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Exhaled nitric oxide - Wikipedia, the free encyclopedia

Exhaled nitric oxide

From Wikipedia, the free encyclopedia

In medicine, exhaled nitric oxide (eNO) can be measured in a breath

test for asthma or other conditions characterized by airway
inammation. Nitric oxide (NO) is a gaseous molecule produced by
certain cell types in an inammatory response. The fraction of exhaled
NO (FENO) is a promising biomarker for the diagnosis, follow-up and as
a guide to therapy in adults and children with asthma. The breath test
has recently become available in many well-equipped hospitals in
developed countries, although its exact role remains unclear.

Contents

Chemical formula of nitric oxide

(NO) together with its molecular size
(115 pm).

1 Biology
2 Medical use
2.1 Asthma
3 Other conditions
4 Measurement techniques
5 Reference range
6 History
7 Footnotes
8 Further reading
Three-dimensional model of NO.

Biology
In humans, nitric oxide is produced from L-arginine by three enzymes called nitric oxide synthases (NOS):
inducible (iNOS), endothelial (eNOS), and neuronal (nNOS). The latter two are constantly active in endothelial
cells and neurons respectively, whereas iNOS' action can be induced in states like inammation (for example,
by cytokines). In inammation, several cells use iNOS to produce NO, including eosinophils. As such, eNO has
been dubbed an inammometer.[1]
Although iNOS is thought to be the main contributor to exhaled NO in asthmatics,[2][3] studies in mice also
point to a role for nNOS.[4][5]
It was initially thought that exhaled NO derived mostly from the sinuses, which contain high levels of NO. It
has subsequently been shown that the lower airways contribute most of the exhaled NO, and that contamination
from the sinuses is minimal.

Medical use
Asthma
Patients with asthma have higher eNO levels than other people. Their levels also rise together with other
clinical and laboratory parameters of asthma (for example, the amount of eosinophils in their sputum). In
conditions that trigger inammation such as upper respiratory tract infections or the inhalation of allergens or
plicatic acid, eNO levels rise.[6][7] The eNO levels also tend to vary according to the results of lung function
test results such as the degree of bronchial hyperresponsiveness. Furthermore, drugs used to treat asthma (such
as inhaled glucocorticoids or leukotriene receptor antagonists) also reduce eNO levels.
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Clinical trials have looked at whether tailoring asthma therapy based on eNO values is better than conventional
care, in which therapy is gauged by symptoms and the results of lung function tests.[8][9][10] To date, the results
in both adults and children have been modest and this technique can not be universally recommended.[11] It has
also been noted that factors other than inammation can increase eNO levels, for example airway acidity.[12][13]
The fraction of eNO has been found to be a better test to identify asthmatics than basic lung function testing
(for airway obstruction). Its specicity is comparable to bronchial challenge testing, although less
sensitive.[14][15] This means that a positive eNO test might be useful to rule in a diagnosis of asthma; however,
a negative test might not be as useful to rule it out.[16]

Other conditions
The role for eNO in other conditions is even less well established compared to asthma.
Since asthma can be a cause of chronic coughing (it may even be the sole manifestation, such as in coughvariant asthma), studies have looked at whether eNO can be used in the diagnosis of chronic
cough.[17][18][19][20]
Exhaled NO is minimally increased in chronic obstructive pulmonary disease, but levels may rise in sudden
worsenings of the disease (acute exacerbations) or disease progression. Early ndings indicate a possible role
for eNO in predicting the response to inhaled glucocorticoids and the degree of airway obstruction reversibility.
Children with cystic brosis have been found to have low eNO levels. In subjects with bronchiectasis (a state of
localized, irreversible dilatation of part of the bronchial tree) not due to cystic brosis, high levels have been
found. Sarcoidosis could also feature increased eNO. Low levels have been found in primary ciliary dyskinesia,
bronchopulmonary dysplasia, and pulmonary arterial hypertension. In the latter condition, inhaled NO is used
as a diagnostic test of the response of the pulmonary arteries to vasodilators (agents that relax the blood
vessels).
Exposure to air pollution has been associated with decreased,[21] and increased eNO levels.[22][23][24]

