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Reproducibility of exhaled nitric oxide measurements in overweight and obese adults

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Willemien Thijs at Leiden University Medical Centre
Willemien Thijs
Renée de Mutsert
Renée de Mutsert
Renée de Mutsert
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Saskia Le Cessie at Leiden University Medical Centre
Saskia Le Cessie
Pieter S. Hiemstra at Leiden University Medical Centre
Pieter S. Hiemstra
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Background Exhaled nitric oxide is a noninvasive measure of airway inflammation that can be detected by a handheld device. Obesity may influence the reproducibility of exhaled nitric oxide measurements, by - for instance – decreased expiratory reserve volume. Findings We analyzed triple exhaled nitric oxide measurements from 553 participants (aged 45 to 65 years with a body mass index ≥27 kg/m2) of the Netherlands Epidemiology of Obesity Study. The interclass correlation coefficient (single measurement reliability) was 0.965 (95% CI: 0.960, 0.970). Conclusions We conclude that for assessment of exhaled nitric oxide in large cohorts of overweight and obese adults a single measurement suffices.
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S H O R T R E P O R T Open Access
Reproducibility of exhaled nitric oxide
measurements in overweight and obese adults
Willemien Thijs
1*
, Renée de Mutsert
2
, Saskia le Cessie
2,3
, Pieter S Hiemstra
1
, Frits R Rosendaal
2
,
Saskia Middeldorp
4
and Klaus F Rabe
5
Abstract
Background: Exhaled nitric oxide is a noninvasive measure of airway inflammation that can be detected by a
handheld device. Obesity may influence the reproducibility of exhaled nitric oxide measurements, by - for
instance –decreased expiratory reserve volume.
Findings: We analyzed triple exhaled nitric oxide measurements from 553 participants (aged 45 to 65 years with
abodymassindex≥27 kg/m
2
) of the Netherlands Epidemiology of Obesity Study. The interclass correlation
coefficient (single measurement reliability) was 0.965 (95% CI: 0.960, 0.970).
Conclusions: We conclude that for assessment of exhaled nitric oxide in large cohorts of overweight and obese
adults a single measurement suffices.
Keywords: Reproducibility, Exhaled nitric oxide, Obesity
Findings
Introduction
Exhaled nitric oxide (eNO) is a noninvasive marker of
inflammation in the airways. The levels of eNO correlate
well with other markers of inflammation in the airways
of asthmatics, such as sputum eosinophils and airway
eosinophilia in bronchial biopsies [1,2]. Measuring eNO
with a handheld device is a convenient way to assess air-
ways inflammation and has been used to study e.g. occu-
pational hazards or asthma [3,4]. The prevalence of
obesity has risen dramatically in the past decades and an
increasing proportion of participants in studies will be
overweight or obese [5]. Because eNO measurements
take time and generate costs it is important to establish
the reproducibility of eNO measurements in overweight
and obese adults.
How could obesity influence eNO measurements?
Obesity is associated with a loss in expiratory reserve
volume [6], which may influence eNO measurement that
require a slow and steady exhalation. In addition, obesity
is associated with low grade systemic inflammation [7]
which may be accompanied by airways inflammation
resulting in increased eNO levels. However, studies into
the association between obesity and levels of eNO show
conflicting results [8-11]. Therefore it is not clear
whether putatively increased eNO levels may contribute
to decreased reproducibility in obese subjects.
The ATS/ERS recommendations for eNO measure-
ments suggest two measurements of eNO [12]. Because
of the time requirement and costs associated with mul-
tiple eNO measurements in large scale studies, a single
measurement would be preferable. Reproducibility of
eNO measured by the handheld NIOX MINO has been
evaluated in children [13], adults [14], asthma patients
and pregnant women [15], but not in overweight and
obese individuals. Therefore, we used a triplicate meas-
urement to assess the reproducibility of eNO measured
by a handheld NIOX MINO in a cohort study of over-
weight and obese adults, with the aim to assess whether
a single measurement may suffice in large scale studies.
