Background International guidelines for the treatment of asthmarecommend adjusting the dose of inhaled corticosteroids on thebasis of symptoms, bronchodilator requirements, and the resultsof pulmonary-function tests. Measurements of the fraction ofexhaled nitric oxide (FENO) constitute a noninvasive markerthat may be a useful alternative for the adjustment of inhaled-corticosteroidtreatment.
Methods In a single-blind, placebo-controlled trial, we randomlyassigned 97 patients with asthma who had been regularly receivingtreatment with inhaled corticosteroids to have their corticosteroiddose adjusted, in a stepwise fashion, on the basis of eitherFENO measurements or an algorithm based on conventional guidelines.After the optimal dose was determined (phase 1), patients werefollowed up for 12 months (phase 2). The primary outcome wasthe frequency of exacerbations of asthma; the secondary outcomewas the mean daily dose of inhaled corticosteroid.
Results Forty-six patients in the FENO group and 48 in the groupwhose asthma was treated according to conventional guidelines(the control group) completed the study. The final mean dailydoses of fluticasone, the inhaled corticosteroid that was used,were 370 µg per day for the FENO group (95 percent confidenceinterval, 263 to 477) and 641 µg per day for the controlgroup (95 percent confidence interval, 526 to 756; P=0.003),a difference of 270 µg per day (95 percent confidenceinterval, 112 to 430). The rates of exacerbation were 0.49 episodeper patient per year in the FENO group (95 percent confidenceinterval, 0.20 to 0.78) and 0.90 in the control group (95 percentconfidence interval, 0.31 to 1.49), representing a nonsignificantreduction of 45.6 percent (95 percent confidence interval formean difference, –78.6 percent to 54.5 percent) in theFENO group. There were no significant differences in other markersof asthma control, use of oral prednisone, pulmonary function,or levels of airway inflammation (sputum eosinophils).
Conclusions With the use of FENO measurements, maintenance dosesof inhaled corticosteroids may be significantly reduced withoutcompromising asthma control.
Inhaled corticosteroids are the mainstay of treatment for chronicasthma, the doses of which should be adequate to control asthmasymptoms but also as low as possible in order to prevent adverseeffects. Since the dose required is highly variable, both amongpatients and within individual patients, physicians need aneasy, effective, and safe method to guide dose titration. Currenttreatment guidelines recommend that adjustments in doses shouldbe based on asthma symptoms and the results of basic pulmonary-functiontests. Two proof-of-concept studies have demonstrated that theuse of alternative criteria — namely, airway hyperresponsiveness1or eosinophilia in induced sputum2 — to make adjustmentsin doses of inhaled corticosteroids leads to improved outcomes.However, these particular measurements may be time-consumingto obtain or difficult to perform.
The fraction of nitric oxide in the exhaled air (FENO) is amarker of asthma; the magnitude of FENO is increased in proportionto bronchial wall inflammation3 or induced-sputum eosinophilia4as well as to airway hyperresponsiveness.4,5 Increases in FENOare associated with a deterioration in asthma control,5 andFENO levels are reduced in a dose-dependent manner with antiinflammatorytreatment.6,7 However, unlike induced-sputum analysis and bronchial-challengetesting, FENO measurements are easy to perform, reproducible,and associated with a high degree of acceptance by patients.8
Taken together, these data suggest that FENO measurements mayprovide a method of adjusting inhaled corticosteroid doses forpatients with chronic asthma. In a prospective, randomized,single-blind, placebo-controlled trial, we compared the adjustmentof the dose of an inhaled corticosteroid, fluticasone, withuse of a FENO-based algorithm with adjustment with use of analgorithm based on guidelines promulgated by the Global Initiativefor Asthma.9 This study was designed to test the null hypothesisthat there would be no difference in the frequency of asthmaexacerbations between the two approaches.
