[en] ABSTRACT: BACKGROUND: Phenotyping asthma according to airway inflammation allows identification of responders to targeted therapy. Induced sputum is technically demanding. We aimed to identify predictors of sputum inflammatory phenotypes according to easily available clinical characteristics. METHODS: This retrospective study was conducted in 508 asthmatics with successful sputum induction recruited from the University Asthma Clinic of Liege. Receiver-operating characteristic (ROC) curve and multiple logistic regression analysis were used to assess the relationship between sputum eosinophil or neutrophil count and a set of covariates. Equations predicting sputum eosinophils and neutrophils were then validated in an independent group of asthmatics. RESULTS: Eosinophilic (>=3%) and neutrophilic (>=76%) airway inflammation were observed in 46% and 18% of patients respectively. Predictors of sputum eosinophilia >=3% were high blood eosinophils, FENO and IgE level and low FEV1/FVC. The derived equation was validated with a Cohen's kappa coefficient of 0.59 (p < 0.0001). ROC curves showed a cut-off value of 220/mm3 (AUC = 0.79, p < 0.0001) or 3% (AUC = 0.81, p < 0.0001) for blood eosinophils to identify sputum eosinophilia >=3%. Independent predictors of sputum neutrophilia were advanced age and high FRC but not blood neutrophil count. CONCLUSION: Eosinophilic and paucigranulocytic asthma are the dominant inflammatory phenotypes. Blood eosinophils provide a practical alternative to predict sputum eosinophilia but sputum neutrophil count is poorly related to blood neutrophils.
Disciplines :
Cardiovascular & respiratory systems
Author, co-author :
SCHLEICH, FLorence ; Centre Hospitalier Universitaire de Liège - CHU > Pneumologie-Allergologie
Manise, Maïté ; Université de Liège - ULiège > Département des sciences cliniques > Pneumologie - Allergologie
Sele, Jocelyne
HENKET, Monique ; Centre Hospitalier Universitaire de Liège - CHU > Pneumologie-Allergologie
Seidel, Laurence ; Université de Liège - ULiège > Département des sciences de la santé publique > Informatique médicale et biostatistique
LOUIS, Renaud ; Centre Hospitalier Universitaire de Liège - CHU > Pneumologie-Allergologie
Language :
English
Title :
Distribution of sputum cellular phenotype in a large asthma cohort: predicting factors for eosinophilic vs neutrophilic inflammation.
Green RH, Brightling CE, Woltmann G, Parker D, Wardlaw AJ, Pavord ID. Analysis of induced sputum in adults with asthma: identification of subgroup with isolated sputum neutrophilia and poor response to inhaled corticosteroids. Thorax 2002, 57(10):875-879. 10.1136/thorax.57.10.875, 1746199, 12324674.
Haldar P, Brightling CE, Hargadon B, Gupta S, Monteiro W, Sousa A. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med 2009, 360(10):973-984. 10.1056/NEJMoa0808991, 19264686.
Nair P, Pizzichini MM, Kjarsgaard M, Inman MD, Efthimiadis A, Pizzichini E. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med 2009, 360(10):985-993. 10.1056/NEJMoa0805435, 19264687.
Green RH, Brightling CE, McKenna S, Hargadon B, Parker D, Bradding P. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet 2002, 360(9347):1715-1721. 10.1016/S0140-6736(02)11679-5, 12480423.
Jayaram L, Pizzichini MM, Cook RJ, Boulet LP, Lemiere C, Pizzichini E. Determining asthma treatment by monitoring sputum cell counts: effect on exacerbations. Eur Respir J 2006, 27(3):483-494. 10.1183/09031936.06.00137704, 16507847.
Haldar P, Pavord ID. Noneosinophilic asthma: a distinct clinical and pathologic phenotype. J Allergy Clin Immunol 2007, 119(5):1043-1052. 10.1016/j.jaci.2007.02.042, 17472810.
Simpson JL, Powell H, Boyle MJ, Scott RJ, Gibson PG. Clarithromycin targets neutrophilic airway inflammation in refractory asthma. Am J Respir Crit Care Med 2008, 177(2):148-155. 10.1164/rccm.200707-1134OC, 17947611.
Berry MA, Shaw DE, Green RH, Brightling CE, Wardlaw AJ, Pavord ID. The use of exhaled nitric oxide concentration to identify eosinophilic airway inflammation: an observational study in adults with asthma. Clin Exp Allergy 2005, 35(9):1175-1179. 10.1111/j.1365-2222.2005.02314.x, 16164444.