Materials and methods
The Netherlands Epidemiology of Obesity (NEO) Study
is a population-based cohort study in adults aged 45 to
65 years, with an oversampling of participants with over-
weight or obesity [16]. The study was approved by the
ethical committee of the Leiden University Medical Cen-
ter and all participants gave written informed consent.
* Correspondence: W.Thijs@lumc.nl
1
Department of Pulmonology, Leiden University Medical Center, PO Box
9600, Leiden 2300 RC, the Netherlands
Full list of author information is available at the end of the article
© 2014 Thijs et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain
Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article,
unless otherwise stated.
Thijs et al. BMC Research Notes 2014, 7:775
http://www.biomedcentral.com/1756-0500/7/775
The present analysis includes the first 630 participants
with a body mass index (BMI) ≥27 kg/m
2
. Completed
multiple questionnaires including self-reported asthma,
and anthropometric and maximal flow-volume curves
measurements were obtained. Exhaled nitric oxide was
measured using a portable analyzer, the NIOX MINO
(Aerocrine AB, Solna, Sweden). Participants performed a
10 seconds slow steady exhalation. Three successive re-
cordings at 1-minute intervals, expressed as parts per
billion (ppb), were made. The interclass correlation coef-
ficient (ICC) was calculated for the three measurements
in all participants, participants with self reported asthma
and separately for participants with a BMI ≥35 and for
elevated mean eNO levels (>25 ppb and for >50) [17].
The mean intra-participant difference in eNO was calcu-
lated and a Bland-Altman plot was constructed. Statis-
tical analyses were performed with SPSS 20.0 software
(SPSS Inc., Chicago, IL).
Results
Of the first 630 participants of the NEO study, 46 partic-
ipants did not perform eNO measurements because they
did not visit the lung function department due to logistic
problems. In another 31 patients, no measurements were
obtained because of inability to perform the technique
or because of a technical failure with the nitric oxide
machines. As a result, the present analysis includes 553
participants who performed all three eNO measure-
ments. The characteristics of the study population and
results of eNO measurements are presented in Table 1.
The ICC (single measurement reliability) for all partici-
pants was 0.965 (95% CI: 0.960, 0.970), whereas it was
0.926 (95% CI: 0.926, 0.965) for the participants with a
BMI ≥35 (n = 92). The ICC (single measurement reliabil-
ity) for all participants with asthma (n = 39) was 0.988
(95% CI: 0.979, 0.993), whereas it was 0.932 (95% CI:
0.818, 0.981) for the participants with asthma and a
BMI ≥35 (n = 10). The ICC for all eNO measurements
that exceeded 25 ppb (n = 109) was 0.949 (95% CI: 0.931,
Table 1 Clinical characteristics and eNO measurements of
the study population (n = 553)
Characteristic Median or % IQR
Age (years) 56 (50-61)
Sex (women %) 47 NA
Self reported asthma (%) 7 NA
BMI (kg/m
2
) 30 (28-33)
FEV
1
% predicted 103 (92-114)
FVC % predicted 105 (96-115)
First nitric oxide (ppb) 17 (12-23)
Second nitric oxide (ppb) 17 (12-24)
Third nitric oxide (ppb) 17 (13-24)
BMI: Body mass index; IQR: Interquartile range; NA: not applicable; FEV
1
%:
percent predicted of forced expiratory volume; FVC % percent predicted of
forced vital capacity; ppb: parts per billion.
Mean of the first and second NO measurements (ppb)
Difference between the first and the second NO
measurements (ppb)
Figure 1 Bland-Altman plot for the first two eNO measurements by the NIOX MINO (n = 553). The dots represent the difference between
the first and the second measurement.
Thijs et al. BMC Research Notes 2014, 7:775 Page 2 of 3
http://www.biomedcentral.com/1756-0500/7/775
0.963) and for those that exceeded 50 ppb (n = 18) was
0.911 (95% CI: 0.818, 0.963). The mean intra-participant
difference in eNO for all participants was for the second
and first reading: -0.05 ppb (95% CI: -7.14, 7.04); third
and first reading -0.15 ppb (95% CI: -6.8, 7.6); and third
and second reading -0.13 ppb (95% CI: -5.9, 6.5). A
Bland-Altman plot was constructed for the first two
measurements (Figure 1).
