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Editorial |

Toward Personalized Prescription of Systemic Steroids for Patients Hospitalized With COPD Exacerbations FREE TO VIEW

Pierre-Régis Burgel, MD, PhD
Author and Funding Information

FINANCIAL/NONFINANCIAL DISCLOSURES: The author has reported to CHEST the following: P.-R. B. reports personal fees from Astra-Zeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis, Pfizer, and Vertex for attending advisory boards and lecturing during the last 3 years. He was also the principal investigator of a clinical trial sponsored by Novartis and received an unrestricted research grant from Boehringer Ingelheim France.

Department of Respiratory Diseases, Cochin Hospital, Paris, France

CORRESPONDENCE TO: Pierre-Régis Burgel, MD, PhD, Department of Respiratory Diseases, Cochin Hospital, 27 rue du Faubourg St Jacques, 75014, Paris, France


Copyright 2016, American College of Chest Physicians. All Rights Reserved.


Chest. 2016;150(2):268-269. doi:10.1016/j.chest.2016.03.028
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Hospitalized exacerbations are important events in patients with COPD because they are responsible for high costs and have great impact on patient’s symptoms and prognosis. Review of high-quality randomized clinical trials in patients hospitalized for COPD exacerbations has established that systemic steroids significantly reduced treatment failure, were associated with earlier improvement in lung function and dyspnea, and shortened hospital stay. However, beneficial effects of systemic steroids came with high rates of adverse effects (including hyperglycemia), with one extra adverse effect occurring for every six people treated. These conclusions were based on studies that have used various protocols for steroid administration, including studies that used very high doses of steroids and administration of steroids for up to 8 weeks. Subsequent studies have suggested that low-dose steroids (30-40 mg/d) administered orally were not associated with worse outcomes than high-dose intravenous therapy and that a shorter duration (5 days) of oral prednisone was noninferior to 14-day treatment. This led to current recommendations of using low-dose short-term oral steroids in patients hospitalized for COPD exacerbations with the aim of limiting adverse events, which still occurred in approximately one to ten patients. Because results of clinical trials provide only limited information on the individual likelihood of benefiting from or being harmed by a therapy, a more personalized approach of steroid prescription in COPD exacerbation is urgently required, with the aim of limiting steroid prescription to patients who may show high benefits and low rates of adverse effects.

