American Journal of Respiratory and Critical Care Medicine

Rationale: Current asthma guidelines recommend adjusting antiinflammatory treatment on the basis of the results of lung function tests and symptom assessment, neither of which are closely associated with airway inflammation.

Objectives: We tested the hypothesis that titrating corticosteroid dose using the concentration of exhaled nitric oxide in exhaled breath (FeNO) results in fewer asthma exacerbations and more efficient use of corticosteroids, when compared with traditional management.

Methods: One hundred eighteen participants with a primary care diagnosis of asthma were randomized to a single-blind trial of corticosteroid therapy based on either FeNO measurements (n = 58) or British Thoracic Society guidelines (n = 60). Participants were assessed monthly for 4 months and then every 2 months for a further 8 months. The primary outcome was the number of severe asthma exacerbations. Analyses were by intention to treat.

Measurements and Main Results: The estimated mean (SD) exacerbation frequency was 0.33 per patient per year (0.69) in the FeNO group and 0.42 (0.79) in the control group (mean difference, −21%; 95% confidence interval [CI], −57 to 43%; p = 0.43). Overall the FeNO group used 11% more inhaled corticosteroid (95% CI, −17 to 42%; p = 0.40), although the final daily dose of inhaled corticosteroid was lower in the FeNO group (557 vs. 895 μg; mean difference, 338 μg; 95% CI, −640 to −37; p = 0.028).

Conclusions: An asthma treatment strategy based on the measurement of exhaled nitric oxide did not result in a large reduction in asthma exacerbations or in the total amount of inhaled corticosteroid therapy used over 12 mo, when compared with current asthma guidelines.

Clinical trial registered with www.controlled-trials.com (ISRCTN08067387).

Scientific Knowledge on the Subject

Current evidence suggests that exhaled nitric oxide, a noninvasive surrogate marker of airway inflammation, can be used in asthma to reduce treatment and predict preventable asthma exacerbations.

What This Study Adds to the Field

Using exhaled nitric oxide–driven asthma management did not result in fewer asthma exacerbations, or in the use of less treatment, when compared with traditional management, in the largest study of its kind to date.

Asthma is defined and characterized by the presence of symptoms associated with variable airflow obstruction, airway inflammation, and airway hyperresponsiveness (1). It is a common disease that is responsible for significant morbidity, mortality, and health care cost (2). Current guidelines recommend that decisions about treatment are based on assessment of symptoms and airflow obstruction. However, there is no clear relationship between symptom control, variable airflow obstruction, and the extent of eosinophilic airway inflammation (3, 4), and a response to corticosteroids is most closely associated with the presence of eosinophilic airway inflammation (5). There is also evidence that management with the additional aim of decreasing eosinophilic airway inflammation reduces exacerbation frequency in patients managed in secondary care, and that sputum eosinophilia is a marker of preventable, corticosteroid-responsive asthma exacerbations (6). In the United Kingdom, 80% of patients with asthma are managed in primary care (7); assessment of eosinophilic airway inflammation using induced sputum is not applicable in this setting (6).

Recently, the concentration of nitric oxide present in exhaled breath (FeNO) has been evaluated as a tool for assessing asthma (8). FeNO is elevated in patients with asthma (9, 10), is reduced by treatment with inhaled corticosteroids (10), and correlates with eosinophilic airway inflammation measured using bronchial biopsies and induced sputum (11, 12). It is particularly applicable for monitoring asthma in primary care because the test is easy to perform (13), it provides an immediate result, and inexpensive, portable monitors are now available. Two recent studies have investigated the use of FeNO to guide treatment in asthma (14, 15). Neither study showed an improvement in exacerbation frequency, although, in one study, the daily dose of inhaled steroids was lower (14).

Our aim was to test the hypothesis that the use of FeNO for titrating corticosteroid dose results in fewer exacerbations and more efficient use of corticosteroid therapy. We designed a single-blind, randomized controlled trial comparing exacerbation frequency and corticosteroid dosage in patients whose asthma management was based on measurements of FeNO to a control population where management was based on the British Thoracic Society (BTS) and Scottish Intercollegiate Guidelines Network treatment guidelines (16). Results from this work have previously been published as an abstract (17).