Discussion
The ICC and mean intra-participant difference in eNO
for all 553 participants was in line with previous repro-
ducibility studies performed on the NIOX MINO in
other populations [13,14]. The ICC for participants with
aBMI≥35 kg/m
2
was slightly lower (but clinically not
relevant) than within the whole group, possibly as a re-
sult of decreased expiratory reserve volumes. Low grade
inflammation associated with obesity appears a less likely
explanation for the small loss in reproducibility because
only early studies report a positive correlation between
BMI and eNO [8,9]; later studies have not been able to
reproduce these initial findings [10,11]. The reproduci-
bility in participants with self reported asthma was in
line with the results in the whole group but within our
study the reproducibility at higher eNO levels was
slightly lower. In earlier study by Selby et al. [13] it is
concluded that for individual absolute levels two mea-
surements are needed. Similarly, we conclude that in
clinical practice two eNO measurements are advised but
despite small differences of ICC in different analyses,
our results demonstrate that in large cohorts of over-
weight and obese adults a single eNO measurement suf-
fices, which will have significant logistical and financial
consequences for cohort studies.
Abbreviations
BMI: Body mass index; ICC: Inter class correlation; eNO: Exhaled nitric oxide;
Ppb: Parts per billion; NEO: Netherlands Epidemiology of Obesity;
FEV
1
%: Percent predicted of forced expiratory volume; FVC%: Percent
predicted of forced vital capacity; ATS: American Thoracic Society;
ERS: European Respiratory Society.
Competing interests
The authors declare that they have no competing interests.
Authors’contributions
WT participated in the design, performed the statistical analysis and drafted
the manuscript. RM participated in the design, helped to draft the
manuscript and made suggestions for the analyses. SC supervised the
statistical analyses. SM, FR, PH and KR conceived the study, and participated
in its design and coordination and helped to draft the manuscript. All
authors read and approved the final manuscript.
Acknowledgements
Supported by an unrestricted research grant from Astra-Zeneca NL.
Author details
1
Department of Pulmonology, Leiden University Medical Center, PO Box
9600, Leiden 2300 RC, the Netherlands.
2
Department of Clinical
Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.
3
Department of Medical Statistics, Leiden University Medical Center, Leiden,
the Netherlands.
4
Department of Vascular Medicine, Academic Medical
Center, Amsterdam, the Netherlands.
5
LungenClinic Grosshansdorf,
Grosshansdorf, Germany.
Received: 20 December 2013 Accepted: 10 October 2014
Published: 3 November 2014
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Cite this article as: Thijs et al.:Reproducibility of exhaled nitric oxide
measurements in overweight and obese adults. BMC Research Notes
2014 7:775.
Thijs et al. BMC Research Notes 2014, 7:775 Page 3 of 3
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  • Apr 2013
  • EUR J EPIDEMIOL
Obesity is a well-established risk factor for many chronic diseases. Incomplete insight exists in the causal pathways responsible for obesity-related disorders and consequently, in the identification of obese individuals at risk of these disorders. The Netherlands Epidemiology of Obesity (NEO) study is designed for extensive phenotyping to investigate pathways that lead to obesity-related diseases. The NEO study is a population-based, prospective cohort study that includes 6,673 individuals aged 45-65 years, with an oversampling of individuals with overweight or obesity. At baseline, data on demography, lifestyle, and medical history have been collected by questionnaires. In addition, samples of 24-h urine, fasting and postprandial blood plasma and serum, and DNA were collected. Participants underwent an extensive physical examination, including anthropometry, electrocardiography, spirometry, and measurement of the carotid artery intima-media thickness by ultrasonography. In random subsamples of participants, magnetic resonance imaging of abdominal fat, pulse wave velocity of the aorta, heart, and brain, magnetic resonance spectroscopy of the liver, indirect calorimetry, dual-energy X-ray absorptiometry, or accelerometry measurements were performed. The collection of data started in September 2008 and completed at the end of September 2012. Participants are followed for the incidence of obesity-related diseases and mortality. The NEO study investigates pathways that lead to obesity-related diseases. A better understanding of the mechanisms underlying the development of disease in obesity may help to identify individuals who are susceptible to the detrimental metabolic, cardiovascular and other consequences of obesity and has implications for the development of prevention and treatment strategies.
