The clinical utility of biomarkers in asthma and COPD

Current Opinion in Pharmacology

Volumn 8, Issue 3, 2008, Pages 222-235

  Snell, Noel ^a,b   Newbold, Paul ^a  

^a ASTRAZENECA   (United Kingdom)

^b NATIONAL HEART AND LUNG INSTITUTE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIINFLAMMATORY AGENT; BETA 2 ADRENERGIC RECEPTOR STIMULATING AGENT; BIOLOGICAL MARKER; BRONCHODILATING AGENT; C REACTIVE PROTEIN; CILOMILAST; CORTICOSTEROID; FORMOTEROL; GLUCOCORTICOID; LEUKOTRIENE RECEPTOR BLOCKING AGENT; NITRIC OXIDE; OMALIZUMAB; SALBUTAMOL; SALMETEROL;

ASTHMA; BLOOD LEVEL; BRONCHUS BIOPSY; CHRONIC OBSTRUCTIVE LUNG DISEASE; CLINICAL TRIAL; DEATH; DIAGNOSTIC VALUE; DISEASE ACTIVITY; DISEASE SEVERITY; DRUG RESPONSE; EOSINOPHIL; HOSPITALIZATION; HUMAN; LUNG LAVAGE; METHODOLOGY; MONITORING; PREDICTION; PRIORITY JOURNAL; PROGNOSIS; REVIEW; SPUTUM ANALYSIS; URINE LEVEL;

ASTHMA; BIOLOGICAL MARKERS; BIOPSY; BREATH TESTS; BRONCHOALVEOLAR LAVAGE; HUMANS; NITRIC OXIDE; PULMONARY DISEASE, CHRONIC OBSTRUCTIVE; SPUTUM;

EID: 44649195652     PISSN: 14714892     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.coph.2008.04.001     Document Type: Review

References (177)

1. Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 69 (2001) 89-95
2. Baker M. In biomarkers we trust?. Nat Biotechnol 23 (2005) 297-304
3. Stockley R., and Bayley D. Validation of assays for inflammatory mediators in sputum. Eur Respir J 15 (2000) 778-781
4. Smith A.D., Cowan J.O., Filsell S., McLachlan C., Monti-Sheehan G., Jackson P., and Taylor D.R. Diagnosing asthma: comparisons between exhaled nitric oxide measurements and conventional tests. Am J Respir Crit Care Med 169 (2004) 473-478
5. Rutgers S.R., Timens W., Kaufmann H.F., van der Mark T.W., Koeter G.H., and Postma D.S. Comparison of induced sputum with bronchial wash, bronchoalveolar lavage and bronchial biopsies in COPD. Eur Respir J 15 (2000) 109-115
6. Schoonbrood D.F., Lutter R., Habets F.J., Roos C.M., Jansen H.M., and Out T.A. Analysis of plasma-protein leakage and local secretion in sputum from patients with asthma and chronic obstructive pulmonary disease. Am J Respir Crit Care Med 150 (1994) 1519-1527
7. Bhowmik A., Seemungal T.A., Sapsford R.J., Devalia J.L., and Wedzicha J.A. Comparison of spontaneous and induced sputum for investigation of airway inflammation in chronic obstructive pulmonary disease. Thorax 53 (1998) 953-956
8. Pizzichini M.M., Popov T.A., Efthimiadis A., Hussack P., Evans S., Pizzichini E., Dolovich J., and Hargreave F.E. Spontaneous and induced sputum to measure indices of airway inflammation in asthma. Am J Respir Crit Care Med 154 (1996) 866-869
9. Belda J., Leigh R., Parameswaran K., O'Byrne P.M., Sears M.R., and Hargreave F.E. Induced sputum cell counts in healthy adults. Am J Respir Crit Care Med 161 (2000) 475-478
10. Thomas R., Green R., Brightling C., Birring S., Parker D., Wardlaw A., and Pavord I. The influence of age on induced sputum differential cell counts in normal subjects. Chest 126 (2004) 1811-1814
11. van der Vaart H., Postma D., Timens W., Kauffman H., Hylkema M., and ten Hacken N. Repeated sputum inductions induce a transient neutrophilic and eosinophilic response. Chest 130 (2006) 1157-1164
12. Wilson A., Leigh R., Hargreave F., Pizzichini M., and Pizzichini E. Safety of sputum induction in moderate-to-severe smoking-related chronic obstructive pulmonary disease. COPD: J Chron Obst Pulm Dis 3 (2006) 89-93
13. Sethi S., Muscarella K., Evans N., Klingman K.L., Grant B.J.B., and Murphy T.F. Airway inflammation and etiology of acute exacerbations of chronic bronchitis. Chest 118 (2000) 1557-1565
14. in't Veen J., de Gouw H., Smits H., Sont J., Hiemstra P., Sterk P., and Bel E. Repeatability of cellular and soluble markers of inflammation in induced sputum from patients with asthma. Eur Respir J 9 (1996) 2442-2447
15. Boorsma M., Lutter R., van der Pol M., Out T., Jansen H., and Jonkers R. Repeatability of inflammatory parameters in induced sputum of COPD patients. COPD: J Chron Obst Pulm Dis 4 (2007) 321-329
16. Djukanovic R., Sterk P.J., Fahy J.V., and Hargreave F.E. Standardised methodology of sputum induction and processing. Eur Respir J 20 Suppl. 37 (2002) 1s-55s. The most recent consensus recommendations on methodology for obtaining and processing sputum samples.