Methods
Patients
We recruited 110 patients 12 to 75 years of age with chronicasthma10 whose treatment was being managed in a primary caresetting. Each patient had received regular inhaled corticosteroidsfor six months or more, with no change in dose within the previoussix weeks. Exclusion criteria included the following: four ormore courses of oral prednisone in the previous 12 months; admissionto the hospital because of asthma in the previous 6 months orto the intensive care unit because of asthma at any time inthe past; and cigarette smoking, either current or past, witha history of more than 10 pack-years. The use of long-actingbeta-agonists was discontinued because of the recognized confoundingeffect of these agents on asthma exacerbations — the primaryend point of the study. However, subjects who were unable totolerate the attempted withdrawal of long-acting beta-agonistsduring the run-in period were allowed to participate in thestudy if they could continue the use of these agents at a fixeddose.
Study Plan
The study plan is outlined in Figure 1. Exhaled nitric oxidewas measured and spirometry performed after a two-week run-inperiod and at every visit thereafter. At the second visit, allpatients were started on inhaled fluticasone (Flixotide, GlaxoSmithKline),administered twice daily with the use of a combination of twoidentical, unmarked metered-dose inhalers (in order to achievecomplete blinding at all times). The fluticasone was given througha large volume spacer (Volumatic, GlaxoSmithKline). Six treatmentdoses were available: 1000 µg, 750 µg, 500 µg,250 µg, and 100 µg per day, and placebo (0 µg).At each visit, treatment packs were dispensed that containedtwo inhalers; these provided the requisite combination of 0µg, 50 µg, 125 µg, and 250 µg per puff,which enabled the patient to receive the total daily dose asone puff from each inhaler twice daily at all times during thestudy. Subjects were informed that treatment could vary between0 and 1000 µg per day, but they were not informed of theactual prescribed dose at any time.
At the end of the run-in period, patients began receiving 750 µg of fluticasone per day. The dose was then adjusted at each visit according to each patient's assigned algorithm. Patients who were taking less than 200 µg of fluticasone per day (or the equivalent dose of budesonide or beclomethasone) at study entry began receiving 500 µg per day. The dose could be increased, to a maximum of 1000 µg per day, if the measured FENO was greater than 15 parts per billion (ppb) or if asthma remained uncontrolled. The criteria by which loss of control of asthma was determined are listed in Table 1. If, during phase 2, after an upward adjustment, asthma was subsequently found to be controlled at two consecutive visits (i.e., for four months), the dose of fluticasone was reduced by one step — but not below the optimal dose or to 0 µg per day.
Phase 1
During phase 1, the dose of inhaled fluticasone was titrateddownward in a stepwise manner until the optimal dose was deemedto have been achieved. Subjects received 750 µg per dayto start (or 500 µg per day if their inhaled-corticosteroidrequirement before enrollment was less than 200 µg perday of fluticasone or the equivalent). Subjects returned afterfour weeks and were randomly assigned to one of the two managementgroups (the group receiving conventional management, hereafterreferred to as the control group, and the group in which FENOwas used as the basis for dose adjustment), with each grouphaving a different algorithm for titration of the dose of fluticasone(Table 1). Subjects were blinded to their group assignment.
Table 1. Criteria for Adjustment of the Dose of Inhaled Corticosteroid in the Two Study Groups.
The control-group algorithm was derived from criteria establishedby the Global Initiative for Asthma 2002 for the control ofasthma.9 Dose adjustments were based on predetermined thresholdsin regard to symptoms, bronchodilator use, diurnal peak flows,and spirometry. The FENO-group algorithm was based solely onFENO measurements, with 15 parts per billion (ppb) of nitricoxide (at an exhaled flow rate of 250 ml per second) used asthe cutoff point, above which an increase in the dose of inhaledcorticosteroid was prescribed5; this FENO value is equivalentto 35 ppb at a flow rate of 50 ml per second (see part 1 ofthe Supplementary Appendix, available with the full text ofthis article at www.nejm.org). At each study visit, with theuse of the appropriate algorithm, the patient's asthma was deemedto be controlled or uncontrolled. The dose of inhaled fluticasonewas decreased or increased (to a maximum of 1000 µg perday) accordingly.