Setting and Participants

Participants were identified from registers held in general practices around Leicester, United Kingdom. All participants were older than 18 years and had a diagnosis of asthma recorded in their general practitioner's (GP's) notes. Participants were eligible if they had received at least one prescription for any antiasthma medication in the last 12 months. The study was restricted to current nonsmokers with a past smoking history of less than 10 pack-years. Participants were also excluded if they were considered by their physician to be poorly compliant or had had a severe asthma exacerbation, requiring a course of prednisolone, within 4 weeks of study entry. All suitable participants on the registers who responded to an invitation from their GP to be contacted by the research team were invited to participate in the study. Ethics approval for the study was given by ethics committees from both the University Hospitals of Leicester and the Leicester Primary Research Care Alliance; all participants gave written, informed consent.

Participants attended Glenfield Hospital for tests to characterize their asthma. Tests were performed in the following order and at the same time of day for each patient: exhaled nitric oxide levels measured at a flow of 50 ml/second, FEV1 and forced vital capacity (FVC), methacholine challenge test to determine the concentration of methacholine required to provoke a 20% fall in the FEV1, induced sputum analysis, and skin prick tests to common aeroallergens. Participants were seen 2 weeks later and then every month for 4 months; they were then seen every 2 months for a further 8 months to be consistent with our earlier study of inflammation-guided management (6). Each visit occurred at the same time of day and consisted of assessment of exhaled nitric oxide, spirometry, and post-bronchodilator FEV1, 20 minutes after 400 μg albuterol at the end of every visit (Figure 1). Peak flow and symptom diaries were analyzed and compliance assessed by monitoring adherence to prescription script collection. Participants were issued self-management plans based on their best baseline peak flow from the first 2 weeks of the study; if their peak flow fell to less than 70% of their best peak flow for 48 hours during the study, or their asthma deteriorated, they were asked to attend the hospital where they were assessed by a physician (M.A.B.). At the 6- and 12-month visit, induced sputum and methacholine challenge testing were also performed. Full details of the measurements made are provided in the online supplement.

Intervention

After the first visit, participants were randomly allocated to receive treatment either on the basis of their FeNO measurements (FeNO group) or according to a conventional stepwise asthma management plan (control group) (16). Randomization was done by an independent individual (C.E.B.) using the minimization method (18), and was stratified by the baseline sputum eosinophil count, FeNO, and rescue steroid courses in the last year. Participants were seen monthly for the first 4 months and every 2 months thereafter (Figure 1); all visits were at the same time of day. At each visit, the patient's asthma control was determined using the validated Juniper asthma control questionnaire, which scores asthma control from 0 to 6; a score of greater than 1.57 was used to identify poorly controlled asthma (19, 20). In the control group, treatment was doubled if the score was more than 1.57, and treatment was halved if the score was less than 1.57 for 2 consecutive months (Figure E1 of the online supplement). In the FeNO group, treatment was adjusted following a set protocol according to both the FeNO and Juniper scores (Figure E2). If the FeNO was greater than 26 ppb, inhaled corticosteroid treatment was increased; if it was less than 16 ppb or less than 26 ppb on two consecutive occasions, treatment was decreased. Bronchodilator therapy was increased if symptoms were uncontrolled, despite an FeNO of less than 26 ppb. We chose these cutoffs because they have been shown to best identify a sputum eosinophil count of greater than 3% and less than 1%, respectively (21), after correction for expiratory flow (22). Assessment of asthma control was made per protocol by investigators who were unaware of the participants' randomization status. At each visit, two different treatment decisions, one for each randomization group, were made by an independent physician who was also unaware of the randomization status (R.H.G./I.D.P.). The correct treatment decision, according to the participants' group, was communicated to the patient by a separate unblinded physician (D.E.S.).

