Correspondence
Exhaled Nitric Oxide and Asthma
N Engl J Med 2005; 353:732-733August 18, 2005
- Article
To the Editor:
The landmark study by Smith et al. (May 26 issue)1 shows that measurement of exhaled nitric oxide (FeNO) can reduce the dose of inhaled corticosteroids in patients with asthma without impairing control of asthma and, in particular, exacerbations of asthma. Because of the high variability of FeNO among both healthy persons and patients with asthma, it may make sense to consider a personalized “best” cutoff FeNO level, as seen after the dose-optimization phase or after administration of a dose of oral prednisone. In addition, the relatively high exhalation flow rate used (250 ml per second), as compared with the recommended flow rate of 50 ml per second,2 may be a factor. The difference in terms of parts per billion between a patient when in stable condition and the same patient in unstable condition will be much smaller, and perhaps less discriminatory, at 250 ml per second than at 50 ml per second.3 Finally, the numerical trend seen in the reduction of exacerbations suggests that the study was underpowered to assess this outcome.
Philip E. Silkoff, M.B., B.S., M.R.C.P.
715 Bryn Mawr Ave., Narberth, PA 19072
philsilkoff@hotmail.com Dr. Silkoff is an employee of AstraZeneca.
3 References1
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;352:2163-2173
Full Text | Web of Science | Medline2
ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005. Am J Respir Crit Care Med 2005;171:912-930
CrossRef | Web of Science | Medline3
Silkoff PE ,McClean PA ,Slutsky AS , et al. Marked flow-dependence of exhaled nitric oxide using a new technique to exclude nasal nitric oxide. Am J Respir Crit Care Med 1997;155:260-267
Web of Science | Medline
To the Editor:
Smith et al. compared exhaled nitric oxide with clinical criteria (symptoms, bronchodilator requirements, and pulmonary function) as a guide for adjusting the dose of inhaled corticosteroids in patients with mild-to-moderate asthma. They observed fewer mild exacerbations in the FeNO group than in the control group and similar asthma control with lower doses of inhaled corticosteroids in the FeNO group. For patients with asthma that is not controlled with low-dose inhaled corticosteroids (i.e., 500 μg of beclomethasone or the equivalent), guidelines recommend combining inhaled corticosteroids with long-acting beta2-agonists rather than higher doses of the corticosteroid,1 since the combination is more effective.2,3 We believe that had the authors used such a combination for adjustment, they would have obtained different results, given that long-acting beta2-agonists are quite effective in controlling asthma without modifying exhaled nitric oxide.4
4 ReferencesLorenzo Corbetta, M.D.
Leonardo M. Fabbri, M.D.
University of Modena and Reggio Emilia, 41100 Modena, Italy
fabbri.leonardo@unimore. it 1
Global Initiative for Asthma 2002. Update: Global Strategy for Asthma Management and Prevention NHLBI/WHO Workshop report 1995. Bethesda, Md.: National Institutes of Health, 2002. (DHHS publication no. (NIH) 02-3659.) (Accessed July 28, 2005, at http://www.ginasthma.org.)
2
Pauwels RA ,Lofdahl CG ,Postma DS , et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma: Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group. N Engl J Med 1997;337:1405-1411[Erratum, N Engl J Med 1998;338:139.]
Full Text | Web of Science | Medline3
Shrewsbury S ,Pyke S ,Britton M . Meta-analysis of increased dose of inhaled steroid or addition of salmeterol in symptomatic asthma (MIASMA). BMJ 2000;320:1368-1373
CrossRef | Web of Science | Medline4
Yates DH ,Kharitonov SA ,Barnes PJ . Effect of short- and long-acting inhaled beta2-agonists on exhaled nitric oxide in asthmatic patients. Eur Respir J 1997;10:1483-1488
CrossRef | Web of Science | Medline
To the Editor:
Smith et al. succinctly demonstrate that a management algorithm incorporating the measurement of exhaled nitric oxide enables inhaled corticosteroid doses to be back-titrated without loss of asthma control. The authors' findings also raise the exciting possibility that this easy-to-measure surrogate inflammatory biomarker might guide clinicians in the optimal management of persistent asthma with the use of a low-to-moderate dose of inhaled corticosteroid (step 3 of the national asthma guidelines1). Perhaps these symptomatic patients with normal levels of nitric oxide (and probable adequate antiinflammatory therapy) should proceed to a therapeutic trial of a long-acting beta2-agonist.2 For patients with elevated levels of nitric oxide (suggestive of ongoing inflammation) the inhaled corticosteroid dose could first be increased or a leukotriene-receptor antagonist could be added.
