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Titrating Steroids on Exhaled Nitric Oxide in Children with Asthma

A Randomized Controlled Trial

Departments of Pediatrics/Pediatric Respiratory Medicine and Epidemiology and Biostatistics, Erasmus MC/Sophia Children's Hospital, University Medical Center, Rotterdam, The Netherlands

Correspondence and requests for reprints should be addressed to Mariëlle W. Pijnenburg, M.D., Department of Pediatrics/Pediatric Respiratory Medicine, Erasmus University Medical Center/Sophia Children's Hospital, P.O. Box 2060, 3000 CB Rotterdam, The Netherlands. E-mail: m.pijnenburg{at}erasmusmc.nl

	ABSTRACT

TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES

 
Rationale: Corticosteroids are the antiinflammatory treatment of choice in asthma. Treatment guidelines are mainly symptom-driven but symptoms are not closely related to airway inflammation. The fraction of nitric oxide in exhaled air (FE_NO) is a marker of airway inflammation in asthma.

Objective: We evaluated whether titrating steroids on FE_NO improved asthma management in children.

Methods: Eighty-five children with atopic asthma, using inhaled steroids, were allocated to a FE_NO group (n = 39) in which treatment decisions were made on both FE_NO and symptoms, or to a symptom group (n = 46) treated on symptoms only. Children were seen every 3 months over a 1-year period.

Measurements: Symptoms were scored during 2 weeks before visits and 4 weeks before the final visit. FeNO was measured at all visits, and airway hyperresponsiveness and FEV₁ were measured at the start and end of the study. Primary endpoint was cumulative steroid dose.

Results: Changes in steroid dose from baseline did not differ between groups. In the FE_NO group, hyperresponsiveness improved more than in the symptom group (2.5 vs. 1.1 doubling dose, p = 0.04). FEV₁ in the FE_NO group improved, and the change in FEV₁ was not significantly different between groups. The FE_NO group had 8 severe exacerbations versus 18 in the symptom group. The change in symptom scores did not differ between groups. FE_NO increased in the symptom group; the change in FE_NO from baseline differed between groups (p = 0.02).

Conclusion: In children with asthma, 1 year of steroid titration on FE_NO did not result in higher steroid doses and did improve airway hyperresponsiveness and inflammation.

Key Words: airway hyperresponsiveness • corticosteroids • lung function • symptoms • treatment

Chronic airway inflammation is a key feature of asthma, and inhaled corticosteroids (ICS) are the cornerstone of asthma treatment. Decisions to start ICS or change the dose are now mainly based on symptoms reported by the child or parents (1). Symptoms, however, are nonspecific and not closely related to the presence and severity of airway inflammation (2). Symptom-based treatment may thus easily lead to excessive ICS doses, whereas fear of ICS side effects may lead to underdosing, especially in children (3). Lung function tests show no or only marginal correlation with airway inflammation (4, 5). Airway hyperresponsiveness does correlate weakly with airway inflammation, and its incorporation in treatment decision making has shown beneficial effects in a single study in adults, albeit at the cost of high ICS doses (6). The question is whether asthma treatment in children should be targeted at symptoms or at airway inflammation. The airways produce nitric oxide (NO), and its fraction in exhaled air (FE_NO) is elevated in steroid-naive atopic asthma (7–11). In adults and children with atopic asthma, FE_NO correlates with eosinophils in induced sputum and with eosinophil infiltration of the airway wall, and this makes FE_NO the first noninvasive "inflammometer" for asthma (2, 12–15). Treatment with corticosteroids reduces FE_NO levels in patients with asthma in a dose-dependent manner (16, 17). The hypothesis of this study was that titrating ICS on both FE_NO and symptoms, compared with titrating on symptoms only, would result in lower ICS doses and better asthma management. Part of this study has been reported in the form of an abstract (18).

	METHODS

TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES

 
Details of methods used are provided in the online supplement.

Patients
Children aged 6–18 years with atopic asthma were recruited. Patients had been using ICS at a constant dose for at least 3 months preceding the study. The study was approved by the hospital's medical ethics committee.

