Asthma exhaled nitric oxide: Difference between revisions
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==Overview== | ==Overview== | ||
Measurement of [[nitric oxide|fractional nitric oxide]] concentration in exhaled breath | Measurement of [[nitric oxide|fractional nitric oxide]] concentration in exhaled breath (FeNO) is a non-invasive method of assessing underlying airway inflammation.<ref name="pmid15536442">Silkoff PE, Carlson M, Bourke T, Katial R, Ogren E, Szefler SJ (2004) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=15536442 The Aerocrine exhaled nitric oxide monitoring system NIOX is cleared by the US Food and Drug Administration for monitoring therapy in asthma.] ''J Allergy Clin Immunol'' 114 (5):1241-56. [http://dx.doi.org/10.1016/j.jaci.2004.08.042 DOI:10.1016/j.jaci.2004.08.042] PMID: [http://pubmed.gov/15536442 15536442]</ref><ref name="pmid11031334">Sippel JM, Holden WE, Tilles SA, O'Hollaren M, Cook J, Thukkani N et al. (2000) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=11031334 Exhaled nitric oxide levels correlate with measures of disease control in asthma.] ''J Allergy Clin Immunol'' 106 (4):645-50. [http://dx.doi.org/10.1067/mai.2000.109618 DOI:10.1067/mai.2000.109618] PMID: [http://pubmed.gov/11031334 11031334]</ref> However, due to technical complexities associated with the procedure, it is not routinely used.<ref name="pmid12589342">Bates CA, Silkoff PE (2003) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=12589342 Exhaled nitric oxide in asthma: from bench to bedside.] ''J Allergy Clin Immunol'' 111 (2):256-62. PMID: [http://pubmed.gov/12589342 12589342]</ref><ref name="pmid15643344">Smith AD, Taylor DR (2005) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=15643344 Is exhaled nitric oxide measurement a useful clinical test in asthma?] ''Curr Opin Allergy Clin Immunol'' 5 (1):49-56. PMID: [http://pubmed.gov/15643344 15643344]</ref> | ||
==Exhaled Nitric Oxide | ==Exhaled Nitric Oxide== | ||
Asthma is a chronic inflammatory disease with hyper-responsive airways. As a part of the inflammatory process, there is an associated up-regulation in the | Asthma is a chronic inflammatory disease with hyper-responsive airways. As a part of the inflammatory process, there is an associated up-regulation in the nitric oxide synthase observed in the respiratory mucosal epithelium, which contributes to the increased concentrations of nitric oxide released in exhaled breath. | ||
===Benefits of | ===Benefits of Measurement of Exhaled Nitric Oxide in Asthmatics=== | ||
*Asthmatics are associated with higher concentrations of expired nitric oxide and hence expired nitric oxide evaluation may be a useful index to assess the disease severity.<ref name="pmid7633745">Massaro AF, Gaston B, Kita D, Fanta C, Stamler JS, Drazen JM (1995) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=7633745 Expired nitric oxide levels during treatment of acute asthma.] ''Am J Respir Crit Care Med'' 152 (2):800-3. PMID: [http://pubmed.gov/7633745 7633745]</ref> | *Asthmatics are associated with higher concentrations of expired nitric oxide and hence expired nitric oxide evaluation may be a useful index to assess the disease severity.<ref name="pmid7633745">Massaro AF, Gaston B, Kita D, Fanta C, Stamler JS, Drazen JM (1995) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=7633745 Expired nitric oxide levels during treatment of acute asthma.] ''Am J Respir Crit Care Med'' 152 (2):800-3. PMID: [http://pubmed.gov/7633745 7633745]</ref> | ||