Safety Measure

Because there was evidence before study commencement that a high FeNO would not always reflect a high differential sputum eosinophil count (21), we determined a priori that patients in the FeNO group who had their antiinflammatory treatment increased to the equivalent dose of 2,000 μg beclomethasone diproprionate (BDP) per day, and whose FeNO was still greater than 26 ppb and had not fallen to 60% (23) of baseline, would have their differential sputum eosinophil count checked. If there was no eosinophilic airway inflammation present, treatment was reduced in a stepwise fashion unless the FeNO increased by greater than 60% from baseline. An inhaled corticosteroid dose of 2,000 μg BDP was chosen because this is the normal point for referral from primary care for secondary care evaluation.

An asthma exacerbation was defined a priori as an episode of increasing asthma symptoms requiring a course of oral steroids or antibiotics; participants were asked to contact the research nurses if their asthma deteriorated. Participants were assessed and treated according to the BTS guidelines by a physician (M.A.B.) not involved in the regular treatment decisions and blinded to the participants' randomization status. At the end of the study, participants were asked to record which group they thought they had been assigned to as an assessment of the success of blinding.

Analysis

We estimated that we needed 53 participants in each group to give 80% power to detect a 50% reduction in the rate of asthma exacerbations, based on a Poisson regression analysis and a two-sided test at the 5% level. Our power calculation was based on findings from the FACET (Formoterol and Corticosteroids Establishing Therapy) study (24), which found an exacerbation frequency of 0.91 per patient per year, and our own audit data suggesting that exacerbation frequency approximates a Poisson distribution. We confirmed goodness-of-fit to a Poisson distribution before doing the analysis. If participants withdrew from the study, we analyzed their data by intention to treat; the last value recorded was carried forward for inhaled corticosteroid dose and FeNO reading, and for methacholine responsiveness and sputum eosinophils the mean of the previous values was used. FeNO was log transformed, to assume a normal distribution, and expressed as a geometric mean; it was compared over the 12 months as area under the curve using an independent t test. Steroid dose (expressed as equivalent dose to BDP) (6) was also compared over the 12 months of the study as area under the curve using an independent t test. Differential sputum eosinophil count and methacholine PC20 (provocative concentration causing a 20% fall in FEV1) were log transformed to assume a normal distribution, and their changes at 6 and 12 months from baseline were compared using an independent t test. All data were analyzed using SPSS for Windows (version 12; SPSS, Inc., Chicago, IL) and Intercooled Stata for Windows (version 7; Stata Corp., College Station, TX).

A total of 900 participants were contacted by their own GP. Of these, 146 participants declined the invitation and 636 failed to respond (Figure 2). We recruited 119 participants between January 2004 and December 2004; 1 patient could not perform the measurement of exhaled nitric oxide; 58 were allocated to the FeNO group and 60 to the control group. Six participants withdrew from the FeNO group and nine participants withdrew from the control group. None of the participants withdrew because of poorly controlled asthma. The two treatment groups were well matched at baseline for demographic and clinical features (Table 1). Measurement of exhaled nitric oxide was successful on every occasion. Assessed as area under the curve over the 12 months of the study, the FeNO was 24% lower (95% confidence interval [CI], −8 to 55%; p = 0.14) in the FeNO group when compared with the control group. There was no difference in the Juniper asthma control score, peak expiratory flow readings, and FEV1 between the groups over the duration of the study (Figure 3). Nine participants in the FeNO group needed a reassessment of management goals because of corticosteroid-resistant, persistent elevation of FeNO, which was not reflective of eosinophilic airway inflammation.

