Abstract
Tailoring self-treatment by adding exacerbation phenotyping could be explored. Evidence on phenotyping effects, an accurate tool to identify eosinophilic exacerbations, and a validated cut-off point are needed before eosinophils can be used in practice. http://bit.ly/2L4b6SR
From the authors:
We are grateful to the editors of the European Respiratory Journal for the opportunity to respond to the letter to the editor by S. Ramakrishnan and M. Bafadhel, whom we thank for their thoughtful remarks about our COPE-III self-management trial [1]. Whereas our study did not show a significant difference in the number of COPD exacerbation days per year, the results showed that exacerbation action plans for COPD patients with comorbidities, embedded in a patient-tailored self-management intervention, reduced the duration of COPD exacerbations and the risk of respiratory-related hospitalisation, without increasing all-cause mortality [1]. In our study, we did not phenotype COPD exacerbations by airway eosinophilic inflammation prior to randomisation.
Whereas we agree that further tailoring of self-treatment interventions by adding exacerbation phenotyping could be explored in future studies, more robust studies on the effects of phenotyping, an accurate and user-friendly tool to identify eosinophilic exacerbations, and a validated cut-off point are needed before eosinophils can be used in practice to reduce systemic (either oral or intravenous) corticosteroid use, and their potential side-effects during acute COPD exacerbations [2]. In 2012, at the start of our study, treatment of acute exacerbations with a course of systemic corticosteroids for 7 days was common practice and recommended in guidelines [3], and they still are recommended. Moreover, corticosteroids have been shown to reduce the rates of treatment failure and relapse, and to improve lung function and breathlessness [4].
First, there are indications suggesting that systemic corticosteroids may be less efficacious in treating acute COPD exacerbations in patients with lower blood eosinophil levels. A study by Sivapalan et al. [5] in hospitalised COPD patients showed that eosinophil-guided therapy was non-inferior to systemic corticosteroid treatment for the number of days alive and out of hospital and reduced the duration of systemic corticosteroid use. The authors could not, however, entirely exclude a detrimental effect on readmissions with acute COPD exacerbations or death within the first month in the eosinophil-guided group, and therefore recommended larger studies to determine the full safety profile of this strategy, and its role in COPD exacerbation management [5]. Furthermore, patients in both treatment groups received an 80 mg initial dose of prednisolone [5], which could have affected both the eosinophil count and outcome.
Secondly, we are in need of an accurate and easy to use tool to identify eosinophilic exacerbations with a validated cut-off point before integrating it into exacerbation action plans. Peripheral blood eosinophil counts are used as a surrogate biomarker of eosinophilic airway inflammation, but there is significant intra-subject variability in the peripheral blood eosinophil count, and several factors contribute to within-subject variability of blood eosinophil measurements [6]. Furthermore, it was found that blood eosinophils showed a significant but weak association with sputum eosinophil counts [7].
Thirdly, multiple eosinophil cut-off points in blood have been suggested [8]. While Bafadhel et al. [9] used the absolute blood eosinophil count cut-off of ≥2%, Sivapalan et al. [5] administered systemic corticosteroids when the blood eosinophil count was at least 0.3×109 cells per L. Another issue that needs to be considered is the impact of this approach on non-hospitalised patients (i.e. in the outpatient and home setting, including patients who self-manage their exacerbations), for whom a blood sample requirement could potentially delay treatment.
S. Ramakrishnan and M. Bafadhel are correct to note that, in our study, the number of oral prednisolone courses per exacerbation was higher among the self-management group (208 courses, 216 exacerbations) compared to usual care (163 courses, 230 exacerbations) [1]. This was expected as the self-management intervention aimed to improve self-regulation skills as well as targeted uptake and optimal use of appropriate self-management behaviours by early self-recognition and self-treatment of exacerbations. More patients in the self-management group initiated oral prednisolone within 2 days of the onset of a COPD exacerbation, suggesting that patients learned to identify an exacerbation, treat it promptly, and thus reduce its duration [1]. Moreover, there was no over-treatment observed and patients were only directed to activate their action plans (i.e. self-initiating a course of prednisolone) after the onset of a COPD exacerbation or comorbid exacerbation. Hence, patients that could benefit from the self-management intervention were those with at least one exacerbation during the 12-month study period.
In conclusion, our study supports integrating self-management of COPD exacerbations into overall COPD management. COPD self-management interventions reduce COPD exacerbation duration and hospitalisations, and improve quality of life [1, 10]. Acute exacerbations are a major prognostic factor with detrimental effects on symptom severity, hospitalisations and mortality [4], and exacerbation action plans can help patients initiate appropriate treatment promptly and reduce the severity (and impact) of COPD exacerbations. When an accurate, affordable, and user-friendly tool to identify eosinophilic exacerbations becomes available for use at home, this might be an additional tool to further personalise self-treatment of exacerbations. Hence, rather than give up on self-management, as proposed by S. Ramakrishnan and M. Bafadhel, it is time to further expand research in tailoring self-management of COPD exacerbations!
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Supplementary Material
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Footnotes
Conflict of interest: A. Lenferink has nothing to disclose.
Conflict of interest: J. van der Palen has nothing to disclose.
Conflict of interest: P.D.L.P.M. van der Valk has nothing to disclose.
Conflict of interest: M.G. Burt has nothing to disclose.
Conflict of interest: P.A. Frith has nothing to disclose.
Conflict of interest: M.G.J. Brusse-Keizer has nothing to disclose.
Conflict of interest: T.W. Effing has nothing to disclose.
- Received November 20, 2019.
- Accepted November 24, 2019.
- Copyright ©ERS 2020