Effect of gender, age, height and weight in healthy individuals on exhaled nitric oxide (FENO)
values: a systematic review
Afonso Castro1, Ana Catarina Dias Gonçalves Sobral Camões1, Ana Luísa Veiga de Sá1, Cátia Sofia Pereira Cascais dos Reis1, Daniel
Ramos Pereira de Melo1, Daniela Filipa Martins Duarte da Silva1, Joana Rita Gonçalves Ralha Trindade Lyra1, José Luís Ceriz Santos
Lopes Silvano1, José Carlos Barbosa Ferreira Penêda1, Marta Ferreira da Costa1, Pedro José Louçano Calvão Pires1, Rita Filipe1, Rui
Paulo Filipe Magalhães 1 and Tiago Varela Branco1, mimed08064@med.up.pt
Tiago António Queirós Jacinto1, tiagojacinto@med.up.pt; Class Nr. 1
1Faculty
of Medicine, University of Porto, Porto, Portugal
ABSTRACT
BACKGROUND Exhaled nitric oxide (NO) is a biomarker and noninvasive method for the
assessment of asthma. Since all individuals, even healthy ones, exhale nitric oxide, the individual
variations of the FENO (fractional exhaled nitric oxide) values are due not only to possible asthma
related conditions but also to various differences among individuals.
AIM To investigate what are the effects of gender, age, height and weight in healthy individuals on
the exhaled values of NO.
METHODS Our study is a systematic review that will try to summarize the published data available of
primary studies on the effects of the factors mentioned on FENO. The primary method of research is
the search and analysis of original articles published on this topic in various databases (PubMed,
Scopus, ISI Web of Knowledge). Were included studies (1) which measured FENO values in healthy
individuals; (2) used NIOX, Logan, EcoMedics or Sievers analyzers of FENO values; (3) referred
FENO values of people of different age, gender, height and weight; (4) the articles that had made
comparison between this FENO values mentioned with the reference FENO values; (5) only articles
using standardized online method (50 mL/s).
RESULTS After a detailed screening of 243 articles, data extraction and synthesis lead to a total of
16 articles included, enrolling 5599 individuals analyzed. The most mentioned factor was Gender
(88% of the articles), and this factor also showed age-dependency: while there were only 2 in 8
articles performed with children that refer a significant difference between FeNO values in boys and
girls, there were 5 in 6 articles performed with adults that refer statistical higher values of FeNO in
man than in women. The factors age, weight and height also manifest a significant effect on FENO
values, respectively, on 4 (40%), 5 (56%) and 2 (29%) of the studies that referred those factors.
1
KEY-WORDS: Exhaled nitric oxide; healthy individuals; gender; age; height, weight
INTRODUCTION
Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements
play a role. The chronic inflammation is associated with airway hyperresponsiveness that leads to
recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night
or in the early morning. These episodes are usually associated with widespread, but variable, airflow
obstruction within the lung that is often reversible either spontaneously or with treatment [GINA,
2008].
A careful medical history, a physical examination, and tests of lung function provide the information
needed to diagnose asthma. Measurement of lung function is useful both for diagnosis of asthma and
to monitor the course of the disease. The monitoring of airway inflammation may provide evidence of
asthma [Zeidler MR, 2004]. However, in clinical practice, research on asthmatic inflammation is a
difficult process, involving invasive and repeated samples [Sergei A., 2006].
Exhaled biomarkers reveal themselves as a solution, as they may be used for assessment of airway
inflammation and provide a non-invasive procedure that can be performed several times [Snell N,
2008], [Menzies D, 2006]. Nitric Oxide, an endogenous gas exhaled by the human body, is
increasingly being used as a biomarker of inflammation in asthma. The noninvasive procedure of
measuring the fraction of exhaled nitric oxide (FENO) results in values that, when correctly
interpreted, lead to an efficient diagnosis and monitoring of asthma [Katial R, 2007].
However, among healthy individuals, these values express a natural variation that must be taken into
account [Nadziakiewicz P, 2006]. The literature reveals that, for instance, gender, age and body size
(weight and height) induce variations among the values of FENO in a healthy population. [Tsang KW,
2001], [Haight RR, 2006], [Jilma B, 1996], [Taylor DR, 2007], [Olivieri M, 2006], [Maestrelli P, 2007].
