Feno Revision Sistematica Italia 2020

MRM_01 position.
qxp_Hrev_master 18/02/20 15:31 Pagina 1
Multidisciplinary Respiratory Medicine 2020; volume 15:36
POSITION PAPER
Fractional Exhaled Nitric Oxide (FENO) in the management of asthma:

a position paper of the Italian Respiratory Society (SIP/IRS)
and Italian Society of Allergy, Asthma and Clinical Immunology (SIAAIC)
Enrico Heffler,1,2 Giovanna Elisiana Carpagnano,3 Elisabetta Favero,4 Giuseppe Guida,5 Mauro Maniscalco,6
Andrea Motta,7 Giovanni Paoletti,1,2 Giovanni Rolla,8 Eugenio Baraldi,9 Vincenza Pezzella,10 Giorgio Piacentini,11
Stefano Nardini12
1
Personalized Medicine, Asthma and Allergy, Humanitas Clinical and Research Center IRCCS, Rozzano (MI);
2
Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (MI)
3
Department of Medical and Surgical Sciences, University of Foggia; Section of Respiratory Diseases, Hospital d'Avanzo, Foggia
4
Department of Medicine-DIMED, Immunological and Respiratory Rare Disease, Allergologic Clinic Ca’ Foncello Hospital, Treviso
5
Allergy and Pneumology Unit, A.O. S. Croce e Carle, Cuneo
6
Respiratory Rehabilitation Unit, ICS Maugeri, Institute of Telese Terme IRCCS
7
Institute of Biomolecular Chemistry, National Research Council, Pozzuoli (NA)
8
Allergy and Clinical Immunology, University of Turin and A.O. Mauriziano, Turin
9
Department of Woman's and Child's Health, University Hospital of Padua
10Department of Woman, Child and of General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples
11Paediatric Section, Department of Surgery, Dentistry, Paediatrics and Gynaecology, University of Verona
12Italian Respiratory Society-Società Italiana di Pneumologia, Milan, Italy
Asthma prevalence in Italy is on the rise and is estimated to be over 6% of the general population. The diagnosis of
asthma can be challenging and elusive, especially in children and the last two decades has brought evidences that asth-
ma is not a single disease but consists of various phenotypes. Symptoms can be underestimated by the patient or under-
reported to the clinician and physical signs can be scanty. Usual objective measures, like spirometry, are necessary but
ABSTRACT
sometimes not significant. Despite proper treatment, asthma can be a very severe condition (even leading to death),
however new drugs have recently become available which can be very effective in its control. Since asthma is currently
thought to be caused by inflammation, a direct measure of the latter can be of paramount importance. For this purpose,
the measurement of Fractional Exhaled Nitric Oxide (FENO) has been used since the early years of the current century
as a non-invasive, easy-to-assess tool useful for diagnosing and managing asthma. This SIP-IRS/SIAAIC Position
Paper is a narrative review which summarizes the evidence behind the usefulness of FENO in the diagnosis, manage-
ment and phenotypization of asthma.
Key words: Asthma diagnosis; asthma management; Fractional Exhaled Nitric Oxide (FENO).
Correspondence: Stefano Nardini, Italian Respiratory Society-Società Italiana di Pneumologia, Milan, Italy.
E-mail: snardini.pneumologo@gmail.com
Contributions: All the authors made a substantive intellectual contribution, read and approved the final version of the manu-
script and agreed to be accountable for all aspects of the work.
Conflict of interest: EH, SN are consultants of Circassia AB; SN is Coordinator of the Associate Editors of the Editorial Board
of Multidisciplinary Respiratory Medicine. The remaining authors have no conflict of interest to declare.
Funding: This position paper jointly produced by the Italian Society of Asthma, Allergy and Clinical Immunology (SIAAIC) and
the Italian Respiratory Society (SIP-IRS) has been made possible thank to an unconditioned educational grant of Circassia AB,
Hansellisgatan 13, SE-754 50 Uppsala, Sweden.
Ethics approval and consent to participate: Not applicable.

MRM_01 position.qxp_Hrev_master 18/02/20 15:31 Pagina 2
Multidisciplinary Respiratory Medicine 2020; 15:36 - E. Heffler et al.
the Italian Society of Allergy, Asthma and Immunology (SIAAIC)

Introduction and aim of the Position Paper [6,7].
Nowadays, asthma is thought to be a complex, multi-factorial
Asthma affects more than 300 million individuals worldwide.
disease characterized by variable clinical presentations in different
It is characterized by chronic airway inflammation leading to res-
subset of patients (the so-called “phenotypes”), resulting from het-
piratory symptoms (dyspnea, wheezing, chest tightness and
erogeneous expression of inflammatory pathways, involving both
cough). Symptoms can vary over time and intensity and are cou-
innate and adaptive immune systems (the so-called “endotypes”)
pled with variable expiratory airflow limitation [1].
[8]. Accordingly, asthma can be classified at least in two different
The prevalence of asthma in Italy is constantly increasing over
subgroups: one characterized by high expression of type-2
time and it is estimated to be over 6% of the general population
cytokines and associated inflammatory cells (“type-2 high” endo-
[2,3]. The diagnosis of asthma can be challenging. The clinical
types), classically presenting with eosinophilic phenotypes; the
presentation can be not very specific for the disease and it requires
other with low expression of type-2 cytokines and characterized by
the demonstration of variable airflow limitation by means of lung
predominant neutrophilic airway inflammation [9]. A ‘mixed’
function tests (i.e., spirometry, bronchodilation test, bronchial
endotype has been also described coming from an overlap of these
challenges, PEF measurements) and the diagnostic process can be
syndromes [10].
even more challenging in children. Moreover, subjects with asthma
The identification of phenotypes passes through a careful eval-
can be unaware of their sickness or anyway underestimate it, due
uation of any single clinical aspect, lung function patterns, sputum
to infrequent symptoms or exacerbations [1]. Symptoms can be
and systemic inflammatory involvement. The identification of
classically triggered by exposure to allergens, respiratory tract
endotypes passes through reliable and possibly non-invasive bio-
infections, exercise, exposure to cold air, tobacco smoke or pollu-
markers of inflammation. This is crucial for establishing a preci-
tion, and tend to be more frequent at night.
sion medicine-based management [11], including the possibility to
Chronic airway inflammation, enhanced by the above men-
treat patients with novel biologic agents that are showing impres-
tioned triggers, contributes to induce airflow limitation that can be
sive results in controlling more severe asthmatics [12]. Despite the
assessed by lung function tests. This airflow limitation is classical-
central role of airway inflammation in the pathogenesis of asthma,
ly reversible after administration of inhaled bronchodilators (an
the most commonly used diagnostic algorithms, such the one pro-
increase in Forced Expiratory Volume in the first second FEV1 of
posed by the Global Initiative for Asthma (GINA) [1], do not
at least 200 mL and higher than 12% compared with basal value
include any assessment of airway inflammation. FENO is a non-
achieved after inhalation of salbutamol 400 mcg) or after pro-
invasive, easy-to-assess tool to measure airway inflammation, both
longed (i.e., after at least 4 weeks) treatment with inhaled corticos-
in adults and children [13,14], and it could be useful for both asth-
teroids (ICS). Airway hyperresponsiveness can be assessed by
ma diagnosis and management. This SIP-IRS/SIAAIC position
bronchial challenge with bronchoconstrictor drugs such as metha-
paper is a narrative review which aims to summarize the evidence
choline [1]. Histamine or mannitol can also be used. Diagnosis in
behind the usefulness of FENO in the diagnosis, management and
children is even more challenging, since lung function tests cannot
phenotypization of asthma.
be carried out before 5 years of age.
Once clinical and functional diagnosis of asthma has been
established, further evaluations, including a complete allergologi-
cal workup, should be done in order to identify possible specific Nitric oxide
triggers or predisposing conditions that may have an impact on
asthma management. In this context, Fractional Exhaled Nitric Nitric oxide (NO) is a colorless gas that is only slightly soluble
Oxide (FENO) assessment could be taken into consideration to strat- in water (<2 mmol under standard temperature and pressure). NO
ify patients according to the airway inflammatory involvement [1]. is a paramagnetic molecule with an odd number of electrons,
Treatment of asthma is based on controller drugs with anti- which implies that it is a radical with an unpaired electron that
inflammatory activity [mainly ICS, but also other add-on drugs implies an extreme reactivity responsible for many of its biological
such as leukotriene-receptor antagonists (LTRA)], possibly associ- effects [15]. The kinetics of NO autoxidation in aqueous solution
ated with long-acting bronchodilator drugs [generally long-acting depends on its concentration [16]. Accordingly, the half-life is not
beta2-agonists (LABA), or long-acting muscarinic agents a constant value and is inversely proportional to the NO concentra-
(LAMA) for more severe patients] depending on the severity of the tion, becoming much longer as nitric oxide dilution increases. At
disease [1]. The aim of the treatment is to achieve the complete physiological concentrations (1 μM to 10 nM), the half-life of NO
asthma control, defined as the absence of symptoms, normal lung- due to the reaction with oxygen (O2) is estimated to be in the 9-to-
function and no future risk of adverse events [1]. This should be 900 min range [17]. It has been reported that when the partial oxy-
obtained using the least level of treatment as possible, optimizing gen pressure increases in aqueous solution from 150 to 700 mmHg,
the adherence and the ability to correctly use inhaler’s devices as the NO half-life decreases from 6.2 to 3.8 s [18]. The short half-
otherwise patients could not benefit from the given therapy [4]. life and the reactive structure of NO, in the absence of efficient free
This emphasizes the essential role of education just after diagnosis NO storage, require a carefully controlled enzymatic NO synthetic
and in follow up [1]. If symptoms are inadequately controlled activity regulated through complex mechanisms of activation and
despite treatment, adherence and the ability to use inhalers’ devices inactivation.
should be revised, common comorbidities should be properly treat- NO production can occur via enzymatic and non-enzymatic
ed and any other known risk factors should be removed. pathways [19]. The enzymatic synthesis occurs from the semi-
Persistence of poor asthma control and/or frequent exacerbations essential amino acid L-arginine and oxygen via three isoforms of
and/or impaired lung function despite high dose of ICS plus anoth- an enzyme named nitric oxide synthase (NOS), identified in vari-
er controller and/or maintenance treatment with oral corticos- ous tissues, and it is classically classified as constitutive and
teroids (OCS) defines “severe asthma” [5]. A referral to a severe inducible. In fact, NOS-1 and NOS-3 isoforms are constitutively
asthma clinic should be taken into consideration also for treatment expressed, while the third one (NOS-2) is generally expressed in
with novel biological agents [6]. For instance, the Severe Asthma activated cells, although the latter may also be constitutively
Network in Italy (SANI) represents a network of Italian severe expressed and be active in the paranasal sinuses [20]. NOS
asthma centers, by the Italian Respiratory Society (SIP-IRS) and enzymes have different requirements for the activation [21].
Indeed, NOS-1 and NOS-3 are calcium-calmodulin dependent, and inactivate enzymes and other proteins. NO targets many enzymes
are activated in response to a calcium signal. Enzyme activation in this way, particularly those important for the mitochondrial res-
occurs rapidly and transiently. Production of NO is equally tran- piratory chain, which is essential for ATP synthesis [24].
sient, providing a rapid pulse-like signal. NOS-1 and NOS-3 The role of NO in inflammation remains elusive. It is likely
enzymes produce small amounts of NO. Differently from NOS-1 that an excessive amount of NO produced by NOS-2 exerts the
and -3, NOS-2 contains tightly bound calmodulin. NO synthesis same types of effects as does the “physiological” NO, including
does not seem to be regulated but rather controlled at the transcrip- relaxation of smooth muscle cells and vasodilatation. Thus, the
tional level, and once the enzyme is expressed it will produce large increased NO levels in inflammation may be involved in hyper-
amounts of NO for prolonged periods, depending on how long the emia, edema and hypotension. Furthermore, NO may reduce apop-
enzyme is present in a given cell or tissue. NOS-2 expression is tosis of inflammatory cells such as eosinophils. On the other hand,
dependent on transcription factors such as nuclear factor κB (NF- at high concentrations NO downregulates adhesion molecules,
κB), activated by pro-inflammatory cytokines, including tumor suppresses activation of inflammatory cells, and induces their
necrosis factor-α (TNF-α), interleukin-1b (IL-1b) [21], interleukin apoptosis [25].
4 (IL-4) [22] and interleukin 13 (IL-13) (which upregulates NOS- However, a different perspective on NO homeostasis in air-
2 expression and activity) [23]. way inflammation has been outlined [26]. In particular, it has been
Apart from enzymatic synthesis pathways, endogenous pro- suggested that an increased arginase activity, in conjunction with
duction of both NO and H2S can occur through other non-enzy- an abnormal cellular uptake of L-arginine, may represent a major
matic processes that are less well understood. NO can be produced causative factor of NOS dysfunction in asthma. L -arginine is a
in vivo by a reduction of NO3– (nitrate) to NO2– (nitrite), and NO2– substrate for both arginase and NOS, and therefore these enzymes
can produce NO. In fact, at low pH, nitrite will form nitrous acid might affect each other activity through substrate competition. In
(HNO2), which decomposes to various nitrogen oxides, including an allergic inflammatory microenvironment, pro-inflammatory
NO. Nitrite may come from either dietary intake or saliva, through cytokines and “oxidative stress” might upregulate the production
a reduction of nitrate to nitrite performed by bacteria in the oral of NOS-2-derived NO through activation of transcription factors
cavity. [27]. In this situation, the synthesis of strong oxidizing reactive
Figure 1 summarized the enzymatic and non-enzymatic syn- nitrogen species (RNS), such as peroxynitrite, leads to cell dam-
thesis of nitric oxide. age in the airways of asthmatics. In addition, upregulation of
arginase in an inflammatory microenvironment is able to limit L-
arginine bioavailability for NOS-2, which can result in the pro-
duction of both NO and O2 as a consequence of the substrate defi-
Biological functions of nitric oxide ciency. This effect promotes an amplification of peroxynitrite for-
The biological effects of NO in humans are numerous and mation, leading to an enhanced cytotoxic action in the airways. It
involve the whole organism, and only some of those effects are might thus be speculated that a similar pathway can be activated
exerted by direct actions [15]. Indeed, certain physiological and in the inflammatory diseases of the upper airways such as allergic
pathophysiological effects of NO are likely to be due to derivatives rhinitis or nasal polyposis, though this hypothesis needs to be
of NO rather than by this molecule itself. The direct actions of NO experimentally validated.
occur at low concentrations by binding to a number of molecular
targets such as metal containing proteins and DNA. These interac-
tions lead to enzyme activation or inhibition. The most notable of
such processes is the reaction of NO with the heme group of
guanylyl cyclase [15]. The subsequent activation of this enzyme is
responsible for the conversion of guanosine trisphosphate (GTP)
into cyclic guanosine monophosphate (cGMP). cGMP in turn acti-
vates protein kinases that perform several regulatory functions,
including smooth muscle relaxation, neuronal transmission, and
inhibition of platelet aggregation.
On the other hand, NO can inhibit other metallo-proteins such
as cytochrome P-450, cytochrome oxidase and catalase. NO may
also modulate other oxidative reactions by interacting directly with
high energy free radicals, for example inhibiting lipid peroxidation
and reducing the generation of pro-inflammatory lipids.
In contrast to the direct actions of NO, its indirect effects are
mediated by reactive nitrogen oxide species (RNOS) derived from
the interactions of NO with O2 or O2•‒ superoxide anion [24].
Indeed, reactive nitrogen oxides have been suggested to be impor-
tant mediators of the pathophysiological events underlying a broad
spectrum of inflammatory responses. The most common reactive
nitrogen oxide species produced in vivo are dinitrogen trioxide
(N2O3) and peroxynitrite (ONOO–, an unstable structural isomer of
nitrate, NO3−), which can induce both nitrosative and oxidative
chemical stresses often associated with pathological situations
such as inflammation. An example of such phenomena can be
mediated by the potent cytotoxic and oxidant peroxynitrite and its
conjugate peroxynitrous acid ONOOH, which can oxidize thiols,
nitrate tyrosine and guanosine, as well as cleave DNA [24]. RNOS Figure 1. Non-enzymatic (left side) and enzymatic (right side)
can react with sulfhydryl containing amino acids that irreversibly synthesis of nitric oxide. NOS, Nitric Oxide Synthase.
tem, with a sensor that needs replacing between 100 and 300 meas-
Assessment of FENO urements. Patients have to produce a 10-second exhalation of
breath at an exhalation pressure of 10-20 cmH2O in order to main-
Since Gustafsson et al. [28], who reported the first detection of
tain a stable flow rate of 50±5 mls-1. A calibrated electrochemical
NO from human expired breath, several techniques have been
sensor evaluates the final 3 s of exhalation expressing the result in
developed. Nowadays, the most used are chemiluminescence,
ppb in the 5-300 ppb range. The NObreath is a monitoring device
electrochemical sensors and laser-based technology, all of which
that requires 12 seconds of exhalation of breath in adults and 10
present advantages and disadvantages in a clinical setting. FENO
seconds in children. It weighs approximately 400 g, including bat-
could be measured both online and offline [29,30]. Online meas-
teries, which last for up to 120 procedures. As the instrument does
urement may provide a better data quality but offline measurement
not have a set lifetime, it is strongly suggested that the sensor cells
is often more practical [31,32].
be replaced every 2 years [35]. The Medisoft device is semi-
The chemiluminescence method is the gold standard for
portable (weighing approximately 10 kg), and allows for repeat-
exhaled NO analysis. NO molecules contained in the gas sample
able analysis of exhaled NO using an internal sample bag for off-
are detected because of the radiation created after their reaction
line measurements. It has a software package that provides a step-
with ozone (O3), generated in the instrument. The reaction between
by-step, on-line quality control. The measurement range is 0-600
NO and O3 generates nitrogen dioxide molecules (NO2 ) in an
ppb. The NO cells are long lasting, typically 24 months or longer.
electronically excited state. The subsequent reversion of these mol-
The Vivatmo-PRO device is a portable device with an infrared sen-
ecules to their lower energy ground state causes the emission of
sor, which gives a rapid response and may not require storage of
electromagnetic radiation (photons), with wavelengths ranging
the sample in a chamber. In a recent study it has been showed a
between 600-3000 nm, which can be detected and amplified by a
good correlation among some of these devices although the abso-
photomultiplier tube. The resulting output signal is determined and
lute exhaled NO measurements may differ to a clinically relevant
corresponds linearly to the NO concentration in the sample, pro-
extent [36]. Table 1 summarizes the performance characteristics of
vided that O3 is present in excess.
the most representative FENO analysers.
The chemiluminescence equipment is highly sensitive, with a
Recently, the use of optical sensors based on different laser
detection threshold at ppb (parts-per-billion, 1:109) level and a very
technologies and detection methods has been developed for meas-
fast response time (0.5-0.7 s). In addition, the technique allows for
uring of NO concentrations [37]. Schematically, these sensors
direct analysis of the breath in situ, or indirectly by sampling the
include a laser source that produces light that interacts with gas
breath in a balloon that can be analyzed later. However, to ensure
molecules, a gas cell containing the sample to be analyzed, and,
reliability frequent instrument calibration is often required, which
finally, the detection system. For NO detection, the light source in
is achieved by using concentration of NO up to hundreds of ppb.
the optical sensors must probe at the fundamental and strongest
In addition, these analyzers need a source of external NO-free air
absorption band, centered in the mid-infrared region at 5.3 μm
to generate ozone within the equipment, and a vacuum pump sys-
ranging from 5.1 to 5.7 μm.
tem, which rise manufacturing costs with prices ranging between
Previously, the main limitation of the laser-based NO sensors
18,000 and 41,000 EUR [33]. Furthermore, chemiluminescence
in this spectral range was the interference from several other gases,
analyzers are quite large, weighing between 25 and 45 kg. All these
such as CO2 and H2O. Hence, only specific absorption NO lines
limitations have restricted the use of chemiluminescence analyzers
could be targeted, requiring only sensors that could generate the
in routine clinical applications or home monitoring, and currently
specific light spectra to be used.
remain in use solely for laboratory analysis.
Other methods are being developed, based on new technolo-
Current commercially available chemiluminescence FENO ana-
gies, like the smart solid-state microsensors [38]. The optical sen-
lyzers include NOA 280i (Sievers, GE Analytical Instruments,
sor can be used to detect low levels of NO concentration, utilizing
Boulder, CO, USA), NIOX (Circassia, Oxford, UK), Logan model
laser technology to measure the decrease of light intensity due to
LR2149 (Logan Research; Rochester, Kent, UK) and CLD 88 (Eco
absorption by NO; several laser-based sensors have been devel-
Medics, Duernten, Switzerland).
oped to detect also 0.3 ppb of NO within 1 s [39-42].
Electrochemical sensors can also be used to measure exhaled
The American Thoracic Society (ATS) and the European
NO as they convert the gas concentration into an electrical signal
Respiratory Society (ERS) have agreed on a highly standardized
[34]. The principle is based on the amperometric technique, which
procedure for measurements of lower respiratory tract exhaled NO
is achieved in the electrochemical instrument by a buffer system
[43]. According to the guidelines for FENO measurement in adults,
that allows retention of the last portion of the exhalation sample.
a single breath sample is instantly analyzed as the subject performs
Subsequently, the sample is transferred to the sensor for analysis
a breathing maneuver. The subject makes an inhalation to total
where the target gas undergoes a chemical reaction in the presence
lung capacity (TLC) with scrubbed air, not to contaminate the sam-
of active catalytic sensor, and a measurable physical change is
ple with possibly high NO from the environmental air, and then
emitted within an electrical circuit. The sensor output signal, which
presents a high sensitivity, is directly proportional to the partial
pressure, and therefore to the concentration, of NO in the sample.
The optimization of NO selectivity and sensitivity from the
exhaled breath sample relies on catalyst and electrolyte composi-
tion with a complex arrangement of diffusion barrier membranes Table 1. Performance characteristics for representative FENO
and a specific chemical filter system. analyzers.
Several electrochemical or infrared sensor devices are com-
mercially available: NIOX VERO (Circassia, Oxford, UK),
Characteristics Chemiluminescence Electrochemical Laser
NObreath (Bedfont Scientific Ltd, Kent, UK), Medisoft (Hypair, Weight 40 kg 1 kg

Dinant, Belgium) and Vivatmo pro (Bosch, Waiblingen,
Germany).
Sensitivity < 1ppb >5 ppb 1 ppb
The NIOX VERO device is hand-held and portable (less than

Response time <1 s >10 s 1s
1 kg), and can be used for both adults and children [35]. It is pre-
External calibration Yes No No
calibrated, designed to ensure a service- and calibration-free sys- Price 50 kEUR 4 kEUR >100 kEUR
exhales for 10 s at a specified 5-20 cmH2O pressure. This pressure eosinophils ≥3% and identifies patients with a good response to
is necessary to ensure the closure of the soft palate, minimizing the corticosteroids and T2 immunomodulators. FENO values >50 ppb
risk of contamination of the exhaled NO from the paranasal sinus- (>35 ppb in children) are likely connected with airway
es, where NO concentrations are very high. The guidelines also eosinophilic inflammation and this data may be used to predict a
recommend an exhaled flow of 50 ml/s (FEno50), based on the response to anti-inflammatory therapy, while low FENO <25 ppb
hypothetical assumption that the region of interest for the NO (<20 ppb in children) correlates with less eosinophilic inflamma-
excretion is within the lower parts of the airways. This relates to tion and responsiveness to corticosteroids [43]. Diagnostic FENO
the reasoning that the airways are considered similar to a basic tub- cut point in well controlled asthma is usually indicated by normal
ing system through which the expired air is led. If there is no NO values [65]. FENO >30 ppb was associated with uncontrolled asth-
depletion within the airway walls during the air passage, a steady ma [66].
state condition and thereby a stable exhaled concentration level According to GINA guidelines, following the diagnosis of
(plateau) is reached, corresponding to the chosen exhalation flow severe asthma, FENO ≥20 ppb is considered the cut-off characteriz-
rate. The exhalation flow rate can influence the exhaled concentra- ing Type 2 inflammation severe asthma and it is used to assess this
tion level, with low flows resulting in higher levels and vice versa. asthma phenotype, together with other markers like blood and spu-
A normal FENO concentration in healthy adults is in the 10-20 ppb tum eosinophils [1]. Is has been suggested a FENO cut point of 21
range. In inflammatory diseases such as bronchial asthma, not ppb that best fits ≥3% sputum eosinophils in corticosteroid-naive
treated with anti-inflammatory medication, the exhaled NO values patients [67]
can reach more than 100 ppb. Reference values are meant to be used as a general guide,
mindful that they can have significant changes in different patients
[1,43].
Very few data from studies analyzing clinically important
Interpretation of FENO results change of FENO in individual patients is available [62,68-73] and
FENO values can be influenced by several non-disease-related different are the results depending on the considered outcome.
factors, thus filling in a questionnaire for NO measurement is rec- Considering simply the within-subject coefficient of variation, in
ommended [44]. Confounding factors could be related to the healthy subject is approximately 10% (corresponding to a raw
patient, like genetics, sex, weight and height, diet (i.e., coffee) or change up to 4 ppb) [62,68] while it increases to about 20% in
taking drugs such as anti-inflammatory medications; also current patients with asthma [71-73], therefore leading the ATS experts to
smoking and atopy seem to influence FENO levels [45,46]. Allergen recommend a change of at least 20% to indicate a significant rise
exposure is associated with higher levels of FENO but they could or fall in FENO over time or following an intervention [43]. If the
decrease during the early phase of allergic response [47]. Smoking considered outcome is the transition from good control to poorly
is an important determinant of FENO levels and current smokers controlled asthma, a Minimal Clinically Important Difference
exhibit lower levels of FENO in comparison to ex-smokers and (MCID) ranging from 16 ppb to 25 ppb (corresponding to an up to
never smokers [48]. Both active and passive smoking have effects 60% increase from baseline) has been demonstrated [71-73]. On
on lowering FENO as demonstrated in healthy adults and in both the other hand, considering the change in FENO during an acute
adults and children suffering from asthma, regardless their allergy event, the increase of values has been described as 50% higher in
status [49]. Different mechanisms are suggested for explaining the acute asthma attacks compared with when stability was restored
reduced FENO in smokers such as downregulation of NO synthetase [70], and up to 150 ppb during exposure to a relevant allergen
by NO from cigarette smoke, increased breakdown of NO or lack [74,75] or acute infection.
of the required supply of tetrahydrobiopterin [50]
FENO could be influenced also by viral respiratory infections
[43]. Age seems to be important too, especially in children [51],
Extended nitric oxide analysis
but correlation between age and sex has still to be defined [52-54].
Recently, also ethnicity seems to have a role in FENO results, The measurement of exhaled NO at just one exhalation flow
impacting clinical management [55-57]. rate does not allow identification of NO production sites within the
Moreover, there are also technical confounding factors in FENO respiratory system. Therefore, mathematical models have been
measurement, like the NO analyzer used [58], measurement tech- created to calculate the production within lung. George et al. [76]
nique, exhalation flow rate or nasal NO contamination. Spirometry and Hogman et al. [77] have extensively reviewed the different
could also influence FENO results, thus it should not be performed models. When the exhaled NO at different flow rates is detected in
first [43]. FENO could increase due to bronchodilation and it could breath sampler, the NO production sites in the respiratory system
decrease due to bronchoconstriction [47,59]. Over-distension dur- can be calculated. In particular, the NO flux from the airway wall
ing a profound inhalation can affect FENO levels also because the to the lumen (JawNO) and fraction of NO in the gas-phase alveolar
patient may not have control over exhalation flow rate [44]. Thus, region (CANO) can be calculated when NO measurements are
it is mandatory to correctly interpret FENO results in each patient, acquired at multiple high flow rates. Additional mathematical cal-
referring to the clinical context in which the test is being done; it culations with NO measurements obtained at both low and high
is also important to report the device used to make FENO measure- flow rates can give the airway tissue concentration of NO released
ment, how many measurements have been made and the flow rate by the rigid conducting airway system (CawNO) and the transfer
(50 ml/s for approved FDA devices) [43]. All the measurements factor indicating the total airway compartment diffusion capacity
performed can be included but at least the mean value should be (DawNO). Hence, extended NO analysis can shed light on the NO
reported [43]. production sites of the respiratory system in patients.
Reference values have been described for FENO in adults The clinical application of measuring FENO at different flow
[51,52,60,61] and children [59,62-64]. In clinical practice, FENO rates is yet limited to some research setting, however information
<25 ppb in adults (<20 ppb in children) is considered the normal on the contributions of the bronchi (bronchial NO flux) and the
value. FENO levels between 25-50 ppb in adults (20-35 ppb in chil- peripheral lung (alveolar NO concentration) to exhaled NO is
dren) should be contextualized within the clinical context [43]. intriguing [78.]
The eosinophilic asthma phenotype is characterized by sputum Increased alveolar NO concentration has been reported in
severe, nocturnal and treated asthma [79] while NO flux from ber of positive skin-prick tests [91] and IgE-antibody concentra-
bronchial lumen (J’awNO) was associated to cough variant asthma tions [92]. Recently it has been shown that increased levels of
and non-asthmatic eosinophilic bronchitis [80]. exhaled NO in adolescents, 12-15 years old, precede incident self-
In all chemilumiscence analyzers, expiratory flow rates can be reported allergic symptoms to cat and dog within four years [93].
modified by resistors, allowing an extended NO analysis. On the
other hand, most electrochemical sensors are not suitable for mul- Rhinitis
tiple flow analysis. An exception is the Medisoft that allows eval- FENO values are generally reported to be higher in adults with
uation of exhaled NO at multiple flow rates. allergic rhinitis (AR) when compared to healthy controls and
patients with non-allergic rhinitis (NAR) [94]. As up to one third
of patients with rhinitis may have asthma, it is interesting to report
that AR with/without asthma had significantly higher FENO levels
FENO in asthma diagnosis than patients with NAR without asthma, while subjects with NAR
As the GINA guidelines suggest [1], FENO cannot be used as and asthma exhibited elevated FENO levels, similar to AR [95].
the only parameter for ruling in or ruling out a diagnosis of asthma. Natural pollen exposure was found to cause a significant FENO ele-
Its values are higher than normal in asthmatics that are character- vation in allergic individuals. Thus, IgE-mediated allergy has been
ized by Type 2 airway inflammation, and, as previously reported, reported to be responsible for elevated FENO [96]. FENO values that
several factors can affect FENO levels (smoke, bronchoconstriction, were lower in AR compared with asthma were shown to reach sim-
viral respiratory infections). ilar levels after allergen exposure [97]. In patients with rhinitis and
On the other hand, the British National Institute for Health asthma-like symptoms, the presence of asthma was associated with
Care Excellence (NICE) guidelines [81] recommend FENO testing higher FENO values [98]. In a consecutive series of patients referred
in combination with other diagnostic options to help diagnose asth- to an allergy clinic for chronic persistent rhinitis symptoms, airway
ma in adults and children when diagnosis is unclear (i.e., in case of inflammation, evaluated by increased values of FENO, and diagno-
normal lung function), and in those for whom, after initial clinical sis of asthma were significantly more prevalent in patients with AR
examination, an intermediate probability of having asthma is pres- and chronic rhinosinusitis (CRS) compared to patients with non-
ent or in those with confounding factors as obesity, anxiety, etc… allergic rhinitis [99]. One every four subjects with allergic rhinitis
[82]. FENO measurement is recommended by NICE also as an and very high FENO values (>50 ppb) have been shown to develop
option to support asthma management in people who are sympto- asthma at follow up according to a recent report [100].
matic despite using inhaled corticosteroid (ICS) treatment. Chronic rhinosinusitis
FENO measurement could also be used in differentiating
Cough-Variant Asthma (CVA) from other causes of chronic cough Chronic rhinosinusitis is classified into CRS with nasal polyps
[83-86], to distinguish pre-school wheezing phenotypes and to (CRSwNP), characterized by eosinophilic inflammation and CRS
assess the risk of later asthma or impaired lung growth and lung without nasal polyps (CRSsNP). Asthma is more frequently seen in
dysfunction in children [87]. CRSwNP patients than in CRSsNP patients. FENO, blood
According to the available literature, high FENO values increase eosinophil counts, number of eosinophils in nasal polyps, and total
the probability of asthma diagnosis, while a negative test does not IgE are generally all higher in CRSwNP patients than in CRSsNP
necessarily exclude asthma [43]. Data from secondary care patients. FENO values in CRSwNP patients without asthma showed
patients showed a sensitivity of 43–88% and specificity of 60–92% significantly higher FENO values than CRSsNP patients without
[88] for diagnosis of asthma. The Positive Predictive Value (PPV) asthma, while no significant difference in FENO was seen between
and Negative Predictive Value (NPV) were 54-95% and 65-93%, patients with CRSwNP with and without asthma [101]. The pres-
respectively [43]. Thus, around 1 in 5 people with a positive FENO ence of nasal polyps in patients with CRS was associated with
test will not have asthma (false positives), and 1 in 5 people with a increased asthma prevalence as well as increased FENO levels.
negative FENO test will have asthma (false negatives). However, Respiratory symptoms without bronchial hyperresponsiveness
even if data on FENO specificity and sensibility are heterogeneous were associated with eosinophilic airway inflammation and
and could vary between studies, FENO seem to have higher speci- increased FENO only in patients with nasal polyps [102], suggesting
ficity than sensitivity for the diagnosis of asthma, so FENO meas- eosinophilic airway inflammation even in patients without asthma.
urement is better at ruling in rather than to ruling out asthma diag-
nosis [89]. Sensitivity but not specificity could vary significantly
among different FENO devices [89]. Specificity is optimized if
FENO and asthma control
higher FENO cut-off is used. ATS guidelines show that FENO >36
ppb had a sensitivity of 78% and a specificity of 72% for sputum Its intrinsic feature as a biomarker of the underlying T2-medi-
eosinophilia, while a FENO <26 ppb has a negative predictive value ated airway inflammation in asthmatics [103], its ability to predict
of 85% [43]. asthma exacerbation [104,105] and the prompt reduction after anti-
inflammatory treatment initiation [106,107] theoretically make
FENO as a promising biomarker of poor asthma control.
Many studies investigated this aspect both in children and in
FENO and asthma comorbidities adults with contradictory results reported so far: some Authors
reported higher FENO levels in uncontrolled or partially controlled
Atopy asthmatics both in adults [64,108,109] and children [110-112],
Atopy, defined as sensitization to common inhalant allergens, while others failed to find such a correlation [113-119]. A recent
in the absence of allergic diseases, such as rhinitis, has been con- metanalysis including many of these studies concluded that there
sistently reported to be associated with increased FENO values, is only a weak correlation between FENO levels and current asthma
when compared to values observed in non-atopic control subjects, control [120].
in children, but not in adults [90]. In children, exhaled NO corre- This apparent contradiction between the promising role of
lates with the degree of IgE sensitization, in terms of both the num- FENO as a biomarker of asthma control and the reported results may
be explained looking at the clinical characteristics of patients
included into the different studies: in fact, a better correlation association [144-146]. Further studies are therefore needed to clar-
between high FENO levels and poor asthma control was seen in ify if this class of drugs affects FENO.
patients not on regular treatment for asthma [111,112,121], while In any case, when a response to ICS and/or LTRA has been
patients regularly treated with ICS seem to demonstrate weaker or found, FENO decreases rapidly, generally more quickly than other
no correlation between FENO and asthma control [111-113,116- asthmatic features, such as lung function parameters, symptoms or
119,121]. It is also possible that the presence of sino-nasal comor- airway hyperreactivity [106]. This rapid response to anti-inflam-
bidities (such as allergic rhinitis or chronic rhinosinusitis with matory treatments, together with similarly rapid increase before
nasal polyps), which are frequently associated with asthma, may worsening of asthma control and exacerbations [104,147] led
have an influence on the correlation between FENO and asthma researchers to investigate the potential therapeutical strategies
control, as they may independently increase FENO levels [99,102]. based on tailoring the treatment level according to FENO assess-
The performance of FENO as a biomarker of asthma control ment [131]. A recent metanalysis [131] combining data from three
increases when its assessment is combined with lung function previously published Cochrane reviews [148-150], highlighted
parameters [122-123], when it is used to predict the future risk of that tailoring of asthma therapy based on FENO results in a signifi-
losing asthma control [124-128], or when its increase in a given cant reduction of exacerbations in adults and a similar tendency in
time is considered as a marker of loss of asthma control [119]. children, compared to guidelines-based therapeutical strategies;
It is therefore suggestable that combined measurement (at first interestingly, these results were obtained without an increase need
clinical evaluation and during regular follow ups) of FENO and lung in ICS dose, reinforcing the benefit that may be achieved from a
function, which are both easy to obtain in clinical practice, may FENO -based strategy for tailoring asthma therapy.
help clinicians to predict the achievement of asthma control after
treatment initiation. Moreover, considering the easiness of FENO
assessment even in pre-school children, its use to determine asth-
ma control can be reasonable particularly when lung function and FENO and adherence to treatment
self-reported control level are difficult to obtain [110]. A proportion of patients with asthma remains symptomatic
despite prescription of adequate treatment and they should be dis-
tinguished into two categories: patients with possible severe asth-
ma (“difficult-to-control” asthmatics) and those with other causes
FENO and response to asthma treatments
of poor asthma control (“difficult-to-treat” asthmatics) [151];
Glucocorticoids are known to reduce eosinophilic inflamma- among these causes, nonadherence to ICS is a major determinant
tion that characterizes most of the asthma phenotypes; therefore, of poor asthma control and treatment failure accounting about 50%
FENO has the potential properties to be the perfect tool for monitor- of those who had been prescribed long-term treatment [152].
ing the response to inhaled and/or systemic corticosteroid treat- Distinguishing patients with difficult-to-control asthma who may
ments in asthmatic patients. respond to ICS if properly addressed from those really affected by
In steroid-naïve patients, FENO has been shown to be a reliable refractory asthma is an important clinical challenge.
predictor of responsiveness to ICS, with high levels associated FENO has been largely investigated as possible tool to identify
with favorable response to the treatment [105, 129-131]. Higher nonadherence [68,124,153-159]: elevated FENO levels were con-
baseline FENO levels were indeed able to predict ICS response in stantly associated with nonadherence, despite the heterogeneity of
terms of improvement of lung function both in adults [132-134] methods used to assess the adherence to treatment, both in children
and children [135], and in terms of reduction of symptoms and adults; this ability to identify poorly adherent patients was
[133,134] (at least in eosinophilic phenotypes) and improvement constantly reported to be greater for FENO than for other parameters
of asthma-related quality of life [133]. The study by Cowan et al. such as lung function or patient-reported symptoms. Fewer are the
[134] showed that, despite FENO was able to predict the improve- reports of poor correlation between FENO and adherence to treat-
ment of asthmatic symptoms only in patients with eosinophilic ment, probably due to the very small number of patients enrolled
asthma after a short course of 4 weeks of ICS, its high baseline lev- [159].
els were associated to a significant reduction in bronchial hyperre- McNicholl et al. [130] developed the so-called “FENO suppres-
sponsiveness also in patients with non-eosinophilic asthma, sug- sion test”, a practical objective procedure for assessing nonadher-
gesting that these subjects may need longer ICS treatment to obtain ence in difficult-to-treat asthma; they enrolled asthmatic patients
also a clinical response associated with the prompt lung function with persistently elevated FENO despite treatment and administered
improvement. A further subanalysis of the same study confirmed them inhaled budesonide 1600 mg for 7 consecutive days under
the same results [136]. their direct observation. FENO was daily measured for 8 days, then
The ability of FENO to predict ICS response could be even more weekly for 4 weeks to test its suppression after directly observed
clinically relevant when evaluating patients with non-specific res- inhaled corticosteroid (DOICS) treatment; if FENO persisted to be
piratory symptoms (such as isolated cough) and not already clearly higher than 40 ppb after seven days of DOICS, intramuscular tri-
diagnosed with asthma [133,137]. A double-blind randomized amcinolone 80 mg was administered, to demonstrate FENO respon-
placebo-controlled trial published by Price et al. [133] showed that siveness to high-dose systemic corticosteroids. A composite meas-
higher baseline FENO was associated with better response to ICS in ure comprising prescription records, adherence interview, blood
patients with undiagnosed, non-specific respiratory symptoms. testing, and inhaler technique, was used to assess nonadherence.
Interestingly, in this study FENO performance in predicting ICS Using this study design, they were able to reveal that suppression
response was superior than baseline lung function assessment, of FENO after DOICS had a sensitivity of 67%, a specificity of 95%
blood eosinophil count and clinical opinion of asthma. This study and a positive predictive value of 92% in identifying nonadherent
confirmed, using a more robust study design, previous similar patients and differentiating them from patients with proper severe
observation in single-blind design and with limited number of asthma. A subsequent study from the same group of Authors
patients [137]. demonstrated that the FENO suppression test is applicable in a rou-
More controversial is the effect of leukotriene-receptor antag- tine clinical care of reference centers for severe asthma, with the
onists (LTRA) on FENO, as some studies showed a prompt and sus- help of an integrated remote monitoring technology specifically
tained reduction of it [138-143], while others failed to find this developed [158].
functional improvement compared to asthmatic with lower FENO.

FENO in severe asthma Wenzel et al. [170] also confirmed the best role of FENO, among
other Type 2 inflammation biomarkers, in predicting the best
Severe asthma is well known to be a heterogeneous disease
responder to dupilumab.
that comprises multiple factors and that predisposes approximately
Lebrikizumab, a humanized anti IL-13 antibody, showed a
10% of asthmatic patients to suffer daily symptoms and acute
marked reduction in FENO values correlated to improvement in
exacerbations despite the intake of high-dose inhaled corticos-
asthma control compared to placebo [171], while tralokinumab,
teroids (ICS), oral corticosteroids (OCS), and other controllers [5].
another anti IL-13 humanized antibody, showed controversial
Recently, identification of severe asthma mediated by Type 2
results regarding its utility in reducing asthma exacerbation rate in
inflammation has resulted in the successful launch of several bio-
relation with FENO values: in the STRATOS 1 study high-FENO
logic therapies that target specific inflammatory phenotypes.
group (>37 ppb) showed a lower exacerbation rate versus placebo,
Several biomarkers have been proposed for the Type 2 severe asth-
while in the STRATOS 2 study this finding was not confirmed
ma, such FENO, eosinophils in blood or in sputum and periostin.
[172]. In addition, in the MESOS trial tralokinumab showed a sig-
The last GINA guidelines confirmed the role of FENO as a use-
nificant reduction in FENO values in moderate-to-severe asthmatic
ful, easy to perform and cost-effective phenotyping test for severe
patients [173].
asthma management [1]. The possibility of refractory Type 2
Finally, treatment with tezepelumab, a humanized antibody
inflammation should be considered if FENO ≥20 ppb is found while
targeting thymic stromal lymphopoietin (TSLP), was associated
the patient is taking high-dose ICS, together with blood
with a substantial and persistent decreasing in blood eosinophil
eosinophils (>150/µl), sputum eosinophils (>2%) or allergen-driv-
counts and FENO levels [174].
en asthma; blood eosinophils and FENO should be repeated up to 3
FENO, as well as eosinophils, are biomarkers easy to measure
times, on lowest possible OCS dose, before excluding Type 2
in clinical practice and their combined evaluation can identify
severe asthma.
patients with frequent exacerbations and stratify the appropriate
FENO ≥20 ppb may also predict an increase in exacerbations.
therapy for Type 2 inflammation-predominant severe asthma
FENO demonstrated itself to be the strongest predictor of exacerba-
[175].
tion in severe asthmatic patients treated with high dose ICS and
OCS when compared to peripheral blood eosinophils and periostin
[104].
A recent study by Price and collaborators showed that in a pop- FENO in childhood asthma
ulation of asthmatic in ICS treatment, the combination of high
FENO and high blood eosinophil count (≥300 cell/µl) was associat- The first reports about the high level of FENO in children with
ed to a significant increase in severe exacerbation rate, up to four asthma date from 1997 [176,177]. FENO represents an interesting
times or twice if categorized in FENO≥50 ppb or FENO≥35 ppb way to monitor airway inflammation, because of its non-invasive
respectively compared to patients with non-high FENO and non- nature and the relatively easy use. In fact, measurement can be
high blood eosinophils [159]. Furthermore, several studies support obtained in most children starting from 5-6 years old and results
the use of FENO as a marker to guiding OCS increase or escalation are available in a few minutes.
in severe as well as in mild-moderate asthmatics [160,161]. If Recommendations for FENO measurements in children have
patient has good response to Type 2 targeted therapy, internet- been published and are used worldwide [30,178]. FENO measure-
based monitoring of symptom control and FENO may help the clin- ment is performed with a deep inhalation through the mouth and
ician to decide if gradually decreasing or stopping OCS [1]. On the slow exhalation, with feedback of the flow rate for the subject.
other hand, the international ERS/ATS guidelines suggest that clin- Velum closure is mandatory and achieved by using a positive pres-
icians do not use FENO to guide OCS therapy in adults with severe sure of 5-20 cmH2O against exhalation. An approved measure is
asthma [5]. Recently, FENO has also started to be proposed as a pre- one in which the flow rate is within 10% of the target value, i.e. 45-
dictor of efficacy of biologic therapies. The story in this direction 55 ml·s−1 [30,170].
started with the EXTRA study [163] in which FENO showed to be FENO levels correlate with eosinophilic counts in induced spu-
able to identify responders to omalizumab. GINA guidelines [1] tum (5) and bronchoalveolar lavage fluid as well as with
also confirm that FENO ≥20 ppb, associated with blood eosinophils eosinophil infiltration of the airways and peripheral eosinophilia,
≥ 260/μl, allergen-driven symptoms and childhood-onset asthma, mainly in atopic children [179,180]. Correlations were also found
predicts a good response to anti-IgE biologic treatment. with serum total IgE, serum eosinophil cationic protein (ECP) and
Several later studies supported the role of FENO as a good pre- the number of positive skin prick tests [179-181]. Consequently,
dictor of efficacy to omalizumab [164,165]. However, if FENO FENO is considered a marker of the most common asthma endotype
seems to well identify responders to omalizumab, no efficacy has in children, characterized by Th2-mediated airway inflammation,
been demonstrated for alveolar concentration of nitric oxide that eosinophilia and responsiveness to inhaled steroids [182].
did not modify its concentrations after treatment with omalizumab Moreover, some studies suggest that low FENO levels predict a non-
[166]. On the other hand, contrasting data are available on FENO as eosinophilic asthma phenotype better than high levels can predict
a marker of good response to mepolizumab. In the DREAM study an eosinophilic one [183]. It has also been suggested that FENO can
[167], no statistical differences were found in FENO after treatment help us to identify early-onset asthma among preschool-age chil-
with mepolizumab compared to baseline values, suggesting that dren with recurrent wheezing [179,184,185]. At last, several stud-
FENO may not be responsive to modulation through IL-5 pathway. ies demonstrated that FENO is increased in atopic children with and
Accordingly, with the DREAM study, Farah et al. demonstrated without asthma, suggesting that atopy and asthma could be cofac-
that treatment with mepolizumab improves small airway function, tors in determining elevated FENO levels [181,186,187]. It has been
but not spirometry and FENO [168]. also established that baseline FENO levels are elevated in children
FENO has also been evaluated in the identification of patients with exercise-induced bronchoconstriction and relate with the
eligible for dupilumab, a human anti IL-4 and IL-13 antibody. degree of post-exercise bronchoconstriction, suggesting that FENO
Castro et al. [169] found that the subgroup of severe asthmatic may be a predictor of airway hyperresponsiveness to exercise,
with higher FENO treated with dupilumab experienced a more sig- especially in asthmatic children sensitive to indoor allergens [188].
nificant clinical efficacy in terms of reduction of exacerbation and On these bases, it has been proposed a role of FENO in asthma
diagnosis in children. Sensitivity and specificity of FENO measure- went twice-daily fractional exhaled nitric oxide measurement
ments were showed to be acceptable to discriminate asthma from before, during and after period of natural exposure to mite aller-
other non-asthmatic conditions in previous clinical studies [189], gens, observed significant differences between the mite-free base-
though normal FENO levels do not exclude the diagnosis of asthma, line FENO level and FENO levels measured during natural mite
especially in non-atopic subjects. In fact, FENO levels of atopic exposure and after natural mite exposure [203]. Moreover, six chil-
asthmatic are higher than those of non-atopic asthmatics [190]. dren reported asthma symptoms during the mite exposure, and an
Furthermore, it has to be considered that there is a large range in increase in FENO was observed in each case [203].
FENO levels among children, which may reflect the natural hetero- The usefulness of FENO for monitoring children with moderate-
geneity in baseline epithelial nitric oxide synthase activity with the to-severe asthma is still unclear. In fact, studies aimed to evaluate
contribution of other non-eosinophilic factors. FENO usefulness as a predictor of asthma exacerbations show con-
Normal values of FENO and feasibility in children have been flicting results. Moreover, a consensus about the optimal FENO cut-
assessed, showing that FENO levels in healthy children are below point level to define high risk of exacerbation still lack. Cabral et
15 to 25 ppb [60,191]. These values range is the result of several al. showed no benefits in tapering ICS doses in atopic children by
factors: age, gender, height, ethnicity, allergic sensitization, serum monitoring FENO levels, suggesting that this tool has a limited
total IgE, infections, a nitrate rich diet, exercise, smoking, environ- value as a predictor of asthma exacerbations [204]. Conversely,
mental nitric oxide, time of the day, season and environmental pol- some data reported that FENO might be helpful in predicting and
lution [182,192-194). A systematic review and meta-analysis on preventing exacerbations. In a study based on daily FENO values
eight current diagnostic accuracy studies, including 2,933 cases of and symptom scores over 192 days in 41 atopic asthmatic children,
diagnostic performance of FENO in children with asthma, indicates Stern et al. have demonstrated that fluctuation in FENO values and
a FENO values range from 19 ppb to 25 ppb as the best cut-point to their cross-correlation to symptom scores give information on
diagnose asthma [195]. This range showed the equal highest asthma severity and control [205]. They found that the majority of
Youden’s index (sensitivity + specificity -100). subjects had the strongest positive relationship between FENO val-
In a study performed in preschool children, FENO was higher in ues and symptom scores on the same day. Children who had a
those with a frequent recurrent wheeze and a stringent index for the severe or moderate exacerbation had a stronger positive cross-cor-
prediction of [asthma asthma predictive index (API)] than in those relation between FENO values and symptom scores, suggesting that
with a loose index or those with recurrent or chronic cough but no concordance of FENO values and symptom scores is an indicator of
history of wheeze [196,197]. Furthermore, in infants with eczema
increased risk of exacerbation [205]. In another study, Gagliardo et
but not yet wheezing, exhaled nitric oxide was shown to be capable
al. found a significant correlation between FENO levels and other
to provide important insights into the risk of asthma later in child-
markers of inflammation, such as sputum eosinophilia and IL-8,
hood and its airway characteristics [198]. The body of these data is
and the number of severe exacerbations in asthmatic children
in favour of the idea that objective measurement of FENO in addi-
[206]. Van der Valk et al. collected longitudinal daily FENO mea-
tion to the clinical characterization may improve the possibility of
surements in relation to exacerbations in atopic asthmatic children
defining disease presentation and of predicting disease progression
[207]. They have found changes in FENO prior to moderate, but not
in preschool children.
severe exacerbations. Probably, moderate exacerbations are pre-
Therefore, currently, FENO may be regarded as a potential com-
ceded by increased eosinophilic airway inflammation and the level
plementary tool in asthma diagnosis pathway in children.
There is also a strong interest to use FENO as a guide for asthma of cross-correlation between FENO levels and symptoms could
treatment, considering that FENO reflects airway inflammation. In identify children at risk for exacerbations. However, the study
fact, in some studies FENO is validated as a useful tool both in diag- sample size was small and the therapeutic intervention with ICS
nosing and managing children with atopic asthma [60]. Data sug- could have modified the association between FENO and exacerba-
gest that using FENO to tailor the dose of ICS cannot be recom- tions [207]. At last, in a study based on forty-two children with
mended in routine clinical practice, because of the danger of exces- confirmed asthma, Chang et al. has found that FENO values were
sive doses of treatment without significant changes in clinical out- associated with an increased risk for subsequent loss of asthma
comes. In fact, two meta-analyses of paediatric studies showed that control 4 weeks after ICS withdrawal (40). Moreover, subjects
FENO monitoring lead to increased use of ICS, without significant with high FENO values had an earlier LAC respect subjects with
influence on lung function outcomes (FEV1 levels) compared to normal FENO [208]. Their findings suggest that FENO values may be
conventional management [199,200]. Actually, a guideline-based useful to predict subsequent loss of asthma control among asymp-
approach still remains essential [199]. It has been suggested that tomatic children after ICS interruption. In this setting, FENO level
FENO may be more appropriate for tapering, rather than for step- may contribute for clinical follow up decision during childhood
ping up anti-inflammatory treatment and could be used mainly as asthma after ICS withdrawal. Discordant data were found also
an indicator of the child’s compliance with the prescribed therapy about the correlations between FENO and Asthma Control Test
[182]. In fact, the relatively rapid shift of FENO levels after steroid scores, both in adults and in children [209]. A study on 200 asth-
treatment suggests its utility in monitoring adherence to and matic children (47 of them with newly diagnosed asthma and with-
response to therapy [43,201]. out any regular controller therapy) has pointed out that the assess-
For these reasons different authors suggested to use FENO to ment of asthma control by Children-ACT questionnaire in children
rationalize corticosteroid therapy in asthmatic patients, together is significantly related to the level of FENO in newly diagnosed
with the traditional clinical tools (history, physical examination patients, but not in those already under regular follow up [111].
and lung function tests) [43]. Nevertheless, the issue to consider In conclusion, due to the complex nature of the disease, asthma
FENO as a clinical tool to manage asthma treatment in children is control in children needs more than only one item in assessment and
still under debate [202]. both physician evaluation and other objective testing are necessary.
Some previous studies showed that FENO increased in uncon- FENO may provide useful information about airway inflammation,
trolled asthmatic children, especially during exacerbations [202]. playing a complementary role in the management of asthma.
In particular, a study, in which 22 children allergic to mites under-
identify corticosteroid-responsive patients among the non-asthmat-

FENO in respiratory diseases other than asthma ic population with cough.
Chronic obstructive pulmonary disease Acute eosinophilic pneumonia

The clinical value of FENO measurements in patients with Acute eosinophilic pneumonia (AEP) is to be suspected in
established chronic obstructive pulmonary disease (COPD) is not patients with progressive and severe dyspnea less 1-2 weeks in
presently clear. According to a recent systematic review and met- duration and a chest radiograph showing diffuse parenchymal
analysis [210] patients with stable COPD had a mild elevation of opacities. At presentation eosinophilia is not present in peripheral
FENO levels compared to healthy controls, with FENO levels much blood, while there is typical BAL eosinophilia (> 25%). Among 60
higher in ex-smokers than in current smokers. No association was subjects prospectively enrolled with pulmonary infiltrates and a
found between FENO levels and exacerbated COPD. Some studies febrile illness and who were clinically suspected to have AEP, the
show that, at least in the short term, the response to corticosteroids pretreatment FENO levels of the patients with AEP were significant-
is likely to be greater in patients with COPD who also have elevat- ly higher than those of the patients without AEP. The cut-off value
ed FENO [211]. A raised FENO had been shown to predict FEV1 (23.5 ppb) showed that the maximal area under the receiver oper-
response to ICS in COPD [212,213]. ating characteristic curve predicted AEP with a sensitivity of 87%
In a significant number of patients, an overlap syndrome com- and a specificity of 83% [224].
prising features of both asthma and COPD is found [214]. The air- FENO measurement has been shown to be useful for differenti-
way inflammatory cell infiltrate may be mixed, including ating AEP from other types of acute-onset interstitial lung diseases,
eosinophilic inflammation. Asthma-COPD overlap (ACO) is char- regardless of the blood eosinophil levels [225]: forty patients with
acterized by persistent airflow limitation and several manifesta- a combination of illness ≤4 weeks in duration and diffuse radi-
tions usually associated with both asthma and COPD. A ographic infiltrates were classified into groups based on the etiol-
GINA/GOLD document on ACO recommended that both FENO ogy; the median FENO value of patients with AEP (48.1 ppb) was
and blood eosinophils be used as inflammatory biomarkers for dif- significantly higher than that of the other groups (17.4 ppb in cryp-
ferentiating ACO from COPD [215]. According to a recent study, togenic organizing pneumonia, 20.5 ppb in hypersensitivity pneu-
for patients naïve to ICS, FENO level >25.0 ppb combined with a monia, and 12.0 ppb for sarcoidosis). The area under the receiver’s
blood eosinophil count >250 cells/μl showed high specificity operating characteristic curve (AUC) for FENO to identify AEP was
(96.1%) for differentiating ACO from COPD [216]. 0.90 with a cut-off of 23.4 ppb [225].
Obstructive sleep apnea Chronic eosinophilic pneumonia

Obstructive sleep apnoea (OSA) is a sleep disorder that may Chronic eosinophilic pneumonia (CEP) is characterized by
lead to metabolic abnormalities and increased cardiovascular risks. chronic respiratory symptoms, bilateral peripheral lung opacities,
Airway and systemic inflammation has been proposed to have a pulmonary eosinophilia, and peripheral eosinophilia. Symptoms and
central role in the pathophysiology of OSA [217]. Inflammation radiopacities resolve rapidly after corticosteroid treatment, but they
involving the nose, the uvula, the soft palate and the pharyngola- recur frequently after tapering or discontinuing the medication.
ryngeal tract promotes and aggravates oropharyngeal inspiratory FENO levels were measured in 18 patients with CEP at several
muscle dysfunction, upper airway narrowing and collapsibility. A assessment points over one year, showing positive correlation with
slightly increase in levels of NO were detected in the exhaled air peripheral eosinophil count [226]. The median FENO levels were
of OSA compared to healthy subjects, generally between 20 and 25 significantly higher in uncontrolled compared to controlled CEP.
ppb, it is more evident in nonsmoking OSA and after sleep and it The FENO level of 66.0 ppb showed the largest area under the curve
seems to reflect bronchial neutrophilic inflammation [218]. (0.835) for predicting exacerbation of CEP (sensitivity 80%, speci-
Increased FENO in OSA is not consistently positively related to ficity 84%). Authors concluded that FENO may be useful for moni-
the severity of OSA (apnoea / hypopnoea index) thus excluding a toring eosinophilic parenchymal inflammation and determining the
clear role for screening OSA in adults. [219] On the contrary, nasal appropriate corticosteroid dose in CEP [226].
NO (nNO) might have a greater value that FENO in the fact that
correlates to AHI and time of SpO2<90%, potentially reflecting
upper airway inflammation in OAS patients. A nNO higher that
626 ppb could be recommended for confirming OSA by Nasal nitric oxide
polysomnography [220]. As shown by Lundberg et al. in 1995 [226], nasal cavity and
Non-asthmatic eosinophilic bronchitis upper airways represent the major source of nitric oxide detected
in the respiratory tract of adult healthy subjects [227]. They found
Non-asthmatic eosinophilic bronchitis (NAEB) is character- a continuous nitric oxide synthesis in paranasal sinuses, yielding
ized by chronic irritable dry cough, sputum eosinophilia and being very high nitric oxide concentration (3000-25000 ppb) contribut-
responsive well to glucocorticosteroids [221]. In contrast to asth- ing to that found in nasal air.
ma, NAEB presents no airflow obstruction and airway hyperre- The nasal nitric oxide, which represents more than 90% of the
sponsiveness [221]. Some reports indicate that FENO levels in total [228], is produced by all three NOS isoforms that have been
patients with NAEB were significantly higher than those in other identified in the upper airways in epithelial cells of nasal mucosa,
causes of chronic cough [222]. According to a systematic review in parasympathetic neurons innervating nasal vessels, in endothe-
and meta-analysis [223] FENO test might not be precise enough to lial cells and in ciliated epithelial cells [229]. Interestingly, the
predict NAEB in non-asthmatic patients with chronic cough. NOS found in the paranasal sinuses is essentially calcium inde-
Hierarchical summary receiver operating characteristic curve pendent [20], a characteristic usually related to NOS-2, but it is
analyses suggested sensitivity and specificity were 72% and 83%, constitutively expressed and resistant to steroids, the latter being
respectively, with optimal cutoff levels ranging from 30 to 40 ppb. typical features of constitutive NOSs.
Even if FENO measurement might not fully replace induced sputum Nasal NO can have several physiological functions including the
analyses, the clinical utility of FENO should not be dismissed in the participation in non-specific host defense against bacterial, viral and
non-asthmatic population with cough, where FENO may help to fungal infections [230], preserving a sterile microenvironment with-
in the paranasal sinuses, regulating cilia motility [231,232] and the the nasal airway and paranasal sinuses [245], which may affect the
nasal airway resistance to airflow, and entering in the humidification ability to detect alterations in nNO occurring in sino-nasal disor-
and warming mechanisms of inhaled nasal air flow [233]. Nasal NO ders [246]. However, a very recent study suggests to use nNO also
has also been hypothesized to improve the ventilation–perfusion for differentiate AR patients from healthy subjects and may be sig-
ratio in the lungs by the auto-inhalation [231,232], and to act as an nificantly correlated with nasal symptoms and nasal patency of
aerocrine messenger between the upper and lower airways [234]. rhinitis patients [247]. A few data are consistent with the finding of
However, none of these actions has been directly associated with the lower nNO levels in patients with CRS compared with controls,
high levels of NO detected in the nose [19]. and they reported an inverse correlation between nNO level and
As in the lower airways, nasal NO can exert the biological CT changes in patients with CRS [248]. Moreover, testing for nNO
effects of NO by a direct action [21], although some of its physio- was highly predictive of separating CRSwNP , who had the lowest
logical and pathophysiological effects (especially its pro-inflam- values, from patients with CRSsNP, and nNO cutoff value of less
matory actions) are likely to be activated by NO derivatives and than 442 ppb was associated with the best combination of sensitiv-
not by the molecule itself. As discussed above, it can form com- ity and specificity, with a PPV of 87% and an NPV of 91% in
plexes of metal-containing proteins, leading to enzyme activation detecting CRSwNP [242]. A more recent report confirmed the
or inhibition, or directly interact with high energy free radicals and acceptability of the receiver operating characteristic curves in dif-
modulate other oxidative reactions like lipid peroxidation inhibi- ferentiating patients as CRSwNP, CRSsNP, and healthy controls
tion, and limit the generation of pro-inflammatory lipids [21]. and the correlation with sinus computed tomography and
Furthermore, the NO indirect effects are mediated by reactive Sinonasal Outcome Test Scores [249,250].
nitrogen oxide species (RNOS) originating from its interactions The evidence that measurements of nNO during humming
with O2 or O2•– [21]. (which is the production of a tone without opening the lips or form-
Differently from lower airways, there are several methods to ing words) are correlated with ostial function [246,251,252], has
measure nasal NO (nNO). Currently, two methods of nNO assess- led to its potential use as test for osteo-meatal patency. In normal
ment are recommended: nasal aspiration via one nostril during conditions, humming causes a great increase in nNO (humming
velum closure, and nasal exhalation through a tight facemask with responders), whilst, when there is an obstruction of osteo-meatal
fixed flow [30,43]. In the first method, nNO is aspirated from complex, this maneuver does not cause any increase in NO (hum-
patients by the intrinsic suction of analyzer through a line with a ming non-responders). This method may represent a suitable non-
disposable foam olive inserted into one nostril while palate is close invasive test to assess sinus ostium block [246], and might be use-
by exhaling through the mouth (20–40 s) into a disposable resistor ful for screening of sinus disorders and for both post-medical and
(with a resistance of at least 10-cm H2O). Alternatively, nNO is post-surgery follow up in patients with bilateral nasal polyposis
aspirated while the subject breath holds with the velum elevated. [253] and in patients with allergic rhinitis [254]. Therefore, it is
In this case, a suction pump aspirates air through a nasal olive likely that the humming test may also characterize an on–off
placed in one nostril with the subject holding his/her breath after response in the presence of advanced ostium disease [255].
inspiration to total lung capacity. In the second method, the nasal Nasal NO has been also investigated in other non-respiratory
exhalation through a tight facemask with a stable fixed flow is diseases such as inherited retinal dystrophies [256].
used. The subject starts inhaling NO-free air from the analyzer In conclusion, the use of nNO in diagnosis and monitoring of
through the nose during a full inspiration to total lung capacity, and respiratory disorders (e.g., allergic rhinitis, sinusitis, nasal polypo-
then exhales through a tightly fitting mask covering the nose con- sis, CF) is potentially of interest, but more research is needed
nected to the analyzer. The obtained NO values can be in parts per before we understand how clinically useful these tests are.
billion (ppb) or in nl/min (multiplying nasal NO concentration
(ppb) by the sampling flow rate).
Differently from exhaled nitric oxide, nNO measurements
have been proposed as diagnostic tool in only a few diseases. In Cost effectiveness of using FENO in asthma diagnosis
primary ciliary dyskinesia (PCD), nNO is by far the most effective and management
screening tool [235], with a specificity of 88%, a sensitivity of As described above, FENO measurement can be used for differ-
100%, and a positive predictive value of 89% for a correct diagno- ent purposes: from diagnosis to management of asthma, including
sis when using a nNO cut-off concentration of 105 ppb [236]. It the evaluation of corticosteroid responsiveness and adherence, and
has also been reported that a value of nNO less than 100 ppb or 77 phenotypization of patients with severe asthma.
nl/min would strongly suggest PCD [237] and Collins et al. [238] FENO is also promisingly useful in properly prescribing and
using the same cut-off found a sensitivity of 93% and specificity of monitoring the treatment with novel biological agents together
84%, with a positive predictive value of 42.6% and a negative pre- with other biomarkers of T2 inflammation such as serum IgE and
dictive value of 99%. peripheral blood eosinophils.
Some authors suggest that nasal NO measurements could also be Naturally not all the described possible uses have the same
useful in screening for cystic fibrosis (CF) patients, as they present degree of evidences. Guidelines and reviews have graded the evi-
low levels of exhaled NO [239,240]. However, the NO metabolism dence for each of the possible uses. While NICE guidelines on
in CF airways is complex and not yet completely understood, and asthma released in 2017 include FENO assessment among the first-
therefore it is of limited value in the diagnosis of CF. line evaluations for suspect asthma together with lung function
In analogy with other inflammatory diseases, nNO has been tests in both children and adults [75], a Cochrane review [148]
proposed also for the diagnosis of allergic rhinitis [94,241] and for concluded that strategies based on tailoring asthma medications
the diagnosis, prognosis or treatment evaluation of other sino-nasal dose according only to FENO levels do not have enough evidence
diseases [242,243]. However, as showed by Phillips et al. [244], to be translated into clinical practice. Another Cochrane review
data referring to the sino-nasal application of nNO measurements stated that while the use of FENO to guide asthma therapy in chil-
have produced no clear evidence of clinical relevance, except for dren may be beneficial in a subset of children, it cannot be univer-
the impact of sinus surgery. A possible explanation is that nNO sally recommended for all children with asthma [149].
measurements in sino-nasal pathologies are currently hampered by Due to the characteristics of the current technology, the meas-
confounding factors such as the continuous gas exchange between urement of FENO is not expensive and in 2017, in the USA, the pro-
posed reimbursement by Medicaid was around 20 $ [257], a price ing asthmatic patients [258].
that may lead to a cost-saving policy, both in diagnosing and in the In Spain it was calculated that adding FENO to standard asthma
follow managing asthma. care in adults saved 62.53 € per patient/year in adults and
A retrospective observational study conducted in USA on improved QALY, with a potential net yearly saving of €129 million
patients hospitalized or treated in emergency department for asth- in the budget of primary care settings [259].
ma, demonstrated that direct costs related to asthma exacerbations In Italy the situation is patchy; even if FENO measurement has
can be reduced and almost halved by the use of FENO for monitor- been recognized at national level as a diagnostic test that can
deserve reimbursement from public health care system, the Italian
State-Region Conference has not approved a specific code and
reimbursement tariff yet. The result is that each region can use dif-
ferent codes (relating to other tests) to classify and price FENO
measurements. Only one region has a specific code for FENO. All
the other ones use existing codes (not specific to FENO) to get the
reimbursement. The tariff also is a haphazard one. It spans from
23.20 euro to 73.00 euro. The rough median is around 24.00 euro.
Conclusions
FENO is a non-invasive, cheap and easy-to-assess method to assess
airway inflammation, and it has a series of possible advantages
in the management of asthma, both in adults and children
(Figure 2):
- in the diagnostic process, in which high values of FENO, in
patients with consistent symptoms, confirm the suspect of asth-
ma and the need to do further tests to rule in the diagnosis [43];
on the other hand, low values of FENO are rarely associated with
a final diagnosis of asthma, and therefore they should suggest to
investigate other possible differential diagnosis [43]. These were
Figure 2. Fractional exhaled nitric oxide (FENO) usefulness in dif-
the evidence that brought the NICE guidelines [75] to recom-
ferent aspects of the management of asthma.
Figure 3. Proposed diagnostic algorithm for asthma including FENO in assessment of airway inflammation.
mend integrating FENO testing in the diagnostic flowchart for induced sputum. Respirology 2006;11:54-61.
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in combination with lung function assessment and trials with Passalacqua G, et al. Asthma: personalized and precision
ICS (Figure 3). medicine. Curr Opin Allergy Clin Immunol 2018;18:51-8.
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values are associated with an increased probability to achieve Allergy Clin Immunol Pract 2019;7:1394-403.
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py, particularly in difficult-to-treat asthmatics; 2014;113:619-23.
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Received for publication: 4 December 2019. Accepted for publication: 5 February 2020.
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qxp_Hrev_master 18/02/20 15:31 Pagina 1

Multidisciplinary Respiratory Medicine 2020; volume 15:36

Fractional Exhaled Nitric Oxide (FENO) in the management of asthma:

12Italian Respiratory Society-Società Italiana di Pneumologia, Milan, Italy

Ethics approval and consent to participate: Not applicable.

Multidisciplinary Respiratory Medicine 2020; 15:36 - E. Heffler et al.

the Italian Society of Allergy, Asthma and Immunology (SIAAIC)

Multidisciplinary Respiratory Medicine 2020; 15:36 - E. Heffler et al.

Multidisciplinary Respiratory Medicine 2020; 15:36 - E. Heffler et al.

NObreath (Bedfont Scientific Ltd, Kent, UK), Medisoft (Hypair, Weight 40 kg 1 kg

The NIOX VERO device is hand-held and portable (less than

Multidisciplinary Respiratory Medicine 2020; 15:36 - E. Heffler et al.

Multidisciplinary Respiratory Medicine 2020; 15:36 - E. Heffler et al.

Multidisciplinary Respiratory Medicine 2020; 15:36 - E. Heffler et al.

Multidisciplinary Respiratory Medicine 2020; 15:36 - E. Heffler et al.

functional improvement compared to asthmatic with lower FENO.

Multidisciplinary Respiratory Medicine 2020; 15:36 - E. Heffler et al.

Multidisciplinary Respiratory Medicine 2020; 15:36 - E. Heffler et al.

identify corticosteroid-responsive patients among the non-asthmat-

Chronic obstructive pulmonary disease Acute eosinophilic pneumonia

Obstructive sleep apnea Chronic eosinophilic pneumonia

Multidisciplinary Respiratory Medicine 2020; 15:36 - E. Heffler et al.

Multidisciplinary Respiratory Medicine 2020; 15:36 - E. Heffler et al.

Multidisciplinary Respiratory Medicine 2020; 15:36 - E. Heffler et al.

Multidisciplinary Respiratory Medicine 2020; 15:36 - E. Heffler et al.

Multidisciplinary Respiratory Medicine 2020; 15:36 - E. Heffler et al.

Multidisciplinary Respiratory Medicine 2020; 15:36 - E. Heffler et al.

2007;131:1345-52. P, et al. Assessing asthma control: questionnaires and exhaled

Multidisciplinary Respiratory Medicine 2020; 15:36 - E. Heffler et al.

asthma. Thorax 2010;65:384-90. Medicine Initiative (IMI). Thorax 2011;66:910-7.

Multidisciplinary Respiratory Medicine 2020; 15:36 - E. Heffler et al.

(DREAM): a multicentre, double-blind, placebo-controlled IgE. Thorax 2010;65:801-7.

Multidisciplinary Respiratory Medicine 2020; 15:36 - E. Heffler et al.

Multidisciplinary Respiratory Medicine 2020; 15:36 - E. Heffler et al.

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