Advertisement

Blood eosinophils as biomarkers of therapeutic response to chronic obstructive pulmonary disease: Still work in progress

      Highlights

      • Blood eosinophils (BE) as biomarkers may stratify patients in COPD therapy.
      • BE as biomarkers may support the clinical decision in using ICS for COPD.
      • A cut-off value of BE >300 cells/μl might identify patients at benefit with ICS.

      Abstract

      Disease phenotyping is a key step towards an increasingly personalized approach to chronic obstructive pulmonary disease (COPD), leading to a more precise assessment, treatment and definition of disease outcomes.
      The search for biomarkers able to guide the identification of COPD phenotypes are of great importance for both researchers and clinicians. However, while several biomarkers of inflammation [e.g., peripheral blood eosinophils and fractional expired nitric oxide] have been identified and applied in asthma, none has been successfully linked to discrete clinical parameters of COPD such as exacerbations, natural progression, and treatment response or mortality risk.
      Recently, several studies have shown that blood eosinophils are a potential biomarker for patient subset stratification in COPD therapy. Here we reviewed the value of blood eosinophils in predicting the response of COPD patients to treatment.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to European Journal of Internal Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Cantor J.O.
        • Turino G.M.
        COPD pathogenesis: finding the common in the complex.
        Chest. 2019; 155: 266-271
        • Agusti A.G.
        COPD, a multicomponent disease: implications for management.
        Respir Med. 2005; 99: 670-682
        • Stockley R.A.
        • Halpin D.M.G.
        • Celli B.R.
        • Singh D.
        Chronic obstructive pulmonary disease biomarkers and their interpretation.
        Am J Respir Crit Care Med. 2019; 199: 1195-1204
        • Fingleton J.
        • Travers J.
        • Williams M.
        • Charles T.
        • Bowles D.
        • Strik R.
        • et al.
        Treatment responsiveness of phenotypes of symptomatic airways obstruction in adults.
        J Allergy Clin Immunol. 2015; 136: 601-609
        • Mirza S.
        • Benzo R.
        Chronic obstructive pulmonary disease phenotypes: implications for care.
        Mayo Clin Proc. 2017; 92: 1104-1112
        • Castaldi P.J.
        • Benet M.
        • Petersen H.
        • Rafaels N.
        • Finigan J.
        • Paoletti M.
        • et al.
        Do COPD subtypes really exist? COPD heterogeneity and clustering in 10 independent cohorts.
        Thorax. 2017; 72: 998-1006
        • Maniscalco M.
        • Paris D.
        • Carone M.
        • Spanevello A.
        • Vitacca M.
        • Motta A.
        Is there a role for biomarkers in pulmonary rehabilitation?.
        Biomark Med. 2018; 12: 1069-1072
        • Wadsworth S.
        • Sin D.
        • Dorscheid D.
        Clinical update on the use of biomarkers of airway inflammation in the management of asthma.
        J Asthma Allergy. 2011; 4: 77-86
        • Maniscalco M.
        • Motta A.
        Biomarkers in allergic asthma: which matrix should we use?.
        Clin Exp Allergy. 2017; 47: 1097-1098
        • Kostikas K.
        • Bakakos P.
        • Papiris S.
        • Stolz D.
        • Celli B.R.
        Systemic biomarkers in the evaluation and management of COPD patients: are we getting closer to clinical application?.
        Curr Drug Targets. 2013; 14: 177-191
        • Wu D.
        • Li L.
        • Zhang M.
        • Wang J.
        • Wei Y.
        Two inflammatory phenotypes of nasal polyps and comorbid asthma.
        Ann Allergy Asthma Immunol. 2017; 118: 318-325
        • Stanescu D.
        • Sanna A.
        • Veriter C.
        • Kostianev S.
        • Calcagni P.G.
        • Fabbri L.M.
        • et al.
        Airways obstruction, chronic expectoration, and rapid decline of FEV1 in smokers are associated with increased levels of sputum neutrophils.
        Thorax. 1996; 51: 267-271
        • Barnes P.J.
        Inflammatory mechanisms in patients with chronic obstructive pulmonary disease.
        J Allergy Clin Immunol. 2016; 138: 16-27
        • Fahy J.V.
        Type 2 inflammation in asthma--present in most, absent in many.
        Nat Rev Immunol. 2015; 15: 57-65
        • Saetta M.
        • Di Stefano A.
        • Maestrelli P.
        • Turato G.
        • Ruggieri M.P.
        • Roggeri A.
        • et al.
        Airway eosinophilia in chronic bronchitis during exacerbations.
        Am J Respir Crit Care Med. 1994; 150: 1646-1652
        • Eltboli O.