This variation, related with natural characteristics of the individuals, can act as a confounding factor
when evaluating FENO for the assessment of asthma related conditions [Grob, 2008].
There are currently no systematic reviews that evaluate the effects of sex, age, height and weight on
FENO values among healthy individuals that could aid the medical community in the examination of
the values of this biomarker and help the optimization of asthma assessment and monitoring.
Therefore, we’re going to conduct a systematic review on the effect of gender, age, height and weight
in healthy individuals on exhaled nitric oxide (FENO) values.
2
METHODS
Study Participants
Between September 2008 and December 2008, 257 studies were included based on the following
inclusion criteria p: (1) healthy individuals were population sample; (2) used NIOX, Logan, EcoMedics
or Sievers analyzers of FENO values; (3) referred FENO values of people of different age, gender,
height and weight; (4) the articles that had made comparison between this FENO values mentioned
with the reference FENO values; (5) only articles using standardized online method (50 mL/s) [Miller
MR, 2005]. We also defined exclusion criteria used in the filtration process : (1) articles not written in
English or Portuguese; (2) Full-text was not available; (3) nasal NO as the only measurement; (4)
articles where the flow rate of FENO was different from 50 ml/s; (6) Exhaled Breath Condensates
(EBC) as the only measurement; (7) sample only composed by animals.
Study Design
This study is a Systematic Review. We proposed to gather and analyse the information found in
different articles about the effect of gender, age, height and weight in healthy individuals on exhaled
nitric oxide (FENO) values, and establish a valid correlation between their issues.
Data Collection Methods
Articles were searched in 3 different Databases: PubMed, Scopus and ISI Web of Knowledge, using
the query: ((age OR age factors) OR (weight OR body weight) OR (height OR body height) OR
(gender OR sex)) AND (exhaled nitric oxide OR eNO OR FENO) AND (healthy individuals OR
(reference values OR normal values OR normative values) OR effect).
As mentioned, the information was selected according to specific inclusion/exclusion criteria. These
articles were submitted to different exclusion phases that reduced the original number of articles to
16. The first exclusion phase was done using the databases’ tools, in which were excluded articles
not written in English or Portuguese and the ones only referring to animals. Then, the obtained
articles were combined using EndNote XII® software, where the second exclusion phase occurred.
We excluded, assisted by EndNote’s® tools: duplicated articles, articles that referred only to an offline
method of FeNO analysis, reviews and articles with animals. In the third exclusion phase, abstracts
and titles were analysed; in this step were eliminated the ones describing studies in which the
measurement of FENO values was not done by using a Niox, Logan, EcoMedics or Sievers
3
measuring equipment, articles not related with FENO, articles referring only to nasal NO, articles that
describe studies using a FENO flow rate different than 50 mL/s and articles referring only to EBC
(exhaled breath condensate). In the fourth and last exclusion phase, articles that had no full text
available were excluded. After submission to these exclusion criteria, from the 243 articles, the total
included articles were 16.The information from each article was compiled, and its characteristics were
described. The first table regarded: author, country, population, samples’ size, age, eNO analyser;
second table: statistical analysis, studied factors and significant factors; and the third table: the
proposed equation and r² from multiple linear regression analysis.
Statistical Analysis
The final data information was analysed using SPSS 17.0 ® software. This way, the information
compiled from the 16 articles was gathered in one single table and submitted to a statistical analysis
using SPSS 17.0®‘s tools. The parameters were: study, country, population, sample size (N),
classification, age, eNO analyser, statistical analysis, study factors, significant factors, proposed
equation and R2; the frequencies, the percent and the cumulative percent were obtained for each
parameter.
RESULTS
Overall, 243 titles of reports of potentially relevant studies were identified and screened (Fig.1).
Fig.1 – Studies Selection according to specifics inclusion/exclusion criteria.
4
In total, 78 were excluded after the first submission of the exclusion criteria and 165 abstracts were
analyzed in order to apply specific criteria. 16 studies were included after a detailed review of those
165 articles.
After the analysis of their full-texts, the characteristics of the articles included were registered on
tables 1, 2 and 3, according with previous established data collection methods.
STUDY
Buchvald, 2005
Kisson, 2000a
Kisson, 2002b
COUNTRY
Denmark,The
Netherlands,
Italy and
USA
Not
Mencioned
Not
Mencioned
Kovesi, 2008
Canada
Tsang, 2001
China
POPULATION
POPULATION
ORIGIN
N
AGE (years
old)
eNO ANALYSER
Healthy
children
School
405
4 - 17
Niox
Not Mentioned
32
15 - 18
Sievers NOA 280i
Not Mentioned
112
6 - 18
Sievers NOA 280i
School
657
9 - 13
Eco Medics AG CLD 88
General
Population
121
20-79
Sievers NOA 280i
General
Population
1131
25-75
Niox
General
Population
1000
32
Logan Lr 2000
Healthy
children
Healthy
children
Healthy school
children
Non-smoking
healthy
women
General
population of
men and
women
Individuals
born in
Dunedin
Olin, 2007
Sweden
Taylor, 2007
New Zealand
Haight, 2006
USA
Healthy
subjects
General
Population
48
23 - 71
Sievers NOA 280i
Nickmilder ,
2007
Belgium
Healthy
children
Summer
Camps
72
6.5 - 15
Niox
Baraldi, 1999
Italy
Healthy
children
School
159
6 - 15
Ecophysics CLD 700 AlMed
Wong 2005
China
School
531
11 - 18
Niox
895
18 - 40
Sievers NOA 280i
122
20 - 65
Niox
Levesque, 2008
USA
Maestrelli, 2007
Italy
Malmberg, 2006
Finland
Sepponen, 2008
Finland
School
children
Healthy
African
American
adults
Healthy
Caucasian
subjects
Healthy
school-age
children
Students and
employees at
university
campuses
University
Occupation
Health Clinic
School
114
7 - 15
Niox
Healthy school
children
School
66
7 - 13
Sievers NOA 280i
5
Olivieri, 2006
Italy
Healthy
non-smoking
subjects
Medical School
Students and
colleagues
204
19 - 60
Eco Medics AG CLD 88
Table 1 – Data from selected studies: author, country, population, samples’ size (N), age of the population (min-max),
eNO analyser used.
STUDY
STATISTICAL ANALYSIS
STUDIED FACTORS
SIGNIFICANT FACTORS
Buchvald, 2005
Linear regression multivariate
analyses and Pearson correlation
analysis
Age, Gender, Height, Weight
Height (p<0,02); Weight
(p<0,005); no significant
difference: Gender
(p=0,27)
Kisson, 2000a
Determine normality of
distributions, Least-squares
regression, paired Student t tests
used to examine the relationships
between FENO values
Age, Gender, Flow rates, Body
surface area
Gender (p = 0.015 to
0.025); No significant
difference: Age (p=0,26
to 0,91)
Kisson, 2002b
Pearson product-moment
correlation coeficients and paired
Student t tests
Flow rates, Age, Gender
Significant difference:
Gender (p not available);
No significant difference:
Age (p not available);
Analysis of variance, multivariate
regression using general linear
models
Age, Gender, Height, Race,
Body mass index, Body
surface area, Pulmonary
function, Prematurity, Exercise
performed on the day of
testing
Race (p < 0,001); Age (p
= 0,007); Height (p=
0,023); no significant
difference: Gender
(p=0,73);
Tsang, 2001
Multiple linear regression model
Age, Gender, Weight, Height,
Body mass index and Body
surface area
Gender (p=0,001); Height
(p=0,02); Weight
(p<0,001); no significant
difference: Age (p=0,17)
Olin 2007
Multiple linear regression model
Age, Height.
Not mentioned
Univariate and multivariate linear
regression
Wilcoxon rank sum test
paired student's test, one-way
ANOVA, Dunnett'se multiple
comparison test,
Kolmogorov-Smirnov (K-S) test,
student’s t-test and pearson
correlation coefficients
Gender , Height , Weight ,
Lung Function Indices
Age
Age, Height, Weight, Body
Mass Index, Sex and ambient
O3 Concentration
Gender, Age, Height
p < 0.05
Wong 2005
------------
Gender
p < 0,001
Levesque, 2008
Shapiro-Wilk W test, univariate and
multivariate analysis, Student t
tests, Multiple linear regression
analyses Multiple linear regression
Maestrelli, 2007
Stepwise regression analysis
Malmberg, 2006
Stepwise regression analysis,
Logistic regression analysis
Height, Age, Weight,
Body surface area
Sepponen, 2008
Shapiro–
Wilk’s test, Mann–Whitney U-test,
Age, Height, Weight
Kovesi, 2008
Taylor 2007
Haight, 2006
Nickmilder, 2007
Baraldi, 1999
Blood Pressure, Age, Gender,
Height, Weight, Body Mass
Index and Serum Total Ige,
Eosinophil Cationic Protein, CReactive Protein
Gender, Body size, Body
Weight (Body mass index,
Body surface area and dead
space volume)
Gender (p< 0.001)
p < 0,001
p<0.05
Age (p=.0764); Gender
(p<.0001);
Height(p<.0001); Weight
(p=.0096)
Gender (p<0,001);
Weight (p<0,0001)
Height (p<0.0001), Age
(p<0.0001), Weight
(p<0.0001)
Age(p=0.344), Height
(p<0,001), Weight
6
Wilcoxon test, Spearman’s rank
(p=0.568)
correlation, Linear regression
Spearman's correlation test, nonGender (p=0,01);
parametric analysis of variance,
Olivieri, 2006
Gender, Age
no significant difference:
Kruskal-Wallis test, Mann-Whitney
Age (p=0,21)
U test, multivariate analysis
Table 2 - Statistical analysis, studied factors and significant factors referred in the selected studies
STUDY
PROPOSED EQUATION
R (SQUARED)
Buchvald, 2005
Not Mentioned
Height: 0,115; Weight: 0,139
Kisson, 2000a
FENO = (-0,0022 * flow) + (1,047 * body surface area) + (0,113 *
age) + (0,767 * FEF 25-75)
0,98
Kisson, 2002b
FENO = -0,007*flow + 0,23 * (age + 0,781 + body surface area)
+ 2,367 * (FEV + 0,109 + time to plateau (sec))
0,99
Kovesi, 2008
FENO = 1.097 + 1.074 x age
Age: 0,009; Height: 0,01
Tsang, 2001
Not mentioned
Age: 0,0144; Height: 0,0529;
Weigth: 0,1156
Olin 2007
Ln(FENO) = 0.057 + 0.013 x height (in centimeters) + 0.0088 x
age (in years); non atopic subjects: Ln(FENO) = -0.0026 + 0.013
x height (in centimeters) + 0.010 x age (in years)
0,11
Taylor 2007
Not mentioned
Not mentioned
Haight, 2006
Not Mentioned
Not Mentioned
Nickmilder, 2007
Not Mentioned
Not Mentioned
Baraldi, 1999
Not Mentioned
Age and Height: 0,04 or less
Wong 2005
Not mentioned
Not mentioned
Levesque, 2008
Not Mentioned
Sex: 0.2107
Maestrelli, 2007
Not Mentinoned
Not Mentinoned
Malmberg, 2006
Not Mentioned
Height: 0.168, Age: 0.145,
Weight: 0.155
Sepponen, 2008
FeNO = 0.423*height + 0,25
Height: 0,179
Olivieri, 2006
Not Mentioned
Not Mentioned
Table 3 - Proposed equation and r² from multiple linear regression analysis referred in the selected studies
7
After a detailed analysis of all articles included we have summarized the effect of each factor (age,
height, weight and sex) on exhaled nitric oxide values. From the 16 articles included, 9 (56%) were
performed with a sample of children. The total of participants was 5599, 2082 of which were children
under 18 years old (37%). The Table 4 refers the effect of each factor on FENO values, comparing
children and adult participants.
FACTOR
PARTICIPANTS
EFFECT
Increase 5%
Buchvald, 2005
NR
Kisson, 2002b
1,45%
Kovesi, 2008
Children
Age
ARTICLES
Kisson 2002a; Nickmilder,
No significant effect
2007; Baraldi, 1999;
Sepponen, 2008
Adults
Increase 49%
Haight, 2006
No effect
Tsang, 2001; Olin, 2007
Boys higher than girls 21%
Kisson, 2000a
36%
Wong, 2005
Buchvald, 2005; Kisson,
Children
2002b; Kovesi, 2008;
No significant effect
Nickmilder, 2007; Baraldi,
1999; Malmberg, 2006
Gender
Man higher than women 35%
Adults
Children
Height
Children
Weight
Adults
19%
Olin, 2007
25%
Taylor, 2007
25%
Maestrelli,2007
15%
Olivieri, 2006
No significant effect
Levesque, 2008
Increase NR
Buchvald, 2005
NR
Kovesi, 2008
50%
Malmberg, 2006
NR
Sepponen, 2008
No significant effect
Adults
Tsang, 2001
Increase NR
Nickmilder, 2007; Baraldi,
1999; Wong, 2005
Tsang, 2001
No significant effect
Levesque, 2008
Increase NR
Buchvald, 2005
No significant effect
Increase NR
No significant effect
Nickmilder, 2007;Wong, 2005;
Sepponen, 2008
Tsang, 2001
Olin, 2007; Levesque, 2008
Table 4 - Effect of age, gender, height and weight on FENO values, comparing children and adult participants from the 16
articles review. NR – Not Reported.