TABLE 1. BASELINE DEMOGRAPHICS BY GROUP




FeNO Group

Control Group
Number5860
BTS step
 19 (16%)9 (15%)
 224 (41%)22 (37%)
 39 (16%)13 (22%)
 414 (24%)14 (23%)
 52 (3%)2 (3%)
Demographic
 Female3133
 Age, yr*50 (20–75)52 (24–81)
 BMI, kg/m227.5 (5.02)28.1 (5.43)
 Former smokers, %2225
  Oral steroid courses in last yr/patient1.2 (2.0)1.3 (1.8)
 Daily dose inhaled corticosteroid, μg697 (708)652 (533)
Clinical
 Atopy, %6270
 Family history of asthma, %5560
 Rhinitis, %5740
 Nasal polyps, %118
 FEV1, L2.5 (0.92)2.57 (0.99)
 FEV1, % predicted81.4 (20.9)84.9 (20.1)
 FEV1/FVC71 (10.7)72 (9.9)
 Percent change postsalbutamol6.2 (9.4)5.4 (8.6)
 Peak expiratory flow amplitude, % mean23.9 (17.1)18.7 (10.4)
 Sputum eosinophil count, %1.3 (0.3, 5.7)1.7 (0.3, 9.8)
 Sputum neutrophil count, %65.7 (27.7)62.0 (21.6)
 Total cell count (106/ml)1.4 (0.3, 7.0)1.4 (0.3, 6.3)
 Methacholine PC20, mg/ml1.4 (0.1, 16.0)2.2 (0.2, 16.0)
 Juniper asthma control score1.32 (0.65)1.26 (0.75)
 FeNO, ppb
29.2 (14.0, 61.0)
31.2 (13.3, 73.1)

Definition of abbreviation: BMI = body mass index; BTS = British Thoracic Society.

Values are mean (SD) except for those noted with footnote symbols.

*Median (range).

Geometric mean (68% confidence intervals).

There were 18 exacerbations in 12 participants in the FeNO group and 26 exacerbations in 19 participants in the control group. The rate of asthma exacerbation experienced by the FeNO group was 0.33 per patient per year (SD, 0.69) compared with 0.42 (SD, 0.79) in the control group (mean difference, −21%; 95% CI, −57 to 43%; p = 0.43) (Figure 4). The total amount of inhaled corticosteroid used during the study was 11% greater (95% CI, −15 to 37%; p = 0.40) in the FeNO group compared with the control group. However, the final daily dose of inhaled corticosteroid was significantly lower in the FeNO group compared with the control group (557 vs. 895 μg; mean difference, 338 μg; 95% CI, −640 to −37; p = 0.028) (Figure 3). At 6 months, there was a 0.5 doubling-dose improvement in the methacholine PC20 in the FeNO group and a 0.7 doubling-dose worsening in the control group (mean difference, 1.14; 95% CI, −0.09 to 2.36; p = 0.07). At 12 months there was a 0.2 and 0.6 doubling-dose improvement in the PC20 in the FeNO group and control group, respectively (mean difference, −0.34; 95% CI, −1.37 to 0.69; p = 0.51). The differential sputum eosinophil count had reduced at 6 months by 1.6-fold and 1.4-fold in the FeNO group and control group, respectively (p = 0.43), and at 12 months, the eosinophil count had increased by 1.01-fold and 1.31-fold in the FeNO group and control group, respectively (p = 0.48). Overall, five patients (8%) had long-acting β2-agonists started in the FeNO group and seven (12%) patients had them started in the control group.

In a separate subgroup analysis, both groups were split into subjects with and without evidence of variable airflow obstruction, defined as one or more of the following: PC20 of less than 8 mg/ml at the first visit, peak expiratory flow amplitude percentage of mean greater than 20%, and improvement in FEV1 of more than 15% after 400 μg salbutamol at the second visit. The rates of exacerbation were lower in the subgroups without variable airflow obstruction within both the FeNO group (n = 44) and control group (n = 39), respectively, but the differences were not significant. In the FeNO group, exacerbation rates were 0.36 compared with 0.23 exacerbations per patient per year for participants with and without variable airflow obstruction, respectively (p = 0.57); in the control group, the exacerbation rates were 0.49 and 0.29 exacerbations per patient per year for participants with and without variable airflow obstruction, respectively (p = 0.35). There was no significant difference in exacerbation rates in subjects with variable airflow obstruction between the FeNO group and control group (p = 0.44).

