Introduction

Inhaled corticosteroids (ICS) have long been the mainstay of asthma treatment, improving symptom control and reducing the risk of serious exacerbations1. In contrast, there is much debate about the role of ICS relative to long-acting inhaled bronchodilators, i.e. long-acting muscarinic antagonists (LAMAs) and long-acting β2-agonists (LABAs), which in combination represent the mainstay of treatment for chronic obstructive pulmonary disease (COPD)2,3,4.

Although ICS are effective in some patients with COPD, they are less effective in many others. The major clinical benefit of ICS in COPD is a ~25% reduction in exacerbations in frequent or severe exacerbators, with no significant benefits in terms of lung function or mortality5,6. ICS-containing regimens are associated with a higher risk of pneumonia vs. single or dual long-acting bronchodilator therapy, as well as a higher risk of oropharyngeal candidiasis, mycobacterial infections and upper respiratory tract infections7,8. There is also evidence to suggest that long-term ICS use is associated with systemic adverse effects such as reduced bone mineral density (osteopenia), osteoporosis, fractures, diabetes, skin thinning and bruising, as well as ocular adverse effects such as cataract formation and glaucoma8,9,10,11.

Since 2007, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy report has shifted its pharmacotherapy focus from a spirometry-based approach relying on the assessment of forced expiratory volume in 1 s (FEV1; GOLD stages 1–4, GOLD 2007) to an exacerbation and symptom-based algorithm (GOLD grades A–D, GOLD 2011 to 2022; GOLD grades A/B/E, GOLD 2023) (Fig. 1)4,12,13. These changes occurred concurrently with an evolving understanding of the relatively narrow, phenotype-specific benefits of ICS use in COPD14,15. Hence, the 2023 GOLD strategy report includes a practical recommendation for initial treatment with ICS (as LAMA/LABA/ICS; triple therapy) in patients with frequent or severe exacerbations (≥2 moderate exacerbations per year, or ≥1 exacerbation requiring hospitalisation) and a blood eosinophil count ≥300 cells/μl4. In patients with blood eosinophils ≥100 cells/μl who continue to have exacerbations despite LAMA/LABA therapy, treatment can be escalated to triple therapy, after careful consideration of the expected benefits vs. risks. While the use of LABA/ICS is no longer encouraged in COPD4, if patients with COPD have concomitant asthma, the use of ICS is mandatory4.

Fig. 1: GOLD 2023.
figure 1

Initial pharmacological treatment. *Single inhaler therapy may be more convenient and effective than multiple inhalers. Groups C and D from GOLD 2011–2022 have been replaced by Group E in GOLD 20234. CAT COPD Assessment Test, Eos eosinophils, GOLD Global Initiative for Chronic Obstructive Lung Disease, ICS inhaled corticosteroids, LABA long-acting β2-agonist, LAMA long-acting muscarinic antagonist, mMRC modified Medical Research Council. © 2022, 2023, Global Initiative for Chronic Obstructive Lung Disease, available from www.goldcopd.org, published in Deer Park, IL, USA.

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Although the proportion of frequent exacerbators in the COPD population is generally less than 30%, and the proportion of eosinophilic exacerbators even lower (~10%)16,17,18,19,20,21,22,23, observational studies show that ICS-containing pharmacotherapy is prescribed in around 50–80% of patients with COPD20,22,24,25,26,27. Possible factors contributing to the overuse of ICS in COPD are suggested in Table 1. Over-prescription of ICS is illustrated by findings from an analysis of 1528 patients with COPD in Europe, in which only 10.6% of patients were found to have a blood eosinophil count of ≥300 cells/μl and a history of ≥2 moderate/≥1 severe exacerbations in the previous 12 months22. Despite GOLD recommendations indicating that ICS use should be limited to this subset of patients4, as many as 41.5% of GOLD B patients and 68.0% of GOLD D patients were receiving ICS in this study22. ICS overuse is also highlighted by observational data from the COPDGene (n = 1553) and ECLIPSE (n = 1895) studies, in which ICS were used by as many as 48% and 71% of patients with eosinophils <300 cells/μl, respectively20. In addition, many studies have shown that more patients receive ICS-containing therapies at initiation of first maintenance therapy than would be expected based on their exacerbation history20,22,24,25,26,27,28,29,30,31. The consequences of this are serious, as overtreatment with ICS is associated with a significant health-economic burden associated with the increased risk of adverse events such as pneumonia and higher treatment costs32.

