Role of inhaled glucocorticoid therapy in stable COPD

INTRODUCTION — Chronic obstructive pulmonary disease (COPD) is an inflammatory disorder that is characterized by both airway and systemic inflammation [1]. Inhaled glucocorticoid (also called inhaled corticosteroid or ICS) therapy appears to reduce this inflammation [2-6]. Thus, it has been hypothesized that ICS therapy may also improve clinical outcomes.

Clinical evidence that ICS therapy is beneficial to most patients with COPD is limited. Despite this, 40 to 50 percent of patients with COPD receive ICS therapy [7,8]. Among the reasons for widespread use of ICS therapy are the recognition that COPD can have an asthmatic component and trials demonstrating the benefit of ICS in addition to dual bronchodilator therapy in patients with moderate to severe COPD and frequent exacerbations [9,10]. However, inappropriate use of ICS as part of initial therapy is also common [11].

In this topic review, the clinical efficacy of and approach to ICS therapy in patients with COPD are discussed. The adverse effects of inhaled glucocorticoids are discussed in more detail separately. The pharmacologic management of stable COPD and the role of systemic glucocorticoids in COPD exacerbations are also presented separately.

●(See "Major side effects of inhaled glucocorticoids".)

●(See "Stable COPD: Initial pharmacologic management".)

●(See "Stable COPD: Follow-up pharmacologic management".)

●(See "COPD exacerbations: Management".)

CLINICAL EFFICACY — Many studies have examined the impact of inhaled glucocorticoids (ICS) on lung function, respiratory symptoms, exacerbations, mortality, lung cancer, and airway inflammation in patients with COPD. These studies have reported conflicting data for several different outcomes. However, taken together, the data suggest that ICS therapy has minimal impact on lung function, but decreases exacerbations, modestly slows the progression of respiratory symptoms, and may marginally improve COPD mortality.

Lung function — The impact of ICS therapy on disease progression, as measured by the annual rate of decline of forced expiratory volume in one second (FEV₁), has been examined in several randomized trials and three meta-analyses [12-19]. The largest randomized trial [20] and a meta-analysis found that ICS therapy slightly slowed the decline in lung function, whereas several other studies and a different meta-analysis found no beneficial effect on lung function. As examples:

●TORCH trial – The Toward a Revolution in COPD Health (TORCH) trial randomly assigned 6112 patients with moderate to severe COPD – mean FEV₁ was 44 percent of predicted – to one of four treatment arms for three years: salmeterol alone (50 mcg twice daily), fluticasone alone (500 mcg twice daily), combination therapy (salmeterol plus fluticasone), or placebo [16,20]. All active treatments slowed the lung function decline compared with placebo, including fluticasone (-55 versus -42 mL per year). The clinical importance of this small difference is unknown.

●In a meta-analysis of trials longer than two years that included the TORCH trial, the mean difference in the rate of decline in postbronchodilator FEV₁ between ICS and placebo was 7.3 mL/year (95% CI 3.2-11.4 mL/year, 12,502 participants) [19].

The reason for the conflicting data is uncertain but may be a function of different doses and formulations of inhaled glucocorticoids, length of study, or other confounding factors that influence studies over longer periods of time.

Symptoms — Respiratory symptoms were predetermined secondary outcomes in four out of the five randomized trials and one of the meta-analyses [12,14-16,19]. Most demonstrated that ICS therapy slowed the progression of respiratory symptoms modestly [14-16], although one trial found that ICS therapy had no impact on respiratory symptoms [12]. ICS slowed the rate of decline in quality of life compared with placebo, as measured by a standard respiratory disease questionnaire, although the mean difference was not clinically meaningful [19].

Exacerbations — Glucocorticoid-responsive inflammatory factors appear to play an important role in the initiation and severity of exacerbations of COPD. Thus, it has been hypothesized that ICS therapy may prevent or reduce the severity of COPD exacerbations. Many studies support this theory [9,10,14-16,19,21-25], as illustrated by the following:

●A systematic review and meta-analysis demonstrated that ICS therapy decreased the relative risk of exacerbations compared with placebo (rate ratio 0.88; 95% CI, 0.82-0.94, 10,097 participants); most patients were on background single-agent bronchodilator therapy [19]. Three other meta-analyses reported similar results [21,23,25].

●The TORCH trial (n = 6112) described above demonstrated that ICS therapy decreased the rate of moderate or severe exacerbations (rate ratio [RR] 0.82; 95% CI, 0.76-0.89) and the rate of exacerbations requiring systemic glucocorticoids (RR 0.65; 95% CI, 0.58-0.73) compared with placebo [16]. However, it did not reduce the rate of severe exacerbations that required hospitalization and its statistical methods have been criticized [26].