        • Mistry V.
        • Barker B.
        • Brightling C.E.
        Relationship between blood and bronchial submucosal eosinophilia and reticular basement membrane thickening in chronic obstructive pulmonary disease.
        Respirology. 2015; 20: 667-670
        • Bafadhel M.
        • Mckenna S.
        • Terry S.
        • Mistry V.
        • Reid C.
        • Haldar P.
        • et al.
        Acute exacerbations of chronic obstructive pulmonary disease: identification of biologic clusters and their biomarkers.
        Am J Respir Crit Care Med. 2011; 184: 662-671
        • Kostikas K.
        • Brindicci C.
        • Patalano F.
        Blood eosinophils as biomarkers to drive treatment choices in asthma and COPD.
        Curr Drug Targets. 2018; 19: 1882-1896
        • Green R.H.
        • Brightling C.E.
        • Mckenna S.
        • Hargadon B.
        • Parker D.
        • Bradding P.
        • et al.
        Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial.
        Lancet. 2002; 360: 1715-1721
        • Gibson P.G.
        • Dolovich J.
        • Denburg J.
        • Ramsdale E.H.
        • Hargreave F.E.
        Chronic cough: eosinophilic bronchitis without asthma.
        Lancet. 1989; 1: 1346-1348
        • Woodruff P.G.
        • Modrek B.
        • Choy D.F.
        • Jia G.
        • Abbas A.R.
        • Ellwanger A.
        • et al.
        T-helper type 2-driven inflammation defines major subphenotypes of asthma.
        Am J Respir Crit Care Med. 2009; 180: 388-395
        • Schleich F.N.
        • Chevremont A.
        • Paulus V.
        • Henket M.
        • Manise M.
        • Seidel L.
        • et al.
        Importance of concomitant local and systemic eosinophilia in uncontrolled asthma.
        Eur Respir J. 2014; 44: 97-108
        • Wagener A.H.
        • de Nijs S.B.
        • Lutter R.
        • Sousa A.R.
        • Weersink E.J.
        • Bel E.H.
        • et al.
        External validation of blood eosinophils, FE(NO) and serum periostin as surrogates for sputum eosinophils in asthma.
        Thorax. 2015; 70: 115-120
        • Schleich F.N.
        • Manise M.
        • Sele J.
        • Henket M.
        • Seidel L.
        • Louis R.
        Distribution of sputum cellular phenotype in a large asthma cohort: predicting factors for eosinophilic vs neutrophilic inflammation.
        BMC Pulm Med. 2013; 13: 11
        • Kerkhof M.
        • Sonnappa S.
        • Postma D.S.
        • Brusselle G.
        • Agusti A.
        • Anzueto A.
        • et al.
        Blood eosinophil count and exacerbation risk in patients with COPD.
        Eur Respir J. 2017; 50
        • Landis S.
        • Suruki R.
        • Maskell J.
        • Bonar K.
        • Hilton E.
        • Compton C.
        Demographic and clinical characteristics of COPD patients at different blood eosinophil levels in the UK clinical practice research datalink.
        COPD. 2018; 15: 177-184
        • de Groot J.C.
        • Ten Brinke A.
        • Bel E.H.
        Management of the patient with eosinophilic asthma: a new era begins.
        ERJ Open Res. 2015; 1
        • Adir Y.
        • Hakrush O.
        • Shteinberg M.
        • Schneer S.
        • Agusti A.
        Circulating eosinophil levels do not predict severe exacerbations in COPD: a retrospective study.
        ERJ Open Res. 2018; 4
        • Hospers J.J.
        • Schouten J.P.
        • Weiss S.T.
        • Postma D.S.
        • Rijcken B.
        Eosinophilia is associated with increased all-cause mortality after a follow-up of 30 years in a general population sample.
        Epidemiology. 2000; 11: 261-268
        • Schleich F.
        • Brusselle G.
        • Louis R.
        • Vandenplas O.
        • Michils A.
        • Pilette C.
        • et al.
        Heterogeneity of phenotypes in severe asthmatics. The Belgian Severe Asthma Registry (BSAR).
        Respir Med. 2014; 108: 1723-1732
        • Vedel-Krogh S.
        • Nielsen S.F.
        • Lange P.
        • Vestbo J.
        • Nordestgaard B.G.
        Blood eosinophils and exacerbations in chronic obstructive pulmonary disease. the copenhagen general population study.
        Am J Respir Crit Care Med. 2016; 193: 965-974
        • Singh D.
        • Kolsum U.
        • Brightling C.E.
        • Locantore N.
        • Agusti A.
        • Tal-Singer R.
        • et al.
