SPECIAL ASTHMA SERIES
Non invasive assessment of severe asthma
More details
Hide details
1
Lecturer of Pneumonology Medicine, National and Kapodistrian University of Athens Medical School, Evangelismos Hospita
2
Chest Physician, KEELPNO of Athens, Evangelismos Hospital
3
Professor, Airway Disease Section, National Heart and Lung Institute, Imperial College, Dovehouse St, London SW3 6LY, UK
Corresponding author
Paraskevi Katsaounou
Pneumonology Medicine
University of Athens Medical School,
Evangelismos Hospital
Pneumon 2011;24(4):430-444
KEYWORDS
ABSTRACT
Many non invasive measurements are available that can help in the diagnosis, assessment and treatment of severe asthma. The fraction of exhaled nitric oxide (FeNO) helps in identification of severe asthma phenotypes, assessment of asthma control and detection of types of asthma that will benefit from treatment with corticosteroids or that will need tailored therapy with new drugs. Induced sputum examination is used mainly for distinguishing between the eosinophilic and other phenotypes, and for the monitoring of treatment. High resolution computed tomography (HRCT) of the chest helps to confirm the diagnosis of severe asthma and to detect underlying diseases, and is useful for monitoring airways remodelling. Questionnaires are used in the assessment of asthma control. Other methods, such as the electronic nose (e-nose) and exhaled breath condensate show promise of being useful. These non-invasive methods are very important in the assessment and management of severe asthma, taking into account that although asthma is generally a benign disease, severe asthma is very difficult to treat and requires constant monitoring. Invasive methods have limited utility for severe asthma monitoring since they are not suitable for repeated sampling.
REFERENCES (125)
1.
Wenzel S. Severe asthma in adults. Am J Respir Crit Care Med 2005;172:149-60.
2.
Wenzel SE. Asthma: defining of the persistent adult phenotypes. Lancet, 2006; 368:804-813.
3.
Gibson PG, Wang F, He XY, Brightling CE. Noninvasive assessment of inflammation in severe asthma. Chapter 16. ERJ MONOGRAPH 2011.
4.
Taylor DR. Nitric oxid e as a clinical guide for asthma management. J Allergy Clin Immunol 2006; 117: 259–262.
5.
Barnes PJ, Dweik RA, Gelb AF, et al. Exhaled nitric oxide in pulmonary diseases: a comprehensive review. Chest 2010; 138: 682–692.
6.
Loukidis S, Kostikas K, Barnes P. Non-invasive assessment of airways inflammationin asthma. Paschalidis Publications 2011.
7.
Kostikas K, Minas M, Papaioannou AI, Papiris S, Dweik RA. Exhaled nitric oxide in asthma in adults: the end is the beginning? Curr Med Chem 2011;18:1423-31.
8.
Schleich FN, Seidel L, Sele J, et al. Exhaled nitric oxide thresholds associated with a sputum eosinophil count ≥3% in a cohort of unselected patients with asthma. Thorax, 2010.
9.
Tseliou E, Bessa V, Hillas G, et al. Exhaled nitric oxide and exhaled breath condensate pH in severe refractory asthma. Chest 2010; 138:107-113.
10.
Silkoff PE, Lent AM, Busacker AA, et al. Exhaled nitric oxide identifies the persistent eosinophilic phenotype in severe refractory asthma. J Allergy Clin Immunol 2005; 116:1249-1255.
11.
van Veen IH, Ten Brinke A, Sterk PJ, et al. Exhaled nitric oxide predicts lung function decline in difficult-to-treat asthma. Eur Respir J 2008; 32:344-349.
12.
Moore WC, Meyers DA, Wenzel SE, et al; National Heart, Lung, and Blood Institute’s Severe Asthma Research ProgramIdentification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. Am J Respir Crit Care Med 2010;181:315-23.
13.
Dweik RA, Sorkness RL, Wenzel S, et al; National Heart, Lung, and Blood Institute Severe Asthma Research Program. Use of exhaled nitric oxide measurement to identify a reactive, at-risk phenotype among patients with asthma. Am J Respir Crit. Care Med 2010; 181:1033-1041.
14.
Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma (GINA) 2010.
http://www.ginasthma.org.
15.
Jatakanon A, Lim S, Barnes P.J. Changes in sputum eosinophils predict loss of asthma control. Am J Respir Crit Care Med 2000; 161:64-72.