Study Design
After a 2-week run-in period, children were randomly allocated to one of two groups stratified for baseline FE_NO ( 30 or < 30 ppb) and dose of ICS ( 400 or < 400 µg budesonide or equivalent daily dose) (Figure 1). In one group (FE_NO group), ICS doses were determined by FE_NO and symptoms according to the algorithm in Figure 2 and Table 1; in the other group (symptom group), only symptoms influenced ICS dosing. The study duration was 12 months, with five visits at 3-month intervals. FE_NO was measured at each visit, and the ICS dose was then adapted to FE_NO and/or symptom scores recorded during the previous 2 weeks. Cut-off levels for dose adaptation were a cumulative symptom score of 14 (in 2 weeks) and an FE_NO of 30 ppb. Patients and physicians were blinded for FE_NO; the investigators (M.P., M.B.) provided the physicians with written advice on ICS dose according to the algorithm in Figure 2. Throughout the study, 2 mg budesonide (or equivalent dose of other ICS) was the maximum allowed daily dose. Pulmonary function tests and bronchoprovocation tests with methacholine were performed during Visits 1 and 5. Primary endpoint was the cumulative steroid dose (sum of mean daily steroid doses of Visits 1 to 5); secondary endpoints were mean daily symptom score, mean daily number of bronchodilator doses taken, percentage of symptom-free days during the last 4 weeks of the study, number of oral prednisone courses during the study, and provocative dose of methacholine causing a 20% fall in FEV₁ (PD₂₀), FVC, FEV₁, and maximal expiratory flow at 25% of vital capacity (MEF₂₅) during the final visit.

View larger version (13K): [in this window] [in a new window]   Figure 1. Study design.

View larger version (15K): [in this window] [in a new window]   Figure 2. Treatment algorithm. ICS = inhaled corticosteroids.

Symptom Scores
Symptom scores were obtained from diary cards (20). Mean daily symptom scores (dyspnea, wheezing, cough; daytime and nighttime, each scored 0–3), the use of -2 agonists and the percentage of symptom-free days were calculated over the 2 weeks preceding each visit. At the final visit, the same parameters over the 4 weeks preceding the visit were calculated.

Adherence
In children using dry powder fluticasone or fluticasone/salmeterol combination, adherence with treatment was assessed by asking children to return all used and unused diskus inhalers at every visit. Actually used doses divided by prescribed doses defined adherence.

Statistical Analysis
Power of the study was such that a 30% reduction in cumulative steroid dose could be detected with 80% probability ( = 0.05). The Wilcoxon test, t test, analysis of covariance, and Spearman rank correlation were used for statistical analyses.

	RESULTS

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The patient flow is shown in Figure 3. A total of 108 children were approached to participate in the study. Of those, 16 refused, in the majority of cases because they were too busy with school, and 3 children could not be randomized after run in. In the end, 89 children were included, 42 in the FE_NO group and 47 in the symptom group. They were well matched for age, sex, FE_NO, lung function tests, and initial ICS dose (Table 2). Four patients dropped out, three in the FE_NO group and one in the symptom group. Of the dropouts in the FE_NO group, one was admitted to the intensive care unit for a severe asthma attack. At the visit 5 weeks before this admission, FE_NO in this patient had increased from 46.6 to 84.5 ppb and the ICS dose had been increased from 1,000 to 1,500 µg budesonide equivalent. Other dropouts were related to noncompliance.

View larger version (11K): [in this window] [in a new window]   Figure 3. Patient flow. A total of 108 children were approached to participate in the study, of whom 16 refused. Three children could not be randomized: one was not stable, one was nonadherent to the study protocol, and one was not randomized for reasons not related to the child. In the FENO group, three children dropped out; in the symptom group, one dropped out.

View larger version (13K): [in this window] [in a new window]   Figure 4. Median daily steroid dose (SEM) in both groups at different visits. Differences between both groups are all nonsignificant. Within groups, ICS dose at Visit 1 differed from the dose at Visit 2 (both p < 0.001). ICS doses at Visits 1 and 5 were not significantly different. Closed circles, FENO group; open triangles, symptom group.

Lung Function
In 10 children (4 in the FE_NO and 6 in the symptom group), bronchoprovocation could not be performed due to FEV₁ being less than 70% at Visit 1 and/or Visit 5. In one child, the PD₂₀ at Visit 5 was missing. Figure 5 shows geometric means of PD₂₀ methacholine in the remaining 74 patients who had measurements at both occasions. In 16 children (7 in the FE_NO group and 9 in the symptom group), no PD₂₀ was reached after the maximal provocative dose of methacholine at both Visits 1 and 5. Because no conclusion could be drawn on change in PD₂₀ between Visits 1 and 5 in these 27 children, they were excluded from the analyses of changes in PD₂₀. The proportion of children who did not reach a PD₂₀ at 12 months, adjusted for baseline, did not differ significantly between the two groups (p = 0.11). In the remaining 58 children, the mean increase in PD₂₀ was 2.5 doubling doses in the FE_NO group and 1.1 doubling doses in the symptom group. The difference of these changes between the two groups was significant (1.3 doubling doses; 95% CI, 0.1–2.5; p = 0.04).

View larger version (11K): [in this window] [in a new window]   Figure 5. Airway hyperresponsiveness (SEM) on the y axis at Visits 1 and 5 (x axis). Children who could not perform the test due to baseline obstruction at either occasion were excluded (paired measurements remaining, n = 74). Excluding patients who did not reach a decrease of 20% in FEV1 at both occasions, the mean increase in PD20 was 2.5 doubling doses in the FENO group and 1.1 doubling doses in the symptom group. The difference in change of PD20 between both groups was significant (1.3 doubling doses; 95% CI, 0.1–2.5; p = 0.04). Closed circles, the FENO group; open triangles, the symptom group.

