Related editorial
Fraction of exhaled nitric oxide measurements and asthma control: Are the numbers starting to add up? Louise Fleming, MB, ChB, MD, MRCPCH,a and Andrew Bush, MB BS (Hons), MA, MD, FRCP, FRCPCH, FERSb London, United Kingdom
Key words: Asthma management, exhaled nitric oxide, asthma control
Strategies aimed at achieving asthma control are a common theme in all major asthma guidelines, although the definition of good or complete asthma control is variable and not in the least bit evidence based. The Global Initiative for Asthma guidelines define well-controlled asthma as symptoms and reliever use twice per week or less with no nighttime waking or activity limitation.1 The National Asthma Education and Prevention Program additionally stipulates an FEV1 of greater than 80% of predicted value and allows up to 2 nocturnal awakenings per month and 1 exacerbation per year.2 The British Thoracic Society/Scottish Intercollegiate Guidelines Network guidelines aim for perfection with complete control, which is defined as the absence of any asthma symptoms whatsoever, normal lung function, and minimal medication side effects.3 In practice, only a small proportion of patients achieve full control.4 Is the pursuit of complete control the holy grail of asthma management for all but those with the mildest disease? Certainly the relentless pursuit of the amelioration of all symptoms must be balanced against the aim of achieving minimal treatment side effects. The Gaining Optimal Asthma Control study demonstrated that the majority of patients with uncontrolled asthma could achieve good asthma control after protocolized stepwise escalation of therapy.5 However, less than half achieved total control, and the majority reached the maximum permitted inhaled corticosteroid (ICS) dose over the course of the study. Many patients classify their asthma as well controlled despite frequent symptoms and are reluctant to increase their treatment to attain a level of control acceptable to their physicians.4 With this in mind, Honkoop et al6 have taken a more pragmatic approach and compared strategies aiming for controlled and partially controlled asthma (as defined by the Asthma Control From athe National Heart and Lung Institute, Imperial College, London, and the Department of Paediatric Respiratory Medicine, Royal Brompton and Harefield NHS Foundation Trust, and bPaediatrics Section, Imperial College, Paediatric Respirology, National Heart and Lung Institute, and the Royal Brompton Harefield NHS Foundation Trust, London, United Kingdom. Disclosure of potential conflict of interest: L. Fleming has received consultancy fees from Chiesi, as well as payment for delivering lectures from Novartis. A. Bush declares that he has no other relevant conflicts of interest. Received for publication November 7, 2014; revised December 10, 2014; accepted for publication December 18, 2014. Corresponding author: Louise Fleming, MB, ChB, MD, MRCPCH, Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, Sydney St, London SW3 6NP, United Kingdom. E-mail: [email protected]. J Allergy Clin Immunol 2015;135:689-90. 0091-6749/$36.00 Ó 2015 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaci.2014.12.1920
Questionnaire), the results of which are reported in this issue. Asthma control was not significantly different between the groups. However, medication use (and costs) was lower for the group with partially controlled symptoms. A third strategy added fraction of exhaled nitric oxide (FENO) measurements to a group aiming for controlled asthma. Asthma control improved significantly in this group compared with the partially controlled group, with a similar reduction in medication costs. There were no differences in quality of life or exacerbation rates between the 3 strategies. There was also no difference in the primary outcome, quality-adjusted life years. Despite this, on the basis of similar levels of asthma control compared with standard symptombased care but with reduced treatment costs, the authors conclude that the FENO-based approach is the preferred management strategy. FENO has long been seen as the ideal biomarker in terms of ease of measurement and convenience, but the evidence has hitherto been lacking to support its widespread use for the management of asthma in clinical practice.7 Against a number of negative studies (see the reference list in this article’s Online Repository at www.jacionline.org), this study now adds to recent evidence in favor of FENO-based management strategies.8-10 However, of these, the study by Powell et al9 showed benefit in a highly selected patient group (pregnant women), and the study by Petsky et al8 showed a reduction in exacerbations at the expense of a significantly higher ICS dose. Syk et al10 demonstrated a reduction in exacerbations and improvements in asthma control, although the primary outcome, the mini-Asthma Quality of Life Questionnaire score, was not different between the groups. Honkoop et al6 make the case for a FENO-based strategy partly on the basis that this showed the highest probability of costeffectiveness over a wide range of willingness-to-pay values. This analysis is based on patient-level data on the costs and health effects of alternative interventions. Without a background in health economics, it is difficult to grasp what this means in terms of