17. Erin E., Barnes P., and Hansel T. Optimising sputum methodology. Clin Exp Allergy 32 (2002) 653-657
18. Mikami M., Llewellyn-Jones C., Bayley D., Hill S., and Stockley R. The chemotactic activity of sputum from patients with bronchiectasis. Am J Respir Crit Care Med 157 (1998) 723-728
19. Grebski E., Peterson C., and Medici T. Effect of physical and chemical homogenisation on inflammatory mediators in sputum of asthma patients. Chest 119 (2001) 1521-1525
20. Wooten O., and Dulfano M. Improved homogenization techniques for sputum cytology counts. Ann Allergy 41 (1978) 150-154
21. Woolhouse I., Bayley D., and Stockley R. Effect of sputum processing with dithiothreitol on the detection of inflammatory mediators in chronic bronchitis and bronchiectasis. Thorax 57 (2002) 667-671
22. Pignatti P., Delmastro M., Perfetti L., Bossi A., Balestrino A., Di Stefano A., Pisati P., Balbi B., and Moscato G. Is dithiothreitol affecting cells and soluble mediators during sputum processing? A modified methodology to process sputum. J Allergy Clin Immunol 110 (2002) 667-669
23. Erin E., Jenkins G., Kon O., Zacharasiewicz A., Nicholson G., Neighbour H., Tennant R., Tan A., Leaker B., Bush A., et al. Optimised dialysis and protease inhibition of sputum dithiothreitol supernatants. Am J Respir Crit Care Med 177 (2008) 132-141
24. Louis R., Shute J., Goldring K., Perks B., Lau L., Radermecker M., and Djukanovic R. The effect of processing on inflammatory markers in induced sputum. Eur Respir J 13 (1999) 660-667
25. Workshop, summary and guidelines: investigative use of bronchoscopy, lavage and bronchial biopsies in asthma and other airway diseases. J Allergy Clin Immunol 88 (1991) 808-814
26. Baughman R. Technical aspects of bronchoalveolar lavage: recommendations for a standard procedure. Semin Respir Crit Care Med 28 (2007) 475-485. A useful practical review of bronchoalveolar lavage technique.
27. Reynolds H. Bronchoalveolar lavage. Am Rev Respir Dis 135 (1987) 250-263
28. Trigg C., Freestone D., Lee T., and Mant T. Death of a healthy student volunteer in a US research study: lessons for bronchoscopic practice. Int J Pharm Med 12 (1998) 151-153
29. Dargaville P., South M., Vervaart P., and McDougall P. Validity of markers of dilution in small volume lung lavage. Am J Respir Crit Care Med 160 (1999) 778-784
30. Rose A., and Knox K. Bronchoalveolar lavage as a research tool. Semin Respir Crit Care Med 28 (2007) 561-573
31. Haslam P., and Baughman R. ERS task force report on measurement of acellular components in BAL. Eur Respir Rev 9 (1999) 25-27
32. Gershman N., Liu H., Wong H., Liu J., and Fahy J. Fractional analysis of sequential induced sputum samples during sputum induction: evidence that different lung compartments are sampled at different time points. J Allergy Clin Immunol 104 (1999) 322-328
33. Silkoff P., Trudeau J., Gibbs R., and Wenzel S. The relationship of induced-sputum inflammatory cells to BAL and biopsy. Chest 123 Suppl. (2003) 371S-372S
34. Maestrelli P., Saetta M., Di Stefano A., Calcagni P., Turato G., Ruggieri M., Roggeri A., Mapp C., and Fabbri L. Comparison of leukocyte counts in sputum, bronchial biopsies, and bronchoalveolar lavage. Am J Respir Crit Care Med 152 (1995) 1926-1931
35. Fabbri L., Durham S., Holgate S., O'Byrne P., and Postma D. Assessment of airway inflammation: an overview. Eur Respir J 26 Suppl. (1998) 6S-8S
36. Jeffery P., Holgate S., and Wenzel S. Methods for the assessment of endobronchial biopsies in clinical research: application to studies of pathogenesis and the effects of treatment. Am J Respir Crit Care Med 168 (2003) S1-S17. Authoritative statement on bronchial biopsy assessments in clinical trials.
37. Gamble E., Qiu Y., Wang D., Zhu J., Vignola A., Kroegel C., Morell F., Hansel T., Pavord I., Rabe K., et al. Variability of bronchial inflammation in chronic obstructive pulmonary disease: implications for study design. Eur Respir J 27 (2006) 293-299
38. American Thoracic Society/European Respiratory Society. Recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide. Am J Respir Crit Care Med 171 (2005) 912-930. Generally accepted standards for the measurement of exhaled NO.
