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Original Research: ASTHMA |

Exhaled Nitric Oxide Daily Evaluation Is Effective in Monitoring Exposure to Relevant Allergens in Asthmatic Children* FREE TO VIEW

Alessandro Bodini, MD; Diego Peroni, MD; Attilio Loiacono, MD; Silvia Costella, PhD; Roberta Pigozzi, PhD; Eugenio Baraldi, MD; Attilio L. Boner, MD; Giorgio L. Piacentini, MD
Author and Funding Information

*From the Clinica Pediatrica Università di Verona (Drs. Bodini, Peroni, Pigozzi, Boner, and Piacentini), Verona, Italy; Istituto Pio XII (Drs. Loiacono and Costella), Misurina (BL), Italy; and the Dipartimento di Pediatria (Dr. Baraldi), Università di Padova, Padova, Italy.

Correspondence to: Giorgio L. Piacentini, MD, Dipartimento di Pediatria, Policlinico G.B. Rossi, 37134 Verona, Italy; e-mail: giorgio.piacentini@univr.it



Chest. 2007;132(5):1520-1525. doi:10.1378/chest.07-1025
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Published online

Background: Though asthma is an airway inflammatory disease, the assessment of treatment efficacy is mainly based on symptom monitoring and the evaluation of lung function parameters. This study was aimed to evaluate the feasibility of exhaled nitric oxide monitoring in allergic asthmatic children who were exposed to relevant allergens in their homes.

Methods: Twenty-two children allergic to mites underwent twice-daily fractional exhaled nitric oxide (FeNO) therapy using a portable device (NIOX MINO; Aerocrine AB; Stockholm, Sweden) and peak expiratory flow (PEF) measurements before, during, and after periods of natural exposure to mite allergens. The children were admitted to the study if they had lived in a mite-free environment for 3 months. They were observed in this environment for 10 days and then were moved to a site with natural mite exposure at sea level for 19 days. Finally, they were relocated to the mite-free environment for a period of 6 days for follow-up measurements.

Results: Significant differences were seen between the mite-free baseline FeNO level (26.4 parts per billion [ppb]; range, 19.3 to 36.2 ppb) and FeNO levels measured during natural mite exposure (37.3 ppb; 27.3 to 51 ppb) and after natural mite exposure (34.9 natural mite exposure; 25.2 to 48.2 ppb). Six children reported asthma symptoms during the mite exposure, and an increase in FeNO was observed in each case (p < 0.031); PEF values showed no significant differences, whether between the different environments or between different periods.

Conclusions: These data give further evidence for a possible role of frequent determinations of FeNO in order to promptly assess changes in the level of airway inflammation in asthmatic children.

Figures in this Article

Though asthma is clearly recognized to be an inflammatory disease of the airways and treatment is aimed at controlling airway inflammation, the assessment of treatment efficacy is mainly based on symptom monitoring and the evaluation of lung function parameters such as peak expiratory flow (PEF) or FEV1.1 Since monitoring the effect of antiinflammatory treatment in relation to airway flow obstruction rather than inflammation reflects inconsistency between treatment rationale and assessment, it has been seen in the past few years as a paradox in asthma management.1

In the last few years, exhaled nitric oxide has been recognized as a well-validated method for monitoring the level of eosinophilic airway inflammation in asthmatic patients,23 and also as an objective predictor of asthma relapse in children.4 Nevertheless, the currently available instruments for the measurement of exhaled nitric oxide for clinical purposes are mainly localized in highly specialized asthma centers, usually at university hospitals, and require specifically trained personnel. This means that, in current practice, the measurement of exhaled nitric oxide is still underused.

Recently, a portable instrument (NIOX MINO; Aerocrine AB; Solna, Sweden), much simpler and less expensive than previous analyzers, has been validated for exhaled nitric oxide measurement. One of the main advantages of this instrument is that it can be directly operated by the patient and can thus be proposed for the home monitoring of asthma. The purpose of this study was to evaluate the feasibility of exhaled nitric oxide monitoring in allergic asthmatic children who were exposed to relevant allergens.