Measurement techniques
The most widely used technique to measure eNO is with a chemical reaction that produces light; this is called a
chemiluminescence reaction. The NO in the breath sample reacts with ozone to form nitrogen dioxide in an
excited state. When this returns to its ground state, it emits light in quantities that are proportional to the amount
of exhaled NO.
The subject can exhale directly into a measurement device ('online' technique), or into a reservoir that can
afterwards be connected to the analyser ('ofine' technique).[25] With the former technique, the early and later
NO in the breath sample can be analysed separately. The test requires little coordination from the subject, and
children older than 4 can be tested successfully.[26][27]
The National Institute of Clinical Excellence (NICE) in the UK have published guidance on available
measuring devices: https://www.nice.org.uk/guidance/dg12

Reference range
The upper normal level of eNO in different studies ranges from 20 to 30 parts per billion. However, several
major features inuence the reference values. Men have higher eNO values than women. Smoking notoriously
lowers eNO values, and even former smoking status can inuence results. The levels are higher in people with
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an atopic constitution (a tendency towards allergies).[28] The fraction of

eNO is also ow-dependent (higher at lower ow rates and vice versa),
so measurements are normally measured at 50 ml/s. Age or height could
also considerably confound eNO values in children.[26] The magnitude
of these effects lies in the order of 10%, so even single cut-off values
might be useful.[16]

History
Until the 1980s, nitric oxide, a product of fossil fuel combustion, was
thought only to play a role the detrimental effects of air pollution on the
respiratory tract.[16] In 1987, experiments with coronary arteries showed
that nitric oxide was the long sought endothelium-derived relaxing
factor. After scientists realised that NO played a biological role, its role
as a cell signalling molecule and neurotransmitter became clear from
abundant studies.[29]
NO was rst detected in exhaled breath samples in 1991.[30] In 1992,
NO was voted molecule of the year by the scientic journal Science.[31]
In 1993, researchers from the Karolinska Institute in Sweden were the

An experimental setup used to

measure the fraction of exhaled nitric
oxide (FeNO) in human breath
samples. The subject blows into the
tube (1) after a mouthpiece (2) has
been connected to it. The wires on the
side are part of the system that
measures parameters like breath
velocity, while the exhaled gas is
taken to a FeNO analyzer (3).

rst to report increased eNO in asthmatics.[32]

Today, NO is not only used in breath tests but also as a therapeutic agent
for conditions such as pulmonary arterial hypertension and possibly for
the acute respiratory distress syndrome.

Footnotes
1. Pijnenburg MW, De Jongste JC
(February 2008). "Exhaled
nitric oxide in childhood
asthma: a review". Clin. Exp.
Allergy. 38 (2): 24659.
doi:10.1111/j.13652222.2007.02897.x.
PMID18076708.
2. Lane C, Knight D, Burgess S, et
al. (September 2004).
"Epithelial inducible nitric
oxide synthase activity is the
major determinant of nitric
oxide concentration in exhaled
breath". Thorax. 59 (9): 757
60.
doi:10.1136/thx.2003.014894.
PMC1747143 .
PMID15333851.

https://en.wikipedia.org/wiki/Exhaled_nitric_oxide

3. Brindicci C, Ito K, Barnes PJ,

Kharitonov SA (August 2007).
"Effect of an inducible nitric
oxide synthase inhibitor on
differential ow-exhaled nitric
oxide in asthmatic patients and
healthy volunteers". Chest. 132
(2): 5818.
doi:10.1378/chest.06-3046.
PMID17550932.
4. De Sanctis GT, MacLean JA,
Hamada K, et al. (May 1999).
"Contribution of Nitric Oxide
Synthases 1, 2, and 3 to Airway
Hyperresponsiveness and
Inammation in a Murine
Model of Asthma". J. Exp.
Med. 189 (10): 162130.
doi:10.1084/jem.189.10.1621.
PMC2193630 .
PMID10330441.