Titration downward was repeated one step at a time every fourweeks until the FENO was greater than 15 ppb or until asthmabecame uncontrolled (Table 1), at which point the dose of fluticasonewas increased — again, one step at a time, at four-weekintervals, until the FENO level was less than 15 ppb or untilasthma was again controlled. Once the FENO level had decreasedto less than 15 ppb, or asthma control had been reestablished,the final dose (which possibly included placebo among patientsin whom asthma control was not lost at a dose of 0 µgof fluticasone per day) was deemed to be the optimal dose forthat person.
Phase 2
During phase 2, which lasted for 12 months, maintenance treatmentwith inhaled fluticasone was continued at the optimal dose,although further upward adjustments in the dose were permittedif asthma control was lost. Subjects were evaluated on six occasionsat intervals of two months. At each visit, FENO measurementswere obtained or asthma control was assessed in the same wayas during phase 1. If the FENO was greater than 15 ppb or asthmawas uncontrolled at any visit during phase 2, treatment wasincreased by one step in accordance with the assigned algorithm.Thereafter, if the FENO level remained at less than 15 ppb orif the asthma was controlled for two consecutive visits (i.e.,for four months), the dose was titrated back down one step.However, treatment was not decreased below the optimal dose(below which each patient had previously demonstrated instability)or to placebo during phase 2.
All treatment orders were verified independently by an investigatorwho was blinded to the treatment assignments. (See part 2 ofthe Supplementary Appendix for full details regarding the treatment-assignmentprotocol.) Compliance was determined according to the weightof the study inhalers.
Back-up Strategy for the FENO Group
We did not have a priori evidence that low FENO measurementscould reliably be used to deny patients an increase in inhaled-corticosteroiddose that by all other criteria would be deemed clinically necessary.Thus, for ethical reasons, subjects in the FENO group had apredetermined "safety buffer" by which an upward (one-step)adjustment in the dose was provided to deal with deterioratingasthma in the absence of a rise in measured FENO. The criteriafor intervention can be found in part 3 of the Supplementary Appendix.
Patients were not permitted to adjust their maintenance doseof inhaled corticosteroid except at a study visit. However,again for reasons of safety, all subjects had a personalizedself-management plan, which instructed them to take oral prednisone,40 mg per day, when morning peak flows fell below 70 percentof mean run-in values; they continued this dose until peak flowsincreased above 85 percent, at which time they were to take20 mg per day for the same number of days. Participants had24-hour access to the study investigators.
Measurements
Exhaled nitric oxide was measured in accordance with the recommendationsof the American Thoracic Society11 at a flow rate of 250 mlper second. Additional information regarding technical aspectsof FENO measurements is contained in part 1 of the Supplementary Appendix.Spirometry was performed according to the AmericanThoracic Society criteria.12 Sputum induction was performedon three occasions: at the first, "uncontrolled," visit duringphase 1; at the final visit of phase 1, which occurred afterfour weeks of treatment with the optimal dose of fluticasone;and at the final visit of phase 2. Sputum was obtained and analyzedaccording to published methods with a whole-sample technique.13,14
Subjects completed a daily diary card throughout the study periodto record symptoms, the use of bronchodilators, peak flows,and the use of prednisone. Asthma symptoms were scored for each24-hour period as follows: 0 indicated no symptoms, 1 symptomsfor one short period, 2 symptoms for two or more short periods,3 symptoms most of the time that did not affect normal dailyactivities, 4 symptoms most of the time that did affect normaldaily activities, and 5 symptoms so severe as to disrupt dailyactivities.
