Nitric oxide (nitrogen monoxide) is a chemical compound that was already discovered at the end of the eighth century. Sir Humphry Davy noticed for the first time some special qualities of the molecule – especially its “laughing”(1) charac-teristic, but systematic research on it produced results only in the 20th century. One of the first roles associated with nitric oxide was the vasodilating role, and then it was proven that it is involved in a series of pathophysiological processes; it was one of the first gaseous molecules with a mediator role in the human body that led to the award of the Nobel prize in 1998(2).
Research had continued subsequently in the area of pneu-mology and identified a series of pathogenic involvements of this molecule beginning from the endogenous modulation of airway function to the pro-inflammatory and immu-nomodulatory role in certain pathological situations(3,4,5).
At the end of the 20th century the first analyser of frac-tional excretion of exhaled nitric oxide (FeNO) was intro-duced on a wide scale and the first guideline of the American Thoracic Society (ATS) was published. In 2011 new recom-mendations established the criteria based on which we can use this measurement in diagnosis and monitoring the therapy of respiratory diseases(6).
The general interest for this exploration is due to the fact that monitoring airway (especially bronchial) inflammation in pneumology is a desideratum for which substantial efforts are made. Spirometry allows a quite accurate monitoring of respira-tory volumes and flows, and measurement of the inflammatory factor would allow – via corroboration – a more precise image in the diagnosis and therapy of respiratory diseases.
The FeNO measuring standards were established by chemiluminescence, but the practical utility was obtained via portable electrochemical analysers (e.g., NIOX MINO, Aerocrine, Solna, Sweden) which are more accessible and have a satisfying precision(7). Unlike spirometers, these devices do not need maintenance and calibration at regular time inter-vals; however they have a limited lifetime (e.g., NIOX VERO – 5 years), and after that a new investment is required.
As with spirometers the wide scale FeNO measurement is associated with patient compliance; in pediatrics – although data exists for younger ages(8) – usually it is not possible to obtain reliable values under the age of 5-6 years, even with the improved design of the commonly used new analysers. However, there is research that reports success percentages of over 90% in children around the age of 4 years(9).
The feasibility of the method is a feature most com-monly associated with young age; however another obsta-cle in FeNO measurement in exhaled air is the multitude of factors that may influence the obtained values (con-founding factors). In pediatrics it is already proven that values increase with the age of the child, and also that they are associated with gender or race(10,11). There are other variables, some of them not so obvious at first for the clinician, but they have an effect of altering the values of exhaled nitric oxide (see Table 1).
All these interferences have temperated the initial enthu-siasm of people interested in exhaled nitric oxide due to the fact that the results were sometimes contradictory, and other times they did not have a statistically significant power. The latest assessment performed in the Cochrane database sug-gests that FeNO could be used to monitor the therapy in pediatric asthma, but it also considers that other studies are needed to obtain solid evidence(13).
The experience of the Pediatrics Clinic of the “Filantropia” Municipal Hospital began in 2009 when the first FeNO ana-lyser was purchased (NioxMino – Aerocrine, Sweden). Since then we have performed over 700 tests in children who came to the clinic (generally over the age of 6-7 years, as younger children are less cooperative).
The investigation of the involvement of FeNO in the diagnosis and management of respiratory pathology in chil-dren involved determining a correlation between nitric oxide values and other indicators used for monitoring that already have an established value. Unfortunately, we did not manage to identify a correlation between FeNO and total IgE (also a non-specific marker) or specific serum IgE in children includ-ed in the study(14). Subsequent studies conducted in the Pediatrics Clinic of the “Filantropia” Municipal Hospital in Craiova did not manage to highlight a statistically significant association with therapeutic regimens in children with bron-chial asthma(15) or with environmental factors(16).
These results were somewhat disappointing but unfor-tunately they were confirmed by the latest revision of the Global Initiative for Asthma (GINA) guideline(17) which states that FeNO measurement cannot be used for now in the diag-nosis of asthma in children or adults due to the identification of an increasing number of factors that may interfere with the result of the investigation. Moreover, its role in therapy monitoring is fairly limited, and this is also confirmed by a recent Cochrane meta-analysis(18).
However, the interesting fact regarding the measurement of this molecule is that - although from a pneumological point of view, things seem to stagnate in recent years - more and more medical specialties seem to be interested by the relatively easy measurement of an inflammation marker in the exhaled air.
In rheumatology – including pediatric rheumatology – several authors would like to use this tool to monitor the chronic inflammation that is typical for this type of pathol-ogy(19,20). The ENT specialty is also preoccupied with the relationship between nitric oxide emissions in the mouth and local biofilm-producing bacteria(21). Another implication that may seem surprising at first – is the correlation with anorexia nervosa typical to female adolescents; this means that nitric oxide is also in the focus of the attention of psychiatrists(22,23).
In conