Correspondence

EXHALED NITRIC OXIDE

To the Editor:The article by Buchvald and Bisgaard1 compares the controlof asthma in patients with upper quartile exhaled nitric oxide(FeNO) (�12 ppb) while undergoing treatment with inhaledbudesonide. They report that the addition of montelukast orplacebo did not change the FeNO but that the addition ofsalmeterol increased the FeNO. In the “Discussion” section,the authors stated, “This is consistent with previous reports ofincreased FeNO with the use of LABAs [long-acting �2-agonists].” The references the authors cite are Fuglsang et al2and Yates et al.3 However, the report by Fuglsang et al states,“There was no statistically significant difference in exhaledNO after salmeterol and placebo treatment when mean orpeak levels were analyzed.” The article by Yates et al3 statesthat “regular use of salmeterol resulted in no change inexhaled nitric oxide, either used alone or in combination withinhaled corticosteroid.” The references appear to contradictthe statement of the authors.Buchvald and Bisgaard state that the logic of selecting

FeNO is that “it is probably a more sensitive marker forasthma control than lung function” and reference an article byJones et al.4 Jones et al, in contrast, state that the “predictivevalue of eNO was not surpassed by lung function or symp-toms.” They do not report one being better than the other.Applying the results of Jones et al, the positive predictivevalue for FeNO in determining loss of control in asthma is anincrease greater than 60% or 10 ppb. However, Buchvald andBisgaard report changes with salmeterol of only 33% and 5ppb, which are below the threshold of significant predictivevalue calculated by Jones et al. The article by Buchvald andBisgaard has many excellent references for the reader toreview. I would like clarification of the statements regardingthese references.

DAVID A. STEMPEL, MDBellevue, Washington

REFERENCES1. Buchvald F, Bisgaard H. Comparisons of the complementaryeffect on exhaled nitric oxide of salmeterol vs montelukast inasthmatic children taking regular inhaled corticosteroids. AnnAllergy Asthma Immunol. 2003;91:309–313.

2. Fuglsang G, Vikre-Jergensen J, Agertoth L, Pedersen S. Effectof salmeterol treatment on nitric oxide level in exhaled air anddose-response to terbutaline in children with mild asthma. Pe-diatr Pulmonol. 1998;24:314–321.

3. Yates DH, Kharitonov SA, Barnes PJ. Effect of short- andlong-acting �2-agonists on exhaled nitric oxide in asthmaticpatients. Eur Respir J. 1997;10:1483–1488.

4. Jones SL, Kitelson J, Cowan JO, et al. The predictive value ofexhaled nitric oxide measurements in assessing changes in

asthma control. Am J Respir Crit Care Med. 2001;164:738–743.

Response:We thank Dr. Stempel for his comments on this article. Givenhis great knowledge in the field, we are pleased his onlycomments on our manuscript were regarding the references.Dr. Stempel quotes from the references by Fuglsang et al

and Yates et al and states that no changes in FeNO were notedafter treatment with salmeterol. However, nonsignificanttrends of increased FeNO of 5% to 20% were reported in thestudies by Fuglsang et al and Yates et al, respectively. Thesechanges are similar to the increases in FeNO noted after theuse of short-acting �-agonists.1 The increases in our studywere noted 12 hours after administration of salmeterol at apoint of little if any bronchodilatory effect, and, as stated inthe article, the levels exceeded those previously reportedfollowing maximal bronchodilation. We believe these resultsare of sufficient interest to warrant further study.Dr. Stempel appears to have some reservations regarding

our use of FeNO as a marker for airway inflammation andrefers to the study by Jones et al, quoting that “predictivevalue of eNO was not surpassed by lung function or symp-toms.” In our article, we refer to the publication of Jones et aland state that “FeNO was . . . probably a more sensitivemarker than lung function” In the article by Jones et al, thepredictive value for FeNO measurements was calculated forasthma exacerbations. We did not claim the increased FeNOnecessarily predicts imminent asthma exacerbations, but in-creased FeNO surely seems to be an indication of increasedinflammatory activity in the airways. Several references citedin the article by Jones et al support our opinion on the validityof FeNO as a sensitive marker of airway inflammation. In thestudy by Kharitonov et al,2 FeNO increased after reduction ofbudesonide treatment with no changes in lung function ordaytime symptom score. In the study by Baraldi et al,3 naturalallergen exposure was related to an increase in FeNO withoutany changes in lung function. Additionally, studies evaluatingthe effect of montelukast on markers of inflammation inasthmatic patients found that montelukast reduced FeNOlevel compared with placebo and that FeNO was a moresensitive marker than forced expiratory volume in 1 second indetecting the effect of treatment.1,4Importantly, the predictive value of FeNO in the article by

Jones et al may have been even greater if these measurementshad not been performed at a very high exhalation flow rate of250 mL, which is considerably higher than current recom-mendations as applied in our study with improved separationof asthmatic patients and controls.In his last statement, Dr. Stempel dismisses the significant

33% increase in FeNO reported in our study with addition of

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salmeterol, stating this was below the threshold limit seen inthe study by Jones et al for predictive value for loss of asthmacontrol. The cutoff values from the study by Jones et alcannot be extrapolated to our study, because exhalation flowrates used in measuring FeNO were considerably differentand applied for a different outcome as noted above. Dr.Stempel should appreciate that measurements of FeNO aredependent on the peak expiratory flow rate under which itwas measured,5 and predictive value is clearly outcomedependent.The Global Initiative on Asthma recommends the devel-

opment of noninvasive tests to monitor asthmatic airwayinflammation in children whose asthma control may be dif-ficult to characterize. The results of our trial demonstrate thatFeNO could be used as a sensitive, noninvasive test to mon-itor asthma inflammatory control in pediatric patients andprovides a framework for future studies. The increase inFeNO with salmeterol may represent asthma that is not ade-

quately controlled, and studies should be designed to deter-mine the significance of this finding.

REFERENCES1. Bisgaard H, Loland L, Oj JA. NO in exhaled air of asthmaticchildren is reduced by the leukotriene receptor antagonist mon-telukast. Am J Respir Crit Care Med. 1999;160:1227–1231.

2. Kharitonov SA, Yates DH, Barnes PJ. Inhaled glucocorticoidsdecrease nitric oxide in exhaled air of asthmatic patients. Am JRespir Crit Care Med. 1996;153:454–457.

3. Baraldi E, Carra S, Dario C, et al. Effect of natural grass pollenexposure on exhaled nitric oxide in asthmatic children. Am JRespir Crit Care Med. 1999;159:262–266.

4. Sandrini A, Ferreira IM, Gutierrez C, Jardim JR, Zamel N,Chapman KR. Effect of montelukast on exhaled nitric oxide andnonvolatile markers of inflammation in mild asthma. Chest.2003;124:1334–1340.

5. Baraldi E, de Jongste JC. Measurement of exhaled nitric oxidein children, 2001. Eur Respir J. 2002;20:223–237.

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