Published ahead of print on February 11, 2005, doi:10.1164/rccm.200409-1242OC
© 2005 American Thoracic Society doi: 10.1164/rccm.200409-1242OC
Clinical Use of Noninvasive Measurements of Airway Inflammation in Steroid Reduction in ChildrenDepartments of Respiratory Pediatrics and Health Services Research, Clinical Trials and Evaluation Unit, Royal Brompton Hospital; National Heart and Lung Institute Clinical Studies Unit, Department of Thoracic Medicine, Imperial College, London, United Kingdom; Department of Pediatric and Adolescent Medicine, Pulmonary and Infectious Diseases, Wilhelminenspital, Vienna, Austria; and Department of Pediatric Cardiology and Pulmonology, Heinrich Heine University, Düsseldorf, Germany Correspondence and requests for reprints should be addressed to Angela Zacharasiewicz, M.D., Department of Respiratory Pediatrics, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK. E-mail: angela.zacharasiewicz{at}wienkav.at
The use of noninvasive methods of monitoring airway inflammation, such as exhaled nitric oxide (eNO) and induced sputum, has been shown to improve asthma monitoring and optimize treatment in adult patients with asthma. There is a lack of comparable data in children. Forty children with stable asthma eligible for inhaled steroid reduction were reviewed every 8 weeks, and their inhaled steroid dose halved if clinically indicated. eNO, sputum induction combined with bronchial hyperreactivity testing, and exhaled breath condensate collection were performed at each visit to predict success or failure of reduction of inhaled steroids. Thirty of 40 (75%) children tolerated at least one dose reduction, 12 of 40 (30%) were successfully weaned off, and in total, 15 of 40 (38%) children experienced loss of asthma control. Treatment reduction was successful in all children who had no eosinophils in induced sputum before the attempted reduction. Using multiple logistic regression, increased eNO (odds ratio, 6.3; confidence interval, 3.75–10.58) and percentage of sputum eosinophils (odds ratio, 1.38; confidence interval, 1.06–1.81) were significant predictors of failed reduction. These findings suggest that monitoring airway inflammation may be useful in optimizing treatment in children with asthma.
Key Words: asthma • children • exhaled nitric oxide • sputum eosinophil counts Asthma is characterized by variable degrees of airway obstruction, airway hyperresponsiveness, and chronic airway inflammation. Current guidelines emphasize that inhaled corticosteroid (ICS) treatment is the mainstay of asthma therapy because it targets the underlying airway inflammation. The possible side effects of ICS, particularly when administered in high dosages, are of particular concern (1). It is therefore essential to use the lowest possible dose of ICS compatible with good asthma control (2). Current guidelines for asthma management recommend that, after a period of stability, a reduction of ICS dose should be attempted. In clinical practice, the decision to try to reduce ICS dosage is based on reported symptoms and lung function (3). Reports of symptoms are often inaccurate (4); spirometry depends on cooperation and, even in symptomatic children, is often within the normal range (5). A number of noninvasive methods of assessing inflammation have been developed, such as the measurement of exhaled nitric oxide (eNO), examination of the cellular and soluble content of induced sputum (sometimes in combination with a test of bronchial hyperresponsiveness [BHR]), and to some extent the analysis of exhaled breath condensate (EBC). Most of these methods have been used in cross-sectional studies, and very few of these studies have attempted to assess their utility to guide treatment in the asthma clinic. In a randomized study in adults, a strategy involving the measurement of BHR, and increasing ICS dose if there was an asymptomatic deterioration in this parameter, reduced asthma exacerbations and improved indices of airway remodeling over a 2-year period, at the cost of increased use of ICS (6). Green and colleagues (7) used sputum eosinophils to monitor treatment and showed that a strategy to normalize this parameter, regardless symptom control, reduced asthma exacerbations without increasing the use of ICS (7). Another study compared the ability of eNO, sputum eosinophils, and BHR to predict a relapse in asthma after stopping ICS, and showed that a rise in eNO predicted loss of control (8). Although eNO has been suggested as a potentially useful clinical tool in the management of asthma (9, 10), information is lacking on its use to monitor treatment in children in clinical practice. Despite the availability of methods of assessing airway inflammation, they are not routinely used to guide treatment, and there are no prospective longitudinal studies in children with asthma who are treated with ICS. The aim of this study was to assess the additional value of noninvasive markers of airway inflammation as predictors of success or failure of ICS reduction. We aimed to determine whether in the setting of a pediatric asthma clinic, measuring airway inflammation was of practical value in the management of the individual child, in whom clinically a reduction in ICS dosage was believed appropriate. Some of the results of this study have been previously reported in the form of an abstract (11, 12).