FOR RELATED ARTICLE SEE PAGE 320

In this issue of CHEST, Bafadhel et al examined the role of blood eosinophil counts (a surrogate marker for airway eosinophilia) as a possible marker for predicting the effect of treatment, including systemic steroids, in patients hospitalized for COPD exacerbations. The authors performed a post hoc analysis of data obtained in a previously performed two-center randomized clinical trial, which examined the effect of early rehabilitation intervention in patients with chronic respiratory disorders hospitalized for acute care. Based on data obtained in patients with a confirmed diagnosis of COPD exacerbation and differential full blood count taken within 12 h of admission, patients were stratified into eosinophilic vs noneosinophilic exacerbations using a cutoff value of ≥ 200 cells/μL and/or 2% blood eosinophils. During hospitalization, 90% of the patients received oral corticosteroids that were almost always administered with antibiotic therapy. The authors reported that 25% of subjects hospitalized for a COPD exacerbation had an eosinophilic exacerbation and that the length of hospital stay was shorter by 1.5 days in these patients, whereas long-term (12 months) follow-up showed no difference between the groups. The authors concluded that acute events requiring hospitalization associated with eosinophilic inflammation may show a rapid response to corticosteroid treatment, hence requiring a shorter length of hospital stay. As in any (good) study, there are limitations to the present analyses. Because almost all of the patients received oral steroids, it remains unclear whether the reduced length of stay was related to a better response to steroids or a better outcome (independent of steroid treatment) in patients with eosinophilic exacerbations. Further, the proposed 25% prevalence of eosinophilic exacerbations will need confirmation because this number could have been affected by exclusion of patients with missing data, timing and dose of oral steroids received before entering in the hospital, the inclusion of patients from only two centers, and the choice of the cutoff values (eg, absolute counts vs percentage). For example, in a recent study examining 647 patients with COPD admitted to the ICU for respiratory failure, the prevalence of patients with blood eosinophils > 2% was < 10%. Another study that was based on a retrospective hospital database analysis found that among 3,084 patients hospitalized for acute exacerbations of COPD, 17% had blood eosinophilia ≥ 300 cells/μL and 40% had blood eosinophilia ≥ 2%. Further studies are clearly required to establish the prevalence of eosinophilic exacerbations in various settings as well as the optimal cutoff values. Interestingly, Bafadhel et al found that eosinophil counts and proportion of eosinophilic exacerbations were markedly lower in patients with consolidation on chest radiographs. Recent data from the European COPD audit suggest that COPD exacerbations with alveolar consolidation are treated in approximately 93% of cases with antibiotics and 79% of cases with systemic steroids. If blood eosinophils are indeed a marker of steroid responsiveness, it is tempting to speculate that overprescription of systemic steroids could be particularly high in this group of patients. Finally, it remains unclear whether high blood eosinophil count is triggered by a stimulus at the time of the exacerbation or whether it represents a stable endotype in patients with COPD. A subgroup of patients with stable COPD appear to have mildly elevated blood eosinophils, a feature that has been suggested to predict the efficacy of fixed combination of inhaled corticosteroids/long-acting β-agonists on reducing the risk of exacerbation. However, there also appears to be some variability in longitudinal eosinophil counts because data from a recent clinical trial indicate that one-half of the patients with a history of sputum eosinophils ≥ 3% within the previous year had blood eosinophils < 200 μL at study entry. Longitudinal follow-up of blood eosinophil counts in patients with eosinophilic exacerbations will provide answers to this important question.

In conclusion, severe COPD exacerbations are clearly heterogeneous, and blood eosinophils represent a promising biomarker for personalizing prescription of oral steroids in patients hospitalized with COPD exacerbations. The Bafadhel et al study provides rationale for designing a multicenter randomized clinical trial assessing the possibility of limiting prescription of systemic steroids to patients with eosinophilic COPD exacerbations. Until such data are available, it will not be possible to translate this proposal into daily practice.

References

Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management and prevention of COPD.http://www.goldcopd.org/. Accessed May 24, 2016.
 
Walters J.A. .Tan D.J. .White C.J. .Gibson P.G. .Wood-Baker R. .Walters E.H. . Systemic corticosteroids for acute exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2014;9:CD001288- [PubMed]journal. [PubMed]
 
Lindenauer P.K. .Pekow P.S. .Lahti M.C. .Lee Y. .Benjamin E.M. .Rothberg M.B. . Association of corticosteroid dose and route of administration with risk of treatment failure in acute exacerbation of chronic obstructive pulmonary disease. JAMA. 2010;303:2359-2367 [PubMed]journal. [CrossRef] [PubMed]
 
Leuppi J.D. .Schuetz P. .Bingisser R. .et al Short-term vs conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: the REDUCE randomized clinical trial. JAMA. 2013;309:2223-2231 [PubMed]journal. [CrossRef] [PubMed]
 
Kent D.M. .Hayward R.A. . Limitations of applying summary results of clinical trials to individual patients: the need for risk stratification. JAMA. 2007;298:1209-1212 [PubMed]journal. [CrossRef] [PubMed]
 
Bafadhel M. .Greening N.J. .Harvey-Dunstan T.C. .et al Blood eosinophils and outcomes in severe hospitalized exacerbations of COPD. Chest. 2016;150:320-328 [PubMed]journal
 
Salturk C. .Karakurt Z. .Adiguzel N. .et al Does eosinophilic COPD exacerbation have a better patient outcome than non-eosinophilic in the intensive care unit? Int J Chron Obstruct Pulmon Dis. 2015;10:1837-1846 [PubMed]journal. [PubMed]
 