        Eosinophilic inflammation in COPD: prevalence and clinical characteristics.
        Eur Respir J. 2014; 44: 1697-1700
        • Djukanovic R.
        • Wilson J.W.
        • Britten K.M.
        • Wilson S.J.
        • Walls A.F.
        • Roche W.R.
        • et al.
        Effect of an inhaled corticosteroid on airway inflammation and symptoms in asthma.
        Am Rev Respir Dis. 1992; 145: 669-674
        • Pizzichini E.
        • Pizzichini M.M.
        • Gibson P.
        • Parameswaran K.
        • Gleich G.J.
        • Berman L.
        • et al.
        Sputum eosinophilia predicts benefit from prednisone in smokers with chronic obstructive bronchitis.
        Am J Respir Crit Care Med. 1998; 158: 1511-1517
        • Barnes N.C.
        • Sharma R.
        • Lettis S.
        • Calverley P.M.
        Blood eosinophils as a marker of response to inhaled corticosteroids in COPD.
        Eur Respir J. 2016; 47: 1374-1382
        • Pascoe S.
        • Locantore N.
        • Dransfield M.T.
        • Barnes N.C.
        • Pavord I.D.
        Blood eosinophil counts, exacerbations, and response to the addition of inhaled fluticasone furoate to vilanterol in patients with chronic obstructive pulmonary disease: a secondary analysis of data from two parallel randomised controlled trials.
        Lancet Respir Med. 2015; 3: 435-442
        • Siddiqui S.H.
        • Guasconi A.
        • Vestbo J.
        • Jones P.
        • Agusti A.
        • Paggiaro P.
        • et al.
        Blood eosinophils: a biomarker of response to Extrafine beclomethasone/formoterol in chronic obstructive pulmonary disease.
        Am J Respir Crit Care Med. 2015; 192: 523-525
        • Pavord I.D.
        • Lettis S.
        • Locantore N.
        • Pascoe S.
        • Jones P.W.
        • Wedzicha J.A.
        • et al.
        Blood eosinophils and inhaled corticosteroid/long-acting beta-2 agonist efficacy in COPD.
        Thorax. 2016; 71: 118-125
        • Bafadhel M.
        • Peterson S.
        • De Blas M.A.
        • Calverley P.M.
        • Rennard S.I.
        • Richter K.
        • et al.
        Predictors of exacerbation risk and response to budesonide in patients with chronic obstructive pulmonary disease: a post-hoc analysis of three randomised trials.
        Lancet Respir Med. 2018; 6: 117-126
        • Vestbo J.
        • Papi A.
        • Corradi M.
        • Blazhko V.
        • Montagna I.
        • Francisco C.
        • et al.
        Single inhaler extrafine triple therapy versus long-acting muscarinic antagonist therapy for chronic obstructive pulmonary disease (TRINITY): a double-blind, parallel group, randomised controlled trial.
        Lancet. 2017; 389: 1919-1929
        • Calverley P.
        • Pauwels R.
        • Vestbo J.
        • Jones P.
        • Pride N.
        • Gulsvik A.
        • et al.
        Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial.
        Lancet. 2003; 361: 449-456
        • Cheng S.L.
        • Lin C.H.
        Effectiveness using higher inhaled corticosteroid dosage in patients with COPD by different blood eosinophilic counts.
        Int J Chron Obstruct Pulmon Dis. 2016; 11: 2341-2348
        • Vogelmeier C.
        • Zhong N.
        • Humphries M.J.
        • Mezzi K.
        • Fogel R.
        • Bader G.
        • et al.
        Indacaterol/glycopyrronium in symptomatic patients with COPD (GOLD B and GOLD D) versus salmeterol/fluticasone: ILLUMINATE/LANTERN pooled analysis.
        Int J Chron Obstruct Pulmon Dis. 2016; 11: 3189-3197
        • Cheng S.L.
        Blood eosinophils and inhaled corticosteroids in patients with COPD: systematic review and meta-analysis.
        Int J Chron Obstruct Pulmon Dis. 2018; 13: 2775-2784
        • Magnussen H.
        • Disse B.
        • Rodriguez-Roisin R.
        • Kirsten A.
        • Watz H.
        • Tetzlaff K.
        • et al.
        Withdrawal of inhaled glucocorticoids and exacerbations of COPD.
        N Engl J Med. 2014; 371: 1285-1294
        • Watz H.
        • Tetzlaff K.
        • Wouters E.F.
        • Kirsten A.
        • Magnussen H.
        • Rodriguez-Roisin R.
        • et al.
        Blood eosinophil count and exacerbations in severe chronic obstructive pulmonary disease after withdrawal of inhaled corticosteroids: a post-hoc analysis of the WISDOM trial.
