American Journal of Respiratory and Critical Care Medicine

Rationale: Measurement of the fraction of nitric oxide in exhaled breath (FeNO) has been proposed as a noninvasive marker of airway inflammation. Before the widespread use of this test, there is a need to develop reference ranges to allow clinicians to interpret FeNO measurements.

Objectives: To derive reference ranges for FeNO and to determine which factors in health and disease influence FeNO levels.

Methods: Subjects aged between 25 and 75 years were drawn from a random sample of the predominantly white population of Wellington, New Zealand.

Measurements and Main Results: FeNO was measured using an online nitric oxide monitor in accordance with international guidelines. A detailed respiratory questionnaire and pulmonary function tests were performed. The geometric mean FeNO was 17.9 parts per billion (ppb) with a 90% confidence interval for an individual prediction (reference range) for normal subjects of 7.8 to 41.1 ppb. Sex, atopy, and smoking status significantly affected FeNO levels, and several reference ranges are presented adjusting for these factors. Asthma and allergic rhinitis were associated with higher FeNO. Measurement of FeNO had poor discriminant ability to identify steroid-naive subjects with asthma.

Conclusions: The reference ranges presented may be used to assist in the interpretation of FeNO measurements in white adults.

Scientific Knowledge on the Subject

Measurement of exhaled nitric oxide (FeNO) has been proposed as a noninvasive marker of airway inflammation. Reference ranges have yet to be developed, which severely limits the ability of clinicians to interpret FeNO measurements.

What This Study Adds to the Field

This study presents reference ranges for FeNO derived from a random population sample. It also presents the association between FeNO and disease states, and its utility in the diagnosis of asthma.

Nitric oxide is a molecule with biological activity in humans, with involvement in the regulation of vascular and bronchial tone, inflammation, and neurotransmission (1). It is present in exhaled breath (2) and can be measured relatively simply and reliably by chemoluminescence (3). In health, the fraction of nitric oxide in exhaled breath (FeNO) largely derives from the lower respiratory tract, particularly the airways of the lung, if nasal air is excluded (4, 5). The FeNO correlates with some measures of airway inflammation in bronchial biopsy specimens and induced sputum, suggesting that it may serve as a noninvasive marker of some forms of airway inflammation, particularly eosinophilic inflammation (68). Consistent with this hypothesis, inhaled steroids suppress FeNO in a dose-dependent fashion (9, 10). As such, measuring FeNO may provide significant information about the activity of inflammatory airway diseases such as asthma, without the practical difficulties associated with bronchial biopsy or sputum induction, and this approach has been proposed as a guide to management (11, 12). Furthermore, the observation that FeNO is elevated in subjects with asthma compared with control subjects (1316) has led to the recommended use of FeNO measurements in the diagnosis of asthma (1719).

To facilitate the use of FeNO as a clinical test, measurement techniques have been standardized (20) and an FeNO monitoring device has gained U.S. Food and Drug Administration approval for clinical use (21). However, before the widespread integration of FeNO measurement into clinical practice, reference data for all age groups are required (20). In this study, we present reference ranges for FeNO derived from a large random sample of adults in the community.

Subjects

Study participants, who were part of the Wellington Respiratory Survey, were recruited using a postal questionnaire sent to 3,500 individuals aged 25 to 75 years, randomly selected from the electoral register of Wellington, New Zealand (2224). The 2,319 subjects who completed the postal questionnaire were invited to undertake a detailed interviewer-administered questionnaire, followed by investigative modules including FeNO measurements, pulmonary function tests, chest computed tomography (CT) scan, skin prick tests to common allergens, and a 1-week peak flow diary. Testing was conducted between February 2004 and February 2005. The survey was approved by the Wellington Ethics Committee, and written, informed consent was obtained from each subject.

FeNO Measurement

FeNO was measured by chemoluminescence using an online nitric oxide monitor (NIOX; Aerocrine AB, Solna, Sweden), according to the 1999 American Thoracic Society (ATS) guidelines (25) and consistent with the ATS guidelines published in 2005 (20). Seated subjects exhaled fully, then inhaled ambient air through a nitric oxide scrubber to total lung capacity. Subjects then exhaled against an automatically adjusting resistance to achieve a constant exhalation flow rate of 50 ml · s−1. Resistance was also adjusted so that an upper airway pressure of at least 5 cm H2O was maintained throughout exhalation, sufficient to close the velum and exclude nasal air. FeNO measurements were taken from a stable plateau in exhaled nitric oxide concentration of at least 3 seconds during an exhalation. Exhalations where flow rate and plateau criteria were not met were deemed not acceptable for measurement. Repeated exhalations were performed a maximum of six times to obtain three acceptable measurements that agreed within 10%. The average of these three measurements was used. The nitric oxide monitor was calibrated every 14 days or if the room temperature changed by more than 5°C. Measurements were made before other pulmonary function testing. Subjects avoided eating for 1 hour, smoking tobacco for 2 hours, caffeine ingestion and short-acting bronchodilator use for 6 hours, long-acting bronchodilator use for 36 hours, and antihistamine use for 72 hours before testing. Subjects were not tested within 3 weeks of an upper or lower respiratory tract infection.

Pulmonary Function Testing

Pulmonary function tests were performed using two whole-body constant volume plethysmography units (Erich Jaeger, Wurzburg, Germany), with a pneumotachograph as described previously (22, 24). Static and dynamic lung volumes were measured before and 45 minutes after the administration of 400 μg of salbutamol via a spacer device. Peak flow readings were recorded by subjects twice daily over a 1-week period after instruction in the use of a Breath Alert peak flow meter (Medical Developments, Springvale, Victoria, Australia).

Definitions of Subject Categories

The criteria used to define subject categories are shown in Table 1. Subjects who smoked or who had atopy were not excluded from our normal reference group.

TABLE 1. CRITERIA OF SUBJECT CATEGORIES


Category

Criteria
NormalNo physician diagnosis of respiratory disease* and no symptoms of respiratory disease in the previous 12 mo and no inhaled medication used in the previous 12 mo and no allergic rhinitis, asthma, or COPD
AtopyA positive skin prick test to at least one common allergen
Allergic rhinitisSymptoms of rhinitis and atopy
AsthmaPhysician diagnosis of asthma and symptoms§ in the previous 12 mo or physician diagnosis of asthma and inhaler use in the previous 12 mo or an increase in FEV1 ⩾ 15% compared with baseline after bronchodilator administration or documented diurnal peak flow variation ⩾ 20% in any of the first 7 d of recordings
Moderate to severe persistent asthmaPhysician diagnosis of asthma and symptoms§ in the previous 12 mo and prebronchodilator FEV1 < 80% predicted or prebronchodilator peak flow < 80% predicted or an increase in FEV1 > 30% compared with baseline after bronchodilator administration or documented diurnal peak flow variation > 30% in any of the first 7 d of recordings
COPD
Incompletely reversible airflow obstruction defined as a post-bronchodilator FEV1/FVC ratio < 0.7 and no defined alternative pathology potentially causing airflow obstruction

Definition of abbreviation: COPD = chronic obstructive pulmonary disease.

*Asthma, COPD, chronic bronchitis, emphysema, or bronchiectasis.

Wheeze at any time, or cough and/or sputum production for as much as 3 mo each year.

House dust mite, pine, birch, grass mix, Aspergillus species, cat, dog, feather mix, or cockroach.

§Wheeze, shortness of breath and wheeze at night, or chest tightness at night.

Four subjects were excluded from the COPD group by this criterion on the basis of chest computed tomography: three with bronchiectasis and one with pulmonary sarcoidosis.

Statistical Methods

Simple descriptive statistics were used to describe the subject characteristics. Where the logarithm of FeNO better met normality assumptions, the logarithm-transformed value was used in analyses and was back-transformed by exponentiation to derive FeNO in the units of measurement. The reference range for FeNO was estimated by a general linear multivariate regression. All reference ranges were derived from the 193 normal subjects. Reference ranges were estimated by the 90% confidence interval (CI) for an individual prediction about the value predicted by the regression equation for a particular combination of characteristics. Predictors of FeNO were examined by univariate tests, chi-square, analysis of variance, t tests, and product moment correlation coefficients, where appropriate, and in a general linear multivariate model. SAS version 9.1 (SAS Institute, Inc., Cary, NC) was used for all analyses.

Subjects

The response rate to the postal questionnaire, after excluding 521 questionnaires that were sent to outdated addresses, was 2,319 of 2,979 (78%). Of these respondents, 1,017 completed the detailed questionnaire and 795 attended for the investigative modules. The pulmonary function tests were undertaken in 758 and FeNO measurements were obtained in 528 participants who formed the study group for the analyses. FeNO measurements were not obtained in 230 subjects, including 44 who undertook the investigative modules before obtaining the NIOX machine, 11 who were unable to satisfactorily perform the test, and 175 in whom technical problems with the equipment prevented them from undertaking FeNO measurements at the time of other investigative modules. Subjects completing the investigative modules were broadly similar to those completing the screening questionnaire.

