The Journal of Allergy and Clinical Immunology
Volume 121, Issue 3 , Pages 705-709, March 2008

Exhaled nitric oxide distinguishes between subgroups of preschool children with respiratory symptoms

  • Alexander Moeller, MD

      Affiliations

    • Swiss Pediatric Respiratory Research Group and Division of Respiratory Medicine, University Children's Hospital Zurich, Zurich, Switzerland
    • Corresponding Author InformationReprint requests: Alexander Moeller, MD, Division of Respiratory Medicine, University Children's Hospital, Steinwiesstrasse 75, CH-8032 Zurich, Switzerland.
    • ,
  • Corinne Diefenbacher, MD

      Affiliations

    • Swiss Pediatric Respiratory Research Group and Division of Respiratory Medicine, University Children's Hospital Zurich, Zurich, Switzerland
    • ,
  • Andrea Lehmann, MD

      Affiliations

    • Swiss Pediatric Respiratory Research Group and Division of Respiratory Medicine, University Children's Hospital Zurich, Zurich, Switzerland
    • ,
  • Mascha Rochat, MD

      Affiliations

    • Swiss Pediatric Respiratory Research Group and Division of Respiratory Medicine, University Children's Hospital Zurich, Zurich, Switzerland
    • ,
  • Joanne Brooks-Wildhaber, MPH

      Affiliations

    • Alpine Children's Hospital, Davos, Switzerland
    • ,
  • Graham L. Hall, PhD

      Affiliations

    • Department of Respiratory Medicine, Princess Margaret Hospital for Children and School of Pediatrics and Child Health, University of Western Australia, Perth, Australia
    • ,
  • Johannes H. Wildhaber, MD, PhD

      Affiliations

    • Swiss Pediatric Respiratory Research Group and Division of Respiratory Medicine, University Children's Hospital Zurich, Zurich, Switzerland

Received 6 May 2007; received in revised form 30 October 2007; accepted 1 November 2007. published online 21 January 2008.

Article Outline

Background

Respiratory symptoms are common in early childhood. The clinical characterization of disease presentation and hence its likely disease progression has so far been proven difficult.

Objective

To investigate whether exhaled nitric oxide (NO) could be helpful to distinguish between subgroups of nonwheezy and wheezy young children less than 4 years of age.

Methods

Exhaled NO was measured in 391 children (age 3-47 months) with nonwheezy and wheezy respiratory symptoms. Children were divided into 3 groups: children with recurrent cough but no history of wheeze (group 1), with early recurrent wheeze and a loose index for the prediction of asthma at school age (group 2), and with frequent recurrent wheeze and a stringent index for the prediction of asthma at school age (group 3).

Results

Children from group 3 showed significantly higher median (interquartile range) fractional exhaled NO (FeNO) levels (11.7 [11.85]) than children from groups 1 (6.5 [5.5]; P < .001) and 2 (6.4 [6.5]; P < .001). No difference in FeNO levels was found between children from groups 1 and 2 (P = .91).

Conclusion

Wheezy young children less than 4 years of age with a stringent index for the prediction of asthma at school age have elevated levels of FeNO compared with children with recurrent wheeze and a loose index for the prediction of asthma at school age or children with recurrent cough.

Key words: Exhaled nitric oxide, early childhood asthma, infants, young children

Abbreviations used: AR, Airway responsiveness, FeNO, Fractional exhaled nitric oxide, ICS, Inhaled corticosteroid, NO, Nitric oxide

 

Respiratory symptoms, such as cough and wheeze, are common in young children with as many as 30% of children affected, mainly during a viral lower respiratory tract infection.1, 2 The Tucson Children's Respiratory Study determined that risk factors such as not being breast-fed, sharing a room, having a young mother or a mother with low education, and being exposed to evaporative coolers or tobacco smoke all contribute to the incidence of lower respiratory tract infections.1, 3, 4, 5, 6, 7, 8, 9

The prime focus of the Tucson Children's Respiratory Study longitudinal study was to investigate factors that may be predictive of which children go on to develop chronic respiratory disease, mainly asthma, in later life. The study demonstrated that environmental, socioeconomic, genetic, physiological, and immunologic factors are predictive for the development of asthma in later life.3 These findings have recently been used to define a clinical algorithm to assist in predicting the development of asthma.1, 10

