Don’t Forget to Look Both Ways: The Role of Blood Eosinophil Counts in Identifying Subgroups and Susceptibility in COPD Patients

FOR RELATED ARTICLE, SEE PAGE 515It is very timely to have the latest work from the SPIROMICS study published in this issue of CHEST.1LeMaster W.B. Quibrera P.M. Couper D. et al.Clinical implications of low absolute blood eosinophil count in the SPIROMICS COPD cohort.Chest. 2023; 163: 515-528Abstract Full Text Full Text PDF Scopus (2) Google Scholar It coincides with not only a significant revision of the GOLD COPD strategy2Singh D. Agusti A. Martinez F.J. et al.Blood eosinophils and chronic obstructive pulmonary disease: a global initiative for chronic obstructive lung disease science committee 2022 review.Am J Respir Crit Care Med. 2022; 206: 17-24Crossref PubMed Scopus (29) Google Scholar but also the publication of the Lancet Commission on COPD.3Stolz D. Mkorombindo T. Schumann D.M. et al.Towards the elimination of chronic obstructive pulmonary disease: a Lancet Commission.Lancet. 2022; 400: 921-972Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar Both now champion a more personalized, phenotypic approach to COPD management. Moreover, this work demonstrates the clear benefits of conducting large-scale observational studies, with detailed prospective data collection. This approach improves the identification of and the potential for directing treatment toward subgroups or phenotypes of COPD patients. FOR RELATED ARTICLE, SEE PAGE 515 High sputum and blood eosinophil counts (BEC) are associated with type II airways inflammation and in COPD predict response to inhaled corticosteroids (ICS).4Kolsum U. Damera G. Pham T.-H. et al.Pulmonary inflammation in patients with chronic obstructive pulmonary disease with higher blood eosinophil counts.J Allergy Clin Immunol. 2017; 140: 1181-1184Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar,5Bafadhel M. McKenna S. Terry S. et al.Blood eosinophils to direct corticosteroid treatment of exacerbations of chronic obstructive pulmonary disease: a randomized placebo-controlled trial.Am J Respir Crit Care Med. 2012; 186: 48-55Crossref PubMed Scopus (455) Google Scholar This eosinophilic lung inflammation is associated with infiltration of inflammatory proteins and increased tissue remodeling. It has been natural for us to focus on this group because low BEC (≤100 cells/μL) identify those COPD patients with the lowest probability of response to ICS.6Harries T.H. Rowland V. Corrigan C.J. et al.Blood eosinophil count, a marker of inhaled corticosteroid effectiveness in preventing COPD exacerbations in post-hoc RCT and observational studies: systematic review and meta-analysis.Respir Res. 2020; 21: 3Crossref PubMed Scopus (41) Google Scholar Those COPD patients in GOLD group D with low BEC (≤100 cells/μL) represent a hitherto under-researched population. This subgroup may have distinct pathological and risk characteristics and thus the potential for new therapeutic approaches. The current study1LeMaster W.B. Quibrera P.M. Couper D. et al.Clinical implications of low absolute blood eosinophil count in the SPIROMICS COPD cohort.Chest. 2023; 163: 515-528Abstract Full Text Full Text PDF Scopus (2) Google Scholar has found that COPD patients in the group D subgroup with low BEC were more likely to be current individuals who smoke and have an increased degree of emphysema. Disease progression was also different in this population. Loss of lung capacity was recorded in COPD patients across the different severities of airflow obstruction. Among COPD patients in group D, those with BEC ≤100 cells/μL experienced −68 mL/year change in FEV1, equivalent to 4.7% lung function decline/year. Those COPD patients with BEC >100 cells/μL experienced a change in FEV1 of −23 mL/year, equivalent to a 1.6% decline/year. The COPD patients in group D had mortality rates between 16.4% (BEC ≤ 100 cells/μL) and 13.0% (BEC > 100 cells/μL) per year. These poor outcomes indicate likely missed opportunities for early therapeutic intervention, and we would like to draw attention to them to challenge our acceptance of such figures as normal and acceptable. This can lead to therapeutic nihilism and a complacent approach. The current study1LeMaster W.B. Quibrera P.M. Couper D. et al.Clinical implications of low absolute blood eosinophil count in the SPIROMICS COPD cohort.Chest. 