2 ReferencesGraeme P. Currie, M.D.
Aberdeen Royal Infirmary, Aberdeen AB25 2ZN, United Kingdom
graeme.currie@nhs. net Daniel K.C. Lee, M.D.
Ipswich Hospital, Ipswich IP4 5PD, United Kingdom1
British guideline on the management of asthma. Thorax 2003;58:Suppl 1:i1-i94
CrossRef | Web of Science | Medline2
Currie GP ,Lee DK ,Wilson AM . Effects of dual therapy with corticosteroids plus long acting beta2-agonists in asthma. Respir Med 2005;99:683-694
CrossRef | Web of Science | Medline
Author/Editor Response
Dr. Silkoff raises two important points. First, in any situation where fixed cutoff points are used to determine dose adjustments, outcomes will be significantly influenced by placement of the cutoff points. We acknowledge that this was the case in our study, not only for the FeNO group but also for the control group (in which clinical characteristics were used). The same is probably true of the two earlier “proof of concept” studies.1,2 Dr. Silkoff advocates the use of “personalized `best'” FeNO thresholds as the basis for clinical decision making. We agree that a “one size fits all” approach may be rather crude. But it is a first step. Substantial work is required before any alternative can be recommended.
Both Drs. Currie and Lee and Drs. Corbetta and Fabbri highlight the issue of using long-acting beta2-agonists. First, we accept that using these agents in patients who were symptomatic despite their taking 250 μg or more of fluticasone per day would have conformed more closely to international guidelines. Had we taken such an approach, it might indeed have influenced the overall results. However, because of the confounding effect of the use of long-acting beta2-antagonists on the primary end point (exacerbations), we calculated a priori that this approach would have required a tripling of the number of subjects needed for the study. This was beyond our resources. Second, we agree with Drs. Currie and Lee that when FeNO levels are normal, treatment with additional inhaled corticosteroids is unlikely to be beneficial3; long-acting beta2-antagonists or leukotriene antagonists are more logical alternatives in such circumstances, and normal FeNO results are therefore informative.
We disagree with Drs. Corbetta and Fabbri's assertion that the overall message of the study is misleading. Our message is quite plain: treatment with inhaled corticosteroids should be tailored for each patient. Nothing less and nothing more. FeNO measurements are a helpful prompt in this regard.
3 ReferencesAndrew D. Smith, M.B., Ch.B.
D. Robin Taylor, M.D.
University of Otago, Dunedin, New Zealand
robin.taylor@stonebow. otago. ac. nz 1
Sont JK ,Willems LN ,Bel EH ,van Krieken JH ,Vandenbroucke JP ,Sterk PJ . Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long-term treatment. Am J Respir Crit Care Med 1999;159:1043-1051
Web of Science | Medline2
Green RH ,Brightling CE ,McKenna S , et al. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet 2002;360:1715-1721
CrossRef | Web of Science | Medline3
Smith AD, Cowan JO, Brassett KP, et al. Exhaled nitric oxide: a predictor of steroid response. Am J Respir Crit Care Med (in press).
- Citing Articles (3)
Citing Articles
1
Albert M. LI, Tony W. T. TSANG, Hugh S. LAM, Rita Y. T. SUNG, Anne B. CHANG. (2008) Predictors for failed dose reduction of inhaled corticosteroids in childhood asthma. Respirology 13:3, 400-407
CrossRef2
Steve Turner. (2008) Exhaled nitric oxide in the diagnosis and management of asthma. Current Opinion in Allergy and Clinical Immunology 8:1, 70-76
CrossRef3
Graeme P Currie. (2006) Effects of asthma treatment: the present and future. Expert Review of Clinical Immunology 2:4, 547-560
CrossRef
