Hindawi Publishing Corporation
Journal of Allergy
Volume 2012, Article ID 916926, 6 pages
Stefania La Grutta,1,2,3Giuliana Ferrante,2Velia Malizia,2Fabio Cibella,2and Giovanni
1Health and Environment Unit, Regional Agency for Environment Protection/ARPA, Sicilia, Corso Calatafimi 217,
90129 Palermo, Italy
2Institute of Biomedicine and Molecular Immunology, “Alberto Monroy,” National Research Council of Italy, Via Ugo La Malfa 153,
90146 Palermo, Italy
3Department of Sciences for Woman and Child’s Health, School of Pediatrics, University of Palermo, Via del Vespro 129,
90100 Palermo, Italy
4Institute of Clinical Physiology, National Research Council (CNR) of Italy, Via Trieste 41, 56126 Pisa, Italy
Correspondence should be addressed to Giovanni Viegi, firstname.lastname@example.org
Received 1 May 2011; Revised 31 July 2011; Accepted 29 August 2011
Academic Editor: Mary Beth Hogan
Copyright © 2012 Stefania La Grutta et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
Fractional exhaled nitric oxide (FeNO) is a non-invasive marker of airway inflammation in asthma and respiratory allergy.
Environmental factors, especially indoor and outdoor air quality, may play an important role in triggering acute exacerbations
of respiratory symptoms. The authors have reviewed the literature reporting effects of outdoor and indoor pollutants on FeNO in
children. Although the findings are not consistent, urban and industrial pollution—mainly particles (PM2.5and PM10), nitrogen
dioxide (NO2), and sulfur dioxide (SO2)—as well as formaldehyde and electric baseboard heating have been shown to increase
FeNO, whilst ozone (O3) tends to decrease it. Among children exposed to Environmental Tobacco Smoke (ETS) with a genetic
polymorphisms in nitric oxide synthase genes (NOS), a higher nicotine exposure was associated with lower FeNO levels. Finally,
exposures when taking medical histories for asthma and respiratory allergy. Further research is also needed to assess the effects of
remedial interventions aimed at reducing/abating environmental exposures in asthmatic/allergic patients.
Elevated levels of nitric oxide in exhaled air (fractional
concentration of exhaled nitric oxide, FeNO) are considered
a noninvasive marker of airway inflammation in asthma
and respiratory allergy management . Nitric oxide is
produced endogenously in the airways from L-arginine by
NO synthase. There are two constitutive and one inducible
isoforms involved in airway inflammation; their expression
is stimulated by inflammatory cytokines .
FeNO levels correlate with eosinophilic counts in
induced sputum or bronchoalveolar lavage fluid and with
eosinophil infiltration of the airways, especially of atopic
subjects. Indeed, the interest in FeNO is based on the as-
sumptions that FeNO is a useful noninvasive marker of
asthma and asthma control . In fact, in mild-to-moderate
persistent asthmatic children followed by Childhood Asthma
Research and Education (CARE) Network supported by
NHLBI, a highly significant correlation of FeNO levels with
blood eosinophilia was found .
FeNO assessment is simple to perform and acceptable
for the population, especially in the pediatric age . In
addition, FeNO is faster and easier to obtain than other
measurements of inflammation such as sputum eosinophils
level . For these reasons, some authors use it as a comple-
mentarytool tolung functiontestsin orderto obtain a better
control of clinical symptoms and asthma exacerbations .
2 Journal of Allergy
There is extensive evidence that FeNO is elevated in
patients with untreated asthma, whilst it is decreased as
a consequence of corticosteroid therapy . Besides, high
FeNO levels can suggest a subclinical inflammation of the
airways, even in the absenceof symptoms and impairment of
lung function . Thus, FeNO could represent a helpful tool
for rationalizing the anti-inflammatory therapy in patients
with respiratory allergy.However, data on long-term benefits
of incorporating this kind of measurement in treatment
decisions are still missing .
