlike other studies, they had extensive documentation of clinical presentation and analyzed only pneumonias present at admission. All cases were documented by chest radiographs to show a new or progressive infiltrate, consolidation, cavitation, or pleural effusion and had new-onset purulent sputum or a change in sputum character. They did not have information on the type of ICS prescribed or dose. The unadjusted univariate odds ratio for pneumonia among users of ICSs was 3.28 (95% CI, 2.713.96; P
Pneumonia Associated With Inhaled Corticosteroid Use in Chronic Obstructive Pulmonary Disease: Another Perspective
I
nhaled corticosteroids (ICSs) have had a central role in the management of asthma, even before publication of the first Guidelines for the Diagnosis and Management of Asthma in 1991.1 Much evidence has been amassed in support of asthma treatment with ICSs. Their role in the management of chronic obstructive pulmonary disease (COPD) and other pulmonary diseases has developed despite less than robust scientific support. In recent years, alternative medications have been introduced to treat COPD, and the use of ICSs has been challenged, in part because of concerns for both efficacy and safety. In this issue of Mayo Clinic Proceedings, Festic et al2 examine the use of ICSs in the treatment of COPD and use a novel approach to determine if this management choice is associated with new-onset pneumonia. The use of systemic cortisone therapy for asthma was introduced in 1950,3 and adaptation to ICSs with the introduction of beclomethasone followed in the early 1970s.4 Currently, ICSs have become the mainstay of asthma therapy and are considered the most effective form of therapy.5 The use of ICSs followed in patients with COPD, partly by inference based on similarities with asthma pathophysiology and clinical presentations. Despite relatively weak scientific evidence, with time the use of ICSs became a substantial component of COPD treatment. A 1997 Canadian survey of hospitalized patients discovered that COPD was a more common indication for ICS prescriptions than asthma.6 In the 1990s, it was hypothesized that regular use of ICSs by patients with COPD would slow the accelerated rate of decline in lung function, particularly among current smokers.7 However,
validation studies were not supportive; 3 years of therapy with various formulations of ICSs produced no improvement in the accelerated rate of lung function decline in patients with mild to severe COPD.8-11 However, additional analyses from those trials revealed that ICSs reduced the frequency of acute exacerbations of COPD and improved health status and symptoms of COPD. These factors became the main indications for use of ICSs by patients with severe or very severe COPD or with frequent exacerbations.12 The contemporary use of ICSs in COPD may be oversubscribed, in part because of commercial preparations that combine ICSs with other drugs that have independent efficacy in treating COPD. The commonly available combination preparations of ICSs with long-acting b-adrenergic agonist (LABA) bronchodilators are widely prescribed, and it is estimated that up to 50% to 70% of patients with COPD use ICSs, mostly as combination therapy.13 Meanwhile, there are numerous other medications that reduce exacerbations, including freestanding LABAs,14 longacting muscarinic antagonists,15 the macrolide antibiotic azithromycin,16 and the phosphodiesterase type 4 inhibitor roflumilast.17 To varying degrees, these drugs also improve symptoms, quality of life, and exercise tolerance. The Towards a Revolution in COPD Health (TORCH) trial14 was designed to evaluate a possible survival benefit associated with the use of the combination of the LABA salmeterol and the ICS fluticasone propionate in comparison with placebo. The survival benefit fell short of the predetermined requirement for statistical significance. An independent secondary analysis of the data from the TORCH trial discovered a survival benefit associated with salmeterol that
Mayo Clin Proc. n February 2014;89(2):139-141 n http://dx.doi.org/10.1016/j.mayocp.2013.12.009 www.mayoclinicproceedings.org n ª 2014 Mayo Foundation for Medical Education and Research
See also page 154
139
MAYO CLINIC PROCEEDINGS
was statistically significant, alone and in combination with fluticasone, in comparison with placebo or fluticasone alone.18 The TORCH trial reported, for the first time, an increased risk of pneumonia associated with the use of the ICS compared with the placebo group. Since completion of the TORCH trial, other studies and subsequent meta-analyses have reported a 50% to 70% increase in risk of pneumonia associated with the use of ICSs in COPD.19-21 This conclusion was validated in a recent large cohort-based study.22 The risk has been mostly associated with fluticasone propionate and not budesonide or ciclesonide, and mostly with high doses of fluticasone propionate. Despite these many observations, lingering questions remain. Is this association between ICS use and pneumonia real or an epiphenomenon (ie, are patients who have more severe COPD and use ICSs more frequently more likely to experience pneumonia simply because of their baseline COPD)? Associations between medications and adverse events in observational cohorts may be confounded by indication: patients who use cardioactive medications die of cardiovascular disease more frequently, usually not because of adverse effects of medications but more often because of underlying disease. In the study by Suissa et al,22 for example, users of ICSs to treat COPD had greater than twice as many hospitalizations in the prior year and more than twice as many prescription respiratory medications, as compared with the non-ICS group. If there is indeed a propensity for ICSs to increase the rate of pneumonia in patients with COPD, what is the magnitude of the ICS effect? And how does it compare to the potential benefits of therapy? Pneumonia can be difficult to diagnose with certainty, particularly in patients with underlying lung disease and chronic symptoms. Adverse event reporting in clinical trials is generally not adjudicated, and studies rarely include critical review of either clinical or radiographic evidence in support of the diagnosis. Most studies are unable to distinguish community-acquired pneumonia from hospitalassociated pneumonia. The increased incidence of pneumonia has not been documented to affect overall mortality in most studies of patients with COPD, despite it being a highly morbid and frequently fatal illness.14,19-21 140
Mayo Clin Proc.
n
Festic et al2 used a novel approach to evaluate the possibility that ICS use predisposes patients with COPD to pneumonia. Using an established database from a lung injury study,23 they performed a secondary analysis of patients admitted to the hospital with at least one risk factor for acute respiratory distress syndrome. The cohort included 5584 patients, of which 1234 (22.1%) had pneumonia, 589 (10.6%) had a diagnosis of COPD, and 495 (8.9%) were using ICSs before admission. Unlike other studies, they had extensive documentation of clinical presentation and analyzed only pneumonias present at admission. All cases were documented by chest radiographs to show a new or progressive infiltrate, consolidation, cavitation, or pleural effusion and had new-onset purulent sputum or a change in sputum character. They did not have information on the type of ICS prescribed or dose. The unadjusted univariate odds ratio for pneumonia among users of ICSs was 3.28 (95% CI, 2.713.96; P
