TY - JOUR
T1 - Association of sputum and blood eosinophil concentrations with clinical measures of COPD severity
T2 - an analysis of the SPIROMICS cohort
AU - SPIROMICS investigators
AU - Hastie, Annette T.
AU - Martinez, Fernando J.
AU - Curtis, Jeffrey L.
AU - Doerschuk, Claire M.
AU - Hansel, Nadia N.
AU - Christenson, Stephanie
AU - Putcha, Nirupama
AU - Ortega, Victor E.
AU - Li, Xingnan
AU - Barr, R. Graham
AU - Carretta, Elizabeth E.
AU - Couper, David J.
AU - Cooper, Christopher B.
AU - Hoffman, Eric A.
AU - Kanner, Richard E.
AU - Kleerup, Eric
AU - O'Neal, Wanda K.
AU - Paine, Richard
AU - Peters, Stephen P.
AU - Alexis, Neil E.
AU - Woodruff, Prescott G.
AU - Han, Mei Lan K.
AU - Meyers, Deborah A.
AU - Bleecker, Eugene R.
AU - Anderson, Wayne H.
AU - Boucher, Richard C.
AU - Bowler, Russell P.
AU - Comellas, Alejandro P.
AU - Criner, Gerard J.
AU - Crystal, Ronald G.
AU - Dransfield, Mark T.
AU - Freeman, Christine M.
AU - Kaner, Robert J.
AU - Krishnan, Jerry A.
AU - LaVange, Lisa M.
AU - Lazarus, Stephen C.
AU - Newell, John D.
AU - Oelsner, Elizabeth C.
AU - Rennard, Stephen I.
AU - Tashkin, Donald P.
AU - Scholand, Mary Beth
AU - Wells, J. Michael
AU - Wise, Robert A.
N1 - Funding Information:
ATH, CMD, and DAM report support from the National Heart, Lung, and Blood Institute (NHLBI) and the Foundation for the National Institutes of Health (FNIH) during conduct of study. FJM reports grants from NIH; personal fees from Forest, Janssens, GlaxoSmithKline (GSK), Nycomed/Takeda, Amgen, AstraZeneca, Boehringer Ingelheim, Ikaria/Bellerophon, Genentech, Novartix, Pearl, Pfizer, Roche, Sunovion, Theravance, Axon, CME Incite, California Society for Allergy and Immunology, Annenberg, Informa, Integritas, InThought, Miller Medical, National Association for Continuing Education, Paradigm, Peer Voice, UpToDate, Haymarket Communications, Western Society of Allergy and Immunology, Unity Biotechnology, ConCert, Lucid, Methodist Hospital, Prime, and WebMD. JLC reports grants from NHLBI, National Institute of Allergy and Infectious Disease of the National Institute of Health, the Department of Veterans Affairs, FNIH, and the COPD Foundation. NNH reports grants from AstraZeneca, NIH, the COPD Foundation, Boehringer Ingelheim, and GSK. SC reports grants from MedImmune; personal fees from AstraZeneca; and non-financial support from Genentech. FJM reports grants from NIH; personal fees from Forest, Janssens, GSK, Nycomed/Takeda, Amgen, AstraZeneca, Boehringer Ingelheim, Ikaria/Bellerophon, Genentech, Novartix, Pearl, Pfizer, Roche, Sunovion, Theravance, Axon, CME Incite, California Society for Allergy and Immunology, Annenberg, Informa, Integritas, InThought, Miller Medical, National Association for Continuing Education, Paradigm, Peer Voice, UpToDate, Haymarket Communications, Western Society of Allergy and Immunology, Unity Biotechnology, ConCert, Lucid, Methodist Hospital, Prime, and WebMD. VEO reports personal fees from CSL Behring. RGB reports grants from NIH, FNIH, and the COPD Foundation; grants from Alpha1 Foundation; and personal fees from UpToDate. EEC reports support from NHLBI, FNIH, Genentech, and the COPD Foundation during conduct of study. DJC reports support from NHLBI and the COPD Foundation. CBC reports grants from Equinox Health Clubs, Amgen, and Spiration; personal fees from Equinox Health Clubs, PulmonX, Boehringer Ingelheim, GSK, and SPIRATION; and part-time work for scientific engagement for GSK Global Respiratory Franchise outside of submitted work. EAH is a founder and shareholder of VIDA Diagnostics, a company commercialising lung image analysis software developed, in part, at the University of Iowa. EK reports grants from the NIH and the FNIH; non-financial support (inhalers for spirometry testing) from Boehringer Ingelheim and GSK during the conduct of the study; and grants from Boehringer Ingelheim, Novartis, Pearl/AstraZeneca, and Sunovion/Sepracor. RP reports support from NHLBI and the COPD Foundation; and a grant from the Department of Veterans Affairs. MKH reports support from NIH, FNIH, and the COPD Foundation; consulting fees from GSK, Boehringer Ingelheim, Novartis, AstraZeneca, and Sunovion; and royalties from UptoDate. SPP reports grants from NIH, NHLBI, and the COPD Foundation. PGW reports grants from Medimmune; personal fees from Genentech/Roche, AstraZeneca, Novartis, Neostem, and Janssen; and a patent for Asthma diagnostics pending. All other authors declare no competing interests.