Table 1 Possible factors contributing to ICS overuse in patients with COPD.
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In this article, we briefly summarise evidence for the effectiveness and safety of ICS in COPD, gleaned from both randomised controlled trials (RCTs) and observational studies. We comment on patient characteristics guiding recommended use and the factors contributing to the ongoing overuse of ICS in COPD. We also include strategies for safe ICS withdrawal. Lastly, we provide a practical guide to appropriate ICS prescribing, to help primary care providers identify those patients for whom the benefits of ICS are likely to outweigh the risks. In doing so, we hope to enable and encourage evidence-based use of ICS in COPD.

ICS use in asthma versus COPD

ICS are absorbed systemically from the peripheral lung and exert their immunosuppressant effects locally in the upper and lower airways, as well as potentially inducing systemic immunosuppressant effects. In most patients with asthma, low doses of ICS are highly effective in reducing chronic eosinophilic inflammation of the airways33. However, the lung inflammation characteristic of COPD is predominantly neutrophilic34. This difference in inflammatory endotype accounts for corticosteroid resistance in the majority of patients with COPD, with no effect on inflammation, disease progression or mortality, and only a small improvement in spirometry/reduction in exacerbations33,35,36. Only a minority of patients with COPD have an eosinophilic phenotype37,38,39,40,41 and can therefore be considered corticosteroid sensitive, as reflected in COPD treatment guidelines.

Although the term “asthma-COPD overlap” is no longer in widespread use, patients with COPD can have concomitant asthma. Prevalence estimates vary, and some evidence suggests that asthma is over-diagnosed in patients with COPD42. However, in cases where COPD and asthma are confirmed to coexist, pharmacotherapy should predominantly follow asthma guidelines (i.e. prescription of ICS)4,42.

Key points

  • ICS are very effective in treating asthma, even at low doses, due to their effects on eosinophilic inflammation.

  • In most patients with COPD, airway inflammation is not eosinophilic, and even high doses of ICS have poor efficacy.

  • ICS use should be limited to patients with eosinophilic COPD and those with concomitant asthma.

Randomised controlled trials of ICS in COPD

ICS monotherapy vs. placebo

Although ICS use has been studied more extensively in asthma, many RCTs have evaluated the efficacy and safety of ICS in COPD (Table 2)7. A Cochrane review of treatment with ICS alone (55 primary studies, including >16,000 patients) found that ICS did not modify the long-term decline of FEV1 or mortality in patients with COPD43. This review noted a relatively small but statistically significant reduction in the mean exacerbation rate with ICS. However, the rate of pneumonia increased by >50% in the ICS group. Furthermore, in the TORCH trial, a trend toward higher mortality was observed for patients treated with ICS (fluticasone propionate) alone44. Consequently, the GOLD 2011 report recommended against using ICS monotherapy in COPD45.

Table 2 Strengths and limitations of selected RCTs of ICS in patients with COPD.
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LABA/ICS vs. placebo

From 2000 onwards, many landmark trials have evaluated the efficacy of ICS in combination and comparison with long-acting bronchodilators7. In 2007, TORCH demonstrated a significant reduction in exacerbations and improvement in health status and lung function with LABA/ICS vs. placebo in patients with COPD—a finding that was replicated for exacerbations and lung function in the SUMMIT trial in 201644,46. However, both of these large-scale trials failed to achieve their primary objective: a statistically significant, ICS-related reduction in mortality. Moreover, a post hoc factorial analysis of the TORCH trial showed a survival benefit associated with the LABA, but not the ICS, component (Table 2)47. Like many COPD studies, both trials were confounded by ICS withdrawal prior to randomisation and incomplete post-discontinuation follow-up for all their secondary end points, including exacerbations47,48.

