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Original Research: Asthma |

Fraction of Exhaled Nitric Oxide and Bronchial Responsiveness Are Associated and Continuous Traits in Young Children Independent of AsthmaExhaled Nitric Oxide and Bronchial Responsiveness FREE TO VIEW

Ann-Marie Malby Schoos, MD; Bo Lund Krogsgaard Chawes, MD, PhD; Klaus Bønnelykke, MD, PhD; Hans Bisgaard, MD, DMSc
Author and Funding Information

From the Copenhagen Prospective Studies on Asthma in Childhood, Faculty of Health Sciences, University of Copenhagen, and Copenhagen University Hospital Gentofte, Copenhagen, Denmark.

Correspondence to: Hans Bisgaard, MD, DMSc, Copenhagen Prospective Studies on Asthma in Childhood, Danish Pediatric Asthma Center, Copenhagen University Hospital, Ledreborg Alle 34, 2820 Gentofte, Copenhagen, Denmark; e-mail: bisgaard@copsac.com


Drs Malby Schoos and Chawes contributed equally to this article.

Funding/Support: The Copenhagen Prospective Studies on Asthma in Childhood (COPSAC) is funded by private and public research funds, which are listed at www.copsac.com. The Lundbeck Foundation, Pharmacy Foundation of 1991, Augustinus Foundation, Danish Medical Research Council, and Danish Pediatric Asthma Centre provided core support for COPSAC.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2012;142(6):1562-1568. doi:10.1378/chest.12-0658
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Published online

Background:  Elevated fraction of exhaled nitric oxide (Feno) and bronchial hyperresponsiveness are used as surrogate markers of asthma. These traits may be continuous in the population. The objective of this study was to investigate whether Feno and bronchial responsiveness are associated in both children with and children without a history of asthma symptoms.

Methods:  One hundred ninety-six 6-year-old children with no asthma symptoms, intermittent asthma symptoms, and persistent asthma were randomly included from the Copenhagen Prospective Study on Asthma in Childhood prospective clinical birth cohort of mothers with asthma. Bronchial responsiveness was assessed as the relative change in specific airway resistance after cold dry air hyperventilation. Feno measurements were performed prior to the hyperventilation test. The association between Feno and bronchial responsiveness was assessed by generalized linear models.

Results:  Bronchial responsiveness and Feno exhibited a significant and linear association in the population. A doubling of Feno corresponded to an 8.4% (95% CI, 3.7%-13.1%; P = .0006) increase in airway resistance after challenge testing and remained significant after adjustment for sex, allergic rhinitis, current asthma, inhaled corticosteroid treatment, and upper respiratory tract infections prior to testing. Stratified analyses showed similar associations in children with and without asthma.

Conclusions:  Feno and bronchial responsiveness are associated and continuous traits in young children regardless of asthma symptoms, suggesting a continuous subclinical to clinical process underlying asthma. The findings also suggest caution against the use of these surrogate markers for a dichotomized approach to asthma diagnosis.

Figures in this Article

Surrogate markers for the diagnosis of childhood asthma often are sought in an attempt to increase sensitivity and specificity of the diagnosis. The underlying assumption is that these features are specific to the disease state.

The fraction of exhaled nitric oxide (Feno) is used in the diagnosis and monitoring of asthma.1 It is increased prior to exacerbations in children with asthma2,3 and in preschool children with persistent asthma-like symptoms.4,5 Bronchial hyperresponsiveness can be determined by cold dry air provocation from age approximately 2 years, with acceptable repeatability and good discrimination between children with and without asthma.6,7 Thus, it is presumed that both bronchial hyperresponsiveness and elevated Feno together are robust surrogate markers of childhood asthma.

However, we demonstrated that spontaneous physical activity in 5-year-old children shows an inverse linear relation to bronchial responsiveness in an unselected population, including children with and without asthma symptoms, suggesting a continuity of the bronchial responsiveness underlying asthma symptoms.8 In the present study, we analyzed simultaneous measurements of Feno and bronchial responsiveness to cold dry air by age 6 years in a group of 196 children without selection for asthma symptoms. This was a nested study within the Copenhagen Prospective Studies on Asthma in Childhood prospective clinical birth cohort of asthmatic mothers (COPSAC2000) that has been closely monitored for signs of asthma since birth. The objective was to examine whether childhood asthma is a continuous trait by assessing both Feno and bronchial responsiveness in the full spectrum of healthy children to children with intermittent asthma symptoms to children with persistent asthma. The hypothesis was that asthma is a continuous trait (ie, also present subclinically).