39. Kharitonov S., and Barnes P. Biomarkers of some pulmonary diseases in exhaled breath. Biomarkers 7 (2002) 1-32
40. Haight R., Gordon R., and Brooks S. The effects of age on exhaled breath nitric oxide levels. Lung 184 (2006) 113-119
41. Kovesi T., Ryan K., and Dalls R. Exhaled nitric oxide concentration is affected by age, height, and race in healthy 9- to 12-year-old children. Chest 133 (2008) 169-175
42. Horvath I., Loukides S., Wodehouse T., Csiszer E., Cole P., Kharitonov S., and Barnes P. Comparison of exhaled and nasal nitric oxide and exhaled carbon monoxide levels in bronchiectatic patients with and without primary ciliary dyskinesia. Thorax 58 (2003) 68-72
43. Turner S., Craig L., Harbour P., Forbes S., Martindale S., McNeill G., Seaton A., Ayres J., Devereux G., and Helms P. Carbonated drink consumption and increased exhaled nitric oxide in atopic children. Eur Respir J 30 (2008) 177-178
44. Kharitonov S., Gonio F., Kelly C., Meah S., and Barnes P. Reproducibility of exhaled nitric oxide measurements in healthy and asthmatic adults and children. Eur Respir J 21 (2003) 433-438
45. van Beurden W., Dekhuijzen P., and Smeenk F. Exhaled biomarkers in COPD: their potential role in diagnosis, treatment and prognosis. Monaldi Arch Chest Dis 57 (2002) 258-267
46. Liu J., Sandrini A., Thurston M., Yates D., and Thomas P. Nitric oxide and exhaled breath nitrite/nitrates in chronic obstructive pulmonary disease patients. Respiration 74 (2007) 617-623
47. Zietkowski Z., Kucharewicz I., and Bodzenta-Lukasyk A. The influence of inhaled corticosteroids on exhaled nitric oxide in stable chronic obstructive pulmonary disease. Respir Med 99 (2005) 816-824
48. George S., Hogman M., Permutt S., and Silkoff P. Modeling pulmonary nitric oxide exchange. J Appl Physiol 96 (2004) 831-839
49. Brindicci C., Ito K., Resta O., Pride N., Barnes P., and Kharitonov S. Exhaled nitric oxide from lung periphery is increased in COPD. Eur Respir J 26 (2005) 52-59
50. Kharitonov S., Paredi P., and Barnes P. Reproducibility of exhaled carbon monoxide measurements and its circadian variation in normal subjects. Am J Respir Crit Care Med 157 (1998) 1051-1055
51. Stirling R., Lim S., Kharitonov S., Chung F., and Barnes P. Exhaled breath carbon monoxide is minimally elevated in severe but not mild atopic asthma. Am J Respir Crit Care Med 161 (2000) A922
52. Ramirez M., García-Río F., Viñas A., Prados C., Pino J., and Villamor J. Relationship between exhaled carbon monoxide and airway hyperresponsiveness in asthmatic patients. J Asthma 41 (2004) 109-116
53. Middleton E., and Morice A. Breath carbon monoxide as an indication of smoking habit. Chest 117 (2000) 758-763
54. Horvath I., Hunt J., Barnes P., and on behalf of the ATS/ERS task force on exhaled breath condensate. Exhaled breath condensate: methodological recommendations and unresolved questions. Eur Respir J 26 (2005) 523-548. Detailed and thoughtful review of the topic.
55. Hoffman H., Tabaksblat L., Enghild J., and Dahl R. Human skin keratins are the major proteins in exhaled breath condensate. Eur Respir J 31 (2008) 380-384
56. Liu J., Conrad D., Chow S., Tran V., Yates D., and Thomas P. Collection devices influence the constituents of exhaled breath condensate. Eur Respir J 30 (2007) 807-808
57. Rosias P., Robroeks C., Niemarkt H., Kester A., Vernooy J., Suykerbuyk J., Teunissen J., Heynens J., Hendricks H., Jobsis Q., and Dompeling E. Breath condenser coatings affect measurement of biomarkers in exhaled breath condensate. Eur Respir J 28 (2006) 1036-1041
58. Boot J., Panzer P., and Diamant Z. A critical appraisal of methods used in early clinical development of novel drugs for the treatment of asthma. Pulm Pharmacol Ther 20 (2007) 201-219
59. Wark P., and Gibson P. Clinical usefulness of inflammatory markers in asthma. Am J Respir Med 2 (2003) 11-19
60. Gutiérrez V., Prieto L., Torres V., Trenor R., Pérez C., Bertó J., and Marín J. Relationship between induced sputum cell counts and fluid-phase eosinophil cationic protein and clinical or physiologic profiles in mild asthma. Ann Allergy Asthma Immunol 82 (1999) 559-565
61. Pin I., Freitag A., and O'Byrne P. Changes in the cellular profile of induced sputum after allergen-induced asthmatic responses. Am J Respir Crit Care Med 145 (1992) 1265-1269
62. in't Veen J., Smits H., Hiemstra P., Zwinderman A., Sterk P., and Bel E. Lung function and sputum characteristics of patients with severe asthma during an induced exacerbation by double-blind steroid withdrawal. Am J Respir Crit Care Med 160 (1999) 93-99
63. Di Franco A., Bartoli M., Carnevali S., Cianchetti S., Bacci E., Dente F., Giannini D., Taccola M., Vagaggini B., and Paggiaro P. Analysis of sputum cell counts during spontaneous moderate exacerbations of asthma in comparison to the stable phase. J Asthma 40 (2003) 155-162
64. Gibson P., Simpson J., Hankin R., Powell H., and Henry R. Relationship between induced sputum eosinophils and the clinical pattern of childhood asthma. Thorax 58 (2003) 116-121
65. Park S., Kim J., Chang H., Park S., Lee Y., Park J., Chun I., Lee J., and Park C. Association of interleukin-5 and eotaxin with acute exacerbation of asthma. Int Arch Allergy Immunol 131 (2003) 283-290
66. Jatakanon A., Uasuf C., Maziak W., Lim S., Chung K., and Barnes P. Neutrophilic inflammation in severe persistent asthma. Am J Respir Crit Care Med 160 (1999) 1532-1539
67. Louis R., Lau L., Bron A., Roldaan A., Radermecker M., and Djukanovic R. The relationship between airways inflammation and asthma severity. Am J Respir Crit Care Med 161 (2000) 9-16
68. Maneechotesuwan K., Essilfie-Quaye S., Kharitonov S., Adcock I., and Barnes P. Loss of control of asthma following inhaled corticosteroid withdrawal is associated with increased sputum interleukin-8 and neutrophils. Chest 132 (2007) 98-105
69. Obase Y., Shimoda T., Mitsuta K., Matsuo N., Matsuse H., and Kohno S. Correlation between airway hyperresponsiveness and airway inflammation in a young adult population: eosinophil, ECP, and cytokine levels in induced sputum. Ann Allergy Asthma Immunol 86 (2001) 304-310
70. Berry M., Hargadon B., Shelley M., Shaw D., McKenna S., Bradding P., Brightling C., Wardlaw A., Green R., and Pavord I. Etanercept in refractory asthma: a randomised controlled trial. Am J Respir Crit Care Med 171 Suppl (2005) A569
71. Giannini D., Di Franco A., Cianchetti S., Bacci E., Dente F., Vagaggini B., and Paggiaro P. Analysis of induced sputum before and after withdrawal of treatment with inhaled corticosteroids in asthmatic patients. Clin Exp Allergy 30 (2000) 1777-1784
72. Green R., Brightling C., McKenna S., Hargadon B., Parker D., Bradding P., Wardlaw A., and Pavord I. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet 360 (2002) 1715-1721. Study that demonstrated the value of basing adjustments of treatment on biomarker measurements.