*Exhaled NO has also shown to be associated with other asthmatic clinical parameters such as airway inflammation, sputum eosinophilia and viral infection.<ref name="pmid14610474">Strunk RC, Szefler SJ, Phillips BR, Zeiger RS, Chinchilli VM, Larsen G et al. (2003) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=14610474 Relationship of exhaled nitric oxide to clinical and inflammatory markers of persistent asthma in children.] ''J Allergy Clin Immunol'' 112 (5):883-92. [http://dx.doi.org/10.1016/j.jaci.2003.08.014 DOI:10.1016/j.jaci.2003.08.014] PMID: [http://pubmed.gov/14610474 14610474]</ref><ref name="pmid8542158">Kharitonov SA, Yates DH, Barnes PJ (1996) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=8542158 Inhaled glucocorticoids decrease nitric oxide in exhaled air of asthmatic patients.] ''Am J Respir Crit Care Med'' 153 (1):454-7. PMID: [http://pubmed.gov/8542158 8542158]</ref><ref name="pmid14555563">Sandrini A, Ferreira IM, Gutierrez C, Jardim JR, Zamel N, Chapman KR (2003) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=14555563 Effect of montelukast on exhaled nitric oxide and nonvolatile markers of inflammation in mild asthma.] ''Chest'' 124 (4):1334-40. PMID: [http://pubmed.gov/14555563 14555563]</ref><ref name="pmid11124647">Tsujino I, Nishimura M, Kamachi A, Makita H, Munakata M, Miyamoto K et al. (2000) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=11124647 Exhaled nitric oxide--is it really a good marker of airway inflammation in bronchial asthma?] ''Respiration'' 67 (6):645-51. PMID: [http://pubmed.gov/11124647 11124647]</ref><ref name="pmid20133930">Dweik RA, Sorkness RL, Wenzel S, Hammel J, Curran-Everett D, Comhair SA et al. (2010) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=20133930 Use of exhaled nitric oxide measurement to identify a reactive, at-risk phenotype among patients with asthma.] ''Am J Respir Crit Care Med'' 181 (10):1033-41. [http://dx.doi.org/10.1164/rccm.200905-0695OC DOI:10.1164/rccm.200905-0695OC] PMID: [http://pubmed.gov/20133930 20133930]</ref> | *Exhaled NO has also shown to be associated with other asthmatic clinical parameters such as airway inflammation, sputum eosinophilia and viral infection.<ref name="pmid14610474">Strunk RC, Szefler SJ, Phillips BR, Zeiger RS, Chinchilli VM, Larsen G et al. (2003) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=14610474 Relationship of exhaled nitric oxide to clinical and inflammatory markers of persistent asthma in children.] ''J Allergy Clin Immunol'' 112 (5):883-92. [http://dx.doi.org/10.1016/j.jaci.2003.08.014 DOI:10.1016/j.jaci.2003.08.014] PMID: [http://pubmed.gov/14610474 14610474]</ref><ref name="pmid8542158">Kharitonov SA, Yates DH, Barnes PJ (1996) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=8542158 Inhaled glucocorticoids decrease nitric oxide in exhaled air of asthmatic patients.] ''Am J Respir Crit Care Med'' 153 (1):454-7. PMID: [http://pubmed.gov/8542158 8542158]</ref><ref name="pmid14555563">Sandrini A, Ferreira IM, Gutierrez C, Jardim JR, Zamel N, Chapman KR (2003) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=14555563 Effect of montelukast on exhaled nitric oxide and nonvolatile markers of inflammation in mild asthma.] ''Chest'' 124 (4):1334-40. PMID: [http://pubmed.gov/14555563 14555563]</ref><ref name="pmid11124647">Tsujino I, Nishimura M, Kamachi A, Makita H, Munakata M, Miyamoto K et al. (2000) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=11124647 Exhaled nitric oxide--is it really a good marker of airway inflammation in bronchial asthma?] ''Respiration'' 67 (6):645-51. PMID: [http://pubmed.gov/11124647 11124647]</ref><ref name="pmid20133930">Dweik RA, Sorkness RL, Wenzel S, Hammel J, Curran-Everett D, Comhair SA et al. (2010) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=20133930 Use of exhaled nitric oxide measurement to identify a reactive, at-risk phenotype among patients with asthma.] ''Am J Respir Crit Care Med'' 181 (10):1033-41. [http://dx.doi.org/10.1164/rccm.200905-0695OC DOI:10.1164/rccm.200905-0695OC] PMID: [http://pubmed.gov/20133930 20133930]</ref> | ||