Twenty-two asthmatic children aged 6 to 15 years, sensitized to house dust mite (HDM), were evaluated at the Istituto Pio XII (Misurina, Italy). This is a residential center for asthma treatment and rehabilitation, which is situated in the Italian Alps at an altitude of 1,756 m. Study participants were recruited from inpatient asthmatic children who were spending a school year at the center. Twelve children were receiving treatment with a low-dose inhaled steroid (fluticasone, ≤ 200 μg/d), and their treatment schedule was not changed during the study.

The children admitted to the study had been living at the Istituto Pio XII (an environment free of HDM allergen because of its high-altitude location) for at least 3 months at the time of admission to the study. They were all tested for sensitization to the most relevant aeroallergens by skin-prick test. In order to be admitted to the study protocol, they had to have received a diagnosis of asthma a minimum of 18 months previously and to be able to perform fractional exhaled nitric oxide (FeNO) and PEF measurements correctly. Twice a day, in the morning and evening, FeNO and PEF measurements were performed throughout the baseline period in the mountain environment (P0). When the children left the Istituto Pio XII for their homes at sea level to spend a 19-day Christmas holiday, measurements were continued (P1). A further week of FeNO and PEF measurements was performed after returning to the mountain environment (P2).

Exclusion criteria were respiratory infections in the 2 months before the study period, sensitization to furred pets, and treatment with oral corticosteroids in the last 2 months before the study. None of the children had to have pets in their family houses. Nevertheless, children sensitized to pets were excluded from the study because of the risk they could be exposed to pet allergens in the houses of relatives or friends during the time of the study. Since it was not possible to control for this risk, pet-sensitized children were excluded from the study even if they were not expected to be exposed to pets in their own homes. This study was performed out of the pollen season in order to avoid the interference of outdoor allergens for those patients who were also sensitized to pollens.

Throughout the study period, rescue medication with inhaled salbutamol as required or with oral steroids was allowed in the event of asthma deterioration. Any such medication had to be recorded on personal diary cards,5 along with asthma-related symptoms or infections.

HDM group 1 (Der p 1 and Der f 1) antigen levels were measured by enzyme-linked immunosorbent assay in dust from beds the children used during their stay at the residential center and at their family homes.6 The study was approved by the Istituto Pio XII (Misurina, BL) Ethics Committee, and both children and parents gave informed consent.

FENO and PEF Measurements

FENO levels were evaluated by three repeated measurements performed twice a day, in the morning and in the evening, using a personal device for measuring FeNO levels in each child (NIOX MINO; Aerocrine AB). The function of the device is based on electrochemical analysis, which is in line with published procedures for FeNO measurement. The method has been validated by chemiluminescence technology,711 with an accuracy of ± 5 parts per billion (ppb) compared to the personal device (NIOX MINO; Aerocrine AB).12 In the validation study, data from the analyzer vs the portable device (NIOX; Aerocrine AB) showed a mean disagreement of 0.5 ppb (SD, 3.8 ppb), with high linearity and accuracy compared to reference gases.12

FeNO levels were automatically recorded by the measurement device on an electronic card. PEF measurements were performed (Wright Peak Expiratory Flow Mini-Meter; Clement Clarke International Ltd; Harlow, UK), and the best of three efforts was recorded by the patient on a personal diary card. To avoid possible effects of repeated expiratory efforts on FeNO,3 FeNO was always assessed before PEF was measured. American Thoracic Society/European Respiratory Society guidelines3 were followed with the maximum care. Children were not allowed to consume coffee, and they were asked to avoid consuming caffeinated soft drinks (eg, Coke; Coca Cola; Atlanta, GA) as well during the time of the study. The children were assisted by an adult, either a nurse while at the residential house or a parent while at home, in handling the devices and in performing FeNO and PEF measurements during the study period.