The most referred factor from the articles included was Gender (14 articles, 88%), and from these 7
(50%) reported a significant difference between males and females. This effect was specially
8
reported when the sample was constituted by adult subjects (71%). Age, weight and height also
manifest a significant effect on FENO values, respectively, on 4 (40%), 5 (56%) and 2 (29%) of the
studies that referred those factors.
DISCUSSION
Our study is, to the best of our knowledge, the first to systematically summarize the effects of age,
gender, height and weight on exhaled nitric oxide (FENO) values. The most referred factor from the
articles included in the study was Gender, with half of the studies showing a significant difference
between different genders. Age also was a highly mentioned factor. The results showed us that, only
gender showed that FeNO values were higher in men. In children, height was the only factor to show
an increasing in FeNO levels. Our results suggest that is possible to study and understand the
influence of anthropometric factors in FeNO, in order to find reliable reference values, aiding
clinicians in the diagnosis and management of respiratory diseases.
This is the first systematic review done using the three largest biomedical databases, allowing for a
great number of articles found and studied. There are, however, weaknesses related with the design
of the study, as any systematic review can compensate the limitations inherent of the studies
included; for example, the methods and discussions of the papers were very different from one
another, making both the data selection and the statistical analysis very hard to accomplish. Besides,
the choice of no double revision of the articles could be one of the limitations of the study.
It seems unlikely that NO production in the airways is solely a reflection of differences in airway size,
but rather reflects sex-related differences in endogenous NO production. Several published studies
have focused on the effects of estrogen on NOS2 and endothelial or type III NO synthase expression
and NO production, suggesting that FeNO levels might be lower in women because of increased
estrogen levels. Estrogen suppresses NOS2 expression in endothelial cells and reduces
inflammation in NO-dependent models of inflammation and ischemic injury. We speculate that a
further possible reason is the difference in airway surface area and calibre. The same flow rate in
airways of different calibres may differently dilute NO, which moves by means of gaseous diffusion
into a smaller lumen (i.e. in females), thus leading to a lower NO concentration.The specific effect of
estrogen on FeNO levels remains unclear, but these studies suggest that estrogen might decrease
FeNO levels through reduced respiratory epithelial expression of NOS2. A study of the human airway
9
cell line A549 and of human primary epithelial cells indicated that an estrogen receptor agonist
blocked cytokine-stimulated NOS2 expression [Levesque, 2008].
The reason FENO increases with age is not known, but there is no age-related FENO trend in
adulthood. The age dependency in children may be related to the developmental and maturational
changes; increased lung volume and airway surface area; changes in airway NO diffusion
coefficients, which may be dependent on surface area; or age-dependent induction of inducible nitric
oxide synthase secondary to recurrent immunological stimulation. The use of a constant exhalation
flow rate (50 mL/s) in children of different airway sizes may also be a factor explaining the age
dependency of exhaled NO, because the same flow is relatively higher for young children. A change
in NO in older people is consistent with other physiologic and biochemical changes that occur with
aging such as impaired mucociliary transport, enhanced oropharyngeal colonization, increased
aspiration potential, decreased ability to expectorate, decreased respiratory muscle endurance,
airflow limitation, impaired immune surveillance, decreased ability to mount an appropriate immune
response, impaired neutrophil chemotaxis, and respiratory burst [Haight, 2006].
The correlation between height and bronchial NO flux might be explained by increasing bronchial tree
and mucosal surface area available for NO production in taller children [Sepponen,2008].The strong
relationship with height in the study suggest that size of the children is more important than age,
which might be related to geometrical factors such as the total area of airway mucosa producing NO,
affecting the transfer factor of NO. However, age-related immunological changes may also contribute
to the larger production of NO in the airways of older children.