hard costs. In simple terms it appears that the addition of FENO measurement adds the costs of the measurement to standard clinical care, but this is more than balanced against a reduction in medication costs, and there are similar reported clinical outcomes. The higher cut points used by Honkoop et al6 certainly helped to avoid the pitfalls of previous studies of ever increasing ICS doses. Even if we are to accept the cost-effectiveness argument, is it possible to translate this strategy into a workable approach in reallife clinical care? The management decisions were less didactic than previous studies and allowed a degree of clinician choice, which is more reflective of clinical practice. The medical teams were aided by an online support tool, which helped to combine clinical and FENO measurements into 9 different categories and 689
690 FLEMING AND BUSH
suggest the most appropriate management strategy, including whether the dose of ICS, long-acting b-agonist, or both should be changed. Again, this is attractive because it leads to more tailored treatment changes rather than simply increasing or decreasing the ICS dose. Without the provision of such a tool, FENO measurements have the potential to be wrongly interpreted or used injudiciously. However, in the right hands and with appropriate support, it is possible that FENO measurements could be part of the range of assessments used to guide clinical decision making and possibly reduce overall treatment costs. The study by Honkoop et al6 will not put an end to the debate on the utility of FENO measurement in clinical practice, and the possible cost benefits certainly add a new dimension to the debate. However, if we set aside the FENO argument, this study6 is noteworthy in that it demonstrated similar clinical outcomes in terms of exacerbations and quality of life, at least over a 1-year period, for patients enrolled in the controlled and partially controlled strategies, with a lower treatment burden for the latter. Should the treatment goals of national and international guidelines be more conservative and accept that less-thanperfect control does not always indicate that a treatment step up is needed? The noncompliance data (with both study decisions and prescribed treatment) demonstrate that even enrollment in a study and motivated study teams cannot persuade a significant minority of patients to take their medication at a dose they do not believe would be beneficial. It is likely that many are correct and safe in the choices they make; however, the risks of a severe exacerbation in those with poor asthma control cannot be ignored or trivialized.11 Understanding the patient’s acceptable levels of symptoms and medication use and ensuring they understand the consequences and risks of both should be used when developing treatment goals in partnership with the patient.
J ALLERGY CLIN IMMUNOL MARCH 2015
Whether FENO measurement should be part of that dialogue remains to be seen. REFERENCES 1. Global Initiative for Asthma. Global strategy for asthma management and prevention Available at: www.ginasthma.org. Accessed October 2014. 2. National Heart, Lung and Blood Institute. National Asthma Education and Prevention Program. Expert Panel Report 3: guidelines for the diagnosis and management of asthma Available at: www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm. Accessed July 2009. 3. British Thoracic Society, Scottish Intercollegiate Guidelines Network. British guideline on the management of asthma. Thorax 2014;69(suppl 1):1-192. 4. Partridge MR, van der Molen T, Myrseth SE, Busse WW. Attitudes and actions of asthma patients on regular maintenance therapy: the INSPIRE study. BMC Pulm Med 2006;6:13. 5. Bateman ED, Boushey HA, Bousquet J, Busse WW, Clark TJ, Pauwels RA, et al. Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL study. Am J Respir Crit Care Med 2004;170:836-44. 6. Honkoop PJ, Loijmans RJB, Termeer EH, Snoeck-Stroband JB, van den Hout WB, Bakker MJ, et al. Symptom- and fraction of exhaled nitric oxide–driven strategies for asthma control: a cluster-randomized trial in primary care. J Allergy Clin Immunol 2015;135:682-8. 7. Petsky HL, Cates CJ, Lasserson TJ, Li AM, Turner C, Kynaston JA, et al. A systematic review and meta-analysis: tailoring asthma treatment on eosinophilic markers (exhaled nitric oxide or sputum eosinophils). Thorax 2012;67:199-208. 8. Petsky HL, Li AM, Au CT, Kynaston JA, Turner C, Chang AB. Management based on exhaled nitric oxide levels adjusted for atopy reduces asthma exacerbations in children: a dual centre randomized controlled trial. Pediatr Pulmonol 2014 [Epub ahead of print]. doi:10.1002/ppul.23064. 9. Powell H, Murphy VE, Taylor DR, Hensley MJ, McCaffery K, Giles W, et al. Management of asthma in pregnancy guided by measurement of fraction of exhaled nitric oxide: a double-blind, randomised controlled trial. Lancet 2011;378:983-90. 10. Syk J, Malinovschi A, Johansson G, Unden AL, Andreasson A, Lekander M, et al. Anti-inflammatory treatment of atopic asthma guided by exhaled nitric oxide: a randomized, controlled trial. J Allergy Clin Immunol Pract 2013;1:639-48. 11. Royal College of Physicians. Why asthma still kills: the national review of asthma deaths. Available at: https://www.rcplondon.ac.uk/sites/default/files/why-asthmastill-kills-full-report.pdf. Accessed October 31, 2014.