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*Exhaled nitric oxide levels reduced with the administration of [[steroids]] and [[Leukotriene antagonist|leukotriene receptor blockers]] suggesting that exhaled nitric oxide measurement may be a beneficial marker for assessing the airway inflammation in asthmatics.<ref name="pmid7633745">Massaro AF, Gaston B, Kita D, Fanta C, Stamler JS, Drazen JM (1995) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=7633745 Expired nitric oxide levels during treatment of acute asthma.] ''Am J Respir Crit Care Med'' 152 (2):800-3. PMID: [http://pubmed.gov/7633745 7633745]</ref><ref name="pmid14555563">Sandrini A, Ferreira IM, Gutierrez C, Jardim JR, Zamel N, Chapman KR (2003) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=14555563 Effect of montelukast on exhaled nitric oxide and nonvolatile markers of inflammation in mild asthma.] ''Chest'' 124 (4):1334-40. PMID: [http://pubmed.gov/14555563 14555563]</ref><ref name="pmid11124647">Tsujino I, Nishimura M, Kamachi A, Makita H, Munakata M, Miyamoto K et al. (2000) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=11124647 Exhaled nitric oxide--is it really a good marker of airway inflammation in bronchial asthma?] ''Respiration'' 67 (6):645-51. PMID: [http://pubmed.gov/11124647 11124647]</ref> | *Exhaled nitric oxide levels reduced with the administration of [[steroids]] and [[Leukotriene antagonist|leukotriene receptor blockers]] suggesting that exhaled nitric oxide measurement may be a beneficial marker for assessing the airway inflammation in asthmatics.<ref name="pmid7633745">Massaro AF, Gaston B, Kita D, Fanta C, Stamler JS, Drazen JM (1995) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=7633745 Expired nitric oxide levels during treatment of acute asthma.] ''Am J Respir Crit Care Med'' 152 (2):800-3. PMID: [http://pubmed.gov/7633745 7633745]</ref><ref name="pmid14555563">Sandrini A, Ferreira IM, Gutierrez C, Jardim JR, Zamel N, Chapman KR (2003) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=14555563 Effect of montelukast on exhaled nitric oxide and nonvolatile markers of inflammation in mild asthma.] ''Chest'' 124 (4):1334-40. PMID: [http://pubmed.gov/14555563 14555563]</ref><ref name="pmid11124647">Tsujino I, Nishimura M, Kamachi A, Makita H, Munakata M, Miyamoto K et al. (2000) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=11124647 Exhaled nitric oxide--is it really a good marker of airway inflammation in bronchial asthma?] ''Respiration'' 67 (6):645-51. PMID: [http://pubmed.gov/11124647 11124647]</ref> | ||
===Supportive | ===Supportive Trial Data=== | ||
The role of monitoring exhaled nitric oxide levels is not established according to a [[meta-analysis]] of [[randomized controlled trial]]s by the [[Cochrane Collaboration]].<ref name="pmid27580628">{{cite journal| author=Petsky HL, Kew KM, Turner C, Chang AB| title=Exhaled nitric oxide levels to guide treatment for adults with asthma. | journal=Cochrane Database Syst Rev | year= 2016 | volume= 9 | issue= | pages= CD011440 | pmid=27580628 | doi=10.1002/14651858.CD011440.pub2 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27580628 }} </ref> | |||
*However, two | |||
* An initial trial showed benefit<ref name="pmid15914548">{{cite journal| author=Smith AD, Cowan JO, Brassett KP, Herbison GP, Taylor DR| title=Use of exhaled nitric oxide measurements to guide treatment in chronic asthma. | journal=N Engl J Med | year= 2005 | volume= 352 | issue= 21 | pages= 2163-73 | pmid=15914548 | doi=10.1056/NEJMoa043596 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15914548 }} [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17213062 Review in: Evid Based Med. 2006 Feb;11(1):20] </ref>. The study further reported a significant reduction in the cumulative maintenance dose of inhaled steroid without worsening asthmatic symptoms. | |||