73. Lamkhioued B., Renzi P., Abi-Younes S., Garcia-Zepada E., Allakhverdi Z., Ghaffar O., Rothenberg M., Luster A., and Hamid Q. Increased expression of eotaxin in bronchoalveolar lavage and airways of asthmatics contributes to the chemotaxis of eosinophils to the site of inflammation. J Immunol 159 (1997) 4593-4601
74. Lezcano-Meza D., Negrete-Garcia M., Dante-Escobedo M., and Teran L. The monocyte-derived chemokine is released in the bronchoalveolar lavage fluid of steady-state asthmatics. Allergy 58 (2003) 1125-1130
75. Pilette C., Francis J., Till S., and Durham. CCR4 ligands are up-regulated in the airways of atopic asthmatics after segmental allergen challenge. Eur Respir J 23 (2004) 876-884
76. Liu L., Jarjour N., Busse W., and Kelly E. Enhanced generation of helper T type 1 and 2 chemokines in allergen-induced asthma. Am J Respir Crit Care Med 169 (2004) 1118-1124
77. Itillie-Leblond I., Hammad H., Desurmont S., Pugin J., Wallaert B., Tonnel A., and Gosset P. CC chemokines and interleukin-5 in bronchial lavage fluid from patients with status asthmaticus. Potential implication in eosinophil recruitment. Am J Respir Crit Care Med 162 (2000) 586-592
78. Tonnel A., Gosset P., and Tillie-Leblond I. Characteristics of the inflammatory response in bronchial lavage fluids from patients with status asthmaticus. Int Arch Allergy Immunol 124 (2001) 267-271
79. Carroll N., Cooke C., and James A. The distribution of eosinophils and lymphocytes in the large and small airways of asthmatics. Eur Respir J 10 (1997) 292-300
80. Lim S., Jatakanon A., Meah S., Oates T., Chung K., and Barnes P. Relationship between exhaled nitric oxide and mucosal eosinophilic inflammation in mild to moderately severe asthma. Thorax 55 (2000) 184-188
81. Benayoun L., Druilhe A., Dombret M.-C., Aubier M., and Pretolani M. Airway structural alterations selectively associated with severe asthma. Am J Respir Crit Care Med 167 (2003) 1360-1368
82. Zeidler M., Kleerup E., and Tashkin D. Exhaled nitric oxide in the assessment of asthma. Curr Opin Pulm Med 10 (2003) 31-36
83. Covar R., Szefler S., Martin R., Sundstrom B., Silkoff P., Murphy J., Young D., and Spahn J. Relations between exhaled nitric oxide and measures of disease activity among children with mild-to-moderate asthma. J Pediatr 142 (2003) 469-475
84. Smith A., Cowan J., Brassett K., Herbison P., and Taylor D. Use of exhaled nitric oxide measurements to guide treatment in chronic asthma. N Engl J Med 352 (2005) 2163-2173
85. Harkins M., Fiato K., and Iwamoto G. Exhaled nitric oxide predicts asthma exacerbation. J Asthma 41 (2004) 471-476
86. Parra A., Sanz M., Vila L., Prieto I., Dieguez I., and Oehling A. Eosinophil soluble protein levels, eosinophil peroxidase and eosinophil cationic protein in asthmatic patients. J Invest Allergol Clin Immunol 9 (1999) 27-34
87. Gibson P., Dolovich J., Girgis-Gabardo A., Morris M., Anderson M., Hargreave F., and Denburg J. The inflammatory response in asthma exacerbation: changes in circulating eosinophils, basophils and their progenitors. Clin Exp Allergy 20 (1990) 661-668
88. Tateno H., Nakamura H., Minematsu N., Nakajima T., Takahashi S., Nakamura M., Fukunaga K., Asano K., Lilly C., and Yamaguchi K. Plasma eotaxin level and severity of asthma treated with corticosteroid. Respir Med 98 (2004) 782-790
89. Leung T., Wong G., Ko F., Lam C., and Fok T. Increased macrophage-derived chemokine in exhaled breath condensate and plasma from children with asthma. Clin Exp Allergy 34 (2004) 786-791
90. Kalayi O., Sonna L., Woodruff P., Camargo C., Luster A., and Lilly C. Monocyte Chemotactic Protein-4 (MCP-4; CCL-13): a biomarker of asthma. J Asthma 41 (2004) 27-33
91. Leckie M., ten Brinke A., Khan J., Diamant Z., O'Connor B., Walls C., Mathur A., Cowley H., Chung K., Djukanovic R., et al. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 356 (2000) 2144-2148. Key study that showed lack of clinical response despite achieving biomarker endpoint (reduction in circulating eosinophils). In this case it is likely that the wrong body compartment was chosen: A reduction in local (tissue) eosinophils was probably more relevant to the disease process, and only a modest fall was achieved (see reference [92]).