From the data provided in the diary, a global asthma score of0 to 4 was calculated for each 24-hour period with the use ofpreviously published criteria (Table 2).15 The frequencies ofdays with scores of 0, 1, 2, 3, and 4 were used to describethe control of asthma during phase 2. The same scoring systemwas used to calculate the frequency, duration, and severityof exacerbations of asthma during phase 2. The criteria fordistinguishing between minor and major exacerbations and theirduration have been published previously.15 Briefly, a minorexacerbation was defined as a global daily asthma score of 2on two or more consecutive days; a major exacerbation as a globaldaily asthma score of 3 on two or more consecutive days (orin one day, in the context of a minor exacerbation); a majorexacerbation or medical emergency as a global daily asthma scoreof 4 in one day; and the conclusion of an exacerbation as aglobal daily asthma score that had returned to and remainedat 0 or 1 for three or more days — otherwise the exacerbationwas deemed to be continuing. The number of courses of prednisonefor the treatment of asthma exacerbations was designated asa secondary end point; this end point was independent of thecriteria used to calculate rates of exacerbation.
Table 2. Criteria for Daily Asthma Score Used for the Calculation of Exacerbations.
Study Size and Statistical Analysis
In the studies by Sont et al.1 and Green et al.,2 the use ofalgorithms based on measurements of airway responsiveness andsputum cell counts resulted in a reduction in exacerbationsof 47 percent and 68 percent, respectively. Using data on exacerbationrates obtained from a previous study carried out in our population,15we calculated with the use of the FENO algorithm that 42 patientsper group who completed the study would be required to demonstratea 60 percent reduction in the rate of exacerbations. The datafor patients who withdrew during phase 2 were analyzed on anintention-to-treat basis, and annual exacerbation rates werecalculated by extrapolation. The analysis of the rates of total,minor, and major asthma exacerbations was performed with theuse of negative binomial regression.
The analysis of the mean daily dose of fluticasone was performedwith the use of analysis of covariance, with the fluticasone-equivalentdose at study entry as the covariate. The distribution of dosesof inhaled corticosteroids was compared with the use of theKolmogorov–Smirnov Z test. Sputum cell counts and FENOdata were analyzed after logarithmic transformation. Other normallydistributed data were analyzed with use of the two-sample t-test.Results are expressed as means with 95 percent confidence intervalsunless stated otherwise.
Ethics
The study was approved by the Otago ethics committee, and allparticipants gave written informed consent. The authors weresolely responsible for the study design, data analysis, andinterpretation and for the writing of the manuscript.
Results
One hundred ten patients were recruited, 69 of them (63 percent)women, with a mean age of 44.8 years (range, 12 to 73) and amean duration of asthma of 25.2 years (range, 1 to 65). Sevenpatients withdrew consent before randomization, and six hadunstable asthma. Ninety-seven patients underwent randomizationto a management group. Baseline measurements are shown in Table 3.The mean dose of inhaled corticosteroid at study entry wasnot significantly different in the two management groups —411 µg per day of fluticasone or the equivalent (95 percentconfidence interval, 344 to 478) in the FENO group and 491 µgper day (95 percent confidence interval, 403 to 579) in thecontrol group. Among the 19 patients who were taking long-actingbeta-agonists at study entry, the use of these agents was continuedin 5 of 9 patients in the FENO group and in 8 of 10 in the controlgroup.
Table 3. Demographic and End-Point Data for All Randomized Patients.
Three patients withdrew during phase 1 (two in the FENO group,because of a breast lump and gout, respectively, and one inthe control group because of a respiratory tract infection).Thus, 94 patients (46 in the FENO group and 48 in the controlgroup) completed phase 1 and entered phase 2. Five patientswithdrew during phase 2 but were included in the intention-to-treatanalysis (two in the FENO group, because of a respiratory tractinfection in one and unstable asthma despite taking the maximumdose of fluticasone in the other, and three from the controlgroup, all of whom were lost to follow-up). There were no significantdifferences in the duration of phase 1 for the two groups —mean, 25.4 weeks for the FENO group (95 percent confidence interval,23.2 to 27.7) and 22.4 weeks for the control group (95 percentconfidence interval, 20.2 to 24.7; P=0.07).
Asthma Control, Exacerbations, and Use of Prednisone
The total rate of exacerbations during phase 2 was 0.49 exacerbationper patient per year in the FENO group (95 percent confidenceinterval, 0.20 to 0.78) and 0.90 in the control group (95 percentconfidence interval, 0.31 to 1.49; P=0.27). This 45.6 percentreduction among patients in the FENO group (95 percent confidenceinterval, –78.6 to 54.5) failed to confirm the superiorityof the FENO algorithm (for which a threshold of 60 percent reductionhad been deemed clinically significant). There were no statisticallysignificant differences between the two groups in the exacerbationrates (Figure 2A), the cumulative total numbers of exacerbations(Figure 2B), the times to a first exacerbation (Figure 2C),or the numbers of patients with one or more exacerbations (Figure 2D).The number of patients who had at least one exacerbationwas numerically, but not significantly, greater in the FENOgroup (14 of 46, as compared with 11 of 48 in the control group;P=0.39) (Figure 2C), whereas the overall frequency of exacerbationsper patient was higher in the control group (P=0.27) (Figure 2Band Figure 2D). This pattern could not be accounted for bythe frequency of safety interventions that occurred in the FENOgroup.
Panel A shows the mean rates of total exacerbations of asthma and of minor and major exacerbations during phase 2. Error bars represent SEs. In Panel B, the cumulative number of exacerbations of asthma during phase 2 is shown; P=0.27 for the comparison between groups. Panel C shows the results of a Kaplan–Meier analysis of the time to a first exacerbation of asthma in each group during phase 2. There was no significant difference between the two groups (P=0.39). Panel D shows the frequency distribution of patients who had zero, one, and two or more exacerbations during phase 2.
During phase 2, there were no significant differences in nighttimewaking or use of bronchodilators among patients in the FENOand control groups (Table 3). The percentage of symptom-freedays was similar in the two groups (69.3 percent in the FENOgroup and 63.7 percent in the control group, P=0.44), and thenumber of courses of prednisone that were used did not differsignificantly — 22 in the FENO group and 29 in the controlgroup (P=0.60). The percentages of patients who required treatmentwith prednisone during phase 2 were as follows: zero coursesof treatment, 71.7 percent in the FENO group and 68.8 percentin the control group; one course, 17.4 percent and 18.8 percent,respectively; and two or more courses, 10.9 percent and 12.5percent, respectively.
Doses of Inhaled Corticosteroid
At the end of phase 1, the mean fluticasone dose was 292 µgper day in the FENO group (95 percent confidence interval, 188to 396) and 567 µg per day in the control group (95 percentconfidence interval, 443 to 691; P=0.003); the median doseswere 100 µg per day (25th and 75th percentiles, 0 and500) and 750 µg per day (25th and 75th percentiles, 100and 1000), respectively. The mean fluticasone doses at the endof phase 2 were 370 µg per day in the FENO group (95 percentconfidence interval, 263 to 477) and 641 µg per day inthe control group (95 percent confidence interval, 526 to 756;P=0.003); the median doses were 100 µg per day (25th and75th percentiles, 100 and 750) and 750 µg per day (25thand 75th percentiles, 100 and 1000), respectively (Figure 3A).
Panel A shows the mean dose of inhaled fluticasone at study entry, the optimal dose, and the dose at the final visit. Error bars represent SDs. Panel B shows the distribution of doses of inhaled fluticasone at the end of the study. P=0.008 for the comparison between the two groups.
The mean difference in dose between groups was 270 µgper day (95 percent confidence interval, 112 to 430). The distributionof fluticasone doses at the final study visit differed significantlybetween groups (P=0.008) (Figure 3B). In the FENO group, safety-buffercriteria were used for dose adjustment on 16 occasions (outof 436 assessments), for reasons of clinically significant symptoms(in 10 patients), reduced pulmonary function (4 patients), orboth (2 patients) in the absence of a rise in FENO to greaterthan 15 ppb. The percentage of patients who complied with medicationuse was 84.8 percent in the FENO group and 89.8 percent in thecontrol group, with compliance defined as consumption of 75percent or more of the study medication as determined by weight.