Schleich FN, Seidel L, Sele J, Manise M, Quaedvlieg V, Michils A. Exhaled nitric oxide thresholds associated with a sputum eosinophil count >/=3% in a cohort of unselected patients with asthma. Thorax 2010, 65(12):1039-1044. 10.1136/thx.2009.124925, 20671307.
Louis R, Sele J, Henket M, Cataldo D, Bettiol J, Seiden L. Sputum eosinophil count in a large population of patients with mild to moderate steroid-naive asthma: distribution and relationship with methacholine bronchial hyperresponsiveness. Allergy 2002, 57(10):907-912. 10.1034/j.1398-9995.2002.23608.x, 12269936.
Juniper EF, Guyatt GH, Epstein RS, Ferrie PJ, Jaeschke R, Hiller TK. Evaluation of impairment of health related quality of life in asthma: development of a questionnaire for use in clinical trials. Thorax 1992, 47(2):76-83. 10.1136/thx.47.2.76, 463574, 1549827.
Juniper EF, O'Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of a questionnaire to measure asthma control. Eur Respir J 1999, 14(4):902-907. 10.1034/j.1399-3003.1999.14d29.x, 10573240.
Delvaux M, Henket M, Lau L, Kange P, Bartsch P, Djukanovic R. Nebulised salbutamol administered during sputum induction improves bronchoprotection in patients with asthma. Thorax 2004, 59(2):111-115. 10.1136/thorax.2003.011130, 1746927, 14760148.
Louis R, Godinas L, Schleich F. Induced Sputum - Towards Normal Values. Non Invasive Assessment of airways inflammation in asthma and COPD 2011, 113-123. 14th, tetrapoleos street, Athens, 115 27, Greece: Paschalidis Medical Publications, Paschalidis@Medical-Books.gr ISBN 978-960-489-104-7 Chapter 7..
Spanevello A, Confalonieri M, Sulotto F, Romano F, Balzano G, Migliori GB. Induced sputum cellularity. Reference values and distribution in normal volunteers. Am J Respir Crit Care Med 2000, 162(3 Pt 1):1172-1174.
Thomas RA, Green RH, Brightling CE, Birring SS, Parker D, Wardlaw AJ. The influence of age on induced sputum differential cell counts in normal subjects. Chest 2004, 126(6):1811-1814. 10.1378/chest.126.6.1811, 15596678.
Gibson PG, Simpson JL, Saltos N. Heterogeneity of airway inflammation in persistent asthma: evidence of neutrophilic inflammation and increased sputum interleukin-8. Chest 2001, 119(5):1329-1336. 10.1378/chest.119.5.1329, 11348936.
Simpson JL, Scott R, Boyle MJ, Gibson PG. Inflammatory subtypes in asthma: assessment and identification using induced sputum. Respirology 2006, 11(1):54-61. 10.1111/j.1440-1843.2006.00784.x, 16423202.
McGrath KW, Icitovic N, Boushey HA, Lazarus SC, Sutherland ER, Chinchilli VM. A large subgroup of mild-to-moderate asthma is persistently noneosinophilic. Am J Respir Crit Care Med 2012, 185(6):612-619. 10.1164/rccm.201109-1640OC, 3326288, 22268133.
Shaw DE, Berry MA, Hargadon B, McKenna S, Shelley MJ, Green RH. Association between neutrophilic airway inflammation and airflow limitation in adults with asthma. Chest 2007, 132(6):1871-1875. 10.1378/chest.07-1047, 17925424.
Romagnoli M, Vachier I, Tarodo D, Meziane H, Chavis C, Bousquet J. Eosinophilic inflammation in sputum of poorly controlled asthmatics. Eur Respir J 2002, 20(6):1370-1377. 10.1183/09031936.02.00029202, 12503691.
Woodruff PG, Khashayar R, Lazarus SC, Janson S, Avila P, Boushey HA. Relationship between airway inflammation, hyperresponsiveness, and obstruction in asthma. J Allergy Clin Immunol 2001, 108(5):753-758. 10.1067/mai.2001.119411, 11692100.
Quaedvlieg V, Sele J, Henket M, Louis R. Association between asthma control and bronchial hyperresponsiveness and airways inflammation: a cross-sectional study in daily practice. Clin Exp Allergy 2009, 39(12):1822-1829. 10.1111/j.1365-2222.2009.03332.x, 19817755.
