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(Chest. 2004;126:1540-1545.)
© 2004 American College of Chest Physicians

Measuring Exhaled Nitric Oxide Levels in Adults*

The Importance of Atopy and Airway Responsiveness

Peter J. Franklin, PhD; Stephen M. Stick, PhD; Peter N. Le Souëf, MD; Jon G. Ayres, MD and Stephen W. Turner, MD

* From the Department of Respiratory Medicine (Dr. Stick) and School of Paediatrics and Child Health (Drs. Turner, Souëf, and Franklin), Princess Margaret Hospital for Children, Perth, Australia; and Department of Environmental and Occupational Medicine (Professor Ayres), University of Aberdeen, Scotland.

Correspondence to: Stephen W. Turner, MD, School of Medicine, Department of Child Health, Royal Aberdeen Children’s Hospital, Foresterhill, Aberdeen, AB25 2ZG; e-mail s.w.turner{at}abdn.ac.uk


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Raised exhaled nitric oxide (FENO) levels have been associated with asthma. However, we have found that in children, FENO was increased in atopic children with increased airway responsiveness (AR), and this was independent of a diagnosis of asthma.

Study objectives: The current study was designed to test the hypothesis that in adults there is no association between FENO and asthma after controlling for atopy and AR.

Measurements: One hundred fifteen adults (77 women; mean age, 41 years) underwent an assessment that included FENO measurements, spirometry, skin-prick testing, blood eosinophil count, and inhaled histamine challenge (results are expressed as a dose-response slope [DRS]).

Results: When only atopic individuals were considered (n = 73), FENO was positively associated with the DRS (p = 0.003), male gender (0.02), and negatively associated with current smoking (p = 0.09). Only male gender (p = 0.03) was associated with FENO among nonatopic individuals (n = 36). In multivariate analysis, there was no association between FENO and current asthma, current wheeze, or asthma ever.

Conclusions: We conclude that in adult subjects, elevated FENO measurements are associated with a phenotype characterized by atopy and increased AR regardless of the presence of asthma or asthma-like symptoms.

Key Words: asthma • bronchial hyperreactivity • hypersensitivity • nitric oxide • smoking


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Exhaled nitric oxide (FENO) has been proposed as a noninvasive marker of airway inflammation in asthma.1 FENO levels are elevated in asthmatics,2 fall after treatment with corticosteroids,3 and have been positively correlated with eosinophils in sputum4 and BAL fluid.5 These observations have prompted suggestions that measurement of FENO may be useful in the diagnosis and monitoring of asthma.6 However, the nature of the relationship between raised FENO levels and both asthma and airway inflammation is incompletely understood. Indeed some studies have demonstrated discordance between FENO and changes in asthma symptoms,7 and evidence of airway inflammation present in biopsy specimens.8

Atopy is also associated with increased FENO, and there is now considerable evidence to demonstrate that atopy increases FENO independently of asthma.9101112 Recent studies,1314 including ours, have shown that in children FENO is not elevated in all atopic individuals, but only in atopic children with increased airway responsiveness (AR). Interestingly, in our study, raised FENO identified individuals with atopy and increased AR regardless of a diagnosis of asthma or asthmatic symptoms. The aim of this study was to investigate the relationship between atopy, AR, and diagnosed asthma in adults.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects and Protocol
Subjects for the present study were parents of children enrolled in a prospective birth cohort study of lung function, AR, and atopy.15 This cohort was not selected on the basis of parental asthma. Parents had completed a modified American Thoracic Society questionnaire at enrollment,16 and at the 11-year follow-up of the cohort they were invited to participate in an assessment that included spirometry, inhaled histamine challenge, skin-prick testing (SPT), blood eosinophil count, and measurement of FENO. Current and past respiratory symptoms were assessed using the same modified American Thoracic Society questionnaire, and the results were verified with previous records. An individual was considered to have current physician-diagnosed asthma (PDA) following an affirmative response to the question, "do you currently have asthma diagnosed by a physician?" A history of PDA ever was said to be present if the respondent replied affirmatively to the question, "have you ever had asthma diagnosed by a physician?" Recent wheeze was said to be present if the respondent replied affirmatively to the question, "have you wheezed during the past year?" Current smoking was said to be present if the respondent replied affirmatively to the question, "do you currently smoke tobacco on a regular basis?" Assessments took place either at the home of the family or the hospital. FENO was measured only in those attending the hospital. None of the adults were symptomatic at the time of study. Written consent was provided by all subjects. The study was approved by the Medical Ethics Committee of Princess Margaret Hospital for Children.

FENO
FENO was measured using a fast-response chemiluminescence analyser (NOA 280; Sievers Instruments; Boulder, CO), as previously described.10 Measurements were taken prior to spirometry and histamine challenge.

Pulmonary Function and AR
Pulmonary function testing was performed using a hand-held spirometer (Pneumocheck Spirometer 6100; Welch-Allyn; Skaneateles Falls, NY) in accordance with published guidelines.17 AR to histamine was determined using the rapid dosimeter technique.18 Increased AR was defined as a provocative dose of inhaled histamine causing a 20% fall in FEV1 (PD20) ≤ 7.8 µmol/L.18 A dose-response slope (DRS) was also calculated using the method of O’Connor et al.19

SPT and Eosinophil Count
Skin reactivity to cow milk, egg white, rye grass, mixed grass, Dermatophagoides farinae, Dermatophagoides pteronyssinus, cat dander, dog dander, Alternaria alternans, and Aspergillus fumigatus (Hollister-Stier; Elkhart, IN) was assessed by SPT as described by Pepys.20 The positive control was histamine sulfate (10 mg/mL), and the negative control was 0.9% saline solution. A positive SPT result was defined as a weal at least 3 mm in its longest dimension. Atopy was defined as the presence of at least one positive SPT finding. Blood was collected from the radial vein, and the blood eosinophil count was measured using a flow cytometer (Coulter Maxm; Beckman-Coulter; Fullerton, CA). Values are expressed as absolute cell count.

Statistical Analyses
Values for the DRS, FENO, and blood eosinophil count were skewed and were log10 transformed prior to analysis to achieve a near-normal distribution (a constant of 1 was added to the DRS to allow values of ≤ 0 to be included in the analysis). Univariate analyses using Student t test and simple linear regression were used to determine associations between transformed FENO and the following explanatory variables: current PDA, PDA ever, recent wheeze, atopy, DRS, blood eosinophils, height, gender, age, and FEV1. Due to the established differences between FENO for atopic and nonatopic subjects, separate multivariate regression models were constructed for both atopic and nonatopic individuals using transformed FENO values as the outcome variable. Factors that had a significance level of at least p ≤ 0.1 from univariate analyses were included in these models. These were age, height, gender, history of PDA ever, current PDA, recent wheeze, DRS, current smoking, and atopy. Variables in all models were excluded in a backward step-wise fashion. Regression coefficients were log transformed back, and are reported as the fold difference between categorical variables, eg, symptoms, or fold increase per unit change in continuous variables. FENO levels, DRS, and blood eosinophil values are reported as geometric means with 95% confidence intervals (CIs). All analyses were performed using SPSS version 10.0.7 (SPSS; Chicago, IL).


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Two hundred forty-six study subjects underwent a respiratory assessment; however, only 115 attended the hospital where FENO concentrations were measured. These subjects are included in the analyses for this article. There were no differences between subjects with and without FENO measurements for age, gender, and proportion with asthma, atopy, and PD20 ≤ 7.8. Of the 115 subjects with FENO measurements, 77 were women and the mean age was 41 years (range, 31 to 56 years). The men (mean age, 43 years; SD 4) were older than the women (mean age, 39 years; SD 4) [p < 0.001]. Subject details are presented separately for men and women in Table 1 .


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  		Table 1.. Demographics of Individuals Where FENO Measurements Were Made

 
FENO measurements of two asthmatics treated with regular inhaled steroids were 10.9 ppb and 11.8 ppb, respectively, and due to known effects of inhaled corticosteroids on FENO,21 these data were not included in analyses. SPT was performed in all of the remaining 113 individuals, bronchial challenge in 110 patients, spirometry in 112 patients, and eosinophil count in 112 patients. Seventy-eight study subjects (68%) were atopic, 31 subjects (26%) had a history of PDA ever, 20 subjects (18%) had current PDA, 25 subjects (22%) currently smoked, 19 subjects (17%) reported wheeze in the past 12 months, and 19 subjects (17%) had increased AR (Table 1). Table 2 presents details of respiratory history, atopy, and AR for those subjects with and without PDA.


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  		Table 2.. Comparison of Individuals With and Without PDA*

 
In the univariate analyses (Table 3 ), there was a positive correlation between FENO and both age (r = 0.22, p = 0.02) and height (r = 0.20, p = 0.04). Men had higher FENO than women (17.2 parts per billion [ppb]; 95% CI, 14.4 to 20.4; and 11.6 ppb; 95% CI, 9.8 to 13.8, respectively) [p = 0.006]. FENO was elevated in atopic subjects (15.0 ppb; 95% CI, 12.8 to 17.6) compared with nonatopic subjects (10.2 ppb; 95% CI, 8.2 to 12.6) [p = 0.007], and there was a positive correlation between the number of skin-prick reactions and FENO (r= 0.37, n = 115, p < 0.001). There was a positive correlation between FENO and DRS (r = 0.22, p = 0.015). FENO was higher for subjects with a history of PDA ever (17.4 ppb; 95% CI, 13.1 to 23.3) compared with no history of PDA (11.8 ppb; 95% CI, 10.3 to 13.6) [p = 0.01]. There were nonsignificant trends for FENO to be higher in those with reported recent wheeze (16.7 ppb; 95% CI, 12.1 to 23.0), compared to those without recent wheeze (12.3 ppb; 95% CI, 10.7 to 14.2) [p = 0.06], and individuals with current PDA compared with nonasthmatics (17.2 ppb; 95% CI, 12.0 to 24.7; and 12.4 ppb; 95% CI, 10.8 to 14.3; respectively) [p = 0.07]. Finally, smokers had lower FENO (10.0 ppb; 95% CI, 7.4 to 13.5) compared with nonsmokers (14.3 ppb; 95% CI, 12.4 to 16.6) [p = 0.03]. There was no association between FENO and eosinophil count nor height-adjusted spirometric measurements.


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  		Table 3.. Output From Simple Linear Regression Models Demonstrating the Fold Increases in FENO for Univariate Analysis

 
In the regression model for atopic individuals (Table 4 ), FENO was positively associated with DRS (p = 0.003) [Fig 1 ] and male gender (p = 0.02), and negatively associated with current smoking (p = 0.09). Among nonatopic individuals, only male gender was associated with FENO (p = 0.03) [Table 5 ], while there was a trend for a negative relationship between FENO and DRS (Table 5, Fig 1). There was no association between FENO and PDA, asthma ever, or recent wheeze in either model.


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  		Table 4.. Output From General Linear Model Demonstrating Fold Increases in FENO for Independent Predictive Variables Among Atopic Adults Only (n = 73)*

 


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  		Figure 1.. Relationship between FENO and airway responsiveness (DRS) in atopic ({Delta}) and nonatopic (o) adults. Separate regression lines for atopic and nonatopic adults are included. Only in atopic adults is there a significant relationship between FENO and DRS (r = 0.31, p = 0.008).

 

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  		Table 5.. Output From General Linear Model Demonstrating Fold Increases in FENO for Independent Predictive Variables Among Nonatopic Adults Only (n = 36)*

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We have previously reported an association, independent of asthma, between FENO and atopy and increased AR (as evidenced by DRS) among children.14 In this study, we report a similar relationship between these variables for the parents of these children. In agreement with our findings in children, there was no association between FENO and past or current asthma symptoms or diagnosis in either atopic or nonatopic subjects after controlling for AR. This supports our previous proposition that FENO is associated with a common asthma phenotype, ie, atopy and increased AR, but not asthma per se.

FENO levels are raised in atopic but not nonatopic asthma,12 and there is increasing evidence that the association between FENO and various characteristics of asthma, such as AR91213142223 and eosinophilia,121323 are dependent on atopy. The degree of atopy is also associated with FENO, with increasing levels of FENO reported with the number of positive SPT results in atopic children,1024 and wheal responses to house dust mite allergen in adults.11 The relationship between FENO and asthma symptoms, however, is not so clear. For example, we have shown that in children, that FENO is independent of asthma and asthma-like symptoms after controlling for both atopy and AR.14 Similarly, Leuppi et al9 found that, among atopic children with increased AR, there were no significant differences in FENO between those with and without wheeze. Conversely, Henriksen et al25 found that suspected asthmatic adolescents with both atopy and increased AR had higher FENO levels than healthy subjects with a similar phenotype. Similarly, Steerenberg et al13 found that FENO was associated with respiratory symptoms in atopic children. However, in that study it was unclear if the authors controlled for AR when investigating the association between FENO and symptoms.13 The relationship between FENO and asthma is therefore complex, and the mechanism(s) for raised levels need further investigation.

A potentially interesting finding in this study was a negative association between FENO and DRS in nonatopic subjects. This has not been previously reported. Due to the small number of nonatopics, we used Mahalanobis distance analysis to investigate whether this relationship was influenced by one or more influential data points. This did not appear to be the case; however, this observation should be interpreted with some caution and needs to be confirmed in other cohorts.

There was a small group of individuals with increased AR but not asthma. Asymptomatic increased AR is well described.26 The clinical relevance of hyperreactivity in the absence of respiratory symptoms is not clear, but may be important to the natural history of lung function and the development of obstructive pulmonary disease. In children, asymptomatic increased AR is associated with reduced growth in lung function,27 while in nonasthmatic adults, increased AR is associated with an accelerated decline in pulmonary function.28

In this study, there was no relationship between peripheral blood eosinophil count and FENO, even in the atopic group. This contrasts with our findings14 and those of others29 in atopic children. Inconsistencies in the relationship between FENO and airway mucosal eosinophils between children30 and adults8 have also been reported. This suggests that mechanisms for FENO production may vary for different age groups. Although FENO is thought to reflect eosinophilic inflammation,30 this relationship needs to be further elucidated.

FENO was higher in male than female subjects, and this relationship was independent of atopy. Other studies in adolescents31 and adults323334 have also reported increased FENO levels in men compared with women. However, in young children35 and infants,36 girls have raised FENO levels compared with boys, while there appears to be no gender difference for older children.10143137 The trend for increased FENO for girls compared with boys but men compared with women is in direct contrast to the natural history of asthma, which predominates in boys compared with girls but is higher in women compared with men.38 Our results suggest there is a maturational change in the relationship between FENO and gender. This could be due to relative changes in body mass33 or differences in NO synthase activity between genders.34

Regular tobacco smoking has been associated with reduced FENO39; however, the present analysis suggests that this relationship may only be evident for atopic individuals. The reasons for this are unknown but may result from increased susceptibility of the atopic airway epithelium to environmental irritants40 and consequent disruption of nitric oxide regulation.

Although this was an unselected population, there was a high prevalence of atopy among our subjects. This was unlikely to have influenced the outcomes for the analysis of atopic-only study subjects, but could have influenced the outcomes for nonatopic individuals where there were fewer individuals at risk for elevated FENO. Further, the adults in this study were the parents of the children we previously reported on.14 Similar findings may therefore be the result of shared genetic and environmental factors between children and parents. The relationship between FENO and other variables reported in the present study should therefore be tested elsewhere.

In summary, we have confirmed in adults our findings in children of an interaction of FENO with atopy and increased AR. Importantly, asthma was not directly related to levels of FENO once this interaction was accounted for. Meaningful interpretation of FENO may only be possible when atopy and increased AR are considered.


   Acknowledgements
 
The authors thank Dr. Sally Young for recruiting the cohort. We also thank the parents and children involved in the Osborne Park asthma study.


   Footnotes
 
Abbreviations: AR = airway responsiveness; CI = confidence interval; DRS = dose-response slope; FENO = exhaled nitric oxide; PDA = physician-diagnosed asthma; PD20 = provocative dose of inhaled histamine causing a 20% fall in FEV1; ppb = parts per billion; SPT = skin-prick testing

Drs. Turner, Franklin, and Stick were supported by the National Health and Medical Research Council.

Received for publication March 10, 2004. Accepted for publication June 21, 2004.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Kharitonov, SA, Barnes, PJ (2001) Does exhaled nitric oxide reflect asthma control? Yes, it does! Am J Respir Crit Care Med 164,727-728[Free Full Text]
  2. Alving, K, Weitzberg, E, Lundberg, J Increased amount of nitric oxide in exhaled air of asthmatics. Eur Respir J 1993;6,1368-1370[Abstract]
  3. Kharitonov, SA, Yates, DH, Barnes, PJ Inhaled glucocorticoids decrease nitric oxide in exhaled air of asthmatic patients. Am J Respir Crit Care Med 1996;153,454-457[Abstract]
  4. Piacentini, GL, Bodini, A, Costella, S, et al Exhaled nitric oxide and sputum eosinophil markers of inflammation in asthmatic children. Eur Respir J 1999;13,1386-1390[Abstract]
  5. Warke, TJ, Fitch, PS, Brown, V, et al Exhaled nitric oxide correlates with airway eosinophils in childhood asthma. Thorax 2002;57,383-387[Abstract/Free Full Text]
  6. Kharitonov, SA, Barnes, PJ Exhaled markers of pulmonary disease. Am J Respir Crit Care Med 2001;163,1693-1722[Free Full Text]
  7. Leuppi, JD, Salome, CM, Jenkins, CR, et al Predictive markers of asthma exacerbation during stepwise dose reduction of inhaled corticosteroids. Am J Respir Crit Care Med 2001;163,406-412[Abstract/Free Full Text]
  8. Lim, S, Jatakanon, A, Meah, S, et al Relationship between exhaled nitric oxide and mucosal eosinophilic inflammation in mild to moderately severe asthma. Thorax 2000;55,184-188[Abstract/Free Full Text]
  9. Leuppi, JD, Downs, SH, Downie, SR, et al Exhaled nitric oxide levels in atopic children: relation to specific allergic sensitisation AHR, and respiratory symptoms. Thorax 2002;57,518-523[Abstract/Free Full Text]
  10. Franklin, PJ, Taplin, R, Stick, SM A community study of exhaled nitric oxide in healthy children. Am J Respir Crit Care Med 1999;159,69-73[Abstract/Free Full Text]
  11. Moody, A, Fergusson, W, Wells, A, et al Increased nitric oxide production in the respiratory tract in asymptomatic pacific islanders: an association with skin prick reactivity to house dust mite. J Allergy Clin Immunol 2000;105,895-899[CrossRef][ISI][Medline]
  12. Ho, LP, Wood, FT, Robson, A, et al Atopy influences exhaled nitric oxide levels in adult asthmatics. Chest 2000;118,1327-1331[Abstract/Free Full Text]
  13. Steerenberg, PA, Janssen, NA, de Meer, G, et al Relationship between exhaled NO, respiratory symptoms, lung function, bronchial hyperresponsiveness, and blood eosinophilia in school children. Thorax 2003;58,242-245[Abstract/Free Full Text]
  14. Franklin, PJ, Turner, SW, Le Souëf, PN, et al Exhaled nitric oxide and asthma: complex interactions between atopy, airway responsiveness and symptoms in a community population of children. Thorax 2003;58,1048-1052[Abstract/Free Full Text]
  15. Young, S, Le Souëf, PN, Geelhoed, GC, et al The influence of a family history of asthma and parental smoking on airway responsiveness in early infancy. N Engl J Med 1991;324,1168-1173[Abstract]
  16. Ferris, BG Epidemiology Standardization Project (American Thoracic Society). Am Rev Respir Dis 1978;118,1-120[ISI][Medline]
  17. Gardner, RM, Hankinson, JL, Clausen, JL, et al Standardisation of spirometry, 1987 update. Am Rev Respir Dis 1987;136,1285-1298[ISI][Medline]
  18. Yan, K, Salome, C, Woolcock, AJ Rapid method for measurement of bronchial responsiveness. Thorax 1983;38,760-765[Abstract]
  19. O’Connor, G, Sparrow, D, Taylor, D, et al Analysis of dose-response curves to methacholine: an approach suitable for population studies. Am Rev Respir Dis 1987;136,1412-1417[ISI][Medline]
  20. Pepys, J Skin tests for immediate, type I, allergic reactions. Proc Royal Soc Med 1972;65,271-272
  21. Lim, S, Jatakanon, A, John, M, et al Effect of inhaled budesonide on lung function and airway inflammation: assessment by various inflammatory markers in mild asthma. Am J Respir Crit Care Med 1999;159,22-30[Abstract/Free Full Text]
  22. Ludviksdottir, D, Janson, C, Hogman, M, et al Exhaled nitric oxide and its relationship to airway responsiveness and atopy in asthma. Respir Med 1999;93,552-556[CrossRef][ISI][Medline]
