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            "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Proposal for initial pharmacological treatment&#46; Low risk&#58; Patients who present mild or moderate airflow obstruction&#44; low degree of dyspnea &#40;mMRC of 0&#8211;1&#41; and &#8804;<span class="elsevierStyleHsp" style=""></span>1 exacerbation that has not required admission &#40;all criteria must be met&#41;&#46; High risk&#58; Patients who present severe or very severe airflow obstruction&#44; a high degree of dyspnea &#40;mMRC<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>2&#41; and&#47;or at least &#8805;<span class="elsevierStyleHsp" style=""></span>2 moderate exacerbations in the previous year or at least 1 that required hospital admission &#40;at least 1 criterion must be met&#41;&#46; <span class="elsevierStyleItalic">Abbreviations</span>&#58; LAMA&#58; long-acting muscarinic antagonist&#59; LABA&#58; long-acting &#946;2-agonist&#59; ICS&#58; inhaled corticosteroid&#59; Eo&#58; eosinophils&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">We thank Figueroa-Gon&#231;alves and de Miguel-D&#237;ez for their interest and comments about our manuscript on a new treatment algorithm for COPD&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">1</span></a> In our proposal&#44; we restricted the indication of triple therapy with LAMA&#47;LABA&#47;ICS as initial therapy for exacerbators with &#62;300 blood eosinophils &#40;BEC&#41;&#44; while they suggest that in case of severe exacerbations triple therapy should be recommended at lower levels of BEC &#40;i&#46;e&#46; &#62;100&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">2</span></a> They base their recommendation in the fact that severe exacerbations have a high impact on the natural history of COPD&#44; are followed by a high frequency of readmissions&#44; and that it is not uncommon for admitted patients with COPD to be treatment na&#239;ve&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">2</span></a> There is no discussion about this&#44; but there is currently no concrete evidence that triple therapy will be more effective than dual bronchodilation at discharge in na&#239;ve patients with 100&#8211;300 eosinophils&#44; as suggested by the authors&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">To further support their recommendation&#44; Figueroa-Gon&#231;alves and de Miguel-D&#237;ez indicate that a post hoc analysis of the IMPACT study demonstrates that the initiation of triple therapy after a severe COPD exacerbation provides a greater benefit in terms of the development of future exacerbations than LAMA&#47;LABA in patients with a level of BEC &#62;100&#46; However&#44; it is of note that patients in IMPACT were by no means treatment na&#239;ve&#59; on the contrary&#44; up to 40&#37; were already on triple therapy at screening &#40;therefore&#44; they do not &#8220;initiate&#8221; triple after admission&#41; and a further 41&#37; were on either LABA&#47;ICS or LAMA&#47;LABA&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">3</span></a> Moreover&#44; looking at the mortality results&#44; there was no effect whatsoever of triple therapy in reduction of mortality in patients who were not previously on ICS&#44; which are the closer to treatment na&#239;ve that we can find in IMPACT&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">3</span></a> For these reasons&#44; the IMPACT study results cannot be extrapolated to treatment na&#239;ve subjects with COPD and cannot be used to justify triple therapy in previously na&#239;ve COPD patients after a severe exacerbation in all cases with BEC &#62;100&#46; We do not dispute the indication of triple therapy in discharged patients with BEC &#62;300&#44; since enough evidence exists about the great efficacy of ICS in this population&#44; but na&#239;ve patients with BEC between 100 and 300 should try LABA&#47;LAMA first and only escalate to triple in case of a new episode or frequent moderate exacerbations&#44; as indicated in the GESEPOC guidelines&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">4</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Figueroa-Gon&#231;alves y de Miguel-D&#237;ez also base their recommendation on data from the observational PRIMUS study&#44; which observed lower mortality with the early initiation of triple after an admission compared with delayed initiation&#44; but again patients in PRIMUS were not treatment na&#239;ve and the observational design may involve certain bias&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">2</span></a> There are observational studies suggesting the opposite&#44; for example&#44; Jo et al&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">5</span></a> observed that patients who discontinued their ICS after being discharged from an exacerbation of COPD had a significant reduction of 35&#37; of the risk of re-hospitalisation or death compared with those who continued using their ICS&#46; Therefore&#44; we need to be very cautious with the recommendation to use triple therapy&#44; even in patients after a hospital admission&#44; because benefits do not always outweigh the risks&#44; particularly in previously na&#239;ve patients with less than 300 BEC&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflict of Interests</span><p id="par0020" class="elsevierStylePara elsevierViewall">Marc Miravitlles has received speaker fees from AstraZeneca&#44; Boehringer Ingelheim&#44; Chiesi&#44; Cipla&#44; GlaxoSmithKline&#44; Menarini&#44; Kamada&#44; Takeda&#44; Zambon&#44; CSL Behring&#44; Specialty Therapeutics&#44; Janssen&#44; Grifols and Novartis&#44; consulting fees from AstraZeneca&#44; Atriva Therapeutics&#44; Boehringer Ingelheim&#44; BEAM Therapeutics&#44; Chiesi&#44; GlaxoSmithKline&#44; CSL Behring&#44; Inhibrx&#44; Menarini&#44; Mereo Biopharma&#44; Spin Therapeutics&#44; Specialty Therapeutics&#44; ONO Pharma&#44; Palobiofarma SL&#44; Takeda&#44; Novartis&#44; Novo Nordisk&#44; Sanofi&#44; Zambon&#44; Zentiva and Grifols and research grants from Grifols&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Konstantinos Kostikas has received honoraria for presentations and&#47;or consultancy fees from Alector Pharmaceuticals&#44; AstraZeneca&#44; Boehringer Ingelheim&#44; CSL Behring&#44; Chiesi&#44; ELPEN&#44; GILEAD&#44; GSK&#44; Menarini&#44; Novartis&#44; Pfizer&#44; Sanofi&#44; Specialty Therapeutics&#44; WebMD&#59; his department has received funding and&#47;or grants from AstraZeneca&#44; Boehringer Ingelheim&#44; Chiesi&#44; Innovis&#44; ELPEN&#44; GSK&#44; Menarini&#44; Novartis and NuvoAir&#59; he is a member of the GOLD Assembly&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Nikoletta Bizymi has no conflicts of interest related to this paper&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Nikolaos Tzanakis has received speaker and&#47;or consultancy fees from AstraZeneca&#44; Boehringer Ingelheim&#44; CSL Behring&#44; Chiesi&#44; ELPEN&#44; GILEAD&#44; GSK&#44; Innovis&#44; Menarini&#44; Novartis&#44; Pfizer&#44; Sanofi&#44; Specialty Therapeutics&#44; Help and has received research grants from AstraZeneca&#44; Boehringer Ingelheim&#44; Chiesi&#44; Innovis&#44; GSK&#44; Menarini&#44; and Novartis&#46;</p></span></span>"
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Letter to the Director
Reply to Figueroa-Gonçalves and de Miguel-Díez
Marc Miravitllesa,
Corresponding author
marcm@separ.es

Corresponding author.
, Konstantinos Kostikasb, Nikoletta Bizymic, Nikolaos Tzanakisc
a Pneumology Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, Spain
b Respiratory Medicine Department, University of Ioannina, Greece
c Department of Respiratory Medicine, University Hospital of Heraklion, Medical School, University of Crete, Heraklion, Greece

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