Statistical Analysis

The morning and evening FeNO values each day were the average of three repeated measurements. The logarithms of FeNO were then used to calculate geometric means and 95% confidence intervals. In addition, data from the first and last 3 days in each period were averaged and were used to analyze changes within periods and between periods. PEF was measured once in the morning and once during the evening. Within each period, the individual morning and evening data were averaged, and the mean results during P1 were compared to the mean results during P0 and P2. The Wilcoxon signed rank test was used to compare data between study periods, and the Mann-Whitney test as used to compare differences between groups (eg, treated with inhaled corticosteroids [ICSs] vs untreated). The Friedman test was used for comparisons between all periods during P1 and P2. During P2, individual slopes from linear regression were calculated to assess the development of FeNO. Spearman ρ values were used in the correlation analyses.

A p value of < 0.05 was considered to be significant, whereas p values of < 0.10 were taken to indicate borderline significance. A statistical software package (SPSS, version 11.5; SPSS; Chicago, IL) was used to perform the statistical analyses.

The mean antigen levels for HDM group 1 (Der p 1 and Der f 1) in the dust from beds were 30.9 μg/g dust in the family homes and < 0.05 μg/g dust in the residential center (p < 0.01). One of the children experienced an upper respiratory tract infection during P1 and was excluded from the analyses. Another child did not complete the study for reasons not related to the experimental design and was also excluded from the analysis. Thus, data from 20 children were analyzed. The baseline characteristics of the children are given in Table 1 .

Compliance for FeNO, measured as the number of observed measurements divided by the number of expected measurements, was 85% (minimum, 68%; maximum, 96%). Average PEF values were stable throughout the study period (Table 2 , Fig 1 ).

There were no statistically significant differences between morning and evening PEF, or between PEF levels in different periods (Friedman test). Overall, there were no statistically significant differences between morning and evening FeNO levels. FeNO values were stable during the P0 at the residential house (Fig 1). There were significant differences between mean morning levels during period P0 vs P1, and P0 vs P2, with the morning levels in P0 being lower than those in P1 and P2 (p < 0.025 and p < 0.007, respectively). Mean evening levels in P1 and P2 were significantly higher than the level in P0 (p < 0.008 and p < 0.003, respectively), while levels did not differ significantly in P1 compared to P2. Comparing within-period changes in FeNO by considering data from the first and last 3 days in each period, a significant increase was observed during the time of exposure (P1), followed by a significant decrease a few days after returning to the allergen-free environment (P2). These results are summarized in Table 3 .

For the period P2, when calculating for each individual a linear regression line with FENO as the dependent variable and the day number as the independent variable, the individual slopes for morning measurements show a significant decrease of FeNO from zero (p < 0.014). Differences in individual slopes for evening measurements showed borderline significance from zero (p < 0.08), again with a decrease in FeNO. The difference between FeNO during the first and last days in P2 also showed a significant decrease in morning FeNO (p < 0.034).

Effect of ICS Treatment

There were no statistically significant differences in FeNO levels between children receiving ICS therapy and other children in any period. However, there was a statistically significant difference between children receiving ICS therapy and other children concerning PEF levels in P2, with treated children having lower PEF values (p < 0.028). Borderline significant differences were also found in morning measurements for P0 and P1, and in evening measurements for P0 (p < 0.09) [Table 2].

Symptoms

None of the children reported significant asthma-related symptoms during the 10 days before leaving the residential center (P0). Six of the children participating in the study reported asthma symptoms persisting for at least 3 consecutive days during their stay at their family homes (P1). In all cases, FeNO levels increased before they reported the symptoms in their personal diaries (p < 0.031 [binomial test]), while PEF values were still uninformative.