J ALLERGY CLIN IMMUNOL VOLUME 135, NUMBER 3
REFERENCES E1. Calhoun WJ, Ameredes BT, King TS, Icitovic N, Bleecker ER, Castro M, et al. Comparison of physician-, biomarker-, and symptom-based strategies for adjustment of inhaled corticosteroid therapy in adults with asthma: the BASALT randomized controlled trial. JAMA 2012;308: 987-97. E2. De Jongste JC, Carraro S, Hop WC, Baraldi E. Daily telemonitoring of exhaled nitric oxide and symptoms in the treatment of childhood asthma. Am J Respir Crit Care Med 2009;179:93-7. E3. Fritsch M, Uxa S, Horak F Jr, Putschoegl B, Dehlink E, Szepfalusi Z, et al. Exhaled nitric oxide in the management of childhood asthma: a prospective 6-months study. Pediatr Pulmonol 2006;41:855-62.
FLEMING AND BUSH 690.e1
E4. Pijnenburg MW, Bakker EM, Hop WC, De Jongste JC. Titrating steroids on exhaled nitric oxide in children with asthma: a randomized controlled trial. Am J Respir Crit Care Med 2005;172:831-6. E5. Shaw DE, Berry MA, Thomas M, Green RH, Brightling CE, Wardlaw AJ, et al. The use of exhaled nitric oxide to guide asthma management: a randomized controlled trial. Am J Respir Crit Care Med 2007;176:231-7. E6. Smith AD, Cowan JO, Brassett KP, Herbison GP, Taylor DR. Use of exhaled nitric oxide measurements to guide treatment in chronic asthma. N Engl J Med 2005;352:2163-73. E7. Szefler SJ, Mitchell H, Sorkness CA, Gergen PJ, O’Connor GT, Morgan WJ, et al. 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 2008;372:1065-72.
Fraction of exhaled nitric oxide measurements and asthma control: Are the numbers starting to add up? Louise Fleming, MB, ChB, MD, MRCPCH,a and Andrew Bush, MB BS (Hons), MA, MD, FRCP, FRCPCH, FERSb London, United Kingdom
Key words: Asthma management, exhaled nitric oxide, asthma control
Strategies aimed at achieving asthma control are a common theme in all major asthma guidelines, although the definition of good or complete asthma control is variable and not in the least bit evidence based. The Global Initiative for Asthma guidelines define well-controlled asthma as symptoms and reliever use twice per week or less with no nighttime waking or activity limitation.1 The National Asthma Education and Prevention Program additionally stipulates an FEV1 of greater than 80% of predicted value and allows up to 2 nocturnal awakenings per month and 1 exacerbation per year.2 The British Thoracic Society/Scottish Intercollegiate Guidelines Network guidelines aim for perfection with complete control, which is defined as the absence of any asthma symptoms whatsoever, normal lung function, and minimal medication side effects.3 In practice, only a small proportion of patients achieve full control.4 Is the pursuit of complete control the holy grail of asthma management for all but those with the mildest disease? Certainly the relentless pursuit of the amelioration of all symptoms must be balanced against the aim of achieving minimal treatment side effects. The Gaining Optimal Asthma Control study demonstrated that the majority of patients with uncontrolled asthma could achieve good asthma control after protocolized stepwise escalation of therapy.5 However, less than half achieved total control, and the majority reached the maximum permitted inhaled corticosteroid (ICS) dose over the course of the study. Many patients classify their asthma as well controlled despite frequent symptoms and are reluctant to increase their treatment to attain a level of control acceptable to their physicians.4 With this in mind, Honkoop et al6 have taken a more pragmatic approach and compared strategies aiming for controlled and partially controlled asthma (as defined by the Asthma Control From athe National Heart and Lung Institute, Imperial College, London, and the Department of Paediatric Respiratory Medicine, Royal Brompton and Harefield NHS Foundation Trust, and bPaediatrics Section, Imperial College, Paediatric Respirology, National Heart and Lung Institute, and the Royal Brompton Harefield NHS Foundation Trust, London, United Kingdom. Disclosure of potential conflict of interest: L. Fleming has received consultancy fees from Chiesi, as well as payment for delivering lectures from Novartis. A. Bush declares that he has no other relevant conflicts of interest. Received for publication November 7, 2014; revised December 10, 2014; accepted for publication December 18, 2014. Corresponding author: Louise Fleming, MB, ChB, MD, MRCPCH, Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, Sydney St, London SW3 6NP, United Kingdom. E-mail: [email protected]. J Allergy Clin Immunol 2015;135:689-90. 0091-6749/$36.00 Ó 2015 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaci.2014.12.1920