The addition of objective measures to this algorithm may improve our ability to define which child with respiratory symptoms is likely to develop asthma in later childhood. Reversible airway obstruction and bronchial hyperresponsiveness as well as airway inflammation are key pathophysiological mechanisms of asthma.11 The assessment of respiratory function can be achieved noninvasively with routine standardized measurements. However, although advances have been made in the development of objective measurement of respiratory function (airway obstruction and bronchial hyperresponsiveness), these have yet to achieve widespread use in clinical practice.12 Characterization of airway inflammation in patients suspected of having asthma would likely be of benefit. Some methods, such as bronchial biopsies and bronchoalveolar lavage for the assessment of airway inflammation, are too invasive for the use in small children, whereas the measurement of fractional exhaled nitric oxide (FeNO) has been proven to be noninvasive and suitable for the assessment of airway inflammation, even in infants.13 FeNO has been shown to be helpful in the assessment of asthma in older children, mainly in monitoring therapy, in the way that it measures compliance with treatment and in predicting exacerbations as well as the course of asthma.14, 15, 16 Airway inflammation is recognized as an early component of asthma and may even precede other physiological changes.17 Therefore, it could be hypothesized that differences in FeNO between subgroups of young children less than 4 years of age with nonwheezy and wheezy respiratory symptoms may be present. Hence, the objective measurement of FeNO in addition to the clinical characterization using an algorithm may improve the possibility to define disease presentation and to predict disease progression.

Therefore, the aim of our study was to investigate whether FeNO differentiates between subgroups of young children with nonwheezy or wheezy respiratory symptoms and to assess whether FeNO allows distinction between wheezy children categorized by the clinical algorithm into recurrently wheezy children with a loose index or a stringent index for the prediction of asthma at school age.

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Methods 

Study population 

This is a prospective cohort study with 391 young children less than 4 years of age consecutively undergoing assessment for respiratory symptoms at the University Children's Hospital Zürich, Switzerland, between 2000 and 2004. Exclusion criteria were a diagnosis of a specific respiratory disease such as cystic fibrosis, primary ciliary dyskinesia, interstitial lung disease, pneumonia, or tuberculosis and/or current upper airway infection or inability to obtain an appropriate FeNO measurement. The study was approved by the University Children's Hospital ethics committee. Written informed consent was obtained from all parents.

Procedures 

Children were allocated into 3 diagnostic groups on the basis of history and clinical and laboratory findings. Group 1 consisted of children with chronic persistent or recurrent cough but no history of wheeze. Groups 2 and 3 included young children with a history of wheeze. Wheezy children were classified according to a previously published clinical index that defines the risk of asthma in young children with wheeze: group 2, loose index; group 3, stringent index10 (Table I).

Table I. Definition of diagnostic groups: Clinical index to define the risk of asthma in young children10
Major criteriaMinor criteria
1.Parental physician-diagnosed asthma1.Physician diagnosis of allergic rhinitis
2.Physician diagnosis of atopic dermatitis2.Wheezing apart from colds
3.Eosinophilia (≥4%)
Group 1
Children with chronic persistent or recurrent cough but no history of wheeze
Group 2
“Loose index for the prediction of asthma at school age”10: children with nonfrequent recurrent wheeze, <3 episodes/y, and 1 of the major criteria or 2 of the 3 minor criteria
Group 3
“Stringent index for the prediction of asthma at school age”10: children with frequent recurrent wheeze, ≥3 episodes/y, and at least 1 major or 2 minor criteria

Exhaled nitric oxide (NO) was measured according to American Thoracic Society/European Respiratory Society13 recommendations using an offline-reservoir technique that has been described previously.18 In brief, children were seated on the legs of the mother and breathed through a face mask that was gently placed on the child's face. The face mask was attached to a 2-way valve that allowed the inspiration of NO-free air from a reservoir to prevent contamination with ambient air. After 10 breaths of NO-free air, a reusable inert 750-mL collection bag (Quintron, Milwaukee, Wis) was attached to the expiratory side of the valve, and 5 breaths were collected. Nasal contamination was prevented by closing the velum by exhaling against 5 cm H2O oral pressure, achieved by a resistor between the collection bag and the expiratory side of the valve. If the child was not collaborating (crying, irregular breathing, leak), the collection was repeated after several minutes. If more than 3 attempts did not allow FeNO collection as recommended, the child was not included in the study. The NO concentration in the bags was analyzed within 15 minutes of collection by using a fast-response chemoluminescence analyzer (CLD 77 AM; Eco Medics, Duernten, Switzerland) at a sampling flow of 100 mL/min.