Sputum Cell Counts, FENO Measurements, and Pulmonary Function
Changes in the indexes of airway inflammation and pulmonaryfunction are reported in Table 3. The magnitude of airway inflammation,as measured by the percentage of eosinophils in induced sputumand FENO measurements, was not significantly different betweenthe two study groups at the end of either phase 1 or phase 2.At the end of phase 2, 65.8 percent of patients in the FENOgroup and 65.9 percent in the control group had sputum eosinophilcounts of less than 3 percent. Only at the time of the visitat which airway inflammation or asthma was deemed to be uncontrolled(i.e., the first, uncontrolled, visit) were significant increasesin FENO and sputum eosinophils noted in the FENO group. Thisfinding confirms the appropriateness of the step up in dosethat was undertaken on that occasion.
Discussion
In our study, the use of FENO measurements that were performedon a regular basis in patients with asthma resulted in a lowermaintenance dose of inhaled corticosteroid needed to controlthe asthma, as compared with the use of a dose-adjustment strategybased on conventional guidelines. We demonstrated a 40 percentreduction in the required dose of inhaled corticosteroid withoutcompromising any major clinical outcomes, including exacerbationrates and prednisone use. Despite the significantly lower optimaldose of inhaled corticosteroid in the FENO group, the sputumeosinophil counts were no different: in both management groups,the mean cell counts at the end of both phases were within previouslydefined limits of acceptability (<3 percent).16 The meandose requirement in the FENO group was 370 µg per day,which is consistent with the results of a recent meta-analysisindicating that the major benefits of fluticasone are usuallyachieved at 500 µg or less per day.17 Among the patientswhose asthma treatment was adjusted with the use of the algorithmbased on conventional guidelines, the mean dose was 641 µgper day, suggesting that excessive doses were being used.
The outcomes obtained with the use of FENO measurements areinevitably dependent on the cutoff point used to signal thelikelihood of active airway inflammation (defined in this studyas 15 ppb at a flow rate of 250 ml per second, the equivalentof 35 ppb at 50 ml per second). It could be argued that asthmacontrol remained suboptimal even with a mean rate of exacerbationsof 0.49 event per patient per year in the FENO group. If a lowercutoff point — for example, 10 ppb — had been used,higher mean doses of inhaled corticosteroid would have beenrequired in the FENO group, which in turn might have resultedin a further reduction in the exacerbation rate such that thesuperiority of the use of FENO measurements as a dose-adjustmentstrategy would have been confirmed. The chosen cutoff pointfor our study was based on previous work that showed that aFENO level of 15 ppb (at a flow rate of 250 ml per second) yieldedthe best overall positive and negative values on the basis ofwhich to predict an upcoming loss of asthma control.5 This numberis also consistent with the recently published data that outlinethe "normal range" of FENO levels.8 Our choice of 15 ppb forthe cutoff point may also explain the subtle differences inoutcome between the present study and that of Green et al.2
There is some debate about the optimal strategy for dose adjustmentof inhaled corticosteroids in clinical practice. Both "step-up"and "step-down" approaches are advocated. However, there isagreement among international guidelines that after the controlof asthma has been established, titration downward to the minimalnecessary doses of inhaled corticosteroids ought to be undertaken.9,18This has been tested in randomized controlled trials.19,20,21In one study in which downward titration was used, patientsrequired 25 percent less inhaled corticosteroid during the one-yearfollow-up than did patients in the control group, yet withoutany loss of asthma control.19 In our study, however, downwardtitration with the use of the predominantly symptom-based algorithmto define poor asthma control was possible in only a minorityof patients. In contrast, when FENO measurements were used,we could readily identify patients in whom a reduction in thedose of inhaled corticosteroid could be appropriately achieved.Regardless of the approach taken, the clinician is faced withsignificant heterogeneity in the dose–response to inhaledcorticosteroid for individual patients,22 and this may not bedetermined easily on the basis of either symptoms or pulmonaryfunction.