  23. Silvestri, M, Sabatini, F, Sale, R, et al Correlations between exhaled nitric oxide levels, blood eosinophilia, and airway obstruction reversibility in childhood asthma are detectable only in atopic individuals. Pediatr Pulmonol 2003;35,358-363[CrossRef][ISI][Medline]
  24. Jouaville, LF, Annesi-Maesano, I, Nguyen, LT, et al Interrelationships among asthma, atopy, rhinitis and exhaled nitric oxide in a population-based sample of children. Clin Exp Allergy 2003;33,1506-1511[CrossRef][ISI][Medline]
  25. Henriksen, AH, Lingaas-Holmen, T, Sue-Chu, M, et al Combined use of exhaled nitric oxide and airway hyperresponsiveness in characterizing asthma in a large population survey. Eur Respir J 2000;15,849-855[Abstract]
  26. Boulet, L Asymptomatic airway hyperresponsiveness: a curiosity or an opportunity to prevent asthma? Am J Respir Crit Care Med 2003;167,371-378[Free Full Text]
  27. Xuan, W, Peat, JK, Toelle, BG, et al Lung function growth and its relation to airway hyperresponsiveness and recent wheeze: results from a longitudinal population study. Am J Respir Crit Care Med 2000;161,1820-1824[Abstract/Free Full Text]
  28. Parker, DR, O’Connor, GT, Sparrow, D, et al The relationship of nonspecific airway responsiveness and atopy to the rate of decline of lung function: the Normative Aging Study. Am Rev Respir Dis 1990;141,589-594[ISI][Medline]
  29. Silvestri, M, Spallarossa, D, Frangova Yourukova, V, et al Orally exhaled nitric oxide levels are related to the degree of blood eosinophilia in atopic children with mild-intermittent asthma. Eur Respir J 1999;13,321-326[Abstract]
  30. Payne, D, Adcock, I, Wilson, N, et al Relationship between exhaled nitric oxide and mucosal eosinophilic inflammation in children with difficult asthma, after treatment with oral prednisolone. Am J Respir Crit Care Med 2001;164,1376-1381[Abstract/Free Full Text]
  31. Kissoon, N, Duckworth, LJ, Blake, KV, et al FE(NO): relationship to exhalation rates and online versus bag collection in healthy adolescents. Am J Respir Crit Care Med 2000;162,539-545[Abstract/Free Full Text]
  32. Jilma, B, Kastner, J, Mensik, C, et al Sex differences in concentrations of exhaled nitric oxide and plasma nitrate. Life Sci 1996;58,469-476[CrossRef][ISI][Medline]
  33. Tsang, KW, Ip, SK, Leung, R, et al Exhaled nitric oxide: the effects of age, gender and body size. Lung 2001;179,83-91[CrossRef][ISI][Medline]
  34. Grasemann, H, van’s Gravesande, KS, Buscher, R, et al Effects of sex and of gene variants in constitutive nitric oxide synthases on exhaled nitric oxide. Am J Respir Crit Care Med 2003;167,1113-1116[Abstract/Free Full Text]
  35. Pijnenburg, MW, Lissenberg, ET, Hofhuis, W, et al Exhaled nitric oxide measurements with dynamic flow restriction in children aged 4–8 yrs. Eur Respir J 2002;20,919-924[Abstract/Free Full Text]
  36. Franklin, PJ, Turner, SW, Mutch, R, et al Comparisons of single breath and tidal breathing exhaled nitric oxide levels in infants. Eur Respir J 2004;23,369-372[Abstract/Free Full Text]
  37. Nelson, BV, Sears, S, Woods, J, et al Expired nitric oxide as a marker for childhood asthma. J Pediatr 1997;130,423-427[CrossRef][ISI][Medline]
  38. de Marco, R, Locatelli, F, Sunyer, J, et al Differences in incidence of reported asthma related to age in men and women: a retrospective analysis of the data of the European Respiratory Health Survey. Am J Respir Crit Care Med 2000;162,68-74[Abstract/Free Full Text]
  39. Persson, MG, Zetterstrom, O, Agrenius, V, et al Single-breath nitric oxide measurements in asthmatic patients and smokers. Lancet 1994;343,146-147[CrossRef][ISI][Medline]
  40. Devalia, JL, Bayram, H, Abdelaziz, MM, et al Differences between cytokine release from bronchial epithelial cells of asthmatic patients and non-asthmatic subjects: effect of exposure to diesel exhaust particles. Intern Arch Allergy Immunol 1999;118,437-439[CrossRef][ISI][Medline]



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