Year : 2019 | Volume
: 4 | Issue : 1 | Page : 1--3
Inhaled corticosteroids in chronic obstructive pulmonary disease: Moving toward precision medicine
Ashutosh Nath Aggarwal
Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
Dr. Ashutosh Nath Aggarwal
Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh
|How to cite this article:|
Aggarwal AN. Inhaled corticosteroids in chronic obstructive pulmonary disease: Moving toward precision medicine.Int J Non-Commun Dis 2019;4:1-3
|How to cite this URL:|
Aggarwal AN. Inhaled corticosteroids in chronic obstructive pulmonary disease: Moving toward precision medicine. Int J Non-Commun Dis [serial online] 2019 [cited 2019 Jun 18 ];4:1-3
Available from: http://www.ijncd.org/text.asp?2019/4/1/1/254487
Inhaled corticosteroids (ICS) are the mainstay of maintenance pharmacotherapy in asthma, either alone or in combination with inhaled long-acting beta-agonists (LABAs). ICS are quite effective in controlling the eosinophilic inflammation so characteristic of this disorder. This is not the case with chronic obstructive pulmonary disease (COPD), which is mostly characterized by neutrophilic airway inflammation. Bronchodilators such as inhaled long-acting anti-muscarinic agents (LAMA) and/or LABA remain the preferred mode of COPD treatment. The place of ICS in the management algorithm of COPD has remained a debatable issue. As fresh evidence emerged with respect to the utility and adverse effects of ICS in COPD in the last few years, the position of international experts has witnessed rapid and frequent shifts while framing management guidelines.
Till a few years ago, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines recommended ICS + LABA combination as an initial therapeutic option for managing patients with C or D category of disease (i.e., patients with forced expiratory volume in the first second [FEV1] below 50% predicted, or those with two or more exacerbations, or at least one exacerbation requiring hospitalization, in the past year, irrespective of symptom severity). The Indian guidelines on COPD diagnosis and management also proposed a similar recommendation. Both these guidelines were based on the evidence available till that time. In particular, the large TORCH study had shown that a combination of inhaled fluticasone plus salmeterol (ICS + LABA) given to patients with severe COPD (mean FEV1 44% of predicted) was better than either drug alone in reducing annual exacerbation rate and improving lung function and health status. The INSPIRE study comparing the same combination against tiotropium (a LAMA) yielded similar results. The efficacy of ICS + LABA combination in reducing future exacerbations has been noted in several subsequent studies. The only flipside noted in some of these large studies was an increased risk of pneumonia among COPD patients receiving ICS. A Cochrane meta-analysis has also confirmed the unfavorable association between ICS use and pneumonia, without any impact on pneumonia-related mortality. Overall, the benefit in terms of reduction in exacerbations seemed to outweigh the risk of pneumonia.
In 2017, the GOLD inexplicably shifted its stand and removed ICS + LABA as a primary therapeutic option for GOLD category C and D patients, citing lack of evidence of benefit and an increase in pneumonia risk. LABA + LAMA combinations, for which quality evidence of benefit had just started to trickle in, were proposed as the primary therapeutic option for most patients with frequent exacerbations. The most recent edition of the GOLD guidelines has discarded the “one-size-fits-all” approach and instead shifted to more personalized therapy. LAMA alone is now recommended as the initial therapy for minimally symptomatic patients with high risk of exacerbations (GOLD category C). For more symptomatic patients with high risk of exacerbations (GOLD category D), the initial therapy may be decided based on the COPD phenotype. In general, LAMA alone is the initial therapy of choice for most patients, and it may be combined with LABA for very highly symptomatic patients. If patients show blood eosinophilia (≥300/μL), then ICS + LABA can be offered as the primary choice. Further modulation of inhaled therapy has now been delinked from the baseline GOLD category, and is now recommended across two verticals – dyspnea and exacerbation. ICS are not recommended if patients only have persistent symptoms but infrequent exacerbations. For those with exacerbations, ICS are only recommended as an add-on therapy if blood eosinophils exceed 300/μL (or 100/μL with two or more exacerbations or a single exacerbation requiring hospitalization). The recently updated National Institute for Health and Care Excellence guidelines on COPD largely follow a similar strategy and recommend ICS + LABA only for patients with previous diagnosis of asthma or atopy, eosinophilia, substantial variation in FEV1 over time, or diurnal variation in peak expiratory flow.
The message from these recent guidelines is that only a specific subset of COPD patients require an ICS prescription, and that one must try and identify these ICS responders up front. The evidence for individualizing such treatment has only recently emerged. A retrospective cohort study on elderly Canadian COPD patients reported that ICS + LABA use improved the composite outcome of death or hospitalization for COPD only in those patients who carried a previous diagnosis of asthma. Two major retrospective reviews of randomized trials on ICS + LABA use in COPD have also confirmed that ICS + LABA use was related to a significant reduction in exacerbations only in patients having eosinophilia, as compared to either LABA or LAMA alone., The WISDOM study, which evaluated patients with severe COPD taking ICS + LABA + LAMA therapy, also reported that slow taper of ICS over a 12-week period did not worsen the hazards of moderate-to-severe or severe exacerbation. A post hoc analysis of this trial found that the moderate or severe exacerbation rate after ICS withdrawal was higher in patients with higher eosinophil counts. Patients with sputum eosinophilia also had higher hazards for experiencing COPD exacerbation on ICS withdrawal in another study, indicating that these patients required maintenance ICS therapy. A meta-analysis and meta-regression of studies comparing ICS + LABA + LAMA against LABA + LAMA therapy also found that blood eosinophil count was a significant effect modifier in preventing the risk of moderate or severe exacerbation.
The public health issues arising from these recommendations for personalized ICS therapy are considerable. For one, the existing health programs that rely on ICS + LABA therapy up front to all severe COPD patients, based on a clearly favorable risk–benefit ratio, may need to substantially shift their treatment protocols. Most once-a-day LABA + LAMA combinations currently being promoted are rather expensive and will pose a huge financial burden. Facilities for performing blood and sputum eosinophil counts are not widely available at the primary health-care level. Moreover, there is sparse information on the range of normal blood eosinophil counts in most tropical countries. Owing to a relatively high burden of parasitic infestations in several areas, a higher blood eosinophil count may only be a nonspecific phenomenon, rather than a biomarker of eosinophilic inflammation in COPD. Despite these challenges, it is clear that we are moving toward an era of precision medicine for managing COPD. More evidence, especially real-world data from the developing world, is required before these recommendations can be implemented through national noncommunicable disease programs.
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