LABA/ICS vs. LAMA/LABA/ICS

The Canadian OPTIMAL trial, an independent, non-industry-sponsored trial, notable for its complete exacerbation follow-up, investigated the efficacy of adding LABA/ICS to LAMA in patients with moderate-to-severe COPD, and demonstrated a reduction in exacerbations that did not reach statistical significance49. A post hoc analysis of OPTIMAL demonstrated that the apparent decrease in exacerbations was limited to pre-study ICS users and thus largely attributable to ICS discontinuation on randomisation47.

LABA/ICS vs. LAMA/LABA

In 2016, the FLAME study highlighted the benefits of LAMA/LABA, finding a reduced annual rate of moderate or severe exacerbations and lower incidence of pneumonia vs. LABA/ICS50. However, the superiority of LAMA/LABA over LABA/ICS demonstrated in FLAME was probably exaggerated by its inclusion criteria and 4-week run-in with LAMA and withdrawal of ICS, which is likely to have preserved more LAMA responders relative to ICS responders (Table 2)51.

LAMA/LABA/ICS vs. LAMA/LABA

Following the shift towards more LAMA/LABA use instead of LABA/ICS between 2013 and 2018, the last 5 years have seen a resurgence in ICS use after the approval of triple-therapy inhalers based on the results of pivotal studies such as TRIBUTE, IMPACT, KRONOS and ETHOS5,6,52,53. IMPACT and ETHOS have reported the benefits of using LAMA/LABA/ICS vs. LAMA/LABA in patients with COPD and a high exacerbation risk in terms of reducing exacerbations and mortality, albeit with a higher incidence of pneumonia with triple therapy5,6. However, various publications have commented extensively on methodological issues with the design and analysis of these studies in terms of the populations studied, the confounding effect of ICS withdrawal prior to randomisation, and the inclusion of patients with a history of asthma (Table 3)54,55,56,57,58. While all three trials are confounded by ICS withdrawal on randomisation, this effect is further magnified in IMPACT and ETHOS (vs. TRIBUTE) by the selective inclusion of frequent exacerbators with non-severe airflow limitation (FEV1 > 50%, GOLD 2D), thereby selecting an unusual asthma-like, “ICS-sensitive” study population compared with the general COPD population59. Additionally, in both KRONOS and ETHOS, the trial design included a 1–4-week screening period in which withdrawal of all long-acting bronchodilators induced a very large pre-randomisation dropout rate (38% and 46%, respectively), thus favouring the selective inclusion of “ICS-sensitive” subjects6,53. Thus, for IMPACT and ETHOS, the reported survival benefit in the ICS arms is largely attributable to the transient effect of ICS withdrawal on randomisation in a selected “ICS-sensitive” cohort56,60.

Table 3 Strengths and limitations of RCTs comparing LAMA/LABA with triple therapy.
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The confounding effect of ICS withdrawal is a recurrent limitation in the RCTs of triple therapy. In an optimally designed trial, patients on triple therapy at screening would be excluded outright, and other patients would be randomly allocated to specific treatment arms based on their current therapy54,55. However, in the absence of such trials, observational studies from routine clinical practice can provide valuable evidence by investigating the long-term effect of ICS in larger cohorts of “new users”, avoiding the effect of medication switching/withdrawal on randomisation and better representing the overall population of COPD patients.

Key points

  • The major clinical benefit of ICS in COPD is a ~25% reduction in exacerbations, observed in RCTs of patients with frequent or severe exacerbations.