The volume of anatomic dead space is a factor explaining the body size dependency of exhaled NO
in adults. Variations of dead space volume, and consequently of airway surface area, may modify the
ratio between NO excretion and axial diffusion of NO from the airways to the alveolar regions of the
lungs leading to an increase of FENO when the volume of anatomical dead space increases.
However, even if the balance between NO excretion and its axial molecular diffusion is steady, the
use of a constant exhalation flow rate for the NO measurement for all subjects irrespective of their
airway size will lead to different mean airflow within the conducting airways. When velocities are
increased the exhaled gas has less residence time in the conducting airways, and thus less time for
the airway epithelium to load the bolus of expirate with NO, resulting in a lower exhaled NO
concentrations. For a given exhalation flow rate, mean airflow velocity within conducting airways will
be lower in subjects with a lower volume of anatomic dead space and vice versa [Maestrelli, 2007].
10
A positive relation between the factors age, height, weight or gender and [FeNO] values may have a
remarkable contribution to the accurate diagnosis of asthma, allergic rhinitis and several breathing
diseases. In fact, if our systematic review allows the establishment of standard FeNO values and the
intrinsic variations related to the enunciated factors, these same features will no longer be confusion
factors. Physicians would then be able to compare the patient information with a defined reference,
making the diagnosis not only more precise but also faster. Yet, the importance of finding standard
values for FeNO goes far beyond the detection and diagnosis: it may dramatically simplify the
monitoring and treating process. With the spread of scientific and technical improvements inherent to
a major medical advance, the costs of FeNO analyzers may decrease so much that each patient
could have his own. As a result, the personal monitoring of FeNO values would be the ultimate, but
not disconnected consequence generated by the goal of our systematic review. And finally, further
studies about this subject won’t be repetitive: this area may be exponentially developed, and is our
belief that single factorial studies – for example, studying only the effect of gender in FeNO values –
are the most imperative way of research.
In our systematic review, we have concluded that FeNO values were higher in man than in women in
articles performed with a sample of adults; also, the increasing in age, weight and height, in sames
cases, was correlated with the increasing of FeNO values. Nevertheless, more studies will be needed
to establish stronger relationships and reliable reference FeNO values for each factor.
11
REFERENCES
Baraldi E., Azzolin N. M., Cracco A., Zacchello F. Reference values of exhaled nitric oxide for healthy
children 6-15 years old. Pediatric Pulmonology. 1999; 27(1): 54-58.
Buchvald F., Baraldi E., Carraro S., Gaston B., De Jongste J., Pijnenburg M., W. H., Silkoff P. E.,
Bisgaard H. Measurements of exhaled nitric oxide in healthy subjects age 4 to 17 years. Journal of
Allergy and Clinical Immunology. 2005; 115(6): 1130-1136.
GINA – The Global Initiative for Asthma, December 2007 - www.ginasthma.com
Haight R. R., Gordon R. L., Brooks S. M. The effects of age on exhaled breath nitric oxide levels.
Lung. 2006; 184(2): 113-119.
Jilma B, Kastner J, Mensik C, Vondrovec B, Hildebrandt J, Krejcy K, Wagner OF, Eichler HG. Sex
differences in concentrations of exhaled nitric oxide and plasma nitrate. Life Sci. 1996; 58(6):469-76.
Katial R, Stewart L; Exhaled nitric oxide: a test for diagnosis and control of asthma? Curr Allergy
Asthma Rep. 2007 Nov; 7(6):459-63.
Kissoon N., Duckworth L. J., Blake K. V., Murphy S. P., Taylor C. L., Silkoff P. E. Fe-NO:
Relationship to exhalation rates and online versus bag collection in healthy adolescents. American
Journal of Respiratory and Critical Care Medicine. 2000; 162(2): 539-545.
Kissoon, N., Duckworth L. J., Blake K. V., Murphy S. P., Taylor C. L., DeNicola L. R., Silkoff P. E.
Exhaled nitric oxide concentrations: Online versus offline values in healthy children. Pediatric
Pulmonology. 2002; 33(4): 283-292.
Kovesi T., Kulka R., Dales R. Exhaled nitric oxide concentration is affected by age, height, and race
in healthy 9-to 12-year-old children. Chest. 2008; 133(1): 169-175.