92. Kay A. The role of eosinophils in the pathogenesis of asthma. Trends Mol Med 11 (2005) 148-152
93. Siroux V., Oryszczyn M.-P., Paty E., Kauffmann F., Pison C., Vervloet D., and Pin I. Relationships of allergic sensitization, total immunoglobulin E and blood eosinophils to asthma severity in children of the EGEA Study. Clin Exp Allergy 33 (2003) 746-751
94. Djukanovic R., Wilson S., Kraft M., Jarjour N., Steel M., Chung K., Bao W., Fowler-Taylor A., Matthews J., Busse W., et al. Effects of treatment with anti-immunoglobulin E antibody omalizumab on airway inflammation in allergic asthma. Am J Respir Crit Care Med 170 (2004) 583-593
95. Lanier B., Corren J., Lumry W., Liu J., Fowler-Taylor A., and Gupta N. Omalizumab is effective in the long-term control of severe allergic asthma. Ann Allergy Asthma Immunol 91 (2003) 154-159
96. Fabbri L., Romagnoli M., Corbetta L., Casoni G., Busljetic K., Turato G., Ligabue G., Ciaccia A., Saetta M., and Papi A. Differences in airway inflammation in patients with fixed airflow obstruction due to asthma or chronic obstructive pulmonary disease. Am J Respir Crit Care Med 167 (2003) 418-424
97. Keatings V., Collins P., Scott D., and Barnes P. Differences in interleukin-8 and tumor necrosis factor-alpha in induced sputum from patients with chronic obstructive pulmonary disease or asthma. Am J Respir Crit Care Med 153 (1996) 530-534
98. Keatings V., and Barnes P. Granulocyte activation markers in induced sputum: comparison between chronic obstructive pulmonary disease, asthma, and normal subjects. Am J Respir Crit Care Med 155 (1997) 449-453
99. Stanescu D., Sanna A., Veriter C., Kostianev S., Calcagni P., Fabbri L., and Maestrelli P. Airways obstruction, chronic expectoration, and rapid decline of FEV1 in smokers are associated with increased levels of sputum neutrophils. Thorax 51 (1996) 267-271
100. O'Donnell R., Peebles C., Ward J., Daraker A., Angco G., Broberg P., Pierrou S., Lund J., Holgate S., Davies D., et al. Relationship between peripheral airway dysfunction, airway obstruction, and neutrophilic inflammation in COPD. Thorax 59 (2004) 837-842
101. Yamamoto C., Yoneda T., Yoshikawa M., Fu A., Tokuyama T., Tsukaguchi K., and Narita N. Airway inflammation in COPD assessed by sputum levels of interleukin-8. Chest 112 (1997) 505-510
102. Traves S., Culpitt S., Russell R., Barnes P., and Donnelly L. Increased levels of the chemokines GROα and MCP-1 in sputum samples from patients with COPD. Thorax 57 (2002) 590-595
103. Hill A., Bayley D., and Stockley R. The interrelationship of sputum inflammatory markers in patients with chronic bronchitis. Am J Respir Crit Care Med 160 (1999) 893-898
104. Barnes P., Chowdhury B., Kharitonov S., Magnussen H., Page C., Postma D., and Saetta M. Pulmonary biomarkers in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 174 (2006) 6-14
105. Bhowmik A., Seemungal T., Sapsford R., and Wedzicha J. Relation of sputum inflammatory markers to symptoms and lung function changes in COPD exacerbations. Thorax 55 (2000) 114-120
106. Aaron S., Angel J., Lunau M., Wright K., Fex C., Le Saux N., and Dales R. Granulocyte inflammatory markers and airway infection during acute exacerbation of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 163 (2001) 349-355
107. Hacievliyagil S., Gunen H., Mutlu L., Karabulut A., and Temel I. Association between cytokines in induced sputum and severity of chronic obstructive pulmonary disease. Respir Med 100 (2006) 846-854
108. Sethi S., Muscarella K., Evans N., Klingman K., Grant B., and Murphy T. Airway inflammation and etiology of acute exacerbations of chronic bronchitis. Chest 118 (2000) 1557-1565
109. Gompertz S., O'Brien C., Bayley D., Hill S., and Stockley R. Changes in bronchial inflammation during acute exacerbations of chronic bronchitis. Eur Respir J 17 (2001) 1112-1119
110. 1-antitrypsin deficiency (PiZ). Am J Respir Crit Care Med 160 (1999) 1968-1975
111. Patel I., Vlahos I., Wilkinson T., Lloyd-Owen S., Donaldson G., Wilks M., Reznek R., and Wedzicha J. Bronchiectasis, exacerbation indices, and inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 170 (2004) 400-407
112. Balzano G., Stefanelli F., Iorio C., De Felice A., Melillo E., Martucci M., and Melillo G. Eosinophilic inflammation in stable chronic obstructive pulmonary disease. Relationship with neutrophils and airway function. Am J Respir Crit Care Med 160 (1999) 1486-1492
113. Snoeck-Stroband J., Lapperre T., Gosman M., Boezen H., Timens W., ten Hacken N., Sont J., Sterk P., and Hiemstra P. Chronic bronchitis sub-phenotype within COPD: inflammation in sputum and biopsies. Eur Respir J 31 (2008) 70-77
114. Saetta M., Di Stefano A., Maestrelli P., Turato G., Ruggieri M., Roggeri A., Calcagni P., Mapp C., Ciaccia A., and Fabbri L. Airway eosinophilia in chronic bronchitis during exacerbations. Am J Respir Crit Care Med 150 (1994) 1646-1652