16.
Smith AD, Cowan JO, Brassett KP, et al. Exhaled nitric oxide: a predictor of steroid response. Am J Respir Crit Care Med 2005; 172:453-459.
17.
Cowan DC, Cowan JO, Palmay R, Williamson A, Taylor DR. Effects of steroid therapy on inflammatory cell subtypes in asthma. Thorax 2010; 65:384-390.
18.
Pijnenburg MW, Hofhuis W, Hop WC, De Jongste JC. Exhaled nitric oxide predicts asthma relapse in children with clinical asthma remission. Thorax 2005; 60:215-218.
19.
Zacharasiewicz A, Wilson N, Lex C, et al. Clinical use of noninvasive measurements of airway inflammation in steroid reduction in children. Am J Respir Crit Care Med 2005; 171:1077-1082.
20.
Deykin A, Lazarus SC, Fahy JV, et al. Sputum eosinophil counts predict asthma control after discontinuation of inhaled corticosteroids. J Allergy Clin. Immunol 2005; 115:720-727.
21.
Leuppi JD, Salome CM, Jenkins CR, et al. Predictive markers of asthma exacerbation during stepwise dose reduction of inhaled corticosteroids. Am J Respir Crit Care Med 2001; 163:406-412.
22.
Lopes C, Fonseca J, Delgado L, et al. Assessing asthma control: questionnaires and exhaled nitric oxide provide complementary information. Eur Respir J 2008; 32:1419-1420.
23.
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; 39:1822-1829.
24.
Michils A, Baldassarre S, Van Muylem A. Exhaled nitric oxide and asthma control: a longitudinal study in unselected patients. Eur Respir J 2008; 31:539-546.
25.
Michils A, Louis R, Peche R, Baldassarre S, Van Muylem A. Exhaled nitric oxide as a marker of asthma control in smoking patients. Eur Respir J 2009.
26.
Papaioannou AI, Minas M, Tanou K, Gourgoulianis KI, Kostikas K. Exhaled NO may predict loss of asthma control: the effect of concomitant allergic rhinitis. Eur Respir J 2009; 34:1006-1007.
27.
Harkins MS, Fiato KL, Iwamoto GK. Exhaled nitric oxide predicts asthma exacerbation. J Asthma 2004; 41:471-476.
28.
Gelb AF, Flynn Taylor C, Shinar CM, Gutierrez C, Zamel N. Role of spirometry and exhaled nitric oxide to predict exacerbations in treated asthmatics. Chest 2006; 129:1492-1499.
29.
Perez-de-Llano LA, Carballada F, Castro Anon O, et al. Exhaled nitric oxide predicts control in patients with difficult-to-treat asthma. Eur Respir J 2010; 35:1221-1227.
30.
Taylor DR. An eye to the future: exhaled nitric oxide as a predictor of clinical outcomes in asthma. Eur Respir J 2010; 35:1200-1202.
31.
Macedo P, Hew M, Torrego A, et al. Inflammatory biomarkers in airways of patients with severe asthma compared with non-severe asthma. Clin Exp Allergy 2009; 39: 1668–1676.
32.
Brims FJ, Chauhan AJ, Higgins B, et al. Coagulation factors in the airways in moderate and severe asthma and the effect of inhaled steroids. Thorax 2009; 64:1037–1043.
33.
Shannon J, Ernst P, Yamauchi Y, et al. Differences in airway cytokine profile in severe asthma compared to moderate asthma. Chest 2008; 133:420–426.
34.
Lara A, Khatri SB, Wang Z, et al. Alterations of the arginine metabolism in asthma. Am J Respir Crit Care Med 2008; 178: 673–681.
35.
Saetta M, Di SA, Turato G, et al. Fatal asthma attack during an inhalation challenge with ultrasonically nebulized distilled water. J Allergy Clin Immunol 1995; 95:1285-7.
36.
Bel EH, Zwinderman AH, Timmers MC, Dijkman JH, Sterk PJ. The protective effect of a beta 2 agonist against excessive airway narrowing in response to bronchoconstrictor stimuli in asthma and chronic obstructive lung disease. Thorax 1991; 46:9-14.
37.
ten BA, de LC, Zwinderman AH, Rabe KF, Sterk PJ, Bel EH. Sputum induction in severe asthma by a standardized protocol: predictors of excessive bronchoconstriction. Am J Respir Crit Care Med 2001; 164:749-53.