Levesque M. C., Hauswirth D. W., Mervin-Blake S., Fernandez C. A., Patch K. B., Alexander K. M.,
Allgood S., McNair P. D., Allen A. S., Sundy J. S. Determinants of exhaled nitric oxide levels in
12
healthy, nonsmoking African American adults. Journal of Allergy and Clinical Immunology. 2008;
121(2): 396-402.
Maestrelli P., Ferrazzoni S., Visentin A., Marian E., Dal Borgo D., Accordino R., Fabbri L. M.
Measurement of exhaled nitric oxide in healthy adults. Sarcoidosis Vasculitis and Diffuse Lung
Diseases. 2007; 24: 65-69.
Malmberg L. P., Petays T., Haahtela T., Laatikainen T., Jousilahti P., Vartiainen E., Makela M. J.
Exhaled nitric oxide in healthy nonatopic school-age children: Determinants and height-adjusted
reference values. Pediatric Pulmonology. 2006; 41(7): 635-642.
Menzies D, Nair A, Lipworth BJ. Non-invasive measurement of airway inflammation in asthma. J
Asthma. 2006 Aug; 43(6):407-15.
Miller M.R. et al. Series ATS/ERS task force: standardisation of lung Function testing: General
considerations for lung function testing. Eur Respir J. 2005; 26: 153–161.
Nadziakiewicz P, Knapik P, Rozentryt P, Ziora D, Dworniczak S, Kozielski J, Poloński L. Potential
confounding factors in measurement of exhaled nitric oxide. J Physiol Pharmacol. 2006 Sep; 57
Suppl 4:223-8.
Natalia M. Grob and Raed A. Dweik, MD, FCCP. Exhaled Nitric Oxide in Asthma. Cleveland, OH.
2008
Nickmilder M., Carbonnelle S., Bernard A. House cleaning with chlorine bleach and the risks of
allergic and respiratory diseases in children. Pediatric Allergy and Immunology. 2007; 18(1): 27-35.
Olin A. C., Bake B., Toran K. Fraction of exhaled nitric oxide at 50 mL/s: Reference values for adult
lifelong never-smokers. Chest. 2007; 131(6): 1852-1856.
Olivieri M, Talamini G, Corradi M, Perbellini L, Mutti A, Tantucci C, Malerba M. Reference values for
exhaled nitric oxide (reveno) study. 1: Respir Res. 2006 Jun 30; 7:94.
13
Sepponen A, Lehtimäki L, Huhtala H, Kaila M, Kankaanranta H, Moilanen E. Alveolar and bronchial
nitric oxide output in healthy children. Pediatric Pulmonology. 2008 Dec;43(12):1242-8.
Sergei A, Kharitonov and Peter J. Barnes. Exhaled Biomarkers. Chest 2006;130;1541-1546.
Snell N, Newbold P. The clinical utility of biomarkers in asthma and COPD. Curr Opin Pharmacol.
2008 Jun; 8(3):222-35. Epub 2008 May 28.
Taylor D. R., Mandhane P., Greene J. M., Hancox R. J., Filsell S., McLachlan C. R., Williamson A. J.,
Cowan J. O., Smith A. D., Sears M. R. Factors affecting exhaled nitric oxide measurements: the
effect of sex. Respiratory Research. 2007 Nov; 15(8):82.
Tsang K. W., Ip S. K., Leung R., Tipoe G. L., Chan S. L., Shum I. H., Ip M. S., Yan C., Fung P. C.,
Chan-Yeung M., Lam W. Exhaled nitric oxide: The effects of age, gender and body size. Lung. 2001;
179(2): 83-91.
Tsang KW, Ip SK, Leung R, Tipoe GL, Chan SL, Shum IH, Ip MS, Yan C, Fung PC, Chan-Yeung M,
Lam W. Exhaled nitric oxide: the effects of age, gender and body size. Lung. 2001; 179(2):83-91.
Wong G. W. K., Liu E. K. H., Leung T. F., Yung E., Ko F. W. S., Hui D. S. C., Fok T. F., Lai C. K. W.
High levels and gender difference of exhaled nitric oxide in Chinese schoolchildren. Clinical and
Experimental Allergy. 2005; 35(7): 889-893.
Zeidler MR, Kleerup EC, Tashkin DP. Exhaled nitric oxide in the assessment of asthma: Curr Opin
Pulm Med. 2004 Jan; 10(1):31-6.
14