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Impact of Obesity on Respiratory Function
Article
  • Jan 2012
  • RESPIROLOGY
Obesity has long been recognized as having significant effects on respiratory function. The topic has been studied for at least the last half century, and some clear patterns have emerged. Obese patients tend to have higher respiratory rates and lower tidal volumes. Total respiratory system compliance is reduced for a variety of reasons, which will be discussed. Lung volumes tend to be decreased, especially expiratory reserve volume. Spirometry, gas exchange and airway resistance all tend to be relatively well preserved when adjusted for lung volumes. Patients may be mildly hypoxaemic, possibly due to ventilation-perfusion mismatching at the base of the lungs, where microatelectasis is likely to occur. Weight loss leads to a reversal of these changes. For all of these changes, the distribution of fat, that is, upper versus lower body, may be more important than body mass index.
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Impact of Bariatric Surgery on Pulmonary Function and Nitric Oxide in Asthmatic and Non-Asthmatic Obese Patients
Article
Asthma is an important co-morbidity of obesity. This study evaluated the impact of bariatric surgery on respiratory function in obese patients and compared the outcomes in asthmatic and non-asthmatic subjects. The study was observational and prospective and included subjects on waiting list for bariatric surgery. Pulmonary function, symptoms, and exhaled nitric oxide were assessed before surgery and 1 year after. Twenty-nine severe obese subjects (age range: 25-66 years) with a mean body mass index of 44.8 ± 4.7 kg/m(2) were included. Fourteen of them had also intermittent to moderate asthma. In the whole population, the body mass index decreased from 44.8 ± 4.7 to 41.1 ± 3.9 kg/m(2) (p = .0001) and the forced vital capacity increased from 3.05 ± 0.83 to 3.50 ± 0.81 L (p = .043). No change was seen in forced expiratory volume and oxygen saturation. These results remained valid also analyzing asthmatics and non-asthmatics separately. Concerning nitric oxide, the decrease at 1 year was significantly different between the two populations, since in asthma patients exhaled nitric oxide decreased by 4.86 ppb after bariatric surgery and increased by 0.27 ppb in non-asthmatics (p = .04). Bariatric surgery significantly reduces the intake of inhaled corticosteroids and the levels of exhaled nitric oxide, thus bronchial inflammation, in asthmatics.
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Allergen exposure modifies the relation of sensitization to fraction of exhaled nitric oxide levels in children at risk for allergy and asthma
Article
  • Apr 2011
Studies on airway inflammation, measured as fraction of exhaled nitric oxide (FENO), have focused on its relation to control of asthma, but the contribution of allergen exposure to the increase in FENO levels is unknown. We evaluated (1) whether FENO levels were increased in children with allergic sensitization or asthma; (2) whether specific allergen exposure increased FENO levels in sensitized, but not unsensitized, children; and (3) whether sedentary behavior increased FENO levels independent of allergen exposures. At age 12 years, in a birth cohort of children with a parental history of allergy or asthma, we measured bed dust allergen (dust mite, cat, and cockroach) by means of ELISA, specific allergic sensitization primarily based on specific IgE levels, and respiratory disease (current asthma, rhinitis, and wheeze) and hours of television viewing/video game playing by means of questionnaire. Children performed spirometric maneuvers before and after bronchodilator responses and had FENO levels measured by using electrochemical detection methods (NIOX MINO). FENO levels were increased in children with current asthma (32.2 ppb), wheeze (27.0 ppb), or rhinitis (23.2 ppb) compared with subjects without these respective symptoms/diagnoses (16.4-16.6 ppb, P < .005 for all comparisons). Allergic sensitization to indoor allergens (cat, dog, and dust mite) predicted higher FENO levels and explained one third of the variability in FENO levels. FENO levels were highest in children both sensitized and exposed to dust mite. Greater than 10 hours of weekday television viewing was associated with a 0.64-log increase in FENO levels after controlling for indoor allergen exposure, body mass index, and allergic sensitization. Allergen exposures and sedentary behavior (television viewing/video game playing) might increase airway inflammation, which was measured as the FENO.