Based on our definitions (Table 1), 193 subjects were categorized as normal, 158 had allergic rhinitis, 137 had asthma, 46 had moderate to severe persistent asthma, and 87 had chronic obstructive pulmonary disease (COPD). Of the subjects with asthma, 85 had a physician diagnosis of asthma and current inhaler use, 81 had a physician diagnosis and current symptoms, 34 had an increase in FEV1 of 15% or greater after bronchodilator use, and 50 had documented peak flow variability of 20% or more. Baseline characteristics of the 528 subjects and of the 193 normal subjects are given in Table 2.

TABLE 2. BASELINE CHARACTERISTICS OF SUBJECTS




All Subjects (n = 528) Mean (SD)

Normal Subjects (n = 193) Mean (SD)
Age, yr56.2 (12.9)56.3 (12.9)
 Range26–7627–76
Height, m1.69 (0.09)1.68 (0.09)
n (%)n (%)
Female sex249 (47.2)100 (51.8)
Atopy245 (46.4)46 (23.8)
Current smoker63 (11.9)19 (9.8)
Ex-smoker224 (42.4)84 (43.5)
Nonsmoker
241 (45.6)
90 (46.6)

Reference Ranges

Normality assumptions were not well met for linear regression of FeNO; however, they were met for logarithm-transformed FeNO, and these values were used in subsequent analyses and were back-transformed to give FeNO in the units of measurement. The geometric mean FeNO was 17.9 parts per billion (ppb) with a 90% CI for an individual prediction (reference range) of 7.8 to 41.1 ppb, without adjustment for sex, atopy, and smoking status. The mean FeNO for males was 1.24 (95% CI, 1.08–1.42; p = 0.003) times higher than in females. The mean FeNO for subjects with atopy was 1.20 (95% CI, 1.02–1.42; p = 0.028) times higher than in subjects with no atopy. The mean FeNO for nonsmokers was 1.18 (95% CI, 0.92–1.51; p = 0.20) times higher than in current smokers, and 1.13 (95% CI, 0.97–1.31; p = 0.11) times higher than in ex-smokers. Height correlated weakly with FeNO with a correlation coefficient of 0.16 (p = 0.024). There was no significant correlation between age and FeNO or between time of year and FeNO.

In multivariate analysis, male sex and atopy predicted an increased FeNO, and smoking status was of marginal importance, with nonsmokers having a higher FeNO than current or ex-smokers. In the multivariate analysis, mean FeNO was 1.26 (95% CI, 1.10–1.45, p = 0.001) times greater in male than female subjects, 1.19 (95% CI, 1.01–1.39, p = 0.038) times greater in subjects with atopy than in subjects with no atopy, 1.25 (95% CI, 0.98–1.60, p = 0.072) times greater in nonsmokers than in current smokers, and 1.16 (95% CI, 1.00–1.34, p = 0.043) times greater in nonsmokers than in ex-smokers. After adjustment for other variables, height, age, and time of year were not statistically significant predictors in normal subjects. Reference ranges for the normal subjects derived from the multivariate model are given in Table 3.

TABLE 3. REFERENCE RANGES DERIVED FROM THE MULTIVARIATE MODEL IN NORMAL SUBJECTS


Atopy Status*

Smoking Status

Reference Range for FeNO (ppb)
Female
 No atopyCurrent smoker5.9–30.5
Ex-smoker6.4–32.2
Nonsmoker7.5–37.4
 AtopyCurrent smoker6.9–36.4
Ex-smoker7.6–38.5
Nonsmoker8.8–44.6
Male
 No atopyCurrent smoker7.5–38.4
Ex-smoker8.1–40.8
Nonsmoker9.5–47.4
 AtopyCurrent smoker8.8–45.9
Ex-smoker9.6–48.6

Nonsmoker
11.2–56.5

Definition of abbreviation: FeNO = fraction of nitric oxide in expired breath.

*Atopy: a positive skin prick test to at least one common allergen.

Associations with Disease States

The geometric mean FeNO for subjects with allergic rhinitis was 29.4 ppb, 1.57 (95% CI, 1.40–1.76; p < 0.001) times higher than in subjects with no allergic rhinitis. The geometric mean FeNO for subjects with asthma was 25.0 ppb, 1.24 (95% CI, 1.10–1.40; p < 0.001) times higher than in subjects with no asthma. The geometric mean FeNO for subjects with moderate to severe persistent asthma was 25.6 ppb, 1.26 (95% CI, 1.05–1.52; p = 0.012) times higher than in subjects with no asthma. The geometric mean FeNO for subjects with COPD was 25.5 ppb, 1.23 (95% CI, 1.07–1.43; p = 0.005) times higher than in subjects with no COPD. Subjects taking inhaled steroids had a geometric mean FeNO of 29.9 ppb, 1.47 (95% CI, 1.25–1.72; p < 0.001) times higher than subjects not taking inhaled steroids.

