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Correspondence EXHALED NITRIC OXIDE To the Editor: The article by Buchvald and Bisgaard 1 compares the control of asthma in patients with upper quartile exhaled nitric oxide (FeNO) (12 ppb) while undergoing treatment with inhaled budesonide. They report that the addition of montelukast or placebo did not change the FeNO but that the addition of salmeterol increased the FeNO. In the “Discussion” section, the authors stated, “This is consistent with previous reports of increased FeNO with the use of LABAs [long-acting 2 - agonists].” The references the authors cite are Fuglsang et al 2 and Yates et al. 3 However, the report by Fuglsang et al states, “There was no statistically significant difference in exhaled NO after salmeterol and placebo treatment when mean or peak levels were analyzed.” The article by Yates et al 3 states that “regular use of salmeterol resulted in no change in exhaled nitric oxide, either used alone or in combination with inhaled corticosteroid.” The references appear to contradict the statement of the authors. Buchvald and Bisgaard state that the logic of selecting FeNO is that “it is probably a more sensitive marker for asthma control than lung function” and reference an article by Jones et al. 4 Jones et al, in contrast, state that the “predictive value 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 predictive value for FeNO in determining loss of control in asthma is an increase greater than 60% or 10 ppb. However, Buchvald and Bisgaard report changes with salmeterol of only 33% and 5 ppb, which are below the threshold of significant predictive value calculated by Jones et al. The article by Buchvald and Bisgaard has many excellent references for the reader to review. I would like clarification of the statements regarding these references. DAVID A. STEMPEL, MD Bellevue, Washington REFERENCES 1. Buchvald F, Bisgaard H. Comparisons of the complementary effect on exhaled nitric oxide of salmeterol vs montelukast in asthmatic children taking regular inhaled corticosteroids. Ann Allergy Asthma Immunol. 2003;91:309 –313. 2. Fuglsang G, Vikre-Jergensen J, Agertoth L, Pedersen S. Effect of salmeterol treatment on nitric oxide level in exhaled air and dose-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- and long-acting 2 -agonists on exhaled nitric oxide in asthmatic patients. Eur Respir J. 1997;10:1483–1488. 4. Jones SL, Kitelson J, Cowan JO, et al. The predictive value of exhaled 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. Given his great knowledge in the field, we are pleased his only comments 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 noted after treatment with salmeterol. However, nonsignificant trends of increased FeNO of 5% to 20% were reported in the studies by Fuglsang et al and Yates et al, respectively. These changes are similar to the increases in FeNO noted after the use of short-acting -agonists. 1 The increases in our study were noted 12 hours after administration of salmeterol at a point of little if any bronchodilatory effect, and, as stated in the article, the levels exceeded those previously reported following maximal bronchodilation. We believe these results are 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 and refers to the study by Jones et al, quoting that “predictive value of eNO was not surpassed by lung function or symp- toms.” In our article, we refer to the publication of Jones et al and state that “FeNO was . . . probably a more sensitive marker than lung function” In the article by Jones et al, the predictive value for FeNO measurements was calculated for asthma exacerbations. We did not claim the increased FeNO necessarily predicts imminent asthma exacerbations, but in- creased FeNO surely seems to be an indication of increased inflammatory activity in the airways. Several references cited in the article by Jones et al support our opinion on the validity of FeNO as a sensitive marker of airway inflammation. In the study by Kharitonov et al, 2 FeNO increased after reduction of budesonide treatment with no changes in lung function or daytime symptom score. In the study by Baraldi et al, 3 natural allergen exposure was related to an increase in FeNO without any changes in lung function. Additionally, studies evaluating the effect of montelukast on markers of inflammation in asthmatic patients found that montelukast reduced FeNO level compared with placebo and that FeNO was a more sensitive marker than forced expiratory volume in 1 second in detecting the effect of treatment. 1,4 Importantly, the predictive value of FeNO in the article by Jones et al may have been even greater if these measurements had not been performed at a very high exhalation flow rate of 250 mL, which is considerably higher than current recom- mendations as applied in our study with improved separation of asthmatic patients and controls. In his last statement, Dr. Stempel dismisses the significant 33% increase in FeNO reported in our study with addition of VOLUME 92, MARCH, 2004 381
Transcript of Response
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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