In clinical practice, increased FeNO levels are used as
predictors of failed steroid reduction in stableasthmatic chil-
dren . FeNO values have been related to the occurrence of
disease exacerbation during a 1yr of followup in moderate
asthmatics by Gagliardo et al. , but not by Cabral et
al. . Such inconsistency has led the authors of a recent
systematic review to not include FeNO among the useful
clinical predictors of future asthma exacerbations for all the
children with moderate-to-severe asthma undergoing ICS
In the last decades, there has been an increase in
the prevalence of asthma and allergic diseases, particularly
among children living in the urban areas of economically
developed countries. This has led to suppose that environ-
mental factors, especially indoor and outdoor air quality,
in triggering acute exacerbations of respiratory symptoms
. The role of air pollution in the epidemics of allergies
is still debated, even if experimental studies have suggested
that the effects of air pollutants on the development and the
worsening of allergies are biologically plausible. Children are
particularly vulnerable because they inhale a higher volume
system is incomplete, and their defence mechanisms are
still evolving, with respect to adults. If lung defences are
breached, normal developmental and homeostatic processes
can be disrupted. This could determine disturbances in lung
development and acute damage that can, in turn, lead to a
chronic reduction in lung function. Therefore, a damage to
tional capacity, reducing the functionalreserve in adulthood,
thereby, enhancing susceptibility to the effects of ageing,
infections as well as pollutants .
The aim of this review is to make a reappraisal of the
current evidences on whether environmental factors, such as
outdoor and indoor pollutants, affect FeNO in children.
Since airway inflammation is a hallmark of asthma, FeNO
measurement is potentially useful to evaluate the impact
of air pollution on the inflammatory state of airways in
asthmatic children. Indeed, it is known that air pollution is
associated with FeNO in elderly adults with asthma , in
healthy adults , and in schoolchildren .
There is extensive evidence that outdoor pollutants
present in urban areas do have adverse effects on the
respiratory health of children . Children in general,
to the effects of outdoor pollutants such as ozone (O3),
particulate matter (PM10, PM2.5), nitrogen dioxide (NO2),
and sulphur dioxide (SO2) .
Although the mechanisms involved in the bronchial
inflammation due to pollution exposure are not yet fully
clarified, it is known that the type of air pollutant plays a
main role. In this sense, the oxidative stress, induced by reac-
tive oxygen species (ROS), may activate some transcription
factors, followed by cytokines secretion and inflammatory
cells recruitment. At last, NO is produced by epithelial cells
through the induction of inducible NO synthase (iNOS)
. Furthermore, experimental evidences suggest that PM
organic components have adjuvant effects on airway inflam-
mation, partly through exposure to redox-active chemicals
and oxidative stress . PM organic components can also
children with asthma .
Delfino et al.  found that personal (i.e., measured by
wearable monitors) and ambient air pollution correlate with
increased FeNO concentration from the lower airways of
children with asthma. In particular, in two pollutant models,
the most robust positive association with FeNO levels was
found for personal and ambient elemental carbon and
nitrogen dioxide, and for personal but not ambient PM2.5.
The association between PM and airway inflammation may
be missed using ambient particle mass concentration, which
may not adequately represent causal pollutant components
from fossil fuel combustion. Therefore, the contrasting
results for personal versus ambient air pollution could
suggest that protecting public health using only a particle
mass-based standard may be not sufficient. Supplemental
Rusconi et al.  evaluated lung function and markers
of inflammation and oxidative stress in children and ado-
lescents with and without asthma or wheezing symptoms
living in a petrochemical polluted area versus those living in
a reference area in Sardinia. They found that children living
in the polluted area showed decreased lung function (FEV1,
the increased level of certain pollutants, particularly PM10
and SO2. More recently, Renzetti et al.  have found
significantly decreased FeNO concentrations after relocating
to a rural environment asthmatic children who previously
polluted urban environment.
Similar results were found by Flamant-Hulin et al. 
who showed significantly increased FeNO levels in both
asthmatic and nonasthmatic schoolchildren exposed to high
concentrations of formaldehyde, acetaldehyde and PM2.5.