●The IMPACT, ETHOS, and TRIBUTE trials each compared a single, once-daily inhaler containing inhaled glucocorticoids, a long-acting beta-agonist (LABA), and a long-acting muscarinic antagonist (LAMA) with a combined LABA-LAMA inhaler and other therapies. The annualized rate of moderate to severe exacerbations in the ICS-LAMA-LABA group was lower than with LAMA-LABA alone in each of the three trials (with an absolute improvement ranging from approximately 0.1 to 0.3 per year, RR approximately 0.80). In IMPACT, hospitalizations due to exacerbations were also less frequent (0.13 versus 0.19 per year, RR 0.66). (See "Stable COPD: Follow-up pharmacologic management", section on 'Exacerbations on LAMA-LABA therapy'.)

Post-hoc analyses of these and other trials reveal some evidence that the benefits of inhaled glucocorticoids accrue to patients with higher rather than lower markers of eosinophilic inflammation.

●In one post-hoc analysis of three trials of budesonide-formoterol versus formoterol alone (n = 4528), the presence of eosinophils was associated with decreased exacerbations in the budesonide-formoterol group [27]. Patients with eosinophils >100 cells/microL experienced a 25 percent relative risk reduction compared with patients with fewer than 100 eosinophils/microL; the risk reduction was 50 percent for those with eosinophils >340 cells/microL. Similar results were seen with beclomethasone in the FORWARD study [28].

●Blood eosinophil count appeared similarly important in inhaled glucocorticoid efficacy in post-hoc analyses of trials assessing inhaled ICS-LAMA-LABA combined inhaler therapy [29-32]. For example, in IMPACT, the relative rate reduction in moderate to severe exacerbations with ICS-LAMA-LABA compared with LABA-LAMA alone was 0.88 in patients with a blood eosinophil count <90 cells/microL compared with 0.56 in patients with a blood eosinophil count >310 cells/microL [31]. Improvements in lung function by FEV₁ were similarly eosinophil-dependent in other large trials of triple inhaler therapy (KRONOS and ETHOS) [30,32].

Despite the benefits of inhaled glucocorticoids for patients with moderate to severe COPD, there is also evidence that withdrawal of inhaled glucocorticoids is reasonable in many patients. In the Withdrawal of Inhaled Steroids During Optimized bronchodilator Management (WISDOM) trial, 2485 patients with moderate or severe COPD were treated with triple therapy (tiotropium, salmeterol, and fluticasone, 500 mcg twice daily) for six weeks and then randomly assigned to withdraw fluticasone over 12 weeks or continue triple therapy with ongoing follow-up for 12 months [33]. Comparing withdrawal of ICS with continuation, the hazard ratio (HR) of a first moderate or severe exacerbation of COPD was 1.06 (95% CI 0.94-1.19). Withdrawal was also associated with a small decrement (mean 38 mL at 18 weeks) in FEV₁. Similarly, in the DACCORD observational study, clinicians successfully identified 292 patients as good candidates for a switch from LAMA/LABA/ICS to LAMA/LABA [34]. Compared with 675 patients who remained on LAMA/LABA/ICS therapy, fewer patients who switched had exacerbations or worsening in COPD symptoms (33 versus 56 percent).

Patients most likely to benefit from inhaled glucocorticoids are those with exacerbations refractory to other inhaled therapies or elevated eosinophil levels; however, a broader subset of patients with COPD are often inappropriately prescribed these agents. The WISDOM trial, along with the availability of newer inhaled bronchodilator treatment options, supports withdrawal of inhaled glucocorticoids in selected COPD patients while monitoring for clinical worsening. (See "Stable COPD: Follow-up pharmacologic management", section on 'Pharmacologic adjustment based on assessment'.)

Mortality — ICS therapy likely has a modest impact on COPD mortality, with some evidence that this is driven by a subset of patients with severe disease, frequent exacerbations, and increased eosinophilic inflammation. In a meta-analysis of 60 randomized trials including over 100,000 patients, inhaled glucocorticoids resulted in a small mortality benefit compared with nonglucocorticoid-containing regimens (odds ratio [OR] 0.90, 95% CI 0.84-0.97) [35]. Certain subgroups experienced a greater benefit, including patients with blood eosinophil counts >200 cells/microL (OR 0.58) or >2 percent on the differential (OR 0.61) and patients with two or more moderate to severe exacerbations (OR 0.63).

As one example of a trial that contributed to this analysis, the IMPACT trial compared ICS-LAMA-LABA therapy (fluticasone furoate-umeclidinium-vilanterol) with a once-daily LAMA-LABA inhaler (umeclidinium-vilanterol) or a once-daily glucocorticoid-LABA inhaler (fluticasone furoate-vilanterol) in 10,355 patients with COPD who were at increased risk of exacerbations due to a combination of disease severity and exacerbation history [9]. After nearly complete collection of records, there were deaths in 2.4 percent of patients in the triple therapy group, 2.6 percent of patients in the LABA-ICS group, and 3.2 percent of patients in the LABA-LAMA group [36]. The hazard ratio for triple therapy versus umeclidinium–vilanterol was 0.72 (95% CI, 0.53-0.99). Other large trials included in the meta-analysis, such as TORCH and ETHOS [10,16], showed similar trends towards improved mortality with some ICS-combination therapies [9,10,36,37].

In addition to this evidence from randomized trials, one population-based cohort study compared 5594 new users of a combination ICS-LABA with 2129 new users of a LABA alone [38]. All users were age 66 years or older and met a case definition of COPD. New use of LABAs and ICS was associated with a slightly reduced risk of death compared with new use of LABAs alone (HR 0.92, 95% CI 0.87-0.97).

Lung cancer — Conflicting data have been presented about whether ICS protects against lung cancer in patients with COPD. While observational studies suggested a protective effect [39,40], a systematic review identified four randomized trials (10,200 participants with COPD) that found no significant effect on lung cancer risk [13,15,16,41,42]. Methodologic issues, such as dose, duration, and adherence to ICS treatment and low rates of lung cancer, limit the conclusions that can be made, but data do not support use of ICS to reduce lung cancer risk in COPD.

ADVERSE EFFECTS — Inhaled glucocorticoid therapy has a few well-described adverse effects in patients with chronic obstructive pulmonary disease (COPD). They include dysphonia, skin bruising, and oral candidiasis [13,15,43]. In general, these effects have not been severe enough to alter management but appear to increase at higher doses and with cumulative exposure. There is also accumulating data for an increased risk of lung infection in patients receiving ICS therapy [9,10]. Additional adverse effects, such as subcapsular cataracts, diminished bone density, and hypothalamic-pituitary-adrenal axis suppression, are suspected, but data are conflicting, or the occurrence is less common. A more detailed discussion of adverse effects associated with inhaled glucocorticoids is provided separately. (See "Major side effects of inhaled glucocorticoids".)

GENERAL APPROACH — Pharmacologic therapy for stable COPD is based on a stepwise approach in which inhaled bronchodilators (beta agonists and muscarinic antagonists) are given alone, in combination, or with the addition of inhaled glucocorticoids (ICS) (algorithm 1). The goals of this approach are to control symptoms, decrease exacerbations, and improve patient function and quality of life. ICS therapy is not recommended as monotherapy for patients with stable COPD, because inhaled bronchodilators have greater benefits with fewer adverse effects. COPD patients being considered for treatment with inhaled glucocorticoids will usually have moderate to severe airflow obstruction. (See "Stable COPD: Initial pharmacologic management" and "Stable COPD: Follow-up pharmacologic management".)

Nonpharmacologic therapies (eg, smoking cessation, pulmonary rehabilitation, vaccination, nutrition) should be initiated along with pharmacotherapy. (See "Stable COPD: Overview of management".)

Patient selection

●Addition of ICS based on symptoms and exacerbations – ICS therapy is indicated as an additional therapy for patients with COPD who have symptoms, repeated exacerbations, or severe exacerbations despite an optimal inhaled bronchodilator regimen, typically a long-acting muscarinic antagonist (LAMA) and a long-acting beta-agonist (LABA). This is based on the observation that for patients with moderate to very severe COPD, triple therapy (LAMA-LABA-ICS) decreases exacerbations compared with dual therapy without an ICS [9,10].

●Addition of ICS based on blood eosinophils – For patients using a single bronchodilator who have one COPD exacerbation a year and a blood eosinophil count ≥300 cells/microL, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy suggests consideration of LAMA-LABA-ICS combination as an alternative to a LAMA-LABA combination (algorithm 1) [44]. Conversely, lower levels of blood eosinophils (eg, <100 cells/microL) predict a low likelihood of response to ICS. For patients with frequent exacerbations of COPD despite combined LAMA-LABA and blood eosinophils ≥100 cells/microL, the GOLD strategy recommends changing to triple therapy with LAMA-LABA-ICS, which is associated with a reduced rate of exacerbations (table 1). Patients with frequent exacerbations despite LAMA-LABA therapy and eosinophils <100 cells/microL may benefit from alternative therapies, typically roflumilast or azithromycin. The studies in support of this approach are described separately. (See "Stable COPD: Initial pharmacologic management", section on 'Group E patients presenting with elevated eosinophil counts or hospitalization' and "Stable COPD: Follow-up pharmacologic management", section on 'Blood eosinophils, inhaled corticosteroids, and exacerbations' and "Stable COPD: Follow-up pharmacologic management", section on 'Exacerbations on LAMA-LABA therapy'.)

●Asthma and COPD overlap – An inhaled glucocorticoid may be warranted earlier (ie, at the same time that the long-acting inhaled bronchodilator is initiated) if there are signs of an asthmatic component to the COPD. (See "Asthma and COPD overlap (ACO)".)

Dose — The optimal formulation, dose, and schedule of ICS for COPD are unknown. Several of the large clinical trials evaluating the impact of ICS in patients with COPD have used relatively high doses of ICS, including budesonide at 400 mcg twice daily or fluticasone at 500 mcg twice daily [13,14,16]. Although small clinical benefits were achieved at these doses, adverse systemic effects were also detected (eg, cataracts, possible pneumonia) [16,45]. Subsequent trials, such as ETHOS and IMPACT, demonstrated benefit when a moderate ICS dose (eg, budesonide 160 mcg and 320 mcg twice daily; fluticasone furoate 100 mcg once daily) was added to dual bronchodilator therapy [9,10]. In our practice, we use moderate doses of ICS unless the patient has asthma and COPD overlap or, conversely, risk factors for adverse effects; we increase the dose of ICS if needed in patients who continue to have exacerbations.

Systemic glucocorticoid response not predictive of ICS response — It has been hypothesized that patients with COPD who respond favorably to a course of systemic glucocorticoids are more likely to benefit from ICS therapy. There is little evidence to support this theory; thus, selection of patients based on their response to a trial of systemic glucocorticoid therapy is not recommended.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic obstructive pulmonary disease".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Inhaled corticosteroid medicines (The Basics)")

●Beyond the Basics topics (see "Patient education: Chronic obstructive pulmonary disease (COPD) (Beyond the Basics)" and "Patient education: Chronic obstructive pulmonary disease (COPD) treatments (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Role of inhaled glucocorticoids in COPD – In patients with chronic obstructive pulmonary disease (COPD), inhaled glucocorticoids (also known as inhaled corticosteroids or ICS) have minimal impact on lung function, but decrease exacerbations, modestly slow the progression of respiratory symptoms, and may mildly improve COPD mortality. (See 'Clinical efficacy' above.)

●Adverse effects of inhaled glucocorticoids – Adverse effects of ICS therapy include dysphonia, skin bruising, and oral candidiasis. These adverse effects appear to be more common at higher doses. In addition, ICS therapy may increase the incidence of pneumonia, increase the incidence of cataracts, and diminish bone density. (See 'Adverse effects' above.)

●Inhaled glucocorticoids as a component of stepwise therapy – Pharmacologic therapy for stable COPD is based on a stepwise approach in which inhaled bronchodilators (beta agonists and muscarinic antagonists) are given alone, in combination, or with the addition of ICS (algorithm 1 and table 1). The goals of this approach are to control symptoms, decrease exacerbations, and improve patient function and quality of life. (See 'General approach' above and "Stable COPD: Initial pharmacologic management".)

●Potential indications for ICS – Patients who have persistent symptoms, repeated exacerbations, or severe exacerbations despite a dual long-acting inhaled bronchodilator regimen are good candidates for the addition of ICS therapy. (See 'Patient selection' above.)

●Use of peripheral eosinophils to guide ICS initiation – Analysis of multiple trials including ICS therapy in COPD suggest that efficacy shows good correlation to the degree of peripheral eosinophilia. For both initiation and follow-up therapy, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy suggests peripheral eosinophil thresholds of ≥300 cells/microL and <100 cells/microL to delineate patients likely to benefit and unlikely to benefit, respectively, from the addition of ICS to dual bronchodilator (LAMA-LABA) therapy (algorithm 1 and table 1). (See 'Patient selection' above and "Stable COPD: Follow-up pharmacologic management", section on 'Blood eosinophils, inhaled corticosteroids, and exacerbations'.)

●Asthma and COPD – Inhaled glucocorticoid therapy may be warranted earlier (ie, at the same time that the long-acting inhaled bronchodilator is initiated) if there are signs of an asthmatic component to the COPD. (See 'General approach' above and "Asthma and COPD overlap (ACO)".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Marcia Erbland, MD, who contributed to earlier versions of this topic review.