38.
Pizzichini E PMBAFSC. Sputum induction in stable steroid naive asthmatics: influence of prior use of b2-agonist. Eur Respir J 1998; 28(Suppl.):365S.
39.
Pizzichini MM, Pizzichini E, Clelland L, et al. Sputum in severe exacerbations of asthma: kinetics of inflammatory indices after prednisone treatment. Am J Respir Crit Care Med 1997; 155:1501-8.
40.
Pizzichini E, Pizzichini MM, Leigh R, Djukanovic R, Sterk PJ. Safety of sputum induction. Eur Respir J Suppl 2002; 37:9s18s:9s-18s.
41.
Delvaux M, Henket M, Lau L, et al. Nebulised salbutamol administered during sputum induction improves bronchoprotection in patients with asthma. Thorax 2004; 59:111-5.
42.
Pizzichini MMM, Popov TA, Efthimiadis A, et al. Spontaneous and induced sputum to measure indices of airway inflammation in asthma. Am J Respir Crit Care Med 1996; 154:866-869.
43.
Brims FJ, Higgins B, et al. Coagulation factors in the airways in moderate and severe asthma and the effect of inhaled steroids. Thorax 2009; 64:1037–1043.
44.
Shannon J, Ernst, Yamauchi Y, et al. Differences in airway cytokine profile in severe asthma compared to moderate asthma. Chest 2008; 133:420–426.
45.
Bartoli ML, Bacci E, Carnevali S, et al. Clinical assessment of asthma severity partially corresponds to sputum eosinophilic airway inflammation. Respir Med 2004; 98:184–193.
46.
Haldar P, Pavord ID, Shaw DE, et al. Cluster analysis and clinical asthma phenotypes. Am J Respir Crit Care Med 2008; 178: 218–224.P.IBSON ET AL.
47.
Hastie AT, Moore WC, Meyers DA, et al. Analyses of asthma severity phenotypes and inflammatory proteins in subjects stratified by sputum granulocytes. J Allergy Clin Immunol 2010; 125: 1028–1036.
48.
Kaminska M, Foley S, Maghni K, et al. Airway remodeling in subjects with severe asthma with or without chronic persistent airflow obstruction. J Allergy Clin Immunol 2009; 124: 45–51.
49.
Kulkarni NS, Hollins F, Sutcliffe A, et al. Eosinophil protein in airway macrophages: a novel biomarker of eosinophilic inflammation in patients with asthma. J Allergy Clin Immunol 2010; 126: 61–69.
50.
Dente FL, Bacci E, Bartoli ML, et al. Effects of oral prednisone on sputum eosinophils and cytokines in patients with severe refractory asthma. Ann Allergy Asthma Immunol 2010; 104: 464–470.
51.
Brightling CE, Green RH, Pavord ID. Biomarkers predicting response to corticosteroid therapy in asthma. Treat Respir Med 2005; 4: 309–316.
52.
Pizzichini MM, Pizzichini E, Clelland L, et al. Prednisone-dependent asthma: inflammatory indices in induced sputum. Eur Respir J 1999; 13:15–21.
53.
Duncan CJ, Lawrie A, Blaylock MG, et al. Reduced eosinophil apoptosis in induced sputum correlates with asthma severity. Eur Respir J 2003; 22:484–490.
54.
Dent G, Hadjicharalambous C, Yoshikawa T, et al. Contribution of eotaxin-1 to eosinophil chemotactic activity of moderate and severe asthmatic sputum. Am J Respir Crit Care Med 2004; 169:1110–1117.
55.
Simpson JL, Gibson PG, Wark PAB. Optimization of sputum processing methods for the measurement of interleukin-5: effects of protease inhibition. Respirology 2002; 7:111–116.
56.
Shannon J, Yamauchi Y, et al. Differences in airway cytokine profile in severe asthma compared to moderate asthma. Chest 2008; 133:420–426.
57.
Kikuchi S, Nagata M, Kikuchi I, et al. Association between neutrophilic and eosinophilic inflammation in patients with severe persistent asthma. Int Arch Allergy Immunol 2005; 137(Suppl. 1):7–11.
58.
Vachier I, Bonnans C, Chavis C, et al. Severe asthma is associated with a loss of LX4, an endogenous anti-inflammatory compound. J Allergy Clin Immunol 2005; 115:55–60.