Stronger associations were found in nonasthmatic children
who were atopic, suggesting that they are more sensitive to
air pollution than nonatopic children. In other words, atopy
and asthma appear as cofactors in determining elevated
FeNO levels. In this sense, atopic status is strongly associated
with high FeNO levels, even in asymptomatic individuals.
The relation between atopy and FeNO levels indicates that
Journal of Allergy3
FeNO measurements may help to clarify the relevant role
of sensitization in the complex interplay of multiple factors
determining the translation into clinical allergy.
Liu et al.  demonstrated an important decrement in
small airway function and an increase in airway oxidative
stress in asthmatic children in association with exposure
to SO2, NO2, and PM2.5, but they did not find statistically
significant changes in FeNO associated with these pollutants.
The authors advance some possible interpretations for their
findings: need of a larger sample size to detect significant
changes in airway inflammation and measurement of FeNO
at low flow rate (0.05L/sec) to capture inflammation in
lower airways. Another explanation might be related to the
severe inflammation of the airways that overwhelmed the
effects of air pollution, particularly at low concentrations
of exposure. FeNO had a statistically significant negative
association with O3. This result is counterintuitive because
laboratory studies showed that high levels of O3cause
inflammation in the airways of human subjects. Therefore,
a sound interpretation for this negative association remains
to be found. Indeed, Kim et al. , in an occupational
setting, found a significantly inverse relationship between
ing while PM2.5concentrations increased.
More recently, Berhane et al.  have shown that short-
term increases in PM2.5, PM10, and O3 were significantly
associated with higher FeNO levels, being PM10effects sig-
nificantly higher in the warm season. In addition, the effects
of PM2.5and PM10had relatively shorter lag structures
compared to those of O3that had a longer lag structure (23
reasons for the lagged effects of ambient air pollutants on
FeNO might depend on the different levels of exposures to
pollutants across geographical regions and seasons and on
the variable degree of susceptibility of subjects, in terms
of asthma and/or allergy status. The authors suggest that
current level of ambient pollutants determine a potential
increase of nitrosative stress in both healthy and susceptible
children, leading to an increase of FeNO.
Since people generally spend the majority of their time
indoors, there is growing scientific evidence that indoor
pollution plays a significant role in affecting health. Indoor
environment contributes significantly to human exposure to
pollutants through complex interrelationships with outdoor
pollution . Indoor airborne pollutants are known to
trigger allergic responses in asthmatic patients with con-
sequent airway inflammation . Studies in both adults
and children showed that sensitization to indoor allergens
is associated with an increase in FeNO . In a review by
Sofia et al. it is suggested that FeNO can be used as a marker
for adverse respiratory health effects caused by indoor air
Allergen sensitization may play an important role in ele-
vating NO production in the airways. In a study conducted
by Cibella et al. , only sensitizations to Dermatophagoides
and to cat dander were found to influence FeNO levels. This
result was confirmed in other studies [29, 30]. Similarly,
Leuppi et al.  showed that in atopic children an increased
FeNO level is associated with sensitization to perennial aller-
gens, possibly through long-lasting inflammatory stimuli,
but not with seasonal allergen. Spanier et al. found that
cat and dog sensitizations were associated with increased
FeNO . Differently, Kovesi and Dales  found that
dog ownership, but not cat ownership, was associated with
changes in FeNO levels.
Numerous factors related to housing have been asso-
ciated with airway inflammation in children. Kovesi and
Dales reported that, compared with forced air and hot water
radiant heat, electric baseboard heating is associated with
a higher FeNO . The authors, based on others’ report
that forced air heating is linked to lower indoor dust mite
levels, speculate that the increased levels of indoor dust mite
associated with electric heating may increase the likelihood
of allergic sensitization and FeNO. In addition, it has been
found that electric baseboard heating is related to higher
formaldehyde concentrations in houses , which, in turn,
is associated with increased FeNO levels in children .
As far as the exposure to indoor PM sources is concerned,
a recent work found that self-reported exposure to the use
of woodstoves, candles, or gas cookers was not significantly
associated with increased levels of FeNO [35, 36].