Recent studies have demonstrated that daily monitoring of FeNO by the portable device (NiOX MINO; Aerocrine AB) is a feasible method to monitor airway inflammation in asthmatic patients13 and that the level of exhaled nitric oxide increases during a pollen season, reflecting increased inflammatory disease activity better than lung function measurement and symptom recording.9 The present study evaluated the feasibility of FeNO daily monitoring by the portable device in assessing airway inflammation in HDM allergic asthmatic children who were undergoing a multifactorial environmental intervention, mainly based on the reduction in exposure to HDM antigen in a residential center in the Alps followed by reexposure to family home conditions.

The role of exhaled nitric oxide in the treatment of asthmatic patients has been evaluated mainly in relationship to pharmacologic treatment of the disease. Though the use of methods to monitor airway inflammation can help to predict the success or failure of ICS reduction,14the current evidence would not support the use of FeNO levels to guide treatment, as all three of the prospective trials1517 to date have failed to demonstrate an improvement in exacerbation rate with this approach. However, global management of asthmatic children must consider, along with drug treatment, the effects of environmental determinants, in particular allergen exposure. Moving asthmatic children to a residential center in an Alpine environment has to be considered a multifactorial intervention, involving, in addition to a significant reduction in mite antigen levels, avoidance of tobacco smoke, differences in environmental pollution and humidity, and dietary modifications, most of these factors being difficult to standardize in a small study population. Only a control group without allergies undergoing the same scheme of environmental intervention could allow clear assessment of the actual effect of non–HDM-related environmental differences. However, the importance of such a control group is at best a theoretical consideration since there is no justification for moving nonallergic children to an asthma institute in the Alps.

Previous studies1821 have demonstrated that exhaled nitric oxide can reflect exposure to relevant allergens in allergic asthmatic children. The present data support the conclusions of recent publications13 suggesting the feasibility of daily monitoring of FeNO by a portable instrument.

In agreement with the recent data obtained by Vahlkvist and coworkers9 during a birch pollen season, the present study shows that, also in the case of natural mite antigen exposure, exhaled nitric oxide in a group of mite-sensitized asthmatic children who were assessed by daily evaluation with a portable device shows a gradually increasing curve throughout the whole period of exposure. This increase starts as early as the first few days after leaving the residential center, suggesting a prompt time response of this parameter in reflecting exposure to critical disease factors. In addition, for the six children who reported asthma symptoms during the study period, the level of exhaled nitric oxide, but not PEF, showed a statistically significant trend to a more evident increase 2 or 3 days before the symptom report in the personal diary. This finding is consistent with the observation from a previous study21 showing that the level of exhaled nitric oxide may rise before an exacerbation of asthma in allergic children during the grass pollen season, and it supports the hypothesis of a potential role of such a measurement for a more dynamic treatment of the disease.9,1517,22

Furthermore, in this study group no significant difference in FeNO levels was observed between children receiving ICS therapy and those not receiving it. A possible explanation for this finding could be that in the residential house, FeNO measurement is a part of the asthma control management and the treatment of the children were also tailored for this parameter. Therefore, we had comparable levels of FeNO at the starting time and possibly FeNO levels remained comparable throughout the study period between treated and untreated children since no modification of the treatment, other than for rescue therapy, was allowed.

The results of this study support the view that daily monitoring of FeNO in HDM allergic asthmatic children who have been exposed to relevant allergens can reflect the changes in the levels of airway inflammation due to allergen exposure. In addition, in agreement with the observation by Vahlkvist and coworkers,9 the present data open a new perspective on the potential use of FeNO in the prediction of reexacerbation risk, showing greater sensitivity than PEF monitoring or symptom perception by the patient. Taken together, these data, if confirmed in a larger group of subjects, suggest a role for repeated measurements of FeNO to monitor the level of airway inflammation in asthmatic patients, with possible implications for treatment strategy.

In conclusion, the present data provide further evidence regarding a possible role of frequent determinations of FeNO by a portable device to promptly assess changes in the level of airway inflammation in asthmatic children. The possibility of providing patients with portable instruments for home assessment opens new prospects for more effective management of asthmatic patients, in particular when they are exposed to major changes in environmental disease-related factors.