Hasegawa K. .Camargo C.A. Jr.. Prevalence of blood eosinophilia in hospitalized patients with acute exacerbation of COPD. Respirology. 2016;21:761-764 [PubMed]journal. [CrossRef] [PubMed]
 
Saleh A. .Lopez-Campos J.L. .Hartl S. .Pozo-Rodriguez F. .Roberts C.M. . The effect of incidental consolidation on management and outcomes in COPD exacerbations: data from the European COPD audit. PLoS One. 2015;10:e0134004- [PubMed]journal. [CrossRef] [PubMed]
 
Pavord I.D. .Lettis S. .Locantore N. .et al Blood eosinophils and inhaled corticosteroid/long-acting beta-2 agonist efficacy in COPD. Thorax. 2016;71:118-125 [PubMed]journal. [CrossRef] [PubMed]
 
Brightling C.E. .Bleecker E.R. .Panettieri R.A. Jr..et al Benralizumab for chronic obstructive pulmonary disease and sputum eosinophilia: a randomised, double-blind, placebo-controlled, phase 2a study. Lancet Respir Med. 2014;2:891-901 [PubMed]journal. [CrossRef] [PubMed]
 

Figures

Tables

References

Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management and prevention of COPD.http://www.goldcopd.org/. Accessed May 24, 2016.
 
Walters J.A. .Tan D.J. .White C.J. .Gibson P.G. .Wood-Baker R. .Walters E.H. . Systemic corticosteroids for acute exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2014;9:CD001288- [PubMed]journal. [PubMed]
 
Lindenauer P.K. .Pekow P.S. .Lahti M.C. .Lee Y. .Benjamin E.M. .Rothberg M.B. . Association of corticosteroid dose and route of administration with risk of treatment failure in acute exacerbation of chronic obstructive pulmonary disease. JAMA. 2010;303:2359-2367 [PubMed]journal. [CrossRef] [PubMed]
 
Leuppi J.D. .Schuetz P. .Bingisser R. .et al Short-term vs conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: the REDUCE randomized clinical trial. JAMA. 2013;309:2223-2231 [PubMed]journal. [CrossRef] [PubMed]
 
Kent D.M. .Hayward R.A. . Limitations of applying summary results of clinical trials to individual patients: the need for risk stratification. JAMA. 2007;298:1209-1212 [PubMed]journal. [CrossRef] [PubMed]
 
Bafadhel M. .Greening N.J. .Harvey-Dunstan T.C. .et al Blood eosinophils and outcomes in severe hospitalized exacerbations of COPD. Chest. 2016;150:320-328 [PubMed]journal
 
Salturk C. .Karakurt Z. .Adiguzel N. .et al Does eosinophilic COPD exacerbation have a better patient outcome than non-eosinophilic in the intensive care unit? Int J Chron Obstruct Pulmon Dis. 2015;10:1837-1846 [PubMed]journal. [PubMed]
 
Hasegawa K. .Camargo C.A. Jr.. Prevalence of blood eosinophilia in hospitalized patients with acute exacerbation of COPD. Respirology. 2016;21:761-764 [PubMed]journal. [CrossRef] [PubMed]
 
Saleh A. .Lopez-Campos J.L. .Hartl S. .Pozo-Rodriguez F. .Roberts C.M. . The effect of incidental consolidation on management and outcomes in COPD exacerbations: data from the European COPD audit. PLoS One. 2015;10:e0134004- [PubMed]journal. [CrossRef] [PubMed]
 
Pavord I.D. .Lettis S. .Locantore N. .et al Blood eosinophils and inhaled corticosteroid/long-acting beta-2 agonist efficacy in COPD. Thorax. 2016;71:118-125 [PubMed]journal. [CrossRef] [PubMed]
 
Brightling C.E. .Bleecker E.R. .Panettieri R.A. Jr..et al Benralizumab for chronic obstructive pulmonary disease and sputum eosinophilia: a randomised, double-blind, placebo-controlled, phase 2a study. Lancet Respir Med. 2014;2:891-901 [PubMed]journal. [CrossRef] [PubMed]
 
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