Funding Information:
SPIROMICS was supported by contracts from the NIH/NHLBI (HHSN268200900013C, HHSN268200900014C, HHSN268200900015C, HHSN268200900016C, HHSN268200900017C, HHSN268200900018C HHSN268200900019C, HHSN268200900020C), which were supplemented by contributions made through the FNIH from AstraZeneca; Bellerophon Therapeutics; Boehringer Ingelheim Pharmaceuticals; Chiesi Farmaceutici; Forest Research Institute; GSK; Grifols Therapeutics; Ikaria; Nycomed; Takeda Pharmaceutical Company; Novartis Pharmaceuticals Corporation; Regeneron Pharmaceuticals; Sanofi, and the COPD Foundation. Additional CT analyses were made possible by NIH/NHLBI HL122438. We thank the SPIROMICS participants and participating physicians, investigators, and staff for making this research possible. We would like to acknowledge the following current and former investigators of the SPIROMICS sites and reading centres: Wayne H Anderson, Russell P Bowler, Alejandro P Comellas, Gerard J Criner, Ronald G Crystal, Mark T Dransfield, Christine M Freeman, Robert J Kaner, Jerry A Krishnan, Stephen C Lazarus, John D Newell Jr, Elizabeth C Oelsner, Stephen I Rennard, Donald P Tashkin, Mary Beth Scholand, J Michael Wells, and Robert A Wise.
Publisher Copyright:
© 2017 Elsevier Ltd
PY - 2017/12
Y1 - 2017/12
N2 - Background Increased concentrations of eosinophils in blood and sputum in chronic obstructive pulmonary disease (COPD) have been associated with increased frequency of exacerbations, reduced lung function, and corticosteroid responsiveness. We aimed to assess whether high eosinophil concentrations in either sputum or blood are associated with a severe COPD phenotype, including greater exacerbation frequency, and whether blood eosinophils are predictive of sputum eosinophils. Methods We did a multicentre observational study analysing comprehensive baseline data from SPIROMICS in patients with COPD aged 40–80 years who had a smoking history of at least 20 pack-years, recruited from six clinical sites and additional subsites in the USA between Nov 12, 2010, and April 21, 2015. Inclusion criteria for this analysis were SPIROMICS baseline visit data with complete blood cell counts and, in a subset, acceptable sputum counts. We stratified patients on the basis of blood and sputum eosinophil concentrations and compared their demographic characteristics, as well as results from questionnaires, clinical assessments, and quantitative CT (QCT). We also analysed whether blood eosinophil concentrations reliably predicted sputum eosinophil concentrations. This study is registered with ClinicalTrials.gov (NCT01969344). Findings Of the 2737 patients recruited to SPIROMICS, 2499 patients were smokers and had available blood counts, and so were stratified by mean blood eosinophil count: 1262 patients with low (<200 cells per μL) and 1237 with high (≥200 cells per μL) blood eosinophil counts. 827 patients were eligible for stratification by mean sputum eosinophil percentage: 656 with low (<1·25%) and 171 with high (≥1·25%) sputum eosinophil percentages. The high sputum eosinophil group had significantly lower median FEV1 percentage predicted than the low sputum eosinophil group both before (65·7% [IQR 51·8–81·3] vs 75·7% [59·3–90·2], p<0·0001) and after (77·3% [63·1–88·5] vs 82·9% [67·8–95·9], p=0·001) bronchodilation. QCT density measures for emphysema and air trapping were significantly higher in the high sputum eosinophil group than the low sputum eosinophil group. Exacerbations requiring corticosteroids treatment were more common in the high versus low sputum eosinophil group (p=0·002). FEV1 percentage predicted was significantly different between low and high blood eosinophil groups, but differences were less than those observed between the sputum groups. The high blood eosinophil group had slightly increased airway wall thickness (0·02 mm difference, p=0·032), higher St George Respiratory Questionnaire symptom scores (p=0·037), and increased wheezing (p=0·018), but no evidence of an association with COPD exacerbations (p=0·35) or the other indices of COPD severity, such as emphysema measured by CT density, COPD assessment test scores, Body-mass index, airflow Obstruction, Dyspnea, and Exercise index, or Global Initiative for Chronic Obstructive Lung Disease stage. Blood eosinophil counts showed a weak but significant association with sputum eosinophil counts (receiver operating characteristic area under the curve of 0·64, p<0·0001), but with a high false-discovery rate of 72%. Interpretation In a large, well characterised cohort of former and current smoking patients with a broad range of COPD severity, high concentrations of sputum eosinophils were a better biomarker than high concentrations of blood eosinophils to identify a patient subgroup with more severe disease, more frequent exacerbations, and increased emphysema by QCT. Blood eosinophils alone were not a reliable biomarker for COPD severity or exacerbations, or for sputum eosinophils. Clinical trials targeting eosinophilic inflammation in COPD should consider assessing sputum eosinophils. Funding National Institutes of Health, and National Heart, Lung, and Blood Institute.