Questionnaire), the results of which are reported in this issue. Asthma control was not significantly different between the groups. However, medication use (and costs) was lower for the group with partially controlled symptoms. A third strategy added fraction of exhaled nitric oxide (FENO) measurements to a group aiming for controlled asthma. Asthma control improved significantly in this group compared with the partially controlled group, with a similar reduction in medication costs. There were no differences in quality of life or exacerbation rates between the 3 strategies. There was also no difference in the primary outcome, quality-adjusted life years. Despite this, on the basis of similar levels of asthma control compared with standard symptombased care but with reduced treatment costs, the authors conclude that the FENO-based approach is the preferred management strategy. FENO has long been seen as the ideal biomarker in terms of ease of measurement and convenience, but the evidence has hitherto been lacking to support its widespread use for the management of asthma in clinical practice.7 Against a number of negative studies (see the reference list in this article’s Online Repository at www.jacionline.org), this study now adds to recent evidence in favor of FENO-based management strategies.8-10 However, of these, the study by Powell et al9 showed benefit in a highly selected patient group (pregnant women), and the study by Petsky et al8 showed a reduction in exacerbations at the expense of a significantly higher ICS dose. Syk et al10 demonstrated a reduction in exacerbations and improvements in asthma control, although the primary outcome, the mini-Asthma Quality of Life Questionnaire score, was not different between the groups. Honkoop et al6 make the case for a FENO-based strategy partly on the basis that this showed the highest probability of costeffectiveness over a wide range of willingness-to-pay values. This analysis is based on patient-level data on the costs and health effects of alternative interventions. Without a background in health economics, it is difficult to grasp what this means in terms of hard costs. In simple terms it appears that the addition of FENO measurement adds the costs of the measurement to standard clinical care, but this is more than balanced against a reduction in medication costs, and there are similar reported clinical outcomes. The higher cut points used by Honkoop et al6 certainly helped to avoid the pitfalls of previous studies of ever increasing ICS doses. Even if we are to accept the cost-effectiveness argument, is it possible to translate this strategy into a workable approach in reallife clinical care? The management decisions were less didactic than previous studies and allowed a degree of clinician choice, which is more reflective of clinical practice. The medical teams were aided by an online support tool, which helped to combine clinical and FENO measurements into 9 different categories and 689
690 FLEMING AND BUSH
suggest the most appropriate management strategy, including whether the dose of ICS, long-acting b-agonist, or both should be changed. Again, this is attractive because it leads to more tailored treatment changes rather than simply increasing or decreasing the ICS dose. Without the provision of such a tool, FENO measurements have the potential to be wrongly interpreted or used injudiciously. However, in the right hands and with appropriate support, it is possible that FENO measurements could be part of the range of assessments used to guide clinical decision making and possibly reduce overall treatment costs. The study by Honkoop et al6 will not put an end to the debate on the utility of FENO measurement in clinical practice, and the possible cost benefits certainly add a new dimension to the debate. However, if we set aside the FENO argument, this study6 is noteworthy in that it demonstrated similar clinical outcomes in terms of exacerbations and quality of life, at least over a 1-year period, for patients enrolled in the controlled and partially controlled strategies, with a lower treatment burden for the latter. Should the treatment goals of national and international guidelines be more conservative and accept that less-thanperfect control does not always indicate that a treatment step up is needed? The noncompliance data (with both study decisions and prescribed treatment) demonstrate that even enrollment in a study and motivated study teams cannot persuade a significant minority of patients to take their medication at a dose they do not believe would be beneficial. It is likely that many are correct and safe in the choices they make; however, the risks of a severe exacerbation in those with poor asthma control cannot be ignored or trivialized.11 Understanding the patient’s acceptable levels of symptoms and medication use and ensuring they understand the consequences and risks of both should be used when developing treatment goals in partnership with the patient.