  • Though some RCTs suggest that adding ICS to LAMA/LABA or LABA therapy increases survival in patients with COPD, methodological flaws in these trials have led regulatory authorities to dismiss claims of survival benefit associated with ICS.

  • The study design and populations involved in the pivotal studies of ICS in COPD were very specific and did not represent many patients with COPD, focusing a priori on a small subset of patients who stand to benefit the most from ICS treatment.

Observational and other studies of ICS in COPD

Patients with COPD in primary care may differ significantly from patients enrolled in large-scale RCTs in terms of characteristics such as gender, lung function, quality of life and exacerbations61. Observational studies may provide a more balanced picture as they generally represent a broader population of patients with COPD compared with the narrow subgroups of patients studied in clinical trials such as IMPACT and ETHOS. For example, in the DACCORD observational study, which evaluated LAMA/LABA/ICS (n = 1046) vs. LAMA/LABA (n = 1046) in patients initiating or changing their COPD maintenance therapy, LAMA/LABA was associated with a lower proportion of patients experiencing an exacerbation compared with LAMA/LABA/ICS (15.5% vs. 26.6%; p < 0.001). A greater improvement from baseline in COPD Assessment Test total score (mean ± standard deviation −2.9 ± 5.8 vs. −1.4 ± 5.5; p < 0.001) and a greater proportion of patients having a clinically relevant improvement (61.8% vs. 47.2%; p < 0.001) were also observed21.

Findings from other observational studies comparing LAMA/LABA with triple therapy or LABA/ICS in COPD are summarised in Fig. 2. Of these, only one study replicated the findings of IMPACT/ETHOS (see Voorham et al.62). However, similar to IMPACT and ETHOS, these patients had a history of ≥2 exacerbations in the preceding year62, which is not representative of the general COPD population. Conversely, studies conducted in broader, more representative populations, i.e. less frequent exacerbators and less severe COPD21,63,64,65,66,67,68, have not replicated the findings of IMPACT and ETHOS, showing a similar or lower risk of exacerbations, mortality and pneumonia in patients receiving non-ICS treatment (Fig. 2). In a post hoc pooled analysis including Phase III and IV trials with duration ≥12 months in the tiotropium/olodaterol clinical programme (in which ICS continuation was permitted), no difference in mortality was found between LAMA/LABA and LAMA/LABA/ICS over 52 weeks69. The population of patients with mild-to-very-severe COPD was predominantly of lower exacerbation risk than either IMPACT or ETHOS, excluded patients with a history of asthma and did not include ICS withdrawal69.

Fig. 2: Real-world studies comparing LAMA/LABA with triple therapy or LABA/ICS in patients with COPD*.
figure 2

*Data from Voorham et al.62, Suissa et al.64,65,68, Cabrera et al.66 and Ashdown et al.86 transformed for consistent presentation (favours non-ICS-containing therapy on left; favours ICS-containing therapy on right). †HRs are for time to first event after treatment initiation. Suissa et al.63, patients aged >55 years initiating LAMA/LABA or LABA/ICS; Voorham et al.62, patients aged >40 years with a history of smoking and no maintenance/LAMA therapy and ≥2 exacerbations in the previous year; Suissa et al.64, patients aged >55 years initiating LAMA/LABA/ICS or LAMA/LABA; Suissa et al.65, patients aged >50 years initiating LAMA/LABA/ICS or LAMA/LABA; Cabrera et al.66, patients initiating ICS vs. non-ICS-containing treatments; Quint et al.67, patients aged ≥40 years with ≥1 prescription of LAMA/LABA/ICS or LAMA/LABA; Suissa et al.68, patients aged ≥40 years initiating treatment with single-inhaler LAMA/LABA/ICS, or LAMA/LABA. CI confidence interval, COPD chronic obstructive pulmonary disease, HR hazard ratio, ICS inhaled corticosteroids, LABA long-acting β2-agonist, LAMA long-acting muscarinic antagonist.