A multivariate model was generated using logarithm-transformed FeNO values and data from the 524 subjects with complete information (Table 4). After adjustment for the other variables, COPD and inhaled steroid use were not significantly associated with FeNO. The multivariate model accounted for 22% of the variability in FeNO values. There were no significant interactions between atopy and asthma or between allergic rhinitis and asthma.

TABLE 4. MULTIVARIATE MODEL PREDICTING LOGARITHM FeNO IN ALL SUBJECTS


Predictor

Coefficient (95% CI)

Ratio of Mean FeNO (95% CI)

p Value
Male sex0.20 (0.06–0.33)1.21 (1.07–1.39)0.004
Smoking
 Nonsmoker vs. current smoker0.45 (0.28–0.61)1.56 (1.33–1.83)< 0.0001
 Nonsmoker vs. ex-smoker0.14 (0.033–0.24)1.15 (1.03–1.28)0.01
Height (per meter)0.90 (0.13–1.62)2.41 (1.14–5.05)0.021
Atopy0.14 (0.00–0.28)1.15 (1.00–1.32)0.05
Allergic rhinitis0.26 (0.10–0.41)1.29 (1.11–1.51)0.001
Asthma
0.16 (0.05–0.28)
1.17 (1.05–1.32)
0.007

Definition of abbreviations: CI = confidence interval; FeNO = fraction of nitric oxide in expired breath.

Utility of FeNO in the Diagnosis of Asthma

There were 70 subjects with asthma who were not taking an inhaled steroid and 193 normal subjects who, by definition, were not taking an inhaled steroid. In the combined group of 263 subjects, FeNO measurement had a sensitivity of 49 and 19% and a specificity of 61 and 96% for detecting subjects with asthma at cutoff levels of 20 and 50 ppb, respectively. The area under the receiver operating curve was 0.54. In the combined group of 239 subjects comprising the 46 subjects with moderate to severe persistent asthma and the 193 normal subjects, FeNO had a sensitivity of 67 and 20% and a specificity of 61 and 96% for detecting subjects with moderate to severe persistent asthma. The area under the receiver operating curve was 0.65.

Subjects with an Elevated FeNO

A total of 66 subjects had an FeNO greater than the upper limit of the multivariate reference range (Table 3). Of these 66 subjects, 41 (62.1%) had allergic rhinitis, 34 (51.5%) had asthma, 17 (25.8%) had COPD, and 7 (10.6%) were normal.

In this study, we present reference ranges for FeNO measurements made in accordance with current standards and derived from a large random sample of adults in the community. The reference range for FeNO measurements in normal subjects was 7.8 to 41.1 ppb. Sex, atopy, and, to a lesser extent, smoking status influenced normal values, and these factors were included in the reference ranges derived from the multivariate model. The disease states of allergic rhinitis and asthma were associated with a higher average FeNO, with the presence of multiple factors having a multiplicative effect.

Methodological Issues

The major methodological issues to consider in interpreting these results are the representativeness and generalizability of the sample. The postal survey had a high response rate and is likely to be representative of the source population. There were minor differences between the characteristics of subjects who completed only the postal questionnaire and subjects who completed the full study protocol. However, these differences are unlikely to affect our reference ranges, as we carefully excluded subjects with respiratory symptoms or respiratory disease from the group from which these ranges were derived. Despite using strict criteria, the normal group comprised almost 200 subjects, sufficient to derive reference ranges. Subjects within a 25- to 75-year age range were recruited from a predominantly white urban population. As a result, caution should be used in implementing these reference ranges to nonwhite or rural populations and to individuals outside this age range.

Relation to Other Research

Reference ranges for FeNO measured in accordance with current ATS standards have been reported previously in children (26). Few studies, however, have reported the measurement of FeNO in accordance with current standards in more than 50 healthy adults (15, 2730). Only one of these studies was designed to determine reference ranges (30). In this study, a CLD88 nitric oxide analyzer (Ecomedics, Duernten, Switzerland) was used in accordance with current standards to measure FeNO and derive reference ranges from a nonrandom sample of 204 nonsmoking, nonatopic medical school students and their colleagues in Italy. The upper and lower limits of the reference range reported in the Italian study were 3.8 and 19.7 ppb, levels approximately half of those in the present study and approximately half of those reported elsewhere (27, 29). Systematic differences in measurements made by nitric oxide analyzers of different manufacturers have been reported and these differences may be of sufficient magnitude to explain the discrepancy between the two reference ranges (31).