Abbreviations: FeNO = fraction of exhaled nitric oxide; HDM = house dust mite; ICS = inhaled corticosteroid; PEF = peak expiratory flow; ppb = parts per billion

This study was performed employing instruments kindly provided by Aerocrine AB for the purposes of the study. Aerocrine AB supported the data analysis. The data collection as well as the data and analysis interpretation were performed only by the authors. The article was written by the authors. No financial funding was provided in relationship with this study by Aerocrine AB.

The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Table Graphic Jump Location
Table 1. Baseline Characteristics of the Subjects*
* 

B = birch tree; G = grass pollen; HDM = house dust mite; O = olive tree; P = parietaria; R = ragweed; M = male; F = female; FP = fluticasone propionate.

Table Graphic Jump Location
Table 2. PEF Levels During the Study According to ICS Treatment and for All Subjects
Figure Jump LinkFigure 1. Daily mean (± SEM) PEF and FeNO values throughout the study period.Grahic Jump Location
Table Graphic Jump Location
Table 3. Geometric Means and 95% Confidence Intervals During First/Last 3 Days of Each Period According to Morning and Evening Measurements*
* 

Values are given as ppb for first 3 days/last 3 days (95% confidence intervals for first 3 days/last 3 days) [p value (presented as within-period comparisons)]. NS = not significant.

The authors wish to thank Dr. Mats Carlson and Aerocrine AB, Sweden, for kindly providing NIOX MINO instruments and for their assistance with this study project; Dr. Björn Jonsson for his assistance in data analysis; and Dr. Peter Mean for final editing of the article.

Gibson, PJ (2000) Monitoring the patient with asthma: an evidence-based approach.J Allergy Clin Immunol106,17-26. [PubMed] [CrossRef]
 
Kharitonov, SA, Barnes, PJ Exhaled markers of pulmonary disease.Am J Respir Crit Care Med2001;163,1693-1722. [PubMed]
 
Baraldi, E, De Jongste, JC Measurement of exhaled nitric oxide in children.Eur Respir J2002;20,223-237. [PubMed]
 
Pijnenburg, MW, Hofhuis, W, Hop, WC, et al Exhaled nitric oxide predicts asthma relapse in children with clinical asthma remission.Thorax2005;60,215-218. [PubMed]
 
Piacentini, GL, Bodini, A, Costella, S, et al Exhaled nitric oxide in asthmatic children exposed to relevant allergens: effect of flunisolide.Eur Respir J2000;15,730-734. [PubMed]
 
Chapman, MD, Haymann, PW, Wilkins, SR, et al Monoclonal immunoassay for the major dust mite (Dermatophagoides) allergens, Der p I and Der f I, and quantitative analysis of the allergen content of mite and house dust extracts.J Allergy Clin Immunol1987;80,184-194. [PubMed]
 
Menzies, D, Nair, A, Lipworth, BJ Portable exhaled nitric oxide measurement: comparison with the “gold standard” technique.Chest2007;131,410-414. [PubMed]
 
Gill, M, Graff, GR, Adler, AJ, et al Validation study of fractional exhaled nitric oxide measurements using a handheld monitoring device.J Asthma2006;43,731-734. [PubMed]
 
Vahlkvist, S, Sinding, M, Skamstrup, K, et al Daily home measurements of exhaled nitric oxide in asthmatic children during natural birch pollen exposure.J Allergy Clin Immunol2006;117,1272-1276. [PubMed]
 
McGill, C, Malik, G, Turner, SW Validation of a hand-held exhaled nitric oxide analyzer for use in children.Pediatr Pulmonol2006;41,1053-1057. [PubMed]
 
Alving, K, Janson, C, Nordvall, L Performance of a new hand-held device for exhaled nitric oxide measurement in adults and children.Respir Res2006;20,7:67
 