59.
The ENFUMOSA Study Group. The ENFUMOSA cross-sectional European multicentre study of the clinical phenotype of chronic severe asthma. Eur Respir J 2003; 22:470–477.
60.
Jatakanon A, Uasuf C, Maziak W, et al. Neutrophilic inflammation in severe persistent asthma. Am J Respir Crit Care Med 1999; 160:1532–1539.
61.
Louis R, Lau LC, Bron AO, Roldaan AC, Radermecker M, Djukanovic R. The relationship between airways inflammation and asthma severity. Am J Respir Crit Care Med 2000; 161:9–16.
62.
Jensen SP, Lynch DA, Brown KK, Wenzel SE, Newell JD. Highresolution CT features of severe asthma and bronchiolitis obliterans. Clin Radiol 2002; 57:1078–1085.
63.
Cox G. Glucocorticoid treatment inhibits apoptosis in human neutrophils: separation of survival and activation outcomes. J Immunol 1995; 154:4719–4725.
64.
Mann BS, Chung KF. Blood neutrophil activation markers in severe asthma: lack of inhibition by prednisolone therapy. Respir Res 2006; 7: 59.
65.
Green RH, Brightling CE, McKenna S, et al. Asthma exacerbations and sputum eosinophil counts: a randomized controlled trial. Lancet 2002; 360:1715–1721.
66.
Fens N, Zwinderman AH, van der Schee MP, et al. Exhaled breath profiling enables discrimination of chronic obstructive pulmonary disease and asthma. Am J Respir Crit Care Med 2009; 180:1076–1082.
67.
Nair P, Pizzichini MM, Kjarsgaard M, et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med 2009; 360: 985–993.
68.
Haldar P, Brightling CE, Hargadon B, et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med 2009; 360: 973–984.
69.
Montuschi P, Santonico M, Mondino C, et al. Diagnostic performance of an electronic nose, fractional exhaled nitric oxide, and lung function testing in asthma. Chest 2010; 137: 790–796.
70.
Lemiere C, Ernst P, Olivenstein R, et al. Airway inflammation assessed by invasive and noninvasive means in severe asthma: eosinophilic and non eosinophilic phenotypes. J Allergy Clin Immunol 2006; 118: 1033–1039.
71.
Simpson JL, Phipps S, Gibson PG. Inflammatory mechanisms and treatment of obstructive airway diseases with neutrophilic bronchitis. Pharmacol Ther 2009; 124: 86–95.
72.
Simpson JL, Powell H, Boyle MJ, et al. Clarithromycin targets neutrophilic airway inflammation in refractory asthma. Am J Respir Crit Care Med 2008; 177:148–155.
73.
Simpson JL, Baines KJ, Boyle MJ, et al. Oncostatin M (OSM) is increased in asthma with incompletely reversible airflow obstruction. Exp Lung Res 2009; 35:781–794.
74.
ten Brinke A, Zwinderman AH, Sterk PJ, et al. Factors associated with persistent airflow limitation in severe asthma. Am J Respir Crit Care Med 2001; 164: 744–748.
75.
Proceedings of the ATS workshop on refractory asthma: current understanding, recommendations, and unanswered questions. American Thoracic Society. Am J Respir Crit Care Med 2000;162:2341-51.
76.
Romagnoli M, Caramori G, Braccioni F, et al. Near-fatal asthma phenotype in the ENFUMOSA cohort. Clin Exp Allergy 2007; 37: 552–557.
77.
Delimpoura V, Bakakos P, Tseliou E, et al. Increased levels of osteopontin in sputum supernatant in severe refractory asthma. Thorax. 2010;65:782-6.
78.
Zietkowski Z, Tomasiak MM, Skiepko R, et al. RANTES in exhaled breath condensate of stable and unstable asthma patients. Respir Med 2008; 102:1198–1202.
79.
Zietkowski Z, Skiepko R, Tomasiak MM, et al. Endothelin-1 in exhaled breath condensate of stable and unstable asthma patients. Respir Med 2008; 102:470–474.
80.
Elias JA, Zhu Z, Chupp G, et al. Airway remodeling in asthma. J Clin Invest 1999;104:1001-6.
81.
Lynch DA, Newell JD, Tschomper BA, et al. Uncomplicated asthma in adults: comparison of CT appearance of the lungs in asthmatic and healthy subjects. Radiology 1993;188:829-33.