Hastie AT, Moore WC, Meyers DA, Vestal PL, Li H, Peters SP. Analyses of asthma severity phenotypes and inflammatory proteins in subjects stratified by sputum granulocytes. J Allergy Clin Immunol 2010, 125(5):1028-1036. 10.1016/j.jaci.2010.02.008, 2878277, 20398920.
Dahl M, Tybjaerg-Hansen A, Vestbo J, Lange P, Nordestgaard BG. Elevated plasma fibrinogen associated with reduced pulmonary function and increased risk of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001, 164(6):1008-1011. 10.1164/ajrccm.164.6.2010067, 11587987.
Shields MD, Brown V, Stevenson EC, Fitch PS, Schock BC, Turner G. Serum eosinophilic cationic protein and blood eosinophil counts for the prediction of the presence of airways inflammation in children with wheezing. Clin Exp Allergy 1999, 29(10):1382-1389. 10.1046/j.1365-2222.1999.00667.x, 10520059.
Aldridge RE, Hancox RJ, Cowant JO, Frampton CM, Town GI, Taylor DR. Eosinophils and eosinophilic cationic protein in induced sputum and blood: effects of budesonide and terbutaline treatment. Ann Allergy Asthma Immunol 2002, 89(5):492-497. 10.1016/S1081-1206(10)62087-X, 12452208.
Baigelman W, Chodosh S, Pizzuto D, Cupples LA. Sputum and blood eosinophils during corticosteroid treatment of acute exacerbations of asthma. Am J Med 1983, 75(6):929-936. 10.1016/0002-9343(83)90871-9, 6650547.
Yap E, Chua WM, Jayaram L, Zeng I, Vandal AC, Garrett J. Can we predict sputum eosinophilia from clinical assessment in patients referred to an adult asthma clinic?. Intern Med J 2013, 43(1):46-52. 10.1111/j.1445-5994.2011.02565.x, 21790924.
Pizzichini E, Pizzichini MM, Efthimiadis A, Dolovich J, Hargreave FE. Measuring airway inflammation in asthma: eosinophils and eosinophilic cationic protein in induced sputum compared with peripheral blood. J Allergy Clin Immunol 1997, 99(4):539-544. 10.1016/S0091-6749(97)70082-4, 9111500.
Asai K, Kitaura J, Kawakami Y, Yamagata N, Tsai M, Carbone DP. Regulation of mast cell survival by IgE. Immunity 2001, 14(6):791-800. 10.1016/S1074-7613(01)00157-1, 11420048.
Bettiol J, Radermecker M, Sele J, Henquet M, Cataldo D, Louis R. Airway mast-cell activation in asthmatics is associated with selective sputum eosinophilia. Allergy 1999, 54(11):1188-1193. 10.1034/j.1398-9995.1999.00177.x, 10604555.
Louis RE, Cataldo D, Buckley MG, Sele J, Henket M, Lau LC. Evidence of mast-cell activation in a subset of patients with eosinophilic chronic obstructive pulmonary disease. Eur Respir J 2002, 20(2):325-331. 10.1183/09031936.02.00286302, 12212963.
Abraham E, Nick JA, Azam T, Kim SH, Mira JP, Svetkauskaite D. Peripheral blood neutrophil activation patterns are associated with pulmonary inflammatory responses to lipopolysaccharide in humans. J Immunol 2006, 176(12):7753-7760.
Norzila MZ, Fakes K, Henry RL, Simpson J, Gibson PG. Interleukin-8 secretion and neutrophil recruitment accompanies induced sputum eosinophil activation in children with acute asthma. Am J Respir Crit Care Med 2000, 161(3 Pt 1):769-774.
Baines KJ, Simpson JL, Wood LG, Scott RJ, Gibson PG. Systemic upregulation of neutrophil alpha-defensins and serine proteases in neutrophilic asthma. Thorax 2011, 66(11):942-947. 10.1136/thx.2010.157719, 21785157.
Shirai A. Modeling neutrophil transport in pulmonary capillaries. Respir Physiol Neurobiol 2008, 163(1-3):158-165.
Dakin CJ, Numa AH, Wang H, Morton JR, Vertzyas CC, Henry RL. Inflammation, infection, and pulmonary function in infants and young children with cystic fibrosis. Am J Respir Crit Care Med 2002, 165(7):904-910. 10.1164/ajrccm.165.7.2010139, 11934712.
Peterson-Carmichael SL, Harris WT, Goel R, Noah TL, Johnson R, Leigh MW. Association of lower airway inflammation with physiologic findings in young children with cystic fibrosis. Pediatr Pulmonol 2009, 44(5):503-511. 10.1002/ppul.21044, 19382221.