Design

The study is reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology guidelines.9 Participants comprised children from COPSAC2000, a single-center, prospective clinical birth cohort study of 411 children born to mothers with asthma recruited between 1998 and 2000 in greater Copenhagen, Denmark.1012 The children were enrolled at age 1 month and attended the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC) clinical research unit at 6-month intervals for scheduled clinical investigations according to standard operating procedures.1012 Additional visits were arranged for acute respiratory exacerbations.

The Copenhagen Ethics Committee (KF 01-289/96) and the Danish Data Protection Agency (2008-41-2434) approved the study, and informed consent was obtained from both parents at enrollment. Recruitment and baseline characteristics of the participants have been previously described in detail elsewhere.10

Cold Dry Air Hyperventilation Challenge

A 4-min hyperventilation challenge of −18°C cold, dry air was performed at the 6-year visit.6,7 The air was generated by a respiratory heat exchange system (Erich Jaeger GmbH & Co KG). The test was done as a single-step isocapnic hyperventilation test. An animated computer program guided the child to maintain an adequate frequency of breathing, aiming at 1 L/min/kg body weight6 (software available at www.copsac.com). A face mask fitted with a mouthpiece was used during hyperventilation, which ensured mouth breathing and prevented inhalation of room air. Bronchial responsiveness to cold, dry air was determined as the relative change in specific airway resistance (sRaw)7,13,14 and analyzed as a continuous variable. A positive challenge test was defined as a ≥ 25% increase in sRaw from baseline.6 When a child attempted and completed a challenge test with sufficient cooperation and without technical problems, the test was considered completed.

Feno Measurements

Baseline Feno was measured < 30 min before the cold dry air challenge on the same day of the 6-year visit to the research unit by an online technique4 using NIOX Flex (Aerocrine) in accordance with international guidelines.15 The child was comfortably seated and breathing quietly for about 5 min to acclimatize. Thereafter, a nose clip was applied, and the child inhaled to near total lung capacity and immediately exhaled at a constant flow of 50 mL/s until an Feno plateau of ≥ 2 s could be identified. An exhalation lasted at least 4 s, and the expiratory pressure was maintained at 5 to 20 cm H2O to close the velum. During exhalation, the child was guided by an exhalation flow-driven animated computer program. Two repeated measurements that agreed within 5% were completed, and the mean Feno was recorded.

The children withheld any use of short-acting β2-agonists 6 h prior to the cold dry air challenge and Feno measurements; no children were treated with long-acting β2-agonists. Inhaled corticosteroid treatment was not paused prior to testing, but we adjusted the analyses for any use of inhaled corticosteroids in the 4 weeks prior to testing.

Asthma

Current asthma during the sixth year of life was diagnosed by the physician at the research unit according to the GINA (Global Initiative for Asthma) guidelines, as previously detailed,11,12 and based on daily respiratory symptom diaries kept by the parents and the need for short-acting β2-agonists. Children were given a 3-month trial of inhaled budesonide 200 μg bid based on a strict algorithm with a symptom burden of (1) five episodes of troublesome lung symptoms within 6 months, each episode lasting at least 3 consecutive days; (2) 4 weeks of continuous troublesome lung symptoms; or (3) acute severe asthma requiring hospitalization or prescription of oral corticosteroids. Asthma was diagnosed if the child improved on the budesonide treatment and relapsed after stopping the initial trial and was judged by the study physician to present symptoms typical of childhood asthma (ie, exercise-induced symptoms, prolonged nocturnal cough, recurrent cough outside common cold, symptoms causing wakening at night) requiring intermittent rescue use of an inhaled β2-agonist. When an asthma diagnosis was established, budesonide was prescribed for an extended period of 6 months. In case of new relapses, further 12-month courses were prescribed. The study group was categorized as (1) children with asthma as defined previously; (2) children with intermittent asthma symptoms treated with an inhaled β2-agonist but not meeting the criteria for budesonide treatment; and (3) children without any asthma symptoms (ie, absence of exercise-induced symptoms, coughing, wheezing, dyspnea).