82.
Paganin F, Séneterre E, Chanez P, et al. Computed tomography of the lungs in asthma: influence of disease severity and etiology. Am J Respir Crit Care Med 1996;153:110-4.
83.
Awadh N, Müller NL, Park CS, et al. Airway wall thickness in patients with near fatal asthma and control groups: assessment with high resolution computed tomographic scanning. Thorax 1998;53:248-53.
84.
Teel GS, Engeler CE, Tashijian JH, et al. Imaging of small airways disease. Radiographics 1996;16:27-41.
85.
Gupta S, Siddiqui S, Haldar P, et al. Qualitative analysis of highresolution CT scans in severe asthma. Chest 2009;136:1521-8. Epub 2009 Jun 19.
86.
Park JW, Hong YK, Kim CW, et al. High-resolution computed tomography in patients with bronchial asthma: correlation with clinical features, pulmonary functions and bronchial hyperresponsiveness. J Investig Allergol Clin Immunol 1997; 7:186-92.
87.
Machado D, Pereira C, Teixeira L, et al. Thoracic high resolution computed tomography (HRCT) in asthma. Eur Ann Allergy Clin Immunol 2009;41:139-45.
88.
Vignola AM, Paganin F, Capieu L, et al. Airway remodelling assessed by sputum and high-resolution computed tomography in asthma and COPD. Eur Respir J 2004; 24: 910–917.
89.
Sumit Gupta, Salman Siddiqui, Pranab Haldar, et al. Quantitative analysis of high-resolution computed tomography scans in severe asthma subphenotypes. Thorax 2010;65:775e781.
90.
Young-Mok Lee, Jai-Soung Park, Jung-Hwa Hwang, et al. HighResolution CT Findings in Patients with Near-Fatal Asthma: Comparison of Patients With Mild-to-Severe Asthma and Normal Control Subjects and Changes in Airway Abnormalities Following Steroid Treatment. Chest 2004;126;1840-1848.
91.
Bumbacea D, Campbell D, Nguyen L et al. Parameters associated with persistent airflow obstruction in chronic severe asthma. Eur Respir J 2004; 24:122–128.
92.
Jensen SP, Lynch DA, Brown KK, et al. High-resolution CT features of severe asthma and bronchiolitis obliterans. Clin Radiol 2002;57:1078-85.
93.
Bandeira T, Negreiro F, Ferreira R, et al. Clinical, radiological, and physiological differences between obliterative bronchiolitis and problematic severe asthma in adolescents and young adults: the early origins of the overlap syndrome? Pediatr Pulmonol. 2011 Jan 18.
94.
Little SA, Sproule MW, Cowan MD, et al. High resolution computed tomographic assessment of airway wall thickness in chronic asthma: reproducibility and relationship with lung function and severity. Thorax 2002;57:247–253.
95.
de Blic J, Scheinmann P. The use of imaging techniques for assessing severe childhood asthma. J Allergy Clin Immunol 2007;119:808-10.
96.
Menzies-Gow A, Gibeon D, Hui C, et al. Management of difficultto-treat severe asthma. Eur Respir Mon 2011; 51, 282–296.
97.
Sumino K, Djukanovic R, Castro M. Evaluation of the difficultto-treat severe asthma patient in the clinic. Eur Respir Mon 2011; 51:16–27.
98.
Gupta S, Raj V, Castro M, et al. Imaging in severe asthma. Eur Respir Mon 2011; 51:160–181.
99.
Bateman ED, Hurd SS, Barnes PJ, et al. Global strategy for asthma management and prevention: GINA executive summary. Eur Respir J 2008; 31: 143–178.
100.
Schatz M, Sorkness CA, Li JT, et al. Asthma Control Test: reliability, validity, and responsiveness in patients not previously followed by asthma specialists. J Allergy Clin Immunol 2006; 117:549-56.
101.
Nathan RA, Sorkness CA, Kosinski M, et al. Development of the asthma control test: a survey for assessing asthma control. J Allergy Clin Immunol 2004;113:59-65.
102.
Juniper EF, O’Byrne PM, Guyatt GH, et al. Development and validation of a questionnaire to measure asthma control. Eur Respir J 1999;14:902-7.
103.