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Observational evidence also suggests that elevated blood eosinophil counts may predict COPD exacerbation risk in ex-smokers, but not current smokers70. However, there is a possibility of selection bias in such trials as it is not known what triggered blood testing in the first place. Reduced sensitivity to ICS in current vs. ex-smokers has also been shown in analyses of the SUMMIT, IMPACT and FLAME studies71,72,73, and in a pooled analysis of data from ILLUMINATE, LANTERN and FLAME74.

Key points

  • Data from observational studies, which are generally conducted in broader populations and are more representative of clinical practice, provide no evidence that the benefits of ICS observed in RCTs are generalisable to the COPD population as a whole.

  • Current smokers with COPD are likely to have a reduced sensitivity to ICS compared with ex-smokers.

Identifying ICS responders in COPD

Exacerbation frequency/phenotype

Global treatment guidelines for COPD state that patients with frequent or severe exacerbations (≥2 moderate exacerbations per year, or ≥1 exacerbation requiring hospitalisation) and a blood eosinophil count ≥300 cells/μl are more likely to benefit from the addition of ICS4. However, when identifying frequent exacerbators, it is not just the frequency of exacerbations that is important, but also the type of exacerbation. Not all exacerbations are the same and they have different underlying triggers, which unlike eosinophilic inflammation, are not steroid responsive. For example, 50–70% of exacerbations are attributed to respiratory infections, 10% to environmental pollution and up to 30% are of unknown aetiology75. Notably, hospital admissions for COPD exacerbations nearly halved during the COVID-19 pandemic, likely due to a reduction in respiratory viral infections triggering exacerbations76. Comorbidities such as heart failure or gastroesophageal reflux may also be drivers of exacerbations, as well as mental health conditions such as anxiety and depression75,77,78.

Before considering use of ICS in frequent exacerbators, it is important to consider the phenotype and cause of the exacerbations in order to tailor treatment, rather than taking a “one-size-fits-all” approach to treatment73,79,80.

Eosinophil threshold

Analysis of several RCTs has shown an association between eosinophil count and ICS responsiveness in terms of preventing future exacerbations when used in combination with long-acting bronchodilators in patients with COPD5,52,81,82,83,84. Some post hoc analyses of RCTs have suggested that the benefit of ICS begins at a blood eosinophil threshold of 100 cells/μl72,81. However, the ETHOS results bring into question this threshold as no treatment benefit of triple therapy vs. non-ICS dual therapy on the annual rate of moderate or severe exacerbations was observed in a subgroup analysis of patients with eosinophils <150 cells/μl (at either dose of budesonide)6. In the IMPACT study, the authors state that the benefits of triple therapy on the annual rate of moderate/severe exacerbations were seen regardless of eosinophil level, though they acknowledge a greater reduction in exacerbation rate in the ≥150 cells/μl subgroup5. In a post hoc analysis of data from IMPACT, triple therapy was associated with a lower exacerbation rate vs. LAMA/LABA in patients with eosinophils ≥100 cells/μl, but only in those with a history of frequent moderate or severe exacerbations. In patients with a history of a single moderate exacerbation, a lower exacerbation rate in the triple therapy arm was only observed at higher eosinophil levels (≥200 cells/μl)85.

Since findings on eosinophil thresholds can be affected by selection bias for certain patient populations (such as frequent exacerbators) in RCTs, as described earlier in this article, the threshold derived from observational studies may be more reliable. Several observational studies have shown that the optimal blood eosinophil count threshold for ICS response in terms of the ability to reduce exacerbations is considerably higher (300–450 cells/μl)86,87,88 than findings from RCTs (100–150 cells/μl)5,6,72,81. However, other analyses have not replicated these findings. In a systematic review of 11 RCTs and 5 observational studies, an overall association between blood eosinophil count and the effect of ICS in reducing exacerbation risk was found. However, this association was not observed in four of the five observational studies, suggesting that the predictive effect of eosinophils may not apply to the real-world COPD population89.