Subjects Forty children (age, 6–17 years) with asthma (1) diagnosed by a pediatric respiratory physician (13) and (2) stable for at least 2 months (bronchodilator use < 3 times/week in past 2 months) on a constant ICS dose were recruited from the pediatric outpatients clinic.
Study Design
Assessment of Inflammation
Sputum induction with combined BHR testing.
Sputum processing.
EBC.
Definition of Loss of Asthma Control
Statistical Analysis
Steroid Reduction Demographic data are given in Table 1, and trial profile in Figure 1. After the first ICS reduction, 30 of 40 (75%) children were stable for at least 2 months.
Fifteen children tolerated further reduction steps successfully. Ten of 40 (25%) children had an exacerbation after the first reduction, and 5 of 40 (13%) after the subsequent reductions; therefore, 15 of 40 children were unable to tolerate a reduction in ICS despite one being clinically indicated. For those remaining stable, the median starting dose before reduction was 400 µg (range, 200–500) ICS. Similarly, the median daily dose in those who subsequently suffered an exacerbation during ICS reduction was also 400 µg (range, 200–800). The median ICS dose immediately before exacerbation was 250 µg (range, 100–750). The median time to exacerbation was 40 days (range, 25–71). Complete weaning off was successful in 12 of 40 (30%) children. There was no difference in atopic status between children who subsequently exacerbated and those who remained stable.
Induced Sputum, BHR testing, eNO, and EBC
Exacerbations.
Predicting result of ICS reduction.
In the combined logistic regression model, we only used the binary variable of eNO (eNO  22 ppb) because it had shown a strong statistical significance in the single model. Sputum eosinophils and eNO were statistically significant predictors of exacerbation, whereas BHR lost statistical significance in the multiple logistic regression model (Table 3).
Statistically significant correlations using Spearman rank correlations were found for eNO and sputum eosinophils, as well as for BHR and eosinophils and eNO (see Table E1 in the online supplement).
Data for prediction in individuals.
Inhaled steroid reduction was successful in all children in the absence of eosinophils in sputum. Figure 3 shows the receiver operator characteristic curves for sputum eosinophils and eNO at various cutoff points.
This is the first article to report prospectively the predictive value of monitoring airway inflammation using noninvasive methods during ICS reduction in children with asthma. The percentage of sputum eosinophil and an eNO of 22 ppb or greater were significant predictors for failed ICS reduction in children with apparently well-controlled asthma. Using these methods as part of a clinical assessment of the individual patient could help optimize therapy because 22% (15 children in 71 visits) of children failed reduction, despite fulfilling clinical guideline criteria. A retrospective analysis of the visits before exacerbation showed that excluding children with an eNO of 22 ppb or greater could have prevented an exacerbation in 11 of 14 (78%) children and, in the case of sputum eosinophils of 3% or more, an exacerbation could have been predicted in 8 of 11 (72%) children. On the other hand, if these values were used as indicators not to reduce treatment, a sputum eosinophil count of 3% or more would have prevented an attempted inhaled steroid reduction in 6 of 28 (21%) and elevated eNO levels in 19 of 49 (39%) occasions, where ICS reduction was in fact successful. Inhaled steroid reduction was always successful in asymptomatic children without sputum eosinophils. This study was not designed to determine whether it is better to risk an exacerbation in some children by aggressively reducing ICS dose or "play for safety" at a risk of overtreatment. Clearly, however, this is an important question.