Pasquale et al.  tested the hypothesis that chlorine
exposure is associated with increased concentrations of
exhaled NO, as a marker of eosinophilic airway inflamma-
tion, in children regularly attending (for 1 to 2 hours a
week) swimming pools. FeNO level was similar in children
who regularly attended a swimming pool and in those
who did not, whereas it was higher both in children with
upper airway infections in the last week and in those who
had a history of asthmatic symptoms. This suggests that
eosinophilic airway inflammation.
In addition, two studies evaluated the influence on FeNO
of exposure to polyvinyl chloride (PVC) material which
today represents a common indoor pollutant. Tuomainen et
al.  did not observe changes in FeNO levels in exposed
individuals. On the contrary, Kolarik et al.  found a
significant increase of FeNO compared to the reference
condition (clean outdoor air), suggesting that exposure
to plastic materials can be associated with a subclinical
inflammation of the airways.
4.Smoking and FeNO
Many studies investigated the effects of smoking on FeNO
values in both adults and children. There is consistent
evidence that active smoking and acute cigarette smoke
exposure lead to a transient decrease in FeNO levels in
healthy and asthmatic adults [39, 40]. As far as we know,
no study has yet demonstrated a link between passive smoke
and FeNO values in healthy children. In asthmatic children,
results are discordant probably due to methodological biases
(small sample sizes, heterogeneous study populations, lack
4 Journal of Allergy
of control for potential confounding factors) . Different
studies have not found a significant association of FeNO and
environmental tobacco smoke (ETS) exposure in children
with asthma [32, 42]. In particular, Laoudi et al. 
observed lower FeNO levels in exposed asthmatic children
than in unexposed children. This could be explained by
different mechanisms according to the type of exposure.
Acute exposure induces a marked but transient reduction in
FeNO levels related to a negative feedback of iNOS activity,
since tobacco smoke contains high concentrations of NO. In
the case of daily exposure, the mechanism is still unknown,
but one plausible hypothesis is that the progressive negative
feedback leads to the inhibition of iNOS gene expression.
Genetic differences may explain some of the conflicting
results in studies evaluating the effects of tobacco exposure
on FeNO levels. Spanier et al. found that a NO synthase gene
(NOS3) polymorphism (a mutation in exon 7) modifies the
effect of nicotine exposure on FeNO. The authors noticed
that this polymorphism determines decreased FeNO levels
in children exposed to increasing nicotine concentrations,
possibly through a decreased enzyme activity due to a
combination of genetic and environmental factors .
variants in the NO synthesis pathway genes contribute to
variation in FeNO levels in children. Particularly, the authors
found that four NOS2A single nucleotide polymorphisms
(SNPs) and one ARG2 SNP are significantly associated
with lower FeNO. They also noticed that the ARG2 SNP
modify the effect of NOS2A on FeNO. Therefore, FeNO
levels depend on variants in both ARG2 and NOS2A.
This gene-gene interaction may be due to a competition
for a common substrate, L-arginine, since arginase can
inhibit iNOS expression reducing NO synthesis. Some of
the observed genetic influences were stronger in children
with asthma. Therefore, asthma status can be considered an
important factor for determining the contributions of these
genetic variants to FeNO levels.
Most of referred data show that FeNO assessment is a com-
plementary tool to evaluate the effects of environmental pol-
lutants exposure in children. Nevertheless, some variations
exist among the studies. Such variations are mainly related to
the population studied (i.e., genetic variation, atopic versus
nonatopic, and asthmatic versus nonasthmatic), including
the treatment effects (i.e., inhaled steroid in asthmatics),
and to the variable pollutants exposure (i.e., personal versus
ambient, level of exposure, and short term versus long
Up to date, there are only few data about the influences
of genetic variations of NO synthesis pathway on FeNO
levels, suggesting that the genetic factors play a key role
in determining FeNO levels and have to be considered to
understand interindividual differences, especially when there
are host susceptibility factors, such as asthma and/or atopy.
Previous studies found that atopy status is per se able
to significantly influence FeNO levels, even in asymptomatic
individuals [21, 31]. In our experience, a significant relation
exists between FeNO levels and number of positive skin tests,
and the highest FeNO levels are observed in atopic children
with physician-diagnosed asthma. Thus, the association of
of increased FeNO level .