An observational study comparing initial COPD treatment with LABA/ICS or LAMA suggests that while the exacerbation benefit of initiating LABA/ICS is demonstrated only in patients with high blood eosinophil counts (>300 cells/μl), the increased pneumonia risk with LABA/ICS is observed at all eosinophil concentrations87. Based on this, the authors conclude that initial treatment with a LAMA should be preferred in patients with blood eosinophil concentrations ≤300 cells/μl due to its superior risk/benefit profile87. A blood eosinophil threshold of ≥300 cells/μl forms the basis of the guidance for initial treatment of COPD in the GOLD 2022 strategy report, aiming to identify exacerbating COPD patients that are likely to derive the greatest benefit from ICS4.

Key points

  • It is important to assess the number and type of exacerbations before prescribing ICS to patients with COPD (ICS reduce eosinophilic exacerbations but not infection-based exacerbations).

  • In patients with a history of frequent or severe exacerbations, global treatment guidelines recommend starting with dual bronchodilator therapy (LAMA/LABA).

  • Addition of ICS to LAMA/LABA is recommended for frequent/severe exacerbators with blood eosinophil levels ≥300 cells/µl (or ≥100 cells/µl if exacerbations are not well controlled by LAMA/LABA).

Increased risk of adverse events and cost implications associated with ICS therapy

Pneumonia

The higher risk of pneumonia in COPD patients treated with ICS is well documented and is acknowledged in the GOLD 2023 report4. In a systematic review of 19 RCTs by Miravitlles et al., exposure to ICS for ≥1 year increased the risk of pneumonia by 41% (risk ratio 1.41, 95% confidence interval 1.23–1.61)8. The risk varied according to the type of ICS used, with fluticasone propionate or furoate having the highest risk (10 studies: n = 45,870)8. Conversely, exposure to budesonide (six studies: n = 13,479) was not associated with an increased risk of pneumonia, although a high degree of heterogeneity was observed due to one large study that reported an increased risk8. These findings are in contrast to a European Medicines Agency Pharmacovigilance Risk Assessment Committee review of the known risk of pneumonia in patients with COPD receiving ICS, which reported no conclusive evidence of differences in the risk of pneumonia between different products90. However, in support of the Miravitlles systematic review, a large observational analysis of 39,362 new users of triple therapy (either fluticasone- or budesonide-based) showed a lower incidence of severe pneumonia in patients on budesonide-containing regimens compared with fluticasone91.

As shown by one US database study of 135,445 patients with COPD, the use of ICS in newly diagnosed patients was associated with a dose-related increase in the risk of pneumonia30. In an observational study of patients recruited from routine clinical practice in the UK (the Salford Lung Study), mortality after admission with pneumonia was higher than after admission with an exacerbation, suggesting that pneumonia may have a greater impact on survival than exacerbations92. Real-world data such as these are important in the interpretation of fatal pneumonia risk associated with ICS use in COPD, as data from randomised controlled trials are often confounded by the exclusion of patients at highest risk of pneumonia, e.g. those with low lung function, very low BMI or significant comorbidities30. However, it should also be acknowledged that definitions of pneumonia and acute exacerbations of COPD often overlap within electronic health records. As such, they may not always be as rigorously differentiated from each other as they should be, compared with clinical trials, in which an X-ray diagnosis of pneumonia is often a requirement.

Variations in the risk of pneumonia and other adverse events associated with ICS use in patients with COPD may possibly be explained by their effects on the composition of the lung microbiome93,94,95,96,97,98. Several studies have reported changes in airway microbiome composition following ICS treatment, including reductions in α-diversity, increases in sputum bacterial load/modification of sputum microbial composition and increased airway load of potentially pathogenic bacteria, e.g., increased risk of acquiring the respiratory pathogen Pseudomonas aeruginosa93,94,97,98. However, further studies are needed to clarify the effects of ICS on the lung microbiome. Most recently, ICS withdrawal in the INCOGNITO study was associated with potentially beneficial changes in microbiome composition and altered the exacerbation endotype, with a reduction in bacterial-associated exacerbations99,100. The increased risk of respiratory infections with ICS treatment may be linked with their immunosuppressive effects, including reductions in T-cell, macrophage and neutrophil function in the lung101,102.