Allergic Rhinitis

Allergic rhinitis was diagnosed by age 6 years as a significant problem with sneezing or blocked or runny nose that severely affected the well-being of the child in the past 12 months during periods without accompanying cold or influenza. The significance of symptoms was judged by severity, length of periods, and time of year16,17 (e-Appendix 1).

Statistical Methods

The association between Feno and the cold dry air challenge was investigated using generalized linear models with Feno as a continuous explanatory variable and bronchial responsiveness as a continuous outcome variable. Feno level was log2 transformed prior to analysis to obtain normal distribution of data. Therefore, the effect on bronchial responsiveness from Feno is reported per doubling of Feno level.

We investigated the crude association between Feno and bronchial responsiveness and subsequently adjusted for sex, allergic rhinitis, current asthma, use of inhaled corticosteroids (yes/no) 4 weeks prior to Feno measurement and challenge testing, and upper respiratory tract infections (yes/no) 1 week prior to Feno measurement and challenge testing. The association between Feno and bronchial responsiveness was further explored by stratifying the study group as children with asthma vs intermittent asthma symptoms vs no asthma symptoms. The stratified analysis was not adjusted.

Results are reported as medians with 95% CIs. P ≤ .05 was considered significant. All analyses were done with SAS, version 9.1 for Windows (SAS Institute Inc) statistical software. Additional methodologic details are given in e-Appendix 1.

Baseline

An unselected group of 196 children from COPSAC2000 completed the cold dry air hyperventilation challenge and baseline Feno measurement with acceptable cooperation and without technical difficulties on the same day as the 6-year visit to the COPSAC research clinic. Figure 1 shows the study group flowchart, and Table 1 shows the demographics of the selected cohort and nonenrollees. The study group characteristics, including baseline Feno level and bronchial responsiveness to the cold dry air challenge, are outlined in Table 2.

Figure Jump LinkFigure 1. Study group flowchart. COPSAC = Copenhagen Prospective Study on Asthma in Childhood; FeNO = fraction of exhaled nitric oxide.Grahic Jump Location
Table Graphic Jump Location
Table 1 —Demographics of the Selected Cohort and Nonenrollees

Data are presented as % (No.). Comparisons were done with univariate χ2 test. COPSAC = Copenhagen Prospective Study on Asthma in Childhood.

a 

Dropout due to either resting status, insufficient cooperation for cold dry air challenge and fraction of exhaled nitric oxide assessment, or technical problems during testing.

b 

Any allergic sensitization (specific IgE > 0.35 kU/L) against 15 common inhalant and food allergens (cat, dog, horse, birch, timothy grass, mugwort, house dust mite, molds, hen’s egg, cow’s milk, fish, wheat, peanut, soybean, and shrimp).

Table Graphic Jump Location
Table 2 —Study Group Characteristics

Data are presented as % (No.) or median (interquartile range). Feno = fraction of exhaled nitric oxide; ppb = parts per billion; sRaw = specific airway resistance.

a 

Comparison among subgroups of healthy children, children with intermittent asthma symptoms, and children with asthma.

b 

Inhaled corticosteroid treatment within the 4 weeks prior to challenge testing and Feno measurement.

c 

Fisher exact test.

d 

χ2 test.

e 

Upper respiratory tract infection within the week prior to challenge testing and Feno measurements; 15 had missing data.

f 

Wilcoxon rank sum test.

Feno level was slightly, but significantly higher in children with an incomplete vs a complete cold dry air challenge test (P = .04), whereas no differences were found with respect to sex, allergic rhinitis, current asthma, inhaled corticosteroid treatment, or upper respiratory tract infections prior to testing. The full comparison between children with a complete vs an incomplete challenge test is presented in e-Table 1.

Association Between Bronchial Responsiveness and Feno Among All Participants

A positive cold dry air challenge (≥ 25% increase in sRaw from baseline) could be defined in 45 of the 196 children (23%). Baseline Feno was significantly higher in children with a positive challenge test compared with those with a negative test (8.3 parts per billion vs 6.8 parts per billion, respectively; P = .002 unpaired t test).