Baseline log FeNO correlated with log sputum eosinophil count (r2 = 0.455, p < 0.001; Figure 5). An FeNO of less than 26 ppb was associated with a differential sputum eosinophil count of less than 3% for 85% of all visits when both were measured. However, on more than half of the occasions when both were measured, an FeNO of greater than 26 ppb was associated with a sputum eosinophil count of less than 3%. In participants with sputum eosinophils of more than 3% and an FeNO of more than 26 ppb exacerbation frequency was 0.38 versus 0.67 exacerbations per patient per year in the FeNO group compared with the control group, respectively. In participants with sputum eosinophils of less than 3% and an FeNO of more than 26 ppb, exacerbation frequency was 0.09 versus 0 exacerbations per patient per year in the FeNO group compared with the control group, respectively. The demographic details of each group were not different. The assessment of blinding revealed that 49% of participants were not sure which group they had been assigned to, 33% correctly identified their group, and 18% incorrectly identified their group.

Our study was designed to evaluate the use of FeNO to guide asthma management in primary care, a setting in which the technique is likely to be particularly applicable. The use of FeNO measurements to guide treatment decisions did not result in lower exacerbation frequency or in a lower maintenance dose of inhaled corticosteroid when compared with traditional asthma management. Although participants in the FeNO group finished the study while receiving a significantly lower dose of inhaled corticosteroid, use of inhaled corticosteroid over the 12 months of the study was not different between the groups.

Participants randomized to both groups experienced a considerably lower exacerbation frequency compared with that initially estimated and with that experienced over the previous year. This improvement was not seen in the control arm of an earlier study in participants with more severe asthma recruited from secondary care (6), suggesting that the improvement in asthma control was because of more intensive monitoring in a secondary care setting. As a result of this improvement, our study was underpowered to exclude a 50% reduction in exacerbation frequency.

Our findings are consistent with those of two recent studies (14), neither of which found a significant reduction in exacerbation frequency with FeNO-directed management. The study by Smith and colleagues found that FeNO-directed management was associated with a significant decrease in inhaled corticosteroid dose (14); the number of prednisolone courses administered was 0.48 and 0.6 per patient per year in the FeNO and control groups, respectively (14). Pijnenburg and coworkers reported an improvement in airway hyperresponsiveness, but no reduction in corticosteroid dosage or exacerbation rates using FeNO-directed management in a population of 85 children (15); 7 children experienced an exacerbation (defined as course of oral prednisolone) in the FeNO group and 10 experienced an exacerbation in the control group, respectively; both groups experienced a significant increase in inhaled corticosteroid dose during the study. Comparison across studies is not straightforward because there were important differences in management protocols and FeNO target ranges. In particular, use of long-acting β-agonists, which has been associated with a lower exacerbation frequency, was not allowed in the study by Smith and colleagues (14). However, the effect of FeNO-guided management on exacerbation rates is consistent across studies. This increases our confidence that a large effect of FeNO-guided management on exacerbation frequency is unlikely. We cannot exclude a smaller, albeit clinically relevant, effect. Longer and larger studies will be required to do this.