Allergy testing was performed from a blood sample by RAST (Unicap; Pharmacia, Duebendorf, Switzerland), and the child was considered allergic by a RAST class ≥2 (≥0.7 kU/L) for at least 1 of the tested inhaled or food allergen. Peripheral blood eosinophils were determined in a venous blood sample by a fully automated blood cell counter (SE 9000; Sysmex, Digitana, Horgen, Switzerland) and expressed as the percentage of total leukocyte counts.

Statistical analysis 

Results were expressed as mean (SD) or, if not normally distributed or in the case of categorical variables, as median (interquartile range). Levels of FeNO were logarithmically (base10) transformed because of skewed distribution.

Differences in FeNO and clinical and anthropometric data between groups were assessed with 1-way ANOVA for normally distributed data or Kruskal-Wallis 1-way ANOVA on ranks for nonnormally distributed data. Post hoc comparisons were tested with the Tukey test. Multiple linear regression and backward stepwise regression were used to test for significant associations between FeNO in groups 1, 2, and 3 and factors known to influence FeNO levels (age, sex, allergic sensitization, parental smoking, and the use of inhaled corticosteroids). A P value of <.05 was considered significant. All analyses were performed by using SigmaStat for Windows 2.03 (SPSS Inc, Chicago, Ill).

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Results 

Group 1 (children with cough) consisted of more girls (P = .023) and older children (P < .026) compared with groups 2 and 3. Allergic sensitization as assessed by RAST was more frequent in group 3 compared with groups 1 and 2. No differences between groups were noted for percentage of blood eosinophils or prenatal or postnatal passive smoke exposure. Less than 1/3 of the children were on current inhaled corticosteroid (ICS) treatment at the time of FeNO measurement, significantly more in groups 2 and 3 than in group 1 (Table II).

Table II. Patient characteristics for the subgroups
Group 1Group 2Group 3P valueTest post hoc P value
Number80190121
Sex: female/male42/3866/12446/75.023†P1,2 = .01
P1,3 = .45
P2,3 = .071
Age (m)∗30 (25.5)21 (27)23 (18.5).047P1,2 = .024
P1,3 = .026
P2,3 = .76
History of hay fever10%16.5%24.8%.021†P1,2 = .25
P1,3 = .015
P2,3 = .091
History of food allergy3.8%4.2%14.9%<.001†P1,2 = .05
P1,3 = .022
P2,3 = .002
History of atopic eczema6.3%9.5%20.7%.002†P1,2 = .53
P1,3 = .009
P2,3 = .009
Allergic sensitization10%12.6%33.4%<.001†P1,2 = .065
P1,3 < .001
P2,3 < .001
Percentage of eosinophils‡2.7 ± 2.082.7 ± 1.793.82 ± 2.9.075
Passive smoke exposure23.75%21.05%25.62%.63†
ICS therapy10%33.7%40.5%<.001†P1,2 < .001
P1,3 < .001
P2,3 = .18
Leukotriene receptor antagonist therapy1.25%4.4%7.4%.115†
β-Agonist use17.5%25.3%29.8%.38†
FeNO∗6.5 (5.55)6.4 (6.5)11.65 (11.85)<.001P1,2 = .49
P1,3 = .001
P2,3 < .001

∗Median (interquartile range).

†χ2 Analysis.

‡Mean ± SD.

The overall median FeNO value (interquartile range) was 7.5 ppb (8.7). Children from group 3 had significantly higher FeNO levels compared with group 1 (P = .001) and group 2 (P < .001), whereas children from group 1 and group 2 showed similar FeNO levels (P = .49; Table II; Fig 1). In neither group 2 nor group 3 was there a significant correlation between FeNO and number of wheezing episodes (r = 0.16, P = .073 for group 2 and r = −0.11, P = .32 for group 3, respectively). When FeNO and the number of wheezy episodes were analyzed for both groups together (group 2 and 3 merged), there was a significant but weak correlation (r = 0.2; P = .01) between the number of wheezy episodes and FeNO. Regression analysis revealed that phenotype as defined by the disease groups 1 to 3 was the only significant factor to influence FeNO levels, with none of the investigated demographic or clinical variables (age, sex, number of wheeze episodes, passive smoke exposure, allergic sensitization, blood eosinophil count, and treatment (ICS and or leukotriene receptor antagonists) influencing FeNO. However, when the different subgroups were analyzed separately according to their treatment with or without ICS, we found higher FeNO levels in ICS-naive and ICS-treated children from group 3 with allergic sensitization as defined by a positive RAST test (14.2 [16.95] ppb and 7.3 [8.45] ppb, respectively; P = .017). In all other children (groups 1 and 2 and children from group 3 without allergic sensitization), FeNO levels were similar in both children receiving ICS treatment and steroid-naive children (P = .385, P = .584, and P = .27, respectively). Further, when the different subgroups were analyzed separately, parental-reported passive smoke exposure did not influence the FeNO levels.