2023; 163: 515-528Abstract Full Text Full Text PDF Scopus (2) Google Scholar can help us, in conjunction with other data, to propose potential mechanisms for the findings and thus possible treatments. A greater proportion of COPD patients in the group D subgroup with low BEC required antibiotics for the treatment of acute exacerbations of COPD than did those in the subgroup with high BEC. This finding is consistent with the differing airway microbiome, in particular the presence of increased airway proteobacteria, phyla that includes Haemophilus influenzae,7Dicker A.J. Huang J.T.J. Lonergan M. et al.The sputum microbiome, airway inflammation, and mortality in chronic obstructive pulmonary disease.J Allergy Clin Immunol. 2021; 147: 158-167Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar and the probable increased susceptibility to bacterial infection and increased risk of pneumonia8Pavord I.D. Lettis S. Anzueto A. Barnes N. Blood eosinophil count and pneumonia risk in patients with chronic obstructive pulmonary disease: a patient-level meta-analysis.Lancet Respir Med. 2016; 4: 731-741Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar among COPD patients with low BEC. Efforts should be made to identify COPD patients with “persistently low” BEC who may exhibit a limited clinical response to ICS5Bafadhel M. McKenna S. Terry S. et al.Blood eosinophils to direct corticosteroid treatment of exacerbations of chronic obstructive pulmonary disease: a randomized placebo-controlled trial.Am J Respir Crit Care Med. 2012; 186: 48-55Crossref PubMed Scopus (455) Google Scholar but whose microbiome suggests an increased risk of infection with H influenzae.9Martinez-Garcia M.A. Faner R. Oscullo G. et al.Inhaled steroids, circulating eosinophils, chronic airway infection, and pneumonia risk in chronic obstructive pulmonary disease: a network analysis.Am J Respir Crit Care Med. 2020; 201: 1078-1085Crossref PubMed Scopus (0) Google Scholar Steady-state BEC in COPD help us understand the risk of exacerbation and response to treatment, and at the moment of exacerbation, they are clearly a prognostic marker. COPD patients with low BEC during severe exacerbations have higher rates of respiratory failure, a greater need of ventilator support, and higher rates of mortality.10Ruiying W. Zhaoyun Jianying X. Clinical features and three-year prognosis of AECOPD patients with different levels of blood eosinophils.Heart Lung. 2022; 56: 29-39Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar Those with higher BEC respond well to treatment but have a higher rate of recurrent exacerbation. The relationship between BEC and outcomes in COPD is not linear and not fully defined or understood. For example, Casanova et al11Casanova C. Celli B.R. de-Torres J.P. et al.Prevalence of persistent blood eosinophilia: relation to outcomes in patients with COPD.Eur Respir J. 2017; 501701162Crossref Scopus (108) Google Scholar found that exacerbation frequency in COPD patients was not associated with BEC but that all-cause mortality was lower in those with high eosinophils compared with those with BEC < 300 cells/μL.11Casanova C. Celli B.R. de-Torres J.P. et al.Prevalence of persistent blood eosinophilia: relation to outcomes in patients with COPD.Eur Respir J. 2017; 501701162Crossref Scopus (108) Google Scholar A high BEC may not be protective, because this has been associated with an increased risk of exacerbations in COPD patients within general population studies.12Vedel-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: 965-974Crossref PubMed Scopus (298) Google Scholar As recommended by the GOLD guidance, a personalized management plan for COPD patients comprising a clinical assessment with recording of exacerbation frequency, the measurement of BEC, and an assessment of the airway microbiome should be undertaken to determine appropriate preventive treatment.2Singh D. Agusti A. Martinez F.J. et al.Blood eosinophils and chronic obstructive pulmonary disease: a global initiative for chronic obstructive lung disease science committee 2022 review.Am J Respir Crit Care Med. 2022; 206: 17-24Crossref PubMed Scopus (29) Google Scholar Although the focus is on those patients with raised BEC, clearly we also need to consider those with BEC ≤ 100 cells/μL. These COPD patients may benefit from close monitoring after the clinical course and an assessment to detect bacterial colonization of the airways, thus allowing appropriate treatment. Much remains to be discovered about the role of both high and low blood eosinophils in COPD, and this will be a rich vein for research from the molecular level to the epidemiology of these patients. Both low and high blood eosinophil levels present challenges to patients and opportunities for researchers and clinicians. Is there an optimum blood eosinophil level in COPD? From our current knowledge and this new data mandate, clearly we need to look both ways! T. H. H. is supported by an NIHR Academic Clinical Lectureship. R. E. K. R. is supported by the Oxford Respiratory NIHR BRC.