Feno level was significantly and linearly associated with bronchial responsiveness among the 196 children comprising the entire disease spectrum; a doubling of Feno level corresponded to an increase in bronchial responsiveness of 8.4% (95% CI, 3.7%-13.1%; r2 = 0.06; P = .0006). Adjusting the analyses for sex, allergic rhinitis, current asthma, use of inhaled corticosteroids 4 weeks prior to Feno measurement and challenge testing, and upper respiratory tract infection 1 week prior to Feno measurement and challenge testing did not substantially modify the results (change in bronchial responsiveness per doubling of Feno, +7.7%; 95% CI, 2.0%-13.3%; r2 = 0.10; P = .009). In particular, there was no evidence for interaction with current asthma (P = .16 for interaction).

Association Between Bronchial Responsiveness and Feno in Children With and Without Asthma

Feno level was similarly associated with bronchial responsiveness in the strata of children with and without asthma symptoms as follows: (1) children without any asthma symptoms (change in bronchial responsiveness per doubling of Feno, +6.1%; 95% CI, 0.6%-11.6%; P = .03); (2) children with intermittent asthma symptoms (change in bronchial responsiveness per doubling of Feno, +11.1%; 95% CI, −1.1%-23.3%; P = .07); and (3) children with persistent asthma (change in bronchial responsiveness per doubling of Feno, +12.0%; 95% CI, −2.5%-26.5%; P = .10) (Fig 2).

Figure Jump LinkFigure 2. Association between FeNO and the cold dry air challenge stratified for symptoms of asthma. The cold dry air challenge is presented as the percentage of change in sRaw from baseline. The FeNO values are plotted on a log scale. Regression lines in the strata of healthy children, children with intermittent asthma symptoms, and children with asthma are drawn based on generalized linear models, with log-FeNO as the explanatory variable and bronchial responsiveness as the outcome variable. ppb = parts per billion; sRaw = specific airway resistance. See Figure 1 legend for expansion of other abbreviation.Grahic Jump Location

Bronchial responsiveness and Feno were associated and continuous traits independent of asthma symptoms in this population of 6-year-old Danish children born to mothers with asthma.

Study Strengths and Limitations

A major strength of the current study is the high data quality and standardized objective assessments of Feno and bronchial responsiveness. All tests were done by the same experienced examiners according to standard operating procedures, ensuring consistency in objective measurements. Quality control and data management procedures were rigorous, including external monitoring, online data collection into a dedicated database, and locking of data after data verification with a routine audit trail.

Another strength of this study is that the risk of misclassification was reduced because all cohort families used the COPSAC physicians rather than their family practitioners for diagnosis and treatment of any respiratory symptom. The use of daily diary cards since the children’s’ birth, the scheduled 6-month visits to the physician at the research unit, and additional visits at the onset of any acute respiratory symptoms reduced the risk of recall bias. In addition, all mothers had a history of asthma, which improved parental recognition and interpretation of symptoms. Therefore, the segmentation of subjects into symptom categories was very well documented and reliable in this longitudinal clinical birth cohort study, and the risk of missing early asthmatic symptoms was minimal.

The unselected nature of the study group, including a majority of children without asthma symptoms, is a limitation of the study power in the stratified analyses of asthma, which may explain the borderline P values found in the strata of children with asthma and intermittent asthma symptoms. In addition, more than one-half of the children with asthma received inhaled budesonide 200 μg bid 4 weeks prior to testing, which potentially modified Feno levels and possibly explains the borderline association between Feno and bronchial responsiveness among the children with asthma.

The principal limitation of the study is the setting of a high-risk cohort, which may require replication in a population-based sample. However, the analyses are based on within-subject associations between baseline Feno level and bronchial provocation testing, which is unlikely to be affected by the increased risk of atopic disease.

Meaning of the Study

This study included the simultaneous assessment of Feno and bronchial responsiveness in a large population comprising the full spectrum of children with and without asthma symptoms and different degrees of asthma, contrasting previous studies that focused on subjects with established asthma18,19 or with elevated Feno.1 We found an association between Feno and bronchial responsiveness in all the children studied. The observed association between bronchial responsiveness and Feno in this closely monitored group suggests a continuous trait in the population irrespective of asthma symptoms (ie, only quantitative differences between children with and without asthma with no obvious cutoff). The findings of the stratified analysis showed a significant association between Feno and bronchial responsiveness in the group of healthy children, underlining the continuity of this disease trait in the population. Similar associations were observed in the children with asthma and intermittent asthma symptoms, although these were of borderline significance probably because of the small numbers in these strata.

These findings adhere to previous studies showing higher levels of Feno among children with asthma compared with control subjects2,3 and elevated Feno levels in children with asthma with imminent exacerbations4,5 supporting the continuity of bronchial inflammation from health to disease. Likewise, we reported an inverse linear association between bronchial responsiveness assessed by cold dry air hyperventilation and the spontaneous physical activity in 5-year-old children monitored minute by minute for 4 weeks, regardless of asthma.8

To the clinician, the findings are a reminder of the risk of missing subclinical disease. Early signs and symptoms of childhood asthma and asthma exacerbations often are unnoticed by children, caregivers, and physicians. Feno levels, therefore, have been studied with the purpose of guiding early diagnosis20 and treatment of childhood asthma.2123 However, the studies use different Feno cutoff values, ranging from 20 to 40 parts per billion, and show ambiguous results. Despite this, both Feno and bronchial responsiveness testing have found wide use among pediatricians to support a diagnosis of asthma. The present data caution against clinical decisions based on the dichotomized interpretation of Feno or bronchial responsiveness when in fact these are continuous traits that need to be evaluated together with other clinical end points, such as lung function, symptoms, and symptom history.

To the expert deciding on treatment guidelines, the findings may inform treatment because the disease appears to be driven by a uniform pathophysiology on a continuum from health to disease. Development of childhood asthma as a continuous bronchoinflammatory trajectory aligns with a study showing that bronchial hyperresponsiveness at age 6 years is a significant risk factor for the development of asthma later in life.24 The present data indicate that this process may reflect ongoing subclinical bronchial airway inflammation demonstrated by raised values of Feno and not nonspecific asymptomatic bronchial hyperresponsiveness.

To the researcher, the findings highlight that asthma and associated surrogate markers are continuous end points. Any attempt of dichotomizing into with or without disease, therefore, is inevitably missing important information on what appears to be a continuous trait.

Feno and bronchial responsiveness to cold dry air challenge are associated and continuous traits in the population, regardless of asthma, suggesting that childhood asthma develops along a from subclinical-to-clinical trajectory. These findings caution against the use of surrogate markers for a dichotomized approach to asthma diagnosis.

Author contributions: Dr Bisgaard had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Dr Malby Schoos: contributed to the data acquisition, analysis, and interpretation and important intellectual input to and approval of the final manuscript.

Dr Chawes: contributed to the data acquisition, analysis, and interpretation and important intellectual input to and approval of the final manuscript.

Dr Bønnelykke: contributed to the data acquisition, analysis, and interpretation and important intellectual input to and approval of the final manuscript.

Dr Bisgaard: contributed to the study conception, design, and conduct; data acquisition, analysis, and interpretation; writing of the manuscript; and important intellectual input to and approval of the final manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsors had no role in the design of the study, the collection and analysis of the data, or in the preparation of the manuscript.

Other contributions: We thank the children and families of the COPSAC cohort study for all their support and commitment and acknowledge and appreciate the unique efforts of the COPSAC research team.

Additional information: The e-Appendix and e-Table can be found in the “Supplemental Materials” area of the online article.

COPSAC

Copenhagen Prospective Study on Asthma in Childhood

COPSAC2000

Copenhagen Prospective Study on Asthma in Childhood prospective clinical birth cohort of asthmatic mothers

Feno

fraction of exhaled nitric oxide

sRaw

specific airway resistance

Petsky HL, Cates CJ, Li A, Kynaston JA, Turner C, Chang AB. Tailored interventions based on exhaled nitric oxide versus clinical symptoms for asthma in children and adults. Cochrane Database Syst Rev. 2009;;(4):CD006340.
 