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Adiposity, Adipokines, and Exhaled Nitric Oxide in Healthy Adults Without Asthma
Article
Epidemiological studies have shown that obesity/adiposity is closely associated with asthma in terms of development, severity, and control of asthma. However, effects of obesity/adiposity on airway inflammation are not well known in subjects without asthma. We assessed whether fractional exhaled nitric oxide (FeNO), a marker of eosinophilic airway inflammation, was associated with obesity/adiposity in nonasthmatic healthy adults. We measured FeNO and serum levels of adipose-derived hormones and adipokines in 117 adult subjects without a previous diagnosis of asthma or current asthmatic symptoms. Associations between FeNO and measures of obesity/adiposity [body mass index (BMI), body fat mass, and body fat percentages] were examined by correlation analyses and uni- and multivariate linear regression analyses. FeNO was not significantly associated with BMI, body fat mass, or body fat percentage by a multivariate linear regression model, adjusting for age, gender, chronic rhinitis, atopy, and lung function. No significant association of FeNO with serum levels of leptin, adiponectin, tumor necrosis factor (TNF)-α, or interleukin (IL)-6 was observed. These findings suggest that in healthy subjects without asthma, obesity/adiposity has no significant effect on eosinophilic airway inflammation and that hormones and systemic inflammation derived from adipose tissue do not affect eosinophilic airway inflammation.
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Exhaled Nitric Oxide in Pregnant Healthy and Asthmatic Women
Article
Measurement of fractioned exhaled nitric oxide (FE(NO)) is useful for monitoring airway inflammation in asthma. Asthma is one of the most common diseases complicating pregnancy, and FE(NO) may be helpful for monitoring asthma in pregnancy. However, some physiological alterations of FE(NO) may be expected during healthy pregnancy due to vascular nitric oxide production. Until now no study assessed the level of FE(NO) in asthmatic pregnant patients. We aimed to assess the possible use and reproducibility of FE(NO) measurements in pregnant asthmatic women. We compared FE(NO) concentrations between four groups of subjects: healthy nonpregnant and pregnant females and asthmatic nonpregnant and pregnant patients. We also investigated the relationship between FE(NO) values and the level of asthma control in pregnant asthmatic patients. A total of 102 female subjects (35 healthy nonpregnant and 27 healthy pregnant females; 20 nonpregnant and 20 pregnant asthmatic women) were included in this cross-sectional study. Two FE(NO) measurements were performed in each subject using an electrochemical sensor based device (NIOX MINO, Aerocrine, Solna, Sweden). Data are given as median with range. The repeatability of FE(NO) measurement was similar in pregnant and nonpregnant subjects. FE(NO) levels did not differ significantly between healthy pregnant versus nonpregnant subjects (16.0 [8, 31] vs. 16.0 [9, 35] ppb). FE(NO) levels were significantly increased in asthmatic women compared to healthy females (nonpregnant asthmatics: 38 [9, 54] ppb, p < 0.001 vs. healthy nonpregnant; pregnant asthmatic patients: 28 [10, 56] ppb; p < 0.05 vs. healthy pregnant). FE(NO) level is not influenced by healthy pregnancy. In pregnant asthmatic patients FE(NO) level is elevated compared to healthy pregnant subjects and correlates with the level of asthma control. Further studies are required to assess the use of FE(NO) measurement to monitor asthma in this patient group.
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