AB - Background Increased concentrations of eosinophils in blood and sputum in chronic obstructive pulmonary disease (COPD) have been associated with increased frequency of exacerbations, reduced lung function, and corticosteroid responsiveness. We aimed to assess whether high eosinophil concentrations in either sputum or blood are associated with a severe COPD phenotype, including greater exacerbation frequency, and whether blood eosinophils are predictive of sputum eosinophils. Methods We did a multicentre observational study analysing comprehensive baseline data from SPIROMICS in patients with COPD aged 40–80 years who had a smoking history of at least 20 pack-years, recruited from six clinical sites and additional subsites in the USA between Nov 12, 2010, and April 21, 2015. Inclusion criteria for this analysis were SPIROMICS baseline visit data with complete blood cell counts and, in a subset, acceptable sputum counts. We stratified patients on the basis of blood and sputum eosinophil concentrations and compared their demographic characteristics, as well as results from questionnaires, clinical assessments, and quantitative CT (QCT). We also analysed whether blood eosinophil concentrations reliably predicted sputum eosinophil concentrations. This study is registered with ClinicalTrials.gov (NCT01969344). Findings Of the 2737 patients recruited to SPIROMICS, 2499 patients were smokers and had available blood counts, and so were stratified by mean blood eosinophil count: 1262 patients with low (<200 cells per μL) and 1237 with high (≥200 cells per μL) blood eosinophil counts. 827 patients were eligible for stratification by mean sputum eosinophil percentage: 656 with low (<1·25%) and 171 with high (≥1·25%) sputum eosinophil percentages. The high sputum eosinophil group had significantly lower median FEV1 percentage predicted than the low sputum eosinophil group both before (65·7% [IQR 51·8–81·3] vs 75·7% [59·3–90·2], p<0·0001) and after (77·3% [63·1–88·5] vs 82·9% [67·8–95·9], p=0·001) bronchodilation. QCT density measures for emphysema and air trapping were significantly higher in the high sputum eosinophil group than the low sputum eosinophil group. Exacerbations requiring corticosteroids treatment were more common in the high versus low sputum eosinophil group (p=0·002). FEV1 percentage predicted was significantly different between low and high blood eosinophil groups, but differences were less than those observed between the sputum groups. The high blood eosinophil group had slightly increased airway wall thickness (0·02 mm difference, p=0·032), higher St George Respiratory Questionnaire symptom scores (p=0·037), and increased wheezing (p=0·018), but no evidence of an association with COPD exacerbations (p=0·35) or the other indices of COPD severity, such as emphysema measured by CT density, COPD assessment test scores, Body-mass index, airflow Obstruction, Dyspnea, and Exercise index, or Global Initiative for Chronic Obstructive Lung Disease stage. Blood eosinophil counts showed a weak but significant association with sputum eosinophil counts (receiver operating characteristic area under the curve of 0·64, p<0·0001), but with a high false-discovery rate of 72%. Interpretation In a large, well characterised cohort of former and current smoking patients with a broad range of COPD severity, high concentrations of sputum eosinophils were a better biomarker than high concentrations of blood eosinophils to identify a patient subgroup with more severe disease, more frequent exacerbations, and increased emphysema by QCT. Blood eosinophils alone were not a reliable biomarker for COPD severity or exacerbations, or for sputum eosinophils. Clinical trials targeting eosinophilic inflammation in COPD should consider assessing sputum eosinophils. Funding National Institutes of Health, and National Heart, Lung, and Blood Institute.
UR - http://www.scopus.com/inward/record.url?scp=85035061634&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85035061634&partnerID=8YFLogxK
U2 - 10.1016/S2213-2600(17)30432-0
DO - 10.1016/S2213-2600(17)30432-0
M3 - Article
C2 - 29146301
AN - SCOPUS:85035061634
VL - 5
SP - 956
EP - 967
JO - The Lancet Respiratory Medicine
JF - The Lancet Respiratory Medicine
SN - 2213-2600
IS - 12
ER -