Hemmingsson, T, Linnarsson, D, Gambert, R Novel hand-held device for exhaled nitric oxide-analysis in research and clinical applications.J Clin Monit Comput2004;18,379-387. [PubMed]
 
Pjjnenburg, MW, Floor, ME, Hop, WC, et al Daily ambulatory exhaled nitric oxide measurements in asthma.Pediatr Allergy Immunol2006;17,189-193. [PubMed]
 
Zacharasiewicz, A, Wilson, N, Lex, C, et al Clinical use of noninvasive measurements of airway inflammation in steroid reduction in children.Am J Respir Crit Care Med2005;171,1077-1082. [PubMed]
 
Smith, AD, Cowan, JO, Brasset, KP, et al Use of exhaled nitric oxide measurements to guide treatment in chronic asthma.N Engl J Med2005;352,2163-2173. [PubMed]
 
Pijnenburg, MW, Bakker, EM, Hop, WC, et al Titrating steroids on exhaled nitric oxide in asthmatic children: a randomized controlled trial.Am J Respir Crit Care Med2005;172,831-836. [PubMed]
 
Shaw, DE, Berry, MA, Thomas, M, et al The use of exhaled nitric oxide to guide asthma management: a randomised controlled trial.Am J Respir Crit Care Med2007;176,231-237. [PubMed]
 
Piacentini, GL, Bodini, A, Costella, S, et al Allergen avoidance is associated with a fall in exhaled nitric oxide in asthmatic children.J Allergy Clin Immunol1999;104,1323-1324. [PubMed]
 
Baraldi, E, Carra, S, Dario, C, et al Effect of natural grass pollen exposure on exhaled nitric oxide in asthmatic children.Am J Respir Crit Care Med1999;159,262-266. [PubMed]
 
Simpson, A, Custovic, A, Pipis, S, et al Exhaled nitric oxide, sensitization, and exposure to allergens in patients with asthma who are not taking inhaled steroids.Am J Respir Crit Care Med1999;160,45-49. [PubMed]
 
Roberts, G, Hurley, C, Bush, A, et al Longitudinal study of grass pollen exposure, symptoms, and exhaled nitric oxide in childhood seasonal allergic asthma.Thorax2004;59,752-756. [PubMed]
 
Taylor, DR Nitric oxide as a clinical guide for asthma management.J Allergy Clin Immunol2006;117,259-262. [PubMed]
 

Figures

Figure Jump LinkFigure 1. Daily mean (± SEM) PEF and FeNO values throughout the study period.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. Baseline Characteristics of the Subjects*
* 

B = birch tree; G = grass pollen; HDM = house dust mite; O = olive tree; P = parietaria; R = ragweed; M = male; F = female; FP = fluticasone propionate.

Table Graphic Jump Location
Table 2. PEF Levels During the Study According to ICS Treatment and for All Subjects
Table Graphic Jump Location
Table 3. Geometric Means and 95% Confidence Intervals During First/Last 3 Days of Each Period According to Morning and Evening Measurements*
* 

Values are given as ppb for first 3 days/last 3 days (95% confidence intervals for first 3 days/last 3 days) [p value (presented as within-period comparisons)]. NS = not significant.

References

Gibson, PJ (2000) Monitoring the patient with asthma: an evidence-based approach.J Allergy Clin Immunol106,17-26. [PubMed] [CrossRef]
 
Kharitonov, SA, Barnes, PJ Exhaled markers of pulmonary disease.Am J Respir Crit Care Med2001;163,1693-1722. [PubMed]
 
Baraldi, E, De Jongste, JC Measurement of exhaled nitric oxide in children.Eur Respir J2002;20,223-237. [PubMed]
 
Pijnenburg, MW, Hofhuis, W, Hop, WC, et al Exhaled nitric oxide predicts asthma relapse in children with clinical asthma remission.Thorax2005;60,215-218. [PubMed]
 