Skinner EA, Diette GB, Algatt-Bergstrom PJ, et al. The Asthma Therapy Assessment Questionnaire (ATAQ) for children and adolescents. Dis Manag 2004;7:305-13.
104.
LeBlanc A, Robichaud P, Lacasse Y, et al. Quantification of asthma control: validation of the Asthma Control Scoring System. Allergy 2007;62:120-5.
105.
Liu AH, Zeiger R, Sorkness C, et al. Development and crosssectional validation of the Childhood Asthma Control Test. J Allergy Clin Immunol 2007; 119:817-25. Epub 2007 Mar 13.
106.
Wallenstein GV, Carranza-Rosenzweig J, Kosinski M, et al. A psychometric comparison of three patient-based measures of asthma control. Curr Med Res Opin 2007; 23:369-77.
107.
Halbert RJ, Tinkelman DG, Globe DR , et al. Measuring asthma control is the first step to patient management: a literature review. J Asthma 2009;46:659-64.
108.
Yoo KH, Jeong JW, Yoon HJ, et al. Customized Asthma Control Test with reflection on sociocultural differences. J Korean Med Sci 2010;25:1134-9.
109.
Leite M, Ponte EV, Petroni J, et al. Evaluation of the asthma control questionnaire validated for use in Brazil. J Bras Pneumol 2008;34:756-63.
110.
Picado C, Badiola C, Perulero N, et al. Validation of the Spanish version of the Asthma Control Questionnaire. Clin Ther 2008;30:1918-31.
111.
Zhou X, Ding FM, Lin JT, et al. Validity of asthma control test for asthma control assessment in Chinese primary care settings. Chest 2009;135:904-10. Epub 2008 Dec 31.
112.
Grammatopoulou EP, Stavrou N, Myrianthefs P, et al. Validity and reliability evidence of the Asthma Control Test--ACT in Greece. J Asthma 2011;48:57-64. Epub 2010 Nov 1.
113.
Tan WC, Tan JW, Wee EW, et al. Validation of the English version of the Asthma Quality of Life Questionnaire in a multi-ethnic Asian population. Qual Life Res 2004;13:551-6.
114.
O’Byrne PM, Reddel HK, Eriksson G, et al. Measuring asthma control: a comparison of three classification systems. Eur Respir J 2010;36:269-76.
115.
Sullivan SD, Wenzel SE, Bresnahan BW, et al. Association of control and risk of severe asthma-related events in severe or difficult-to-treat asthma patients. Allergy 2007;62:655-60.
116.
Kikuchi Y, Okabe S, Tamura G, et al. Chemosensitivity and perception of dyspnea in patients with a history of near-fatal asthma. N Engl J Med 1994; 330:1329–1334.
117.
Barreiro E, Gea J, Sanjuas C, et al. Dyspnoea at rest and at the end of different exercises in patients with near-fatal asthma. Eur Respir J 2004;24:219–225.
118.
Leung TF, Ko FW, Sy HY, et al. Identifying uncontrolled asthma in young children: clinical scores or objective variables? J Asthma 2009;46:130-5.
119.
Liu AH, Zeiger RS, Sorkness CA, et al. The Childhood Asthma Control Test: retrospective determination and clinical validation of a cut point to identify children with very poorly controlled asthma. J Allergy Clin Immunol 2010;126:267-73, 273.
120.
Meltzer EO, Busse WW, Wenzel SE, et al. Use of the Asthma Control Questionnaire to predict future risk of asthma exacerbation. J Allergy Clin Immunol 2011;127:167-72.
121.
Jane Clatworthya, David Priceb, Dermot Ryanb, et al. The value of self-report assessment of adherence, rhinitis and smoking in relation to asthma control. Prim Care Respir J 2009; 18:300- 305.
122.
Juniper EF, Chauhan A, Neville E, et al. Clinicians tend to overestimate improvements in asthma control: an unexpected observation. Prim Care Respir J 2004;13:181-4.
123.
Foster JM, Lavoie KL, Boulet L-P. Treatment adherence and psychosocial factors in severe asthma. Eur Respir Mon 2011; 51:28–49.
124.
Barnes PJ. European Respiratory Society Monograph 2011; 51 Chapter 19.
125.
Penny Moraitaki, Despina Papamichail, Niki GeorgatouSevere Asthma: Definitions, risk factors and phenotype characterization. Pneumon 2010; 23:276-292.