Earlier studies showed that FeNO levels are raised in
asthmatic children, especially if asthma is uncontrolled
and during asthma exacerbation. Instead, FeNO levels are
reduced after corticosteroid treatment [1, 44]. Therefore,
asthma condition may be an effect modifier in the relation-
ship air pollution FeNO; it is associated with high FeNO
levels according to several authors [2, 10, 45], with decreased
FeNO according to others [22, 43].
The contrasting results of FeNO values for ambient
and personal air pollution may be related to the individual
susceptibility and to the considered pollutant. In this sense,
Berhane et al.  underline that current levels of ambient
pollution have the potential to increase nitrosative stress
in both healthy and susceptible children. Heterogeneity is
increased by the different level of exposure reported in the
mainly at the proximity level of individuals . Indeed,
the use of multipollutant models might improve in the
final interpretation of interaction of pollution exposure with
In agreement with Berhane et al. , we think that
the inconsistencies on FeNO level interpretation about the
duration of the lags might be overcome including the time-
activity patterns to avoid the misclassification of exposure
Finally, in light of the evidence that the variations in
FeNO measurements show many inconsistencies in children
exposed to environmental pollutants, further research is
warranted to examine whether FeNO could be used as
a useful tool to identify the most susceptible children to
adverse respiratory effects from exposure to pollutants.
Since many factors such as atopy, sex, season, and corticos-
teroid treatment influence FeNO values [4, 29], clinicians
and researchers should know an individual FeNO baseline in
asthmatic children management before studying the effect of
other determinants. In addition, clinicians should take into
account some indoor pollution factors, like indoor allergens
[4, 31, 32], mainly Dermatophagoides and pets, electric
baseboard heating , higher formaldehyde concentrations
in houses , using of woodstoves, candles or gas cookers
[35, 36], chlorine, or PVC exposure [36, 38] for which
increase FeNO values are found in children. Furthermore,
the possibility that a low FeNO level in an asthmatic child
is related to ETS exposure should be considered by the
clinicians [41–43, 45].
As environmental interventions are an important com-
ponent of asthma management, FeNO might be useful to
Journal of Allergy5
integrate the control of environmental triggers into asthma
of the airways to airborne irritants is reversible, it may
be expected that limiting air pollution will reduce airway
inflammation . Therefore, FeNO assessment may help in
to major changes in environmental disease-related factors
Even considering that we reviewed this topic from a
public health perspective, the literature impacts into the
clinical practice should include the more recent findings
on the higher FeNO levels significantly associated with the
short-term increases in PM2.5, PM10, and O3. Therefore,
we would recommend clinicians to obtain more complete
information on outdoor and indoor exposure of susceptible
subjects for the sake of an accurate interpretation of the
FeNO levels in the real life management of allergic asthmatic
children. The observed reduction of the FeNO levels in
asthmatic children after one week relocation to the rural
environment , the lower level of FeNO in children living
in the reference area in comparison to those living in the
high polluted area , as well as the higher FeNO levels in
children living in homes with high average of formaldehyde
levels versus those living at a lower concentration 
suggest that FeNO assessment might be a useful marker also
to monitor the variation in airway inflammation due to the
In light of the reviewed evidence, we would recommend
that further research is carried out firstly by organizing a
cross-sectional multicentre epidemiological study in differ-
ent countries characterized by different genetic background
and level of environmental pollutants in order to better
investigate the effect of gene and environment interactions
on FeNO levels; such study design would also help obtaining
reliable reference values of FeNO. Subsequently, nested case-
control studies should be performed in order to assess the
impact of remedial interventions regarding the previously
cited factors affecting a FeNO concentration; such study
design would allow clinicians to implement a public health
perspective in the individual-physician relationship. Lastly, it
would be helpful to expand the medical histories of children
enrolled in pharmaceutical clinical trials, through collecting
information on exposome, in order to reduce the residual
variability of therapeutic treatment.
Conflict of Interests
The authors have no conflict of interests to disclose in the
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