NIOX VERO Medical device for

measurement of exhaled nitric oxide

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5. De Sanctis GT, Mehta S,

Kobzik L, et al. (October 1997).
"Contribution of type I NOS to
expired gas NO and bronchial
responsiveness in mice". Am. J.
Physiol. 273 (4 Pt 1): L8838.
PMID9357865.
6. Vahlkvist S, Sinding M,
Skamstrup K, Bisgaard H (June
2006). "Daily home
measurements of exhaled nitric
oxide in asthmatic children
during natural birch pollen
exposure". J. Allergy Clin.
Immunol. 117 (6): 12726.
doi:10.1016/j.jaci.2006.03.018.
PMID16750986.
7. Obata H, Dittrick M, Chan H,
Chan-Yeung M (March 1999).
"Sputum eosinophils and
exhaled nitric oxide during late
asthmatic reaction in patients
with western red cedar asthma".
Eur. Respir. J. 13 (3): 48995.
doi:10.1183/09031936.99.1334
8999. PMID10232414.
8. Smith AD, Cowan JO, Brassett
KP, Herbison GP, Taylor DR
(May 2005). "Use of exhaled
nitric oxide measurements to
guide treatment in chronic
asthma". N. Engl. J. Med. 352
(21): 216373.
doi:10.1056/NEJMoa043596.
PMID15914548.
9. Shaw DE, Berry MA, Thomas
M, et al. (August 2007). "The
use of exhaled nitric oxide to
guide asthma management: a
randomized controlled trial".
Am. J. Respir. Crit. Care Med.
176 (3): 2317.
doi:10.1164/rccm.2006101427OC. PMID17496226.
10. Szeer SJ, Mitchell H,
Sorkness CA, et al. (September
2008). "Adding Exhaled Nitric
Oxide to Guideline-based
Asthma Treatment in Inner-City
Adolescents and Young Adults:
a randomized controlled trial".
Lancet. 372 (9643): 106572.
doi:10.1016/S01406736(08)61448-8.
PMC2610850 .
PMID18805335.

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Exhaled nitric oxide - Wikipedia, the free encyclopedia

11. Petsky HL, Cates CJ, Li AM,

Kynaston JA, Turner C, Chang
AB (2008). Petsky, Helen L, ed.
"Tailored interventions based
on exhaled nitric oxide versus
clinical symptoms for asthma in
children and adults". Cochrane
Database Syst Rev (2):
CD006340.
doi:10.1002/14651858.CD0063
40.pub2. PMID18425949.
12. Hunt JF, Fang K, Malik R, et al.
(March 2000). "Endogenous
airway acidication.
Implications for asthma
pathophysiology". Am. J.
Respir. Crit. Care Med. 161 (3
Pt 1): 6949.
doi:10.1164/ajrccm.161.3.9911
005. PMID10712309.
13. Shin HW, Shelley DA,
Henderson EM, Fitzpatrick A,
Gaston B, George SC (March
2007). "Airway nitric oxide
release is reduced after PBS
inhalation in asthma". J. Appl.
Physiol. 102 (3): 102833.
doi:10.1152/japplphysiol.01012
.2006. PMID17110506.
14. Malmberg LP, Pelkonen AS,
Haahtela T, Turpeinen M (June
2003). "Exhaled nitric oxide
rather than lung function
distinguishes preschool children
with probable asthma". Thorax.
58 (6): 4949.
doi:10.1136/thorax.58.6.494.
PMC1746693 .
PMID12775859.
15. Miedinger D, Chhajed PN,
Tamm M, Stolz D, Surber C,
Leuppi JD (June 2007).
"Diagnostic tests for asthma in
reghters". Chest. 131 (6):
17607. doi:10.1378/chest.062218. PMID17400683.
16. Turner S (February 2008).
"Exhaled nitric oxide in the
diagnosis and management of
asthma". Curr Opin Allergy
Clin Immunol. 8 (1): 706.
doi:10.1097/ACI.0b013e3282f3
b4b0. PMID18188021.

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17. Fujimura M, Ohkura N, Abo M,

et al. (May 2008). "Exhaled
nitric oxide levels in patients
with atopic cough and cough
variant asthma". Respirology.
13 (3): 35964.
doi:10.1111/j.14401843.2008.01273.x.
PMID18399857.
18. Oh MJ, Lee JY, Lee BJ, Choi
DC (June 2008). "Exhaled
Nitric Oxide Measurement is
Useful for the Exclusion of
Non-asthmatic Eosinophilic
Bronchitis in Chronic Cough
Patients". Chest. 134 (5): 990
5. doi:10.1378/chest.07-2541.
PMID18583518.
19. Sato S, Saito J, Sato Y, et al.
(July 2008). "Clinical
usefulness of fractional exhaled
nitric oxide for diagnosing
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102 (10): 14529.
doi:10.1016/j.rmed.2008.04.01
8. PMID18614345.
20. Hahn PY, Morgenthaler TY,
Lim KG (November 2007).
"Use of exhaled nitric oxide in
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PMID17976354.
21. Jacobs, L; Nawrot, Tim S; De
Geus, Bas; Meeusen, Romain;
Degraeuwe, Bart; Bernard,
Alfred; Sughis, Muhammad;
Nemery, Benoit; Panis, Luc
(Oct 2010). "Subclinical
responses in healthy cyclists
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PMC2984475 .
PMID20973949.
22. Van Amsterdam, Jan G. C.; et
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Arch Environ Health. 54 (5):
331335.
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96. PMID10501149.

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Exhaled nitric oxide - Wikipedia, the free encyclopedia

23. Adar SD; et al. (2007).

"Ambient and
Microenvironmental Particles
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Before and After a Group Bus
Trip". Environ Health Perspect.
115 (4): 507512.
doi:10.1289/ehp.9386.
PMC1852653 .
PMID17450216.
24. Bos, I; De Boever, P; Vanparijs,
J; Pattyn, N; Int Panis, Luc;
Meeusen, Romain (2013).
"Subclinical effects of aerobic
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Medicine and Science in Sports
and Exercise. 45 (3): 43947.
doi:10.1249/MSS.0b013e31827
767fc. PMID23073213.
25. American Thoracic, Society;
European Respiratory, Society
(April 2005). "ATS/ERS
recommendations for
standardized procedures for the
online and ofine measurement
of exhaled lower respiratory
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oxide, 2005". Am. J. Respir.
Crit. Care Med. 171 (8): 912
30. doi:10.1164/rccm.200406710ST. PMID15817806.
26. Buchvald F, Baraldi E, Carraro
S, et al. (June 2005).
"Measurements of exhaled
nitric oxide in healthy subjects
age 4 to 17 years". J. Allergy
Clin. Immunol. 115 (6): 11306.
doi:10.1016/j.jaci.2005.03.020.
PMID15940124.
27. Napier E, Turner SW (August
2005). "Methodological issues
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Pulmonol. 40 (2): 97104.
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PMID15965893.
28. Travers J, Marsh S, Aldington
S, et al. (August 2007).
"Reference ranges for exhaled
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29. Turner S (May 2007). "The role

of exhaled nitric oxide in the
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635. PMID17504190.
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"Endogenous nitric oxide is
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31. Koshland DE (December

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Further reading
Taylor DR, Pijnenburg MW, Smith AD, De Jongste JC (September 2006). "Exhaled nitric oxide
measurements: clinical application and interpretation". Thorax. 61 (9): 81727.
doi:10.1136/thx.2005.056093. PMC2117092 . PMID16936238.

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