115. Laperre T., Snoeck-Stroband J., Gosman M., Stolk J., Sont J., Jansen D., Kerstjens H., Postma D., and Sterk P. Dissociation of lung function and airway inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 170 (2004) 499-504
116. Tzanakis N., Chrysofakis G., Tsoumakidou M., Kyriakou D., Tsiligianni J., Bouros D., and Siafakis N. Induced sputum CD8+ T-lymphocyte subpopulations in chronic obstructive pulmonary disease. Respir Med 98 (2004) 57-65
117. Pesci A., Balbi B., Majori M., Cacciani G., Bertacco S., Alciato P., and Donner C. Inflammatory cells and mediators in bronchial lavage of patients with chronic obstructive pulmonary disease. Eur Respir J 12 (1998) 380-386
118. Soler N., Ewig S., Torres A., Filella X., Gonzalez J., and Zaubet A. Airway inflammation and bronchial microbial patterns in patients with stable chronic obstructive pulmonary disease. Eur Respir J 14 (1999) 1015-1022
119. Hodge G., Nairn J., Holmes M., Reynolds P., and Hodge S. Increased intracellular T helper 1 proinflammatory cytokine production in peripheral blood, bronchoalveolar lavage and intraepithelial T cells of COPD subjects. Clin Exp Immunol 150 (2007) 22-29
120. Riise G., Ahlstedt S., Larsson S., Enander I., Jones I., Larsson P., and Andersson B. Bronchial inflammation in chronic bronchitis assessed by measurement of cell products in bronchial lavage fluid. Thorax 50 (1995) 360-365
121. Miller M., Ramsdell J., Friedman P., Cho J., Renvall M., and Broide D. Computed tomographic scan-diagnosed chronic obstructive pulmonary disease-emphysema: eotaxin-1 is associated with bronchodilator response and extent of emphysema. J Allergy Clin Immunol 120 (2007) 1118-1125
122. Pesci A., Majori M., Cuomo A., Borciani N., Bertacco S., Cacciani G., and Gabrielli M. Neutrophils infiltrating bronchial epithelium in chronic obstructive pulmonary disease. Respir Med 92 (1998) 863-870
123. Bocchino V., Bertorelli G., Bertrand C., Ponath P., Newman W., Franco C., Marruchella A., Merlini S., DelDonno M., Zhuo X., and Olivieri D. Eotaxin and CCR3 are upregulated in exacerbations of chronic bronchitis. Allergy 57 (2002) 17-22
124. Di Stefano A., Capelli A., Lusardi M., Balbo P., Vecchio C., Maestrelli P., Mapp C., Fabbri L., Donner C., and Saetta M. Severity of airflow limitation is associated with severity of airway inflammation in smokers. Am J Respir Crit Care Med 158 (1998) 1277-1285
125. Qiu Y., Zhu J., Bandi V., Atmar R., Hattotuwa K., Guntupalli K., and Jeffery P. Biopsy neutrophilia, neutrophil chemokine and receptor gene expression in severe exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 168 (2003) 968-975
126. Corradi M., Majori M., Cacciani G., Consigli G., de'Munari E., and Pesci A. Increased exhaled nitric oxide in patients with stable chronic obstructive pulmonary disease. Thorax 54 (1999) 572-575
127. Agusti A., Villaverde J., Togores B., and Bosch M. Serial measurements of exhaled nitric oxide during exacerbations of chronic obstructive pulmonary disease. Eur Respir J 14 (1999) 523-528
128. Maziak W., Loukides S., Culpitt S., Sullivan P., Kharitonov S., and Barnes P. Exhaled nitric oxide in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 157 (1998) 998-1002
129. Ansarin K., Chatkin J., Ferreira I., Gutierrez C., Zamel N., and Chapman K. Exhaled nitric oxide in chronic obstructive pulmonary disease: relationship to pulmonary function. Eur Respir J 17 (2001) 934-938
130. Papi A., Romagnoli M., Baraldo S., Braccioni F., Guzzinati I., Saetta M., Ciaccia A., and Fabbri L. Partial reversibility of airflow limitation and increased exhaled NO and sputum eosinophilia in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 162 (2000) 1773-1777
131. Ferreira I., Hazari M., Gutierrez C., Zamel N., and Chapman K. Exhaled nitric oxide and hydrogen peroxide in patients with chronic obstructive pulmonary disease. Effects of inhaled beclomethasone. Am J Respir Crit Care Med 164 (2001) 1012-1015
132. Loppow D., Schleiss M., Kanniess F., Taube C., Jorres R., and Magnussen H. In patients with chronic bronchitis a four week trial with inhaled steroids does not attenuate airway inflammation. Respir Med 95 (2001) 115-121
133. Paredi P., Kharitonov S., Leak D., Ward S., Cramer D., and Barnes P. Exhaled ethane, a marker of lipid peroxidation, is elevated in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 162 (2000) 369-373
134. Montuschi P., Collins J., Ciabattoni G., Lazzeri N., Corradi M., Kharitonov S., and Barnes P. Exhaled 8-isoprostane as an in vivo biomarker of lung oxidative stress in patients with COPD and healthy smokers. Am J Respir Crit Care Med 162 (2000) 1175-1177