Piacentini, GL, Bodini, A, Costella, S, et al Exhaled nitric oxide in asthmatic children exposed to relevant allergens: effect of flunisolide.Eur Respir J2000;15,730-734. [PubMed]
 
Chapman, MD, Haymann, PW, Wilkins, SR, et al Monoclonal immunoassay for the major dust mite (Dermatophagoides) allergens, Der p I and Der f I, and quantitative analysis of the allergen content of mite and house dust extracts.J Allergy Clin Immunol1987;80,184-194. [PubMed]
 
Menzies, D, Nair, A, Lipworth, BJ Portable exhaled nitric oxide measurement: comparison with the “gold standard” technique.Chest2007;131,410-414. [PubMed]
 
Gill, M, Graff, GR, Adler, AJ, et al Validation study of fractional exhaled nitric oxide measurements using a handheld monitoring device.J Asthma2006;43,731-734. [PubMed]
 
Vahlkvist, S, Sinding, M, Skamstrup, K, et al Daily home measurements of exhaled nitric oxide in asthmatic children during natural birch pollen exposure.J Allergy Clin Immunol2006;117,1272-1276. [PubMed]
 
McGill, C, Malik, G, Turner, SW Validation of a hand-held exhaled nitric oxide analyzer for use in children.Pediatr Pulmonol2006;41,1053-1057. [PubMed]
 
Alving, K, Janson, C, Nordvall, L Performance of a new hand-held device for exhaled nitric oxide measurement in adults and children.Respir Res2006;20,7:67
 
Hemmingsson, T, Linnarsson, D, Gambert, R Novel hand-held device for exhaled nitric oxide-analysis in research and clinical applications.J Clin Monit Comput2004;18,379-387. [PubMed]
 
Pjjnenburg, MW, Floor, ME, Hop, WC, et al Daily ambulatory exhaled nitric oxide measurements in asthma.Pediatr Allergy Immunol2006;17,189-193. [PubMed]
 
Zacharasiewicz, A, Wilson, N, Lex, C, et al Clinical use of noninvasive measurements of airway inflammation in steroid reduction in children.Am J Respir Crit Care Med2005;171,1077-1082. [PubMed]
 
Smith, AD, Cowan, JO, Brasset, KP, et al Use of exhaled nitric oxide measurements to guide treatment in chronic asthma.N Engl J Med2005;352,2163-2173. [PubMed]
 
Pijnenburg, MW, Bakker, EM, Hop, WC, et al Titrating steroids on exhaled nitric oxide in asthmatic children: a randomized controlled trial.Am J Respir Crit Care Med2005;172,831-836. [PubMed]
 
Shaw, DE, Berry, MA, Thomas, M, et al The use of exhaled nitric oxide to guide asthma management: a randomised controlled trial.Am J Respir Crit Care Med2007;176,231-237. [PubMed]
 
Piacentini, GL, Bodini, A, Costella, S, et al Allergen avoidance is associated with a fall in exhaled nitric oxide in asthmatic children.J Allergy Clin Immunol1999;104,1323-1324. [PubMed]
 
Baraldi, E, Carra, S, Dario, C, et al Effect of natural grass pollen exposure on exhaled nitric oxide in asthmatic children.Am J Respir Crit Care Med1999;159,262-266. [PubMed]
 
Simpson, A, Custovic, A, Pipis, S, et al Exhaled nitric oxide, sensitization, and exposure to allergens in patients with asthma who are not taking inhaled steroids.Am J Respir Crit Care Med1999;160,45-49. [PubMed]
 
Roberts, G, Hurley, C, Bush, A, et al Longitudinal study of grass pollen exposure, symptoms, and exhaled nitric oxide in childhood seasonal allergic asthma.Thorax2004;59,752-756. [PubMed]
 
Taylor, DR Nitric oxide as a clinical guide for asthma management.J Allergy Clin Immunol2006;117,259-262. [PubMed]
 
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