Influences on FeNO in Health

The strongest influences on FeNO in healthy subjects were those of sex, atopy, and smoking status. The finding of a higher FeNO in male compared with female subjects is consistent with previous reports (15, 29, 30). The reason for this association remains unclear and was not explained by differences in height, vital capacity, or total lung capacity. The finding of a higher FeNO in normal subjects with atopy has been reported previously (32) but contrasts with that of other investigators who found that the influence of atopy on FeNO was confined to subjects with asthma or rhinitis (13, 27). Regardless of the distinction, it remains important to ascertain the atopic status of an individual to accurately interpret FeNO measurements and to relate an individual to the multivariate reference ranges presented here. It will not always be practical for the clinician to perform skin prick testing before measuring FeNO, in which case the univariate reference ranges for male and female subjects provide a reasonable approximation. Age and height were not statistically significant predictors of FeNO in the normal group, but they have been demonstrated to be important predictors in younger individuals (26).

Disease Influences on FeNO

The strongest disease influences on FeNO were the presence of allergic rhinitis and asthma. As discussed above, the exact relationship between asthma, rhinitis, and atopy has been difficult to define. For example, it has been reported that adolescent subjects with nonatopic asthma do not have elevated FeNO (33). This contrasts with our findings, in which asthma alone, allergic rhinitis alone, and atopy alone were each associated with higher FeNO. Together, these factors were multiplicative in their effect on FeNO in the multivariate model, and there was no significant interaction between asthma and allergic rhinitis or between asthma and atopy.

Influence of Inhaled Steroids

Inhaled steroids produce a dose-dependent fall in FeNO (9, 10), and so inhaled steroid use may be a confounding variable in epidemiologic studies, masking the effect of respiratory disease on FeNO. We found that, although the mean FeNO was higher in subjects who reported inhaled steroid use, this effect was not important after controlling for other variables. One explanation is that, in this study, the expected reduction in FeNO produced by inhaled steroids may have been cancelled out by inhaled steroid use being a marker for more severe airway disease.

Use of FeNO for the Diagnosis of Asthma

FeNO was a poor discriminant between normal subjects and steroid-naive subjects with asthma in this community study. Although an FeNO greater than 50 ppb had good specificity for asthma (96%), it lacked sensitivity (19–20%), regardless of whether asthma is defined by the more inclusive study definition or by the more selective definition of moderate to severe persistent asthma. These findings contrast with those of other studies in which FeNO has been evaluated as a diagnostic test for asthma (1719). In each of these studies, individuals with active respiratory symptoms and suspected asthma attending a hospital outpatient clinic or pulmonary function laboratory had FeNO measured and compared against various “gold standards” for the diagnosis of asthma, such as bronchodilator reversibility, bronchial hyperresponsiveness, and a clinical diagnosis. FeNO performed well with sensitivity ranging between 82 and 88% and specificity between 79 and 89%. Although the difference between these results and those of the present study may relate in part to our inclusion of subjects with mild or well-controlled asthma, our observation that the diagnostic accuracy of FeNO was only marginally better when analysis was restricted to subjects with moderate to severe persistent asthma suggests that this is unlikely to be the full explanation. These findings suggest that, although the measurement of FeNO may be useful in the diagnosis of asthma in a selected hospital-based population, if measurement of FeNO is applied widely as a diagnostic test for asthma, many individuals in the community may be incorrectly classified.

Conclusions

There has been great research interest in the development of noninvasive markers of respiratory disease, with FeNO being foremost among these markers. We have presented reference ranges for FeNO derived from a random community sample, providing another necessary step in the progression of this measurement from a research tool to a useful test, integrated into clinical practice.

The authors thank Joan Soriano and Hana Muellerova for their contribution to the design of the Wellington Respiratory Survey (WRS) program. They thank Denise Fabian, Avrille Holt, Patricia Heuser, and Eleanore Chambers for their contribution to the WRS program.

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Correspondence and requests for reprints should be addressed to Professor Richard Beasley, D.Sc., Medical Research Institute of New Zealand, P.O. Box 10055, Wellington, 6143 NZ. E-mail:

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