135. Biernacki W., Kharitonov S., and Barnes P. Increased leukotriene B4 and 8-isoprostane in exhaled breath condensate of patients with exacerbations of COPD. Thorax 58 (2003) 294-298
136. Corradi M., Rubinstein I., Andreoli, Manini P., Caglieri A., Poli D., Alinovi R., and Mutti A. Aldehydes in exhaled breath condensate of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 167 (2003) 1380-1386
137. Carpagnano G., Kharitonov S., Foschino-Barbaro M., Resta O., Gramiccioni E., and Barnes P. Increased inflammatory markers in the exhaled breath condensate of cigarette smokers. Eur Respir J 21 (2003) 589-593
138. Bucchioni E., Kharitonov S., Allegra L., and Barnes P. High levels of interleukin-6 in the exhaled breath condensate of patients with COPD. Respir Med 97 (2003) 1299-1302
139. Montuschi P., Kharitonov S., Ciabattoni G., and Barnes P. Exhaled leukotrienes and prostaglandins in COPD. Thorax 58 (2003) 585-858
140. Agusti A., Noguera A., Sauleda J., Sala E., Pons J., and Busquets X. Systemic effects of chronic obstructive pulmonary disease. Eur Respir J 21 (2003) 347-360
141. Frohlich M., Sund M., Lowel H., Imhof A., Hoffmeister A., and Koenig W. Independent association of various smoking characteristics with markers of systemic inflammation in men. Results from a representative sample of the general population (MONICA Augsburg Survey 1994/95). Eur Heart J 24 (2003) 1365-1372
142. Noguera A., Busquets X., Sauleda J., Villaverde J., MacNee W., and Agusti A. Expression of adhesion molecules and G proteins in circulating neutrophils in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 158 (1998) 1664-1668
143. Dentener M., Creutzberg E., Schols A., Mantovani A., van't Veer C., Buurman W., and Wouters E. Systemic anti-inflammatory mediators in COPD: increase in soluble interleukin 1 receptor II during treatment of exacerbations. Thorax 56 (2001) 721-726
144. Dahl M., Vestbo J., Lange P., Bojesen S., Tybjaerg-Hansen A., and Nordestgaard B. C-reactive protein as a predictor of prognosis in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 175 (2007) 250-255
145. Dev D., Wallace E., Sankaran R., Cunniffe J., Govan J., Wathen C., and Emmanuel F. Value of C-reactive protein measurements in exacerbations of chronic obstructive pulmonary disease. Respir Med 92 (1998) 664-667
146. Weis N., and Almdal T. C-reactive protein-can it be used as a marker of infection in patients with exacerbation of chronic obstructive pulmonary disease?. Eur J Intern Med 17 (2006) 88-91
147. Gompertz S., Bayley D., Hill S., and Stockley R. Relationship between airway inflammation and the frequency of exacerbations in patients with smoking related COPD. Thorax 56 (2001) 36-41
148. Di Francia M., Barbier D., Mege J., and Orehek J. Tumor necrosis factor-alpha levels and weight loss in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 150 (1994) 1453-1455
149. de Godoy I., Donahoe M., Calhoun W., Mancino J., and Rogers R. Elevated TNF-alpha production by peripheral blood monocytes of weight-losing COPD patients. Am J Respir Crit Care Med 153 (1996) 633-637
150. Eid A., Ionescu A., Nixon L., Lewis-Jenkins V., Matthews S., Griffiths T., and Shale D. Inflammatory response and body composition in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 164 (2001) 1414-1418
151. Takabatake N., Nakamura H., Abe S., Inoue S., Hino T., Saito H., Yuki H., Kato S., and Tomoike H. The relationship between chronic hypoxemia and activation of the tumor necrosis factor-α system in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 161 (2000) 1179-1184
152. Vernooy J., Küçükaycan M., Jacobs J., Chavannes N., Buurman W., Dentener M., and Wouters E. Local and systemic inflammation in patients with chronic obstructive pulmonary disease: soluble tumor necrosis factor receptors are increased in sputum. Am J Respir Crit Care Med 166 (2002) 1218-1224
153. Aldonyte R., Eriksson S., Piitulainen E., Wallmark A., and Janciauskiene S. Analysis of systemic biomarkers in COPD patients. COPD: J Chr Obst Pulm Dis 1 (2004) 155-164
154. Fiorini G., Crespi S., Rinaldi M., Oberti E., Vigorelli R., and Palmieri G. Serum ECP and MPO are increased during exacerbations of chronic bronchitis with airway obstruction. Biomed Pharmacother 54 (2000) 274-278
155. Roland M., Bhowmik A., Sapsford R., Seemungal T., Jeffries D., Warner T., and Wedzicha J. Sputum and plasma endothelin-1 levels in exacerbations of chronic obstructive pulmonary disease. Thorax 56 (2001) 30-35
156. Sin D., and Man S. Impaired lung function and serum leptin in men and women with normal body weight: a population based study. Thorax 58 (2003) 695-698
157. Wedzicha J., Seemungal T., MacCallum P., Paul E., Donaldson G., Bhowmik A., Jeffries D., and Meade T. Acute exacerbations of chronic obstructive pulmonary disease are accompanied by elevations of plasma fibrinogen and serum IL-6 levels. Thromb Haemost 84 (2000) 210-215