We chose our FeNO cutoff values on the basis of earlier work identifying them as the best indicators of the presence or absence of a raised sputum eosinophil count (21), a measure that has been consistently shown to be useful in monitoring asthma (6, 25). The fact that FeNO-guided management was most effective in participants in whom FeNO and sputum eosinophil counts were concordant is consistent with the view that FeNO acts as a marker of eosinophilic airway inflammation. The absence of effect of FeNO-guided management on exacerbation frequency makes it unlikely that FeNO is identifying additional aspects of the inflammatory response that are important in the pathogenesis of preventable exacerbations of asthma; it also implies that FeNO is an imperfect marker of eosinophilic airway inflammation. A post hoc analysis indicated that our cutoff for increasing inhaled corticosteroid dose was a sensitive, but not specific, marker of eosinophilic inflammation. This meant that, in a significant proportion of participants, inhaled corticosteroid therapy was increased in the absence of eosinophilic airway inflammation; exacerbation frequency in these participants was low whether they were randomized to the FeNO or control groups. Our study had a built-in safety measure where participants whose FeNO remained raised despite a daily dose of 2,000 μg BDP equivalent had a more detailed evaluation with reference to previously measured induced sputum eosinophil counts. We did this because we reasoned that clinicians would be uncomfortable with increasing therapy beyond this level without specialist review and because current guidelines recommend a review in participants whose asthma is uncontrolled at BTS treatment step 4 (16). As a result of this evaluation, the goals of management were changed in a significant proportion (16%) of participants randomized to FeNO-guided management; this is the most likely explanation for the initial increase and then decrease in the inhaled corticosteroid dose seen in the FeNO group. The presence of a significant proportion of participants with an elevated FeNO associated with a normal sputum eosinophil count who have a good prognosis is an important limitation of the technique. Our study did not identify any obvious clinical characteristics associated with this pattern of inflammatory markers; further work is required to investigate this. Low FeNO values were reliably associated with absence of eosinophilic inflammation, supporting suggestions (26) that a strategy of using of FeNO to guide reduction of inhaled corticosteroid dose might be more effective than the strategy adopted by us.

Our study has several limitations. First, it was not possible to design this study in a double-blinded fashion. However, the potential for bias was reduced by ensuring that the subjects were blind to their randomization status, that treatment decisions were made in strict accordance with the protocol, and that rescue oral corticosteroids or antibiotics were started by a physician who was also unaware of the participants' randomization status. Second, our study could be criticized because we recruited participants with a clinical diagnosis of asthma. It is possible that a clearer reduction in exacerbations would have been seen in participants recruited on the basis of the results of physiological or pathological tests. However, the diagnosis of asthma in the United Kingdom remains a largely clinical one (16) and we were keen to recruit participants who were representative of those currently seen in primary care. Furthermore, a subgroup analysis on participants with objective evidence of variable airflow obstruction did not show a significant reduction in exacerbation rates within the FeNO group. Third, it is possible that more frequent monitoring of FeNO might have led to a better outcome. Future studies should investigate whether this is the case and whether a protocol involving more frequent monitoring of FeNO is achievable in primary care. Finally, there is a concern about the generalizability of our findings because our population had more severe asthma than that seen previously in a primary care population (27). This may be because recruitment of participants was constrained by limitations imposed by the ethics committees, meaning that participants were particularly committed, as they had to respond to both an initial invitation from their primary care practitioner to be contacted and then an invitation to participate. This factor is unlikely to be responsible for the absence of effect of FeNO-guided management because there is evidence that management guided by markers of eosinophilic inflammation works best in participants with more severe asthma, and in those in whom long-acting β2-agonists are used (24). However, we cannot discount the possibility that we recruited a population who were particularly aware of their asthma symptoms and who responded particularly well to traditional management.

In conclusion, we have found that a management strategy using FeNO to guide asthma treatment is feasible in participants with asthma managed in primary care, but this does not lead to a large reduction in either asthma exacerbations or inhaled corticosteroid use when compared with the current treatment strategy.

The authors acknowledge the expert input of the respiratory research nurses—Beverley Hargadon, Sue McKenna, Maria Shelley, and Hilary Pateman—and the laboratory staff—Debbie Parker, Will Monterio, and Natalie Neale; without their hard work, dedication, and skill, the study would not have been possible. They also thank the doctors, nurses, and practice managers of the following GP practices: Markfield, Anstey, Groby, and Glenfield. Above all, the authors thank the volunteers.

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Correspondence and requests for reprints should be addressed to Ian D. Pavord, D.M., F.R.C.P., Consultant Physician and Honorary Professor of Medicine, Institute for Lung Health, Department of Respiratory Medicine and Thoracic Surgery, Glenfield Hospital, Leicester LE3 9QP, United Kingdom. E-mail:

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