J ALLERGY CLIN IMMUNOL MARCH 2015
Whether FENO measurement should be part of that dialogue remains to be seen. REFERENCES 1. Global Initiative for Asthma. Global strategy for asthma management and prevention Available at: www.ginasthma.org. Accessed October 2014. 2. National Heart, Lung and Blood Institute. National Asthma Education and Prevention Program. Expert Panel Report 3: guidelines for the diagnosis and management of asthma Available at: www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm. Accessed July 2009. 3. British Thoracic Society, Scottish Intercollegiate Guidelines Network. British guideline on the management of asthma. Thorax 2014;69(suppl 1):1-192. 4. Partridge MR, van der Molen T, Myrseth SE, Busse WW. Attitudes and actions of asthma patients on regular maintenance therapy: the INSPIRE study. BMC Pulm Med 2006;6:13. 5. Bateman ED, Boushey HA, Bousquet J, Busse WW, Clark TJ, Pauwels RA, et al. Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL study. Am J Respir Crit Care Med 2004;170:836-44. 6. Honkoop PJ, Loijmans RJB, Termeer EH, Snoeck-Stroband JB, van den Hout WB, Bakker MJ, et al. Symptom- and fraction of exhaled nitric oxide–driven strategies for asthma control: a cluster-randomized trial in primary care. J Allergy Clin Immunol 2015;135:682-8. 7. Petsky HL, Cates CJ, Lasserson TJ, Li AM, Turner C, Kynaston JA, et al. A systematic review and meta-analysis: tailoring asthma treatment on eosinophilic markers (exhaled nitric oxide or sputum eosinophils). Thorax 2012;67:199-208. 8. Petsky HL, Li AM, Au CT, Kynaston JA, Turner C, Chang AB. Management based on exhaled nitric oxide levels adjusted for atopy reduces asthma exacerbations in children: a dual centre randomized controlled trial. Pediatr Pulmonol 2014 [Epub ahead of print]. doi:10.1002/ppul.23064. 9. Powell H, Murphy VE, Taylor DR, Hensley MJ, McCaffery K, Giles W, et al. Management of asthma in pregnancy guided by measurement of fraction of exhaled nitric oxide: a double-blind, randomised controlled trial. Lancet 2011;378:983-90. 10. Syk J, Malinovschi A, Johansson G, Unden AL, Andreasson A, Lekander M, et al. Anti-inflammatory treatment of atopic asthma guided by exhaled nitric oxide: a randomized, controlled trial. J Allergy Clin Immunol Pract 2013;1:639-48. 11. Royal College of Physicians. Why asthma still kills: the national review of asthma deaths. Available at: https://www.rcplondon.ac.uk/sites/default/files/why-asthmastill-kills-full-report.pdf. Accessed October 31, 2014.
J ALLERGY CLIN IMMUNOL VOLUME 135, NUMBER 3
REFERENCES E1. Calhoun WJ, Ameredes BT, King TS, Icitovic N, Bleecker ER, Castro M, et al. Comparison of physician-, biomarker-, and symptom-based strategies for adjustment of inhaled corticosteroid therapy in adults with asthma: the BASALT randomized controlled trial. JAMA 2012;308: 987-97. E2. De Jongste JC, Carraro S, Hop WC, Baraldi E. Daily telemonitoring of exhaled nitric oxide and symptoms in the treatment of childhood asthma. Am J Respir Crit Care Med 2009;179:93-7. E3. Fritsch M, Uxa S, Horak F Jr, Putschoegl B, Dehlink E, Szepfalusi Z, et al. Exhaled nitric oxide in the management of childhood asthma: a prospective 6-months study. Pediatr Pulmonol 2006;41:855-62.
FLEMING AND BUSH 690.e1
E4. Pijnenburg MW, Bakker EM, Hop WC, De Jongste JC. Titrating steroids on exhaled nitric oxide in children with asthma: a randomized controlled trial. Am J Respir Crit Care Med 2005;172:831-6. E5. Shaw DE, Berry MA, Thomas M, Green RH, Brightling CE, Wardlaw AJ, et al. The use of exhaled nitric oxide to guide asthma management: a randomized controlled trial. Am J Respir Crit Care Med 2007;176:231-7. E6. Smith AD, Cowan JO, Brassett KP, Herbison GP, Taylor DR. Use of exhaled nitric oxide measurements to guide treatment in chronic asthma. N Engl J Med 2005;352:2163-73. E7. Szefler SJ, Mitchell H, Sorkness CA, Gergen PJ, O’Connor GT, Morgan WJ, et al. 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 2008;372:1065-72.