158. Groenewegen K., Dentener M., and Wouters E. Longitudinal follow-up of systemic inflammation after acute exacerbations of COPD. Respir Med 101 (2007) 2409-2415
159. Dahl M., Tyboerg-Hansen A., Vestbo J., Lang P., and Nordestgaad B. Elevated plasma fibrinogen associated with reduced pulmonary function and increased risk of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 164 (2001) 1008-1011
160. Rohde G., Gevaert P., Holtappels G., Fransen L., Borg I., Wiethage A., Arinir U., Tavernier J., Schultze-Werninghaus G., and Bachert C. Soluble interleukin-5 receptor alpha is increased in acute exacerbations of chronic obstructive pulmonary disease. Int Arch Allergy Immunol 135 (2004) 54-61
161. Bozinovski S., Thompson M., Hutchinson A., Vlahos R., Black J., Smallwood D., Irving L., and Anderson G. Elevated SAA, but not IP-10, discriminates between non-pathogen and pathogen-associated acute exacerbations of COPD (AECOPD). Respirology 13 Suppl. 2 (2008) A44
162. Balbi B., Pignatti P., Corradi M., Baiardi P., Bianchi L., Brunetti G., Radaeli A., Moscato G., Mutti A., Spanevello A., and Malerba M. Bronchoalveolar lavage, sputum and exhaled clinically relevant inflammatory markers: values in healthy adults. Eur Respir J 30 (2008) 769-781. Detailed review of the published data addressing normal values for biomarkers in BAL, sputum, and exhaled breath in healthy adults.
163. Hollander C., Sitkauskiene B., Sakalauskas R., Westin U., and Janciauskiene S. Serum and bronchial lavage fluid concentrations of IL-8, SLPI, sCD14 and sICAM-1 in patients with COPD and asthma. Respir Med 101 (2007) 1947-1953
164. Gan W., Man S., Senthilselvan A., and Sin D. Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis. Thorax 59 (2004) 574-580
165. Brightling C., Green R., and Pavord I. Biomarkers predicting response to corticosteroid therapy in asthma. Treat Respir Med 4 (2005) 309-316
166. Franciosi L., Page C., Celli B., Cazzola M., Walker M., Danhof M., Rabe K., and Della Pasqua O. Markers of disease severity in chronic obstructive pulmonary disease. Pulm Pharmacol Ther 19 (2006) 189-199
167. Costa C., Rufino R., Traves S., Lapa e Silva J., Barnes P., and Donnelly L. CXCR3 and CCR5 chemokines in induced sputum from patients with COPD. Chest 133 (2008) 26-33
168. Walter R., Wilk J., Larson M., Vasan R., Keaney J., Lipinska I., O'Connor G., and Benjamin E. Systemic inflammation and COPD. Chest 133 (2008) 19-25
169. Gamble E., Grootendorst D., Brightling C., Troy S., Qiu Y., Zhu J., Parker D., Matin D., Majumbdar S., Vignola A., et al. Antiinflammatory effects of the phosphodiesterase-4 inhibitor cilomilast (Ariflo) in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 168 (2003) 976-982
170. Siva R., Green R., Brightling C., Shelley M., Hargadon B., McKenna S., Monteiro W., Berry M., Parker D., Wardlaw A., and Pavord I. Eosinophilic airway inflammation and exacerbations of COPD: a randomised controlled trial. Eur Respir J 29 (2007) 906-913
171. Zietkowski Z., Kucharewicz I., and Bodzenta-Lukaszyk A. The influence of inhaled corticosteroids on exhaled nitric oxide in stable chronic obstructive pulmonary disease. Respir Med 99 (2005) 816-824
172. Viglio S., Iadarola P., Lupi A., Trisolini R., Tinelli C., Balbi B., Grassi V., Worlitzch D., Doring G., Meloni F., et al. MEKC of desmosine and isodesmosine in urine of chronic destructive lung disease patients. Eur Respir J 15 (2000) 1039-1045
173. Ma S., Yong L., and Turino G. The effect of tiotropium (TIO) on levels of desmosine and isodesmosine (D/I) in urine, plasma and sputum in COPD. Eur Respir J 30 Suppl. 51 (2007) 355s
174. Sayers I., and Hall I. Pharmacogenetic approaches in the treatment of asthma. Curr Allergy Asthma Rep 5 (2005) 101-108
175. Israel E., Chinchilli V., Ford J., Boushey H., Cherniack R., Craig T., Deykin A., Fagan J., Fahy J., Fish J., et al. National heart, lung, and blood institute's asthma clinical research network: use of regularly scheduled albuterol treatment in asthma: genotype-stratified, randomised, placebo-controlled cross-over trial. Lancet 364 (2004) 1505-1512
176. Bleeker E., Postma D., Lawrance R., Meyers D., Ambrose H., and Goldman M. Effect of ADRB2 polymorphisms on response to longacting β2-agonist therapy: a pharmacogenetic analysis of two randomized studies. Lancet 370 (2007) 2118-2125
177. Cazzola M., MacNee W., Martinez F., Rabe K., Franciosi L., Barnes P., Brusazco V., Burge S., Calverley P., Celli B., et al. Outcomes for COPD pharmacological trials: from lung function to biomarkers. Eur Respir J 31 (2008) 416-468. A detailed review of outcome measures in COPD clinical trials, including biomarkers, from the American Thoracic Society/European Respiratory Society task force on COPD outcomes.