*However, two subsequent studies did not demonstrate any beneficial effect with the use of eNO- guided therapy in comparison to conventional-based therapy. One of the studies, involving 546 patients demonstrated good symptomatic control with conventional management; however, the use of fraction of exhaled NO as an indicator of asthmatic control, resulted in higher doses of [[steroids|inhaled steroids]], without clinically improving symptomatic control.<ref name="pmid18805335">Szefler SJ, Mitchell H, Sorkness CA, Gergen PJ, O'Connor GT, Morgan WJ et al. (2008) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=18805335 Management of asthma based on exhaled nitric oxide in addition to guideline-based treatment for inner-city adolescents and young adults: a randomised controlled trial.] ''Lancet'' 372 (9643):1065-72. [http://dx.doi.org/10.1016/S0140-6736(08)61448-8 DOI:10.1016/S0140-6736(08)61448-8] PMID: [http://pubmed.gov/18805335 18805335]</ref> Another randomized trial that assessed 118 asthmatics, demonstrated that the measurement of exhaled nitric oxide did not cause a significant reduction in the frequency of exacerbations or in the total amount of inhaled corticosteroid therapy used over 12-month period when compared to the current asthma guidelines.<ref name="pmid17496226">Shaw DE, Berry MA, Thomas M, Green RH, Brightling CE, Wardlaw AJ et al. (2007) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=17496226 The use of exhaled nitric oxide to guide asthma management: a randomized controlled trial.] ''Am J Respir Crit Care Med'' 176 (3):231-7. [http://dx.doi.org/10.1164/rccm.200610-1427OC DOI:10.1164/rccm.200610-1427OC] PMID: [http://pubmed.gov/17496226 17496226]</ref> | |||
==References== | ==References== | ||
{{reflist|2}} | {{reflist|2}} | ||
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[[Category:Disease]] | [[Category:Disease]] | ||
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[[Category:Allergology]] | [[Category:Allergology]] | ||
[[Category:Asthma]] | [[Category:Asthma]] | ||
[[Category:Up-To-Date]] | [[Category:Up-To-Date]] | ||
[[Category:Up-To-Date pulmonology]] | [[Category:Up-To-Date pulmonology]] | ||
[[Category:Mature chapter]] | [[Category:Mature chapter]] | ||
Latest revision as of 20:30, 29 July 2020
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Lakshmi Gopalakrishnan, M.B.B.S. [2]
Overview
Measurement of fractional nitric oxide concentration in exhaled breath (FeNO) is a non-invasive method of assessing underlying airway inflammation.[1][2] However, due to technical complexities associated with the procedure, it is not routinely used.[3][4]
Exhaled Nitric Oxide
Asthma is a chronic inflammatory disease with hyper-responsive airways. As a part of the inflammatory process, there is an associated up-regulation in the nitric oxide synthase observed in the respiratory mucosal epithelium, which contributes to the increased concentrations of nitric oxide released in exhaled breath.
Benefits of Measurement of Exhaled Nitric Oxide in Asthmatics
- Asthmatics are associated with higher concentrations of expired nitric oxide and hence expired nitric oxide evaluation may be a useful index to assess the disease severity.[5]
- Exhaled NO has also shown to be associated with other asthmatic clinical parameters such as airway inflammation, sputum eosinophilia and viral infection.[6][7][8][9][10]
- Exhaled nitric oxide closely correlates with the percentage of eosinophils in induced sputum and therefore may be a useful non-invasive marker to assess airway inflammation.[11][12]
- Exhaled nitric oxide levels reduced with the administration of steroids and leukotriene receptor blockers suggesting that exhaled nitric oxide measurement may be a beneficial marker for assessing the airway inflammation in asthmatics.[5][8][9]
Supportive Trial Data
The role of monitoring exhaled nitric oxide levels is not established according to a meta-analysis of randomized controlled trials by the Cochrane Collaboration.[13]
- An initial trial showed benefit[14]. The study further reported a significant reduction in the cumulative maintenance dose of inhaled steroid without worsening asthmatic symptoms.