  • View full-size image.
  • Fig 1. 

    Levels of exhaled NO in infants and children with nonwheezy or wheezy respiratory symptoms. The median is the line bisecting the box, the box limits represent 25th and 75th percentiles, and whiskers extend to the 10th and 90th percentile. The black dots represent outliers.

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Discussion 

We have shown that the measurement of exhaled NO differentiates between subgroups of young children less than 4 years of age with wheezy and nonwheezy respiratory symptoms. Children with frequent recurrent wheeze and a stringent asthma predictive index10 (group 3) showed significantly higher FeNO values than children with nonfrequent recurrent wheeze and a loose asthma predictive index (group 2) or nonwheezy children with chronic or recurrent cough (group 1). Although there was an overlap in the distribution of FeNO values among the 3 groups, our results suggest that wheezy children with a higher risk of persistent asthma at the age of 6 years have higher levels of FeNO, representing airway inflammation, in their first 4 years of life.

Although it is known from previous studies that sex,19 age,20 and exposure to passive smoke21, 22 alter FeNO levels in healthy children and children with asthma, the strongest predictor for FeNO levels in our cohort was the phenotype as defined by the 3 disease groups. The lack of the influence of the findings from the allergy tests is most likely to be explained by the fact that the definition of the disease groups used in this study already includes atopy status.10 The finding is in agreement with results from a recent population-based study in preschool children.23 When taking into account age, sex, and allergic sensitization, the use of ICS at the time of FeNO measurement did not influence the results to a significant degree. This finding may be surprising because it is well known that ICS treatment reduces FeNO levels in a dose-dependent manner in patients with asthma.24, 25, 26, 27 However, this is not the case in all children with asthma.28, 29, 30 In addition, there is evidence of lack of clinical response to inhaled steroids in children with transient wheezing.3, 31 On the other hand, regular ICS treatment reduces wheezing episodes and days on additional asthma medication in atopic and persistent wheezers.32 When children from our study were analyzed for whether they showed allergic sensitization as defined by a positive RAST test, we found significant differences between FeNO levels in children from group 3 with allergic sensitization with or without ICS treatment. This was not the case in the other groups (groups 1 and 2 and children from group 3 without allergic sensitization). This result is in agreement with the findings of Guilbert et al32 and an epidemiologic study in 4-year-old children.23 FeNO is related to underlying mechanisms of both atopy and airway responsiveness (AR),33 and it may be hypothesized that AR is the more relevant mechanism in young children.34 FeNO might therefore be less reactive to the ICS doses used in these children.28 In addition, a confounding factor may be the lack of cooperation with inhalation therapy in this age group, which plays a major role in asthma control.35

The task Force of the American Thoracic Society and ERS published updated recommendations on the measurement of exhaled NO in 2005.13 Despite the documented usefulness of measuring FeNO in older children,14, 15, 16, 17, 29 surprisingly few studies have been performed in infants and preschool children. Both online and offline measurements of FeNO have been used in this age group without sedation19, 36, 37 and with sedation.38 According to the recommendations, we have measured FeNO with an offline method during quiet, regular breathing in children inhaling NO-free air.13 In our study, we included children from 5 to 47 months. Age was not a significant factor influencing FeNO levels in the regression analysis, taking into account all demographic or clinical variables. However, in a separate analysis, we looked at subgroups of children less than 12 months and children from 12 to 47 months. We could show that, whereas in the older children the results were highly statistically significant (P < .001), the differences were less powerful in the children younger than 12 months (P = .016), and the difference between FeNO levels of children from groups 2 and 3 were not significant (P = .107). This finding may be explained by the heterogeneity of wheezing disorders in very young children, the technical limitation of FeNO measurements in this age group, or the evolution of airway inflammation in the first years of life.