View larger version (9K): [in this window] [in a new window]   Figure 6. Results of spirometry. FEV1 (SEM) at Visits 1 and 5. Closed circles, the FENO group; open triangles, the symptom group. There was a significant difference in FEV1 at Visit 5 for the FENO group (p = 0.008).

View larger version (12K): [in this window] [in a new window]   Figure 7. Results of FENO measurements at all clinic visits. Vertical axis depicts FENO; horizontal axis is time. p = 0.02 for the change in FENO from baseline at Visit 5. FENO increased significantly in the symptom group (p = 0.035). Closed circles, the FENO group; open triangles, the symptom group.

Symptom Scores, Use of -2 Agonists, and Symptom-free Days

FE_NO and Asthma Severity
FE_NO at Visit 1 correlated with symptom scores and use of agonists in the 2 preceding weeks (r = 0.28, p = 0.02, and r = 0.28, p = 0.01, respectively). The same was true for FE_NO at Visit 2 (r = 0.22, p = 0.05, and r = 0.24, p = 0.03, respectively). FE_NO did not predict symptom scores in the 2 weeks before the next visit. FE_NO did not correlate with lung function parameters at the same visits. At all time points, FE_NO correlated strongly with later FE_NO values in the same subjects (all p < 0.001).

Decision Making
For both groups separately, at all visits, we conducted analyses to determine if the advised ICS dose would have been different had patients been allocated to the other group. For the whole study population, in 36% of cases the ICS dose would have been the same; in 29 and 35%, the dose would have been higher or lower, respectively. These proportions did not differ between the groups.

Adherence of Patients and Physicians
Median adherence in the subgroup using dry powder fluticasone dipropionate or fluticasone dipropionate/salmeterol (n = 14) was 97% (range, 55–124%).

The study design allowed the patient's physician to deviate from the recommended ICS dose. This happened at 42 occasions (between 1 and 10 children per group at each visit). The distribution over the groups was equal (19 occasions in the FE_NO group, 23 in the symptom group [NS]). The main reasons for deviations were suspected airway infection and preference for other therapeutic interventions.

	DISCUSSION

TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES

 
This study shows that in children with allergic asthma, titration of ICS on FE_NO every 3 months for 1 year did not increase steroid doses and did improve airway hyperresponsiveness compared with titrating on symptoms only. Children treated on symptoms demonstrated an increase of FE_NO, which is suggestive of more airway inflammation.

This is the first prospective, double-blind, randomized controlled trial in children with atopic asthma incorporating FE_NO in treatment algorithms. Conventional measures of asthma control, such as symptoms, use of rescue -2 agonists, and lung function testing, do not accurately reflect ongoing airway inflammation and thus can be considered suboptimal for guiding ICS treatment (2, 21, 22).

Although studies in children are limited, there is some evidence that airway inflammation may already result in remodeling at a young age (23, 24). Indeed, asthma is associated with reduced growth of lung function, and lung function at a young age is a determinant of lung function in adult life (25). Early detection and treatment of inflammation might, therefore, be important in strategies to improve asthma control and long-term prognosis. Two studies in adults support the concept that monitoring of airway inflammation can improve asthma treatment. Green and colleagues (26) conducted a trial in which 68 patients with asthma were managed on induced sputum eosinophil counts or on British Thoracic Society (BTS) guidelines. Patients treated on eosinophils had fewer asthma exacerbations and hospital admissions compared with the BTS group, with similar average daily doses of ICS. Interestingly, after 12 months of treatment, FE_NO was 48% lower in the sputum eosinophils group. Sont and colleagues (6) demonstrated that better asthma control could be achieved in adult patients who received ICS, based on their level of airway hyperresponsiveness, at the cost of higher steroid doses. Hyperresponsiveness correlates weakly with airway inflammation (27). Only a few longitudinal studies have examined the possible clinical relevance of FE_NO in asthma management. Roberts and coworkers (28) have demonstrated that FE_NO relates to previous allergen exposure and asthma control. We demonstrated that FE_NO is helpful in predicting asthma relapse in children who discontinue ICS because of clinical remission (29) and, similarly, Zacharasiewicz and colleagues (30) found that FE_NO predicted loss of asthma control in children with asthma in whom ICS were tapered irrespective of FE_NO. In a recent single-blind controlled trial in adults with asthma, Smith and colleagues showed that using FE_NO for dose adjustments of ICS led to similar asthma control with less ICS in the FE_NO-treated group compared with the group treated on conventional parameters (31). This study showed an increase in ICS dose in the control group, rather than a dose reduction in the FE_NO group, perhaps due to the study design, in which multiple factors could lead to higher ICS doses in the control group but not in the FE_NO group. Hence, the interpretation of these findings is difficult. We now show that airway hyperresponsiveness improved substantially in the FE_NO group compared with the symptom group. In the present study, the ICS doses increased in both groups and were similar at the end of the study (Figure 4). The dose increase is explained by the increase after Visit 1 in both groups. The relatively high median steroid doses in our population probably reflect the tertiary care character of our center.