Pijnenburg MW, Hofhuis W, Hop WC, De Jongste JC. Exhaled nitric oxide predicts asthma relapse in children with clinical asthma remission. Thorax. 2005;60(3):215-218. [CrossRef] [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 Med. 2005;171(10):1077-1082. [CrossRef] [PubMed]
 
Buchvald F, Bisgaard H. FeNO measured at fixed exhalation flow rate during controlled tidal breathing in children from the age of 2 yr. Am J Respir Crit Care Med. 2001;163(3 pt 1):699-704. [PubMed]
 
Moeller A, Diefenbacher C, Lehmann A, et al. Exhaled nitric oxide distinguishes between subgroups of preschool children with respiratory symptoms. J Allergy Clin Immunol. 2008;121(3):705-709. [CrossRef] [PubMed]
 
Nielsen KG, Bisgaard H. Lung function response to cold air challenge in asthmatic and healthy children of 2-5 years of age. Am J Respir Crit Care Med. 2000;161(6):1805-1809. [PubMed]
 
Nielsen KG, Bisgaard H. Cold air challenge and specific airway resistance in preschool children. Paediatr Respir Rev. 2005;6(4):255-266. [CrossRef] [PubMed]
 
Brasholt M, Baty F, Bisgaard H. Physical activity in young children is reduced with increasing bronchial responsiveness. J Allergy Clin Immunol. 2010;125(5):1007-1012. [CrossRef] [PubMed]
 
von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP; STROBE Initiative STROBE Initiative. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. BMJ. 2007;335(7624):806-808. [CrossRef] [PubMed]
 
Bisgaard H. The Copenhagen Prospective Study on Asthma in Childhood (COPSAC): design, rationale, and baseline data from a longitudinal birth cohort study. Ann Allergy Asthma Immunol. 2004;93(4):381-389. [CrossRef] [PubMed]
 
Bisgaard H, Hermansen MN, Loland L, Halkjaer LB, Buchvald F. Intermittent inhaled corticosteroids in infants with episodic wheezing. N Engl J Med. 2006;354(19):1998-2005. [CrossRef] [PubMed]
 
Bisgaard H, Hermansen MN, Buchvald F, et al. Childhood asthma after bacterial colonization of the airway in neonates. N Engl J Med. 2007;357(15):1487-1495. [CrossRef] [PubMed]
 
Bisgaard H, Klug B. Lung function measurement in awake young children. Eur Respir J. 1995;8(12):2067-2075. [CrossRef] [PubMed]
 
Bisgaard H, Nielsen KG. Plethysmographic measurements of specific airway resistance in young children. Chest. 2005;128(1):355-362. [CrossRef] [PubMed]
 
American Thoracic SocietyAmerican Thoracic Society; European Respiratory Society European Respiratory Society. ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005. Am J Respir Crit Care Med. 2005;171(8):912-930. [CrossRef] [PubMed]
 
Chawes BL, Kreiner-Møller E, Bisgaard H. Objective assessments of allergic and nonallergic rhinitis in young children. Allergy. 2009;64(10):1547-1553. [CrossRef] [PubMed]
 
Chawes BL, Bønnelykke K, Kreiner-Møller E, Bisgaard H. Children with allergic and nonallergic rhinitis have a similar risk of asthma. J Allergy Clin Immunol. 2010;126(3):567-573. [CrossRef] [PubMed]
 
Nielsen KG, Bisgaard H. Hyperventilation with cold versus dry air in 2- to 5-year-old children with asthma. Am J Respir Crit Care Med. 2005;171(3):238-241. [CrossRef] [PubMed]
 
Van Schoor J, Joos GF, Pauwels RA. Indirect bronchial hyperresponsiveness in asthma: mechanisms, pharmacology and implications for clinical research. Eur Respir J. 2000;16(3):514-533. [CrossRef] [PubMed]
 
Malmberg LP, Pelkonen AS, Haahtela T, Turpeinen M. Exhaled nitric oxide rather than lung function distinguishes preschool children with probable asthma. Thorax. 2003;58(6):494-499. [CrossRef] [PubMed]
 
de Jongste JC, Carraro S, Hop WC, Baraldi E; CHARISM Study Group CHARISM Study Group. Daily telemonitoring of exhaled nitric oxide and symptoms in the treatment of childhood asthma. Am J Respir Crit Care Med. 2009;179(2):93-97. [CrossRef] [PubMed]
 