        Lancet Respir Med. 2016; 4: 390-398
        • Wedzicha J.A.
        • Banerji D.
        • Chapman K.R.
        • Vestbo J.
        • Roche N.
        • Ayers R.T.
        • et al.
        Indacaterol-Glycopyrronium versus salmeterol-fluticasone for COPD.
        N Engl J Med. 2016; 374: 2222-2234
        • Roche N.
        • Chapman K.R.
        • Vogelmeier C.F.
        • Herth F.J.F.
        • Thach C.
        • Fogel R.
        • et al.
        Blood eosinophils and response to maintenance chronic obstructive pulmonary disease treatment. data from the FLAME trial.
        Am J Respir Crit Care Med. 2017; 195: 1189-1197
        • Anzueto A.R.
        • Kostikas K.
        • Mezzi K.
        • Shen S.
        • Larbig M.
        • Patalano F.
        • et al.
        Indacaterol/glycopyrronium versus salmeterol/fluticasone in the prevention of clinically important deterioration in COPD: results from the FLAME study.
        Respir Res. 2018; 19: 121
        • Agusti A.
        • Fabbri L.M.
        • Singh D.
        • Vestbo J.
        • Celli B.
        • Franssen F.M.E.
        • et al.
        Inhaled corticosteroids in COPD: friend or foe?.
        Eur Respir J. 2018; 52
        • Singh D.
        • Agusti A.
        • Anzueto A.
        • Barnes P.J.
        • Bourbeau J.
        • Celli B.R.
        • et al.
        Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease: the GOLD science committee report 2019.
        Eur Respir J. 2019; 53
        • Wechsler M.E.
        Current and emerging biologic therapies for asthma and COPD.
        Respir Care. 2018; 63: 699-707
        • Pavord I.D.
        Biologics and chronic obstructive pulmonary disease.
        J Allergy Clin Immunol. 2018; 141: 1983-1991
        • Pavord I.D.
        • Chanez P.
        • Criner G.J.
        • Kerstjens H.A.M.
        • Korn S.
        • Lugogo N.
        • et al.
        Mepolizumab for eosinophilic chronic obstructive pulmonary disease.
        N Engl J Med. 2017; 377: 1613-1629
        • Morjaria J.B.
        • Rigby A.
        • Morice A.H.
        Inhaled corticosteroid use and the risk of pneumonia and COPD exacerbations in the UPLIFT study.
        Lung. 2017; 195: 281-288
        • Pavord I.D.
        • Agusti A.
        Blood eosinophil count: a biomarker of an important treatable trait in patients with airway disease.
        Eur Respir J. 2016; 47: 1299-1303
        • Takayama Y.
        • Ohnishi H.
        • Ogasawara F.
        • Oyama K.
        • Kubota T.
        • Yokoyama A.
        Clinical utility of fractional exhaled nitric oxide and blood eosinophils counts in the diagnosis of asthma-COPD overlap.
        Int J Chron Obstruct Pulmon Dis. 2018; 13: 2525-2532
        • Winkel P.
        • Statland B.E.
        • Saunders A.M.
        • Osborn H.
        • Kupperman H.
        Within-day physiologic variation of leukocyte types in healthy subjects as assayed by two automated leukocyte differential analyzers.
        Am J Clin Pathol. 1981; 75: 693-700
        • Oshagbemi O.A.
        • Burden A.M.
        • Braeken D.C.W.
        • Henskens Y.
        • Wouters E.F.M.
        • Driessen J.H.M.
        • et al.
        Stability of blood eosinophils in patients with chronic obstructive pulmonary disease and in control subjects, and the impact of sex age, smoking, and baseline counts.
        Am J Respir Crit Care Med. 2017; 195: 1402-1404
        • Brusselle G.
        • Pavord I.D.
        • Landis S.
        • Pascoe S.
        • Lettis S.
        • Morjaria N.
        • et al.
        Blood eosinophil levels as a biomarker in COPD.
        Respir Med. 2018; 138: 21-31
        • Szefler S.J.
        • Wenzel S.
        • Brown R.
        • Erzurum S.C.
        • Fahy J.V.
        • Hamilton R.G.
        • et al.
        Asthma outcomes: biomarkers.
        J Allergy Clin Immunol. 2012; 129: S9-23
        • Criner G.J.
        • Martinez F.J.
        • Aaron S.
        • Agusti A.
        • Anzueto A.
        • Bafadhel M.
        • et al.
        Current controversies in chronic obstructive pulmonary disease. a report from the global initiative for chronic obstructive lung disease scientific committee.
        Ann Am Thorac Soc. 2019; 16: 29-39