We found that above-normal eNO ( Our study has a number of limitations. First, although we recruited 40 children, our results are based on only 15 exacerbations. We were unable to perform a power calculation before this study because of the lack of relevant previous pediatric data. Many (5 of 15) of these exacerbations could not be verified by the investigator because of the distances some of the children had to travel. Either a detailed history was taken and treatment instructions then given over the phone or, alternatively, some exacerbations were treated by local doctors and only reported retrospectively. However, the drop in FEV1, and rise in eNO and sputum eosinophils in the children we were able to study confirmed that at least these exacerbations were genuine, and implies that the ones we were unable to study, defined by the families on the same clinical criteria, were also likely to be genuine. We tried to reduce ICS in the same manner in all children. Interestingly, on five visits, the clinicians wished to reduce the dose, but the family was unwilling to risk a deterioration, despite the child meeting nationally agreed criteria for a treatment reduction. Likewise, on some visits, either the family or the pediatrician or both believed that a smaller reduction than directed by the protocol would be safer. Although this was subjective and not evidence-based, it is likely to reflect clinical practice in the real world. We aimed to assess loss of asthma control likely to be caused by the decreased steroid dosage. Because the effect of ICS on mild virus-related symptoms in asthma is controversial, and is difficult to quantify, transitory deterioration of symptoms occurring during a clinically diagnosed viral cold and temporarily requiring a more frequent use of short-acting bronchodilators was excluded, and did not preclude a further dose reduction in inhaled steroids. A different basis for poor control of asthma and viral-related symptoms has been supported by others (21). This approach, which only applied to a few children, seems to have been justified, because three of five children successfully continued with ICS reduction despite virus-related symptoms. We also did not ask the children to perform peak flow measurements. This was a deliberate decision, because they have been shown to be unreliable in children, with studies suggesting that more than 60% of the data were fabricated after 2 weeks of monitoring (22–24). We also have no information on adherence to treatment. Metered dose inhalers with inbuilt recorders would have been helpful, but again, are not used in routine clinical practice, where adherence usually has to be taken on trust. Information concerning symptom control was obtained retrospectively from parents and children at the next clinic visit; however, in a routine clinical setting, this is normal practice. In this study, EBC measurements of nitrite/nitrate levels and cysteinyl leukotrienes proved disappointing clinical tools. The small volumes of condensate obtained meant that we had to make arbitrary choices of what to measure, and our results cannot be taken to suggest that EBC has no role in the monitoring of asthma. In particular, and in retrospect, measurement of EBC pH (25) or levels of oxidants and antioxidants (26) might have been worthwhile. Further studies are needed to determine whether components of EBC other than those measured in this study would be valuable in monitoring children with asthma. Our results are in many ways similar to those of adult studies addressing the importance of sputum eosinophils in monitoring disease status or predicting future symptoms. In one study, a higher sputum eosinophil count at baseline was found in patients with subsequent exacerbations (27), and Leuppi and coworkers (28) found percentages of sputum eosinophils to be significantly greater before failure of reduction. In children, eosinophils in sputum were reported to be higher in children with asthma (29, 30), and the change in number was significantly associated with symptoms (31). What is novel in our study is the use of a panel of markers prospectively and the demonstration that some may be helpful in guiding therapy. Our results do differ in some respects from adult studies (7, 8), in which it was suggested that eNO and sputum eosinophilia could be used interchangeably. Jones and coworkers (8) reported eNO and sputum to be equally useful in predicting exacerbation in adults; however, in their study, eNO measurements were made at weekly intervals, compared with every 8 weeks in our study. This, however, is not likely to be practical until a device for home monitoring of eNO becomes available. As previously reported, sputum induction with combined hypertonic saline challenge has been found to be well tolerated, safe, and highly successful in children with asthma (15). A response to hypertonic saline in children is most strongly associated with current asthma and allergy symptoms (32). BHR, however, is not a direct marker of airway inflammation; it has been suggested to be a separate dimension in the description of chronic asthma (33). A considerable number of children had used bronchodilators before attending their clinical appointment; therefore, it was only possible to perform a test of BHR in a subgroup of children. A larger number might have shown a statistical significance in the multiple logistic regression model. However, there was a correlation between BHR and sputum eosinophils and eNO. Therefore, we suggest this test may be a surrogate marker for successful reduction in children in whom eNO measurements or sputum induction cannot be performed. However, a further prospective study is required to confirm this suggestion. In conclusion, we have shown for the first time in children that the use of methods to monitor airway inflammation can help predict success or failure of ICS reduction. The number of exacerbations was relatively small, but inspection of the data suggests that our conclusion that eNO and sputum eosinophil measurements may be helpful is likely to be correct, although the absolute predictive values may be less reliable. These results need to be confirmed by other workers in larger numbers before they can be recommended for widespread clinical use. The data presented here can be used to inform the design of future studies. However, we have presented data, which for the first time provide proof of concept that the use of measurements of airway inflammation may be useful to guide therapy in individual children, and not merely be used to define mechanisms by looking at overlapping differences between groups.
The authors thank Dr. Louise Donnelly for her expertise in the measurement techniques of nitrite/nitrate levels in exhaled breath.
Supported by a scholarship from the Gesellschaft für Pädiatrishe Pneumelogie e.V. (A.Z.). This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org Conflict of Interest Statement: A.Z. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; N.W. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; C.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; E.M.E. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; A.M.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; T.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; M.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; A.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. Received in original form September 20, 2004; accepted in final form January 21, 2005
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