Our treatment algorithm was based on previous findings, clinical experience, and current treatment guidelines on asthma in children (1). In the symptom group, we decided to decrease ICS dose only after 6 months of a stable clinical condition. One could argue that due to this algorithm, patients in the FE_NO group were more prone to receiving lower ICS doses, as they were allowed a decrease in ICS dose after a single low symptom score. On the other hand, ICS doses in the FE_NO group were increased in case FE_NO was above 30 ppb, even when symptoms were low. More frequent visits to measure FE_NO and adjust ICS, or a longer follow-up, might have resulted in better outcomes. As this is the first prospective, long-term, NO-driven dose titration study, we could not be sure about the best algorithm concerning the frequency of follow-up visits, FE_NO measurements, and cut-offs for dose adjustments.

It can be argued that the chosen cut-offs for FE_NO and symptoms in our algorithm were too low. We based our symptom cut-off on experience from a previous study (20). Children in the present study may have had somewhat more severe asthma, as 43% exceeded this cut-off at Visit 1, and this resulted in an increase in ICS dose. In the present algorithm, symptom scores affected treatment decision in both groups, and we cannot know how an alternative cut-off would have affected the outcome.

Our FE_NO cut-off level was based on the +2 SD limit of normality from a recent large reference value study in children using the same equipment and population (32). Therefore, we believe that the 30 ppb cut-off was appropriate. However, it is not known whether efforts to normalize FE_NO with ICS are necessarily feasible and effective. Arguably, the ICS dose increments in our algorithm might have been too small to reduce FE_NO. However, there is no evidence that very high ICS doses produce additional clinical benefit, although they can cause systemic side effects (33). We therefore believe that administering higher doses with the purpose of normalizing FE_NO was not warranted.

Symptom scores were low in both groups throughout the study. There was a significant, small improvement in symptom scores in the symptom group only. This is not surprising, as symptoms were not an inclusion criterion and all children had been stable on ICS for at least 3 months before enrollment. Given the limited room for improvement, we did not consider reduction in symptoms as a suitable endpoint, and we feel that the small difference between both strategies is hardly clinically relevant.

The changes in hyperresponsiveness as a result of the FE_NO strategy, however, are substantial. Airway hyperresponsiveness is a major determinant of asthma prognosis, and is associated with reduced growth of airway caliber in childhood and an accelerated decline of lung function in adulthood (34–38). Hence, we speculate that the FE_NO strategy has the potential to improve the long-term outcome of childhood asthma more than the symptom-based strategy.

Adherence to treatment strongly correlates with FE_NO (39, 40). In the present study, poor adherence may have accounted for elevated FE_NO in some children. However, in the children on dry powder fluticasone or fluticasone/salmeterol, median adherence was 97% (range, 55–124%), which is relatively high compared with average adherence rates of between 63 and 92% reported in the literature (41). Children displaying poor adherence are likely to be distributed equally over both groups. Hence, we feel confident that poor adherence did not affect our comparisons.

What are the practical implications of our findings? ICS dose titration using FE_NO was shown to be feasible and improved important objective endpoints in children with moderate to severe allergic asthma. We feel that the time has come to introduce FE_NO in to the routine assessment of children with asthma in specialist practice, and to take FE_NO into account when treatment decisions are made. Further studies might bring to light whether outcome could be further improved by choosing other cut-off levels for symptoms and FE_NO, or by more frequent dose adjustments.

In conclusion, we have shown that a treatment algorithm using FE_NO for ICS dose titration every 3 months for 1 year is superior to conventional treatment guided by symptoms, and leads to similar clinical asthma control and less airway hyperresponsiveness, obstruction, and inflammation with a similar ICS dose.

	Acknowledgments

 
The authors thank Marjo Affourtit, Ruben Boogaard, Edith van Duijn, Sandra Lever, Aafke Lok, Evelien Nieuwhof, and Els van der Wiel for their help in recruiting patients, performing lung function tests and FE_NO measurements.

	FOOTNOTES

 
Supported by a grant from the Kröger Foundation/Sophia Children's Hospital Foundation.

This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org

Conflict of Interest Statement: M.W.P. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. E.M.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. W.C.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. J.C.D.J. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. The Department of Pediatrics of Erasmus University has received research grants and payments for consultancy services from Aerocrine (manufacturer of NO analyzers).

Received in original form March 22, 2005; accepted in final form June 17, 2005

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