- However, two subsequent studies did not demonstrate any beneficial effect with the use of eNO- guided therapy in comparison to conventional-based therapy. One of the studies, involving 546 patients demonstrated good symptomatic control with conventional management; however, the use of fraction of exhaled NO as an indicator of asthmatic control, resulted in higher doses of inhaled steroids, without clinically improving symptomatic control.[15] Another randomized trial that assessed 118 asthmatics, demonstrated that the measurement of exhaled nitric oxide did not cause a significant reduction in the frequency of exacerbations or in the total amount of inhaled corticosteroid therapy used over 12-month period when compared to the current asthma guidelines.[16]
References
- ↑ Silkoff PE, Carlson M, Bourke T, Katial R, Ogren E, Szefler SJ (2004) The Aerocrine exhaled nitric oxide monitoring system NIOX is cleared by the US Food and Drug Administration for monitoring therapy in asthma. J Allergy Clin Immunol 114 (5):1241-56. DOI:10.1016/j.jaci.2004.08.042 PMID: 15536442
- ↑ Sippel JM, Holden WE, Tilles SA, O'Hollaren M, Cook J, Thukkani N et al. (2000) Exhaled nitric oxide levels correlate with measures of disease control in asthma. J Allergy Clin Immunol 106 (4):645-50. DOI:10.1067/mai.2000.109618 PMID: 11031334
- ↑ Bates CA, Silkoff PE (2003) Exhaled nitric oxide in asthma: from bench to bedside. J Allergy Clin Immunol 111 (2):256-62. PMID: 12589342
- ↑ Smith AD, Taylor DR (2005) Is exhaled nitric oxide measurement a useful clinical test in asthma? Curr Opin Allergy Clin Immunol 5 (1):49-56. PMID: 15643344
- ↑ 5.0 5.1 Massaro AF, Gaston B, Kita D, Fanta C, Stamler JS, Drazen JM (1995) Expired nitric oxide levels during treatment of acute asthma. Am J Respir Crit Care Med 152 (2):800-3. PMID: 7633745
- ↑ Strunk RC, Szefler SJ, Phillips BR, Zeiger RS, Chinchilli VM, Larsen G et al. (2003) Relationship of exhaled nitric oxide to clinical and inflammatory markers of persistent asthma in children. J Allergy Clin Immunol 112 (5):883-92. DOI:10.1016/j.jaci.2003.08.014 PMID: 14610474
- ↑ Kharitonov SA, Yates DH, Barnes PJ (1996) Inhaled glucocorticoids decrease nitric oxide in exhaled air of asthmatic patients. Am J Respir Crit Care Med 153 (1):454-7. PMID: 8542158
- ↑ 8.0 8.1 Sandrini A, Ferreira IM, Gutierrez C, Jardim JR, Zamel N, Chapman KR (2003) Effect of montelukast on exhaled nitric oxide and nonvolatile markers of inflammation in mild asthma. Chest 124 (4):1334-40. PMID: 14555563
- ↑ 9.0 9.1 Tsujino I, Nishimura M, Kamachi A, Makita H, Munakata M, Miyamoto K et al. (2000) Exhaled nitric oxide--is it really a good marker of airway inflammation in bronchial asthma? Respiration 67 (6):645-51. PMID: 11124647
- ↑ Dweik RA, Sorkness RL, Wenzel S, Hammel J, Curran-Everett D, Comhair SA et al. (2010) Use of exhaled nitric oxide measurement to identify a reactive, at-risk phenotype among patients with asthma. Am J Respir Crit Care Med 181 (10):1033-41. DOI:10.1164/rccm.200905-0695OC PMID: 20133930
- ↑ Jatakanon A, Lim S, Kharitonov SA, Chung KF, Barnes PJ (1998) Correlation between exhaled nitric oxide, sputum eosinophils, and methacholine responsiveness in patients with mild asthma. Thorax 53 (2):91-5. PMID: 9624291
- ↑ Warke TJ, Fitch PS, Brown V, Taylor R, Lyons JD, Ennis M et al. (2002) Exhaled nitric oxide correlates with airway eosinophils in childhood asthma. Thorax 57 (5):383-7. PMID: 11978911
- ↑ Petsky HL, Kew KM, Turner C, Chang AB (2016). "Exhaled nitric oxide levels to guide treatment for adults with asthma". Cochrane Database Syst Rev. 9: CD011440. doi:10.1002/14651858.CD011440.pub2. PMID 27580628.
- ↑ Smith AD, Cowan JO, Brassett KP, Herbison GP, Taylor DR (2005). "Use of exhaled nitric oxide measurements to guide treatment in chronic asthma". N Engl J Med. 352 (21): 2163–73. doi:10.1056/NEJMoa043596. PMID 15914548. Review in: Evid Based Med. 2006 Feb;11(1):20
- ↑ Szefler SJ, Mitchell H, Sorkness CA, Gergen PJ, O'Connor GT, Morgan WJ et al. (2008) Management of asthma based on exhaled nitric oxide in addition to guideline-based treatment for inner-city adolescents and young adults: a randomised controlled trial. Lancet 372 (9643):1065-72. DOI:10.1016/S0140-6736(08)61448-8 PMID: 18805335
- ↑ Shaw DE, Berry MA, Thomas M, Green RH, Brightling CE, Wardlaw AJ et al. (2007) The use of exhaled nitric oxide to guide asthma management: a randomized controlled trial. Am J Respir Crit Care Med 176 (3):231-7. DOI:10.1164/rccm.200610-1427OC PMID: 17496226