Shaw DE, Berry MA, Thomas M, et al. The use of exhaled nitric oxide to guide asthma management: a randomized controlled trial. Am J Respir Crit Care Med. 2007;176(3):231-237. [CrossRef] [PubMed]
 
Szefler SJ, Mitchell H, Sorkness CA, et al. Management of asthma based on exhaled nitric oxide in addition to guideline-based treatment for inner-city adolescents and young adults: a randomised controlled trial. Lancet. 2008;372(9643):1065-1072. [CrossRef] [PubMed]
 
Stern DA, Morgan WJ, Halonen M, Wright AL, Martinez FD. Wheezing and bronchial hyper-responsiveness in early childhood as predictors of newly diagnosed asthma in early adulthood: a longitudinal birth-cohort study. Lancet. 2008;372(9643):1058-1064. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1. Study group flowchart. COPSAC = Copenhagen Prospective Study on Asthma in Childhood; FeNO = fraction of exhaled nitric oxide.Grahic Jump Location
Figure Jump LinkFigure 2. Association between FeNO and the cold dry air challenge stratified for symptoms of asthma. The cold dry air challenge is presented as the percentage of change in sRaw from baseline. The FeNO values are plotted on a log scale. Regression lines in the strata of healthy children, children with intermittent asthma symptoms, and children with asthma are drawn based on generalized linear models, with log-FeNO as the explanatory variable and bronchial responsiveness as the outcome variable. ppb = parts per billion; sRaw = specific airway resistance. See Figure 1 legend for expansion of other abbreviation.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Demographics of the Selected Cohort and Nonenrollees

Data are presented as % (No.). Comparisons were done with univariate χ2 test. COPSAC = Copenhagen Prospective Study on Asthma in Childhood.

a 

Dropout due to either resting status, insufficient cooperation for cold dry air challenge and fraction of exhaled nitric oxide assessment, or technical problems during testing.

b 

Any allergic sensitization (specific IgE > 0.35 kU/L) against 15 common inhalant and food allergens (cat, dog, horse, birch, timothy grass, mugwort, house dust mite, molds, hen’s egg, cow’s milk, fish, wheat, peanut, soybean, and shrimp).

Table Graphic Jump Location
Table 2 —Study Group Characteristics

Data are presented as % (No.) or median (interquartile range). Feno = fraction of exhaled nitric oxide; ppb = parts per billion; sRaw = specific airway resistance.

a 

Comparison among subgroups of healthy children, children with intermittent asthma symptoms, and children with asthma.

b 

Inhaled corticosteroid treatment within the 4 weeks prior to challenge testing and Feno measurement.

c 

Fisher exact test.

d 

χ2 test.

e 

Upper respiratory tract infection within the week prior to challenge testing and Feno measurements; 15 had missing data.

f 

Wilcoxon rank sum test.

References

Petsky HL, Cates CJ, Li A, Kynaston JA, Turner C, Chang AB. Tailored interventions based on exhaled nitric oxide versus clinical symptoms for asthma in children and adults. Cochrane Database Syst Rev. 2009;;(4):CD006340.
 
Pijnenburg MW, Hofhuis W, Hop WC, De Jongste JC. Exhaled nitric oxide predicts asthma relapse in children with clinical asthma remission. Thorax. 2005;60(3):215-218. [CrossRef] [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 Med. 2005;171(10):1077-1082. [CrossRef] [PubMed]
 
Buchvald F, Bisgaard H. FeNO measured at fixed exhalation flow rate during controlled tidal breathing in children from the age of 2 yr. Am J Respir Crit Care Med. 2001;163(3 pt 1):699-704. [PubMed]
 
Moeller A, Diefenbacher C, Lehmann A, et al. Exhaled nitric oxide distinguishes between subgroups of preschool children with respiratory symptoms. J Allergy Clin Immunol. 2008;121(3):705-709. [CrossRef] [PubMed]
 
Nielsen KG, Bisgaard H. Lung function response to cold air challenge in asthmatic and healthy children of 2-5 years of age. Am J Respir Crit Care Med. 2000;161(6):1805-1809. [PubMed]
 