An alternative explanation for our results is that in the controlgroup, the dose of inhaled corticosteroid was much higher thannecessary. This may have occurred because, just as in the caseof the FENO algorithm, dose adjustments of inhaled corticosteroidsdepend on the thresholds used to determine "uncontrolled" asthma,and these thresholds may have been inappropriate. In our study,only one of five criteria had to be met in order to determinepoor asthma control. Furthermore, it can be argued that withineach category the cutoff points that were used, particularlyfor symptoms and use of bronchodilators, were too low. Eachof the chosen cutoff points was consistent with current internationalguidelines that advocate the minimization of symptoms and ofbronchodilator use as a goal of asthma therapy. Although weagree with this principle, our results highlight the possibilitythat the rigorous application of these guidelines may in factbe problematic. All the more reason, then, for the monitoringof an objective measure of airway pathology to complement theassessment of patients with symptomatic asthma so that appropriatechoices of treatment can be made.
In the recent Gaining Optimal Asthma Control Study,23 the investigatorssought to achieve asthma control among patients in two groupswith "step-up" titration of either a combination of salmeteroland fluticasone or fluticasone alone with the use of a symptoms-basedalgorithm. Remarkably, "total control" was achieved among only41 percent of the patients receiving salmeterol and fluticasoneand among 28 percent of those receiving fluticasone alone, despitedoses of 1000 µg of fluticasone per day administered to68 percent and 76 percent of patients, respectively. The mediandose requirement was 1000 µg per day in each treatmentgroup, which is similar to the requirement for patients in thecontrol group in our study, in which a similar dose-adjustmentstrategy was used (48 percent of patients required 1000 µgper day). Together, these outcomes strongly suggest that theuse of clinical end points as the basis for adjustments in dosesof inhaled corticosteroids has substantial limitations and maylead to higher doses than are appropriate for many patients.In our study, we did not allow for the concomitant use of long-actingbeta-agonists; this would have required a much larger study.However, the results obtained in our control group stronglysupport a role for therapy with long-acting beta-agonists forpatients who remain symptomatic despite optimal corticosteroidtreatment. This is in keeping with a stepwise approach to asthmamanagement.18
In conclusion, we have shown that in patients with chronic,persistent asthma, treatment with inhaled corticosteroids cansuccessfully be titrated with the use of FENO measurements.The use of FENO measurements may also help to minimize the potentiallong-term side effects that are related to inhaled corticosteroidsand are more likely when higher doses are used.24 FENO measurementsare easy to perform, can be reproduced accurately, and provideimmediate results on which the practitioner can act. Overall,this approach offers a logical alternative to the use of clinicaldata alone as the basis for dose adjustment of inhaled corticosteroidsin the management of asthma.
Funded by the Otago Medical Research Foundation, the Dean'sFund of the Dunedin School of Medicine, and a grant from theUniversity of Otago. Supplies of fluticasone were provided byGlaxoSmithKline (New Zealand). Equipment for the analysis ofnitric oxide in other studies was provided by Aerocrine in December2004.
Dr. Smith reports having received his salary from an educationalgrant from GlaxoSmithKline in New Zealand for the period fromFebruary 2000 to June 2004. Dr. Taylor reports having receivedlecture fees from AstraZeneca and GlaxoSmithKline in New Zealand.
Source Information
From the Respiratory Research Unit, Department of Medicine (A.D.S., J.O.C., K.P.B., D.R.T.), and the Department of Preventive and Social Medicine (G.P.H.), Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
Address reprint requests to Dr. Taylor at the Department of Medicine, Dunedin School of Medicine, P.O. Box 913, Dunedin, New Zealand, or at robin.taylor{at}stonebow.otago.ac.nz.
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Exhaled Nitric Oxide and Asthma
Silkoff P. E., Corbetta L., Fabbri L. M., Currie G. P., Lee D. K.C., Smith A. D., Taylor D. R.
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N Engl J Med 2005;
353:732-733, Aug 18, 2005.
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