The ability of FeNO to differentiate between various groups of young children with respiratory symptoms is in accordance with findings from other studies in preschool children. In 113 children 4 to 14 years of age, FeNO was significantly lower in children without asthma compared with children with asthma. Children with asthma treated with inhaled steroids had lower values than steroid-naive patients.39 A study in 4-year-olds found higher values of FeNO in children with doctor-diagnosed asthma compared with those without.23 However, this study could not distinguish between various wheezing phenotypes. In another study, FeNO differentiated steroid-naive young children with intermittent asthma from healthy children, children without asthma with chronic cough, and children with asthma treated with inhaled steroids.40 In infants, it was shown that first-time wheeze is associated with lower FeNO compared with levels in recurrent wheeze.18 By using a similar technique in sedated children with different airway diseases and nonsedated healthy controls, Gabriele et al41 showed elevated FeNO levels in atopic wheezing infants age 4.6 to 25.2 months compared with healthy controls and infants with cystic fibrosis or bronchopulmonary dysplasia. Exhaled NO increased during an acute wheezy episode and decreased rapidly with anti-inflammatory therapy using inhaled steroids. Levels of FeNO in infants are already influenced by intrauterine factors, such as tobacco smoke exposure, which is also associated with an increased risk of wheeze in early childhood, but not with persistent asthma in later childhood.21 Exhaled NO has been proven to represent a reliable noninvasive measure for airway inflammation. A close correlation of FeNO and direct and indirect measures of airway inflammation (bronchial biopsies,42, 43 bronchoalveolar lavages,44 and sputum45) was found. However, it has also been shown that the relationship between FeNO and asthma may be more complex46: FeNO was raised in children with a combination of both atopy and increased AR, independent of symptoms; however, FeNO was not raised in children with only atopy or increased AR. The importance of the measurement of airway inflammation in young children with respiratory symptoms has been proven, because FeNO has been found to be superior to baseline respiratory function and bronchodilator responsiveness in identifying preschool children with probable asthma.33 According to the asthma predictive index,10 many of the children from group 3 differed only by the number of wheezy episodes from children of group 2. Therefore, the elevated FeNO levels may also represent greater disease activity and/or severity. With the data we present, we are not able to distinguish between current disease activity, hence actual airway inflammation, and a more general elevated expression of NO synthases within the airway epithelial cells that might be at least hypothetically related to an elevated risk for the persistence of asthma at school age. We found a weak but significant correlation between the number of wheezy episodes and FeNO levels. This may suggest that FeNO reflects disease activity, rather than a general difference between disease groups. When the 2 wheezy groups (groups 2 and 3) were analyzed separately, this correlation disappeared, and the number of wheeze episodes was not relevant in the regression analysis. ICSs are widely used to treat persistent cough and wheeze in young children. The indication for ICS treatment is mostly empirical. The clinical dilemma is to differentiate children with transient nonallergic wheeze from those children who will go on to develop persistent asthma. Treatment with ICS has been shown to fail in the prevention of exacerbations in young children with transient wheeze.3, 31 On the other hand, regular ICS treatment reduces wheezy episodes and days on additional asthma medication in atopic and persistent wheezers.32 However, ICS treatment does not influence the natural course of disease.32 It is therefore interesting from not only an epidemiologic but also a clinical point of view to be able to distinguish between subgroups of infants and young children with wheezy and nonwheezy respiratory symptoms, and hence to define which child is likely to respond to ICSs.

The results of this large study suggest that the measurement of FeNO serves as an additional parameter for the differentiation between subgroups of children younger than 4 years of age with wheezy and nonwheezy respiratory symptoms. Children with a stringent index for the prediction of asthma at school age showed higher FeNO values than those with a loose index for the prediction of asthma at school age or children with recurrent or chronic cough.

To determine what effect measuring FeNO has on determining subsequent asthma risk in relation to the asthma predictive index and hence to set a cutoff value for FeNO levels and to calculate sensitivity, specificity, and predictive values, the children have to be reassessed at school age. To date, no single parameter in young children with respiratory symptoms has been shown to be predictive for the development of asthma later on. At this stage, it is likely that an assessment based on clinical history and examination in addition to objective tests such as the measurement of FeNO is needed for a reliable prediction for asthma in later life.

Clinical implications

Our results suggest that the measurement of FeNO in young children serves as an additional parameter for the differentiation between subgroups of preschool children with respiratory symptoms.

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 Supported by an unrestricted grant by GlaxoSmithKline Switzerland.

 Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest.

PII: S0091-6749(07)02219-1

doi:10.1016/j.jaci.2007.11.008

The Journal of Allergy and Clinical Immunology
Volume 121, Issue 3 , Pages 705-709, March 2008

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