Nielsen KG, Bisgaard H. Cold air challenge and specific airway resistance in preschool children. Paediatr Respir Rev. 2005;6(4):255-266. [CrossRef] [PubMed]
 
Brasholt M, Baty F, Bisgaard H. Physical activity in young children is reduced with increasing bronchial responsiveness. J Allergy Clin Immunol. 2010;125(5):1007-1012. [CrossRef] [PubMed]
 
von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP; STROBE Initiative STROBE Initiative. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. BMJ. 2007;335(7624):806-808. [CrossRef] [PubMed]
 
Bisgaard H. The Copenhagen Prospective Study on Asthma in Childhood (COPSAC): design, rationale, and baseline data from a longitudinal birth cohort study. Ann Allergy Asthma Immunol. 2004;93(4):381-389. [CrossRef] [PubMed]
 
Bisgaard H, Hermansen MN, Loland L, Halkjaer LB, Buchvald F. Intermittent inhaled corticosteroids in infants with episodic wheezing. N Engl J Med. 2006;354(19):1998-2005. [CrossRef] [PubMed]
 
Bisgaard H, Hermansen MN, Buchvald F, et al. Childhood asthma after bacterial colonization of the airway in neonates. N Engl J Med. 2007;357(15):1487-1495. [CrossRef] [PubMed]
 
Bisgaard H, Klug B. Lung function measurement in awake young children. Eur Respir J. 1995;8(12):2067-2075. [CrossRef] [PubMed]
 
Bisgaard H, Nielsen KG. Plethysmographic measurements of specific airway resistance in young children. Chest. 2005;128(1):355-362. [CrossRef] [PubMed]
 
American Thoracic SocietyAmerican Thoracic Society; European Respiratory Society European Respiratory Society. ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005. Am J Respir Crit Care Med. 2005;171(8):912-930. [CrossRef] [PubMed]
 
Chawes BL, Kreiner-Møller E, Bisgaard H. Objective assessments of allergic and nonallergic rhinitis in young children. Allergy. 2009;64(10):1547-1553. [CrossRef] [PubMed]
 
Chawes BL, Bønnelykke K, Kreiner-Møller E, Bisgaard H. Children with allergic and nonallergic rhinitis have a similar risk of asthma. J Allergy Clin Immunol. 2010;126(3):567-573. [CrossRef] [PubMed]
 
Nielsen KG, Bisgaard H. Hyperventilation with cold versus dry air in 2- to 5-year-old children with asthma. Am J Respir Crit Care Med. 2005;171(3):238-241. [CrossRef] [PubMed]
 
Van Schoor J, Joos GF, Pauwels RA. Indirect bronchial hyperresponsiveness in asthma: mechanisms, pharmacology and implications for clinical research. Eur Respir J. 2000;16(3):514-533. [CrossRef] [PubMed]
 
Malmberg LP, Pelkonen AS, Haahtela T, Turpeinen M. Exhaled nitric oxide rather than lung function distinguishes preschool children with probable asthma. Thorax. 2003;58(6):494-499. [CrossRef] [PubMed]
 
de Jongste JC, Carraro S, Hop WC, Baraldi E; CHARISM Study Group CHARISM Study Group. Daily telemonitoring of exhaled nitric oxide and symptoms in the treatment of childhood asthma. Am J Respir Crit Care Med. 2009;179(2):93-97. [CrossRef] [PubMed]
 
Shaw DE, Berry MA, Thomas M, et al. The use of exhaled nitric oxide to guide asthma management: a randomized controlled trial. Am J Respir Crit Care Med. 2007;176(3):231-237. [CrossRef] [PubMed]
 
Szefler SJ, Mitchell H, Sorkness CA, et al. Management of asthma based on exhaled nitric oxide in addition to guideline-based treatment for inner-city adolescents and young adults: a randomised controlled trial. Lancet. 2008;372(9643):1065-1072. [CrossRef] [PubMed]
 
Stern DA, Morgan WJ, Halonen M, Wright AL, Martinez FD. Wheezing and bronchial hyper-responsiveness in early childhood as predictors of newly diagnosed asthma in early adulthood: a longitudinal birth-cohort study. Lancet. 2008;372(9643):1058-1064. [CrossRef] [PubMed]
 
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