Other adverse events

In addition to the increased risk of pneumonia, both cohort and nested case–control studies show an association between ICS use and the risk of tuberculosis and mycobacterial disease8. A strong association has also been reported between ICS use and local disorders such as oral candidiasis and dysphonia, although the association with diabetes and bone fractures is less clear and appears significant only at high doses of ICS8,9. Some studies have found a significantly increased risk of cataracts associated with cumulative ICS exposure but results from other studies did not find a significant association8. Of note, elderly patients with COPD have an increased risk of osteoporosis and cataracts11 and non-elderly patients with COPD have an increased risk of osteoporosis101,103,104. ICS also carries an increased risk of developing type 2 diabetes in patients with COPD, particularly at high doses105.

Cost implications

Triple therapy containing ICS may not be the most cost-effective approach, especially as first-line treatment and in patients with less severe COPD. Compared with dual therapy, triple therapy is associated with significant increases in hospitalisation rates and cost of care106. Inappropriate prescription of ICS is associated with poorer physical health status as well as higher costs of COPD management107. Several studies have shown that reducing inappropriate ICS use and increasing use of LAMA/LABA resulted in better outcomes, including a reduction in exacerbations and pneumonia cases, accompanied by lower total COPD costs108,109. As first-line treatment, LAMA/LABA is also associated with significantly lower pharmacy costs attributable to COPD or pneumonia vs. triple therapy and is more cost-effective than triple therapy in patients in GOLD groups A/B vs. GOLD groups C/D67.

Key points

  • ICS-containing therapies increase the risk of many unwanted side effects, in particular, pneumonia, in patients with COPD.

  • Because of this, it is important to consider the benefits vs. the risks of treatment when prescribing ICS.

  • Unnecessary use of ICS has cost implications for primary care providers.

  • We have included a practical guide to the appropriate prescription of ICS, to help identify patients for whom the benefits of ICS are likely to outweigh the risks (Fig. 3).

Fig. 3: Practical guide to prescribing ICS for the treatment of COPD.
figure 3

Adapted from the International Primary Care Respiratory Group (IPCRG) desktop helper for the appropriate use and withdrawal of ICS, 2020. Available at link. *This may include asthmatic features/features suggesting steroid responsiveness, including any previous, secure diagnosis of asthma or atopy, a higher blood eosinophil count, substantial variation in FEV1 over time (at least 400 ml) or substantial diurnal variation in peak expiratory flow (at least 20%). †Or since previous assessment if less than 12 months. ‡For patients with exacerbations despite triple therapy (LAMA/LABA/ICS), consider add-on therapy with roflumilast or macrolides. §If blood eosinophil count is 150–300 cells/μl, reduce ICS dose/switch to an ICS with a better safety profile. If blood eosinophil count is <150 cells/µl, and there is no/questionable asthma history or exacerbation in the previous 12 months, consider withdrawal as risks of ICS are likely to outweigh any benefit. COPD chronic obstructive pulmonary disease, FEV1 forced expiratory volume in 1 s, ICS inhaled corticosteroids, LABA long-acting β2-agonist, LAMA long-acting muscarinic antagonist.

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ICS withdrawal

In an effort to reverse the trend of over-prescribing, ICS withdrawal should be considered. For example, the European Respiratory Society (ERS) guidelines recommend ICS withdrawal in patients with COPD who do not have a history of frequent exacerbations (Fig. 4)110. Similarly, the American Thoracic Society conditionally recommends ICS withdrawal in patients with COPD receiving triple therapy if the patient has had no exacerbations in the past year111. The ERS guidelines strongly recommend that ICS should not be withdrawn in patients with blood eosinophil counts ≥300 cells/μl110. For patients with an eosinophil count <300 cells/μl, withdrawal is conditionally recommended, taking into account patient view and benefits vs. risks. The rationale for withdrawal is clearer at an eosinophil count <150 cells/μl, if there is no history of exacerbations and the patient is receiving no objective benefit from ICS110.

Fig. 4: Summary of the European Respiratory Society guidelines on withdrawal of ICS in COPD110.
figure 4

COPD chronic obstructive pulmonary disease, ICS inhaled corticosteroids. Reproduced with permission of the © ERS 2022. European Respiratory Journal 55 (6) 2000351; https://doi.org/10.1183/13993003.00351-2020 Published 4 June 2020.

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Studies have shown that ICS withdrawal does not have a detrimental effect in patients at a low risk of exacerbations when sufficient bronchodilation is in place27,112. For example, in an observational study of >85,000 patients with COPD who initiated LAMA/LABA/ICS therapy, there was a lower incidence of severe COPD exacerbations requiring hospitalisation in those who discontinued ICS treatment compared with those who continued; however, this was not the case in patients with a history of frequent exacerbations or asthma112. Other observational studies have reported similar findings. In a study of 48,157 patients with elevated blood eosinophil counts, there was no increased risk of moderate and/or severe COPD exacerbations or all-cause mortality among subjects that withdrew from ICS113. In a study of 11,093 patients with COPD that withdrew from ICS for ≥6 months, 69% of patients had no recorded exacerbation event and 89% had no hospitalisation for COPD during the withdrawal114. In a non-interventional study of ~1200 patients, in which physicians identified patients who could be “stepped down” from triple therapy to LAMA/LABA, no overall decline in COPD was observed and outcomes improved in some cases115. Although coding of ICS withdrawal and clinical outcomes may differ between observational studies, these findings suggest that ICS can be safely withdrawn in many patients who are currently prescribed triple therapy, leaving them on bronchodilator therapy.

Key points

  • Withdrawal of ICS should be considered in patients who do not fulfil guideline criteria for ICS use (Fig. 3).

  • If a patient’s eosinophils are low (<150 cells/µl), they have not exacerbated in the previous year, and there is no or questionable asthma history, then consider withdrawal, as risks of ICS are likely to outweigh any benefit.

  • When sufficient bronchodilation is in place, ICS withdrawal does not have a detrimental effect in patients at a low risk of exacerbations.

Conclusions: recommendations for ICS in the COPD treatment paradigm

ICS overuse continues despite the narrow, specific recommendations for ICS use in global COPD guidelines, and the introduction of single-inhaler triple therapy is associated with a resurgence of this concerning trend.

Recent RCTs of single-inhaler triple therapy have demonstrated significant exacerbation and survival benefits, but this is largely attributed to ICS withdrawal in frequent exacerbators, representing a minority of COPD patients. As a result, healthcare regulatory bodies have rejected claims of survival benefit associated with triple therapy116,117. Observational studies conducted in broader, more representative COPD populations have demonstrated that patients treated with LAMA/LABA have a similar or more often lower risk of exacerbations, mortality and pneumonia compared with patients treated with ICS64,65,66. In patients not fulfilling guideline criteria for ICS use, prescription of ICS puts them at unnecessary risk of pneumonia and other long-term adverse events, without any clear benefit in disease control. Inappropriate use of ICS also has cost implications for the management of COPD. ICS should therefore be reserved for the few, not the many, i.e. those with an eosinophilic, frequent/severe exacerbator phenotype. In patients not fulfilling guideline criteria, ICS should be withdrawn in line with global treatment guidelines.

Reporting summary

Further information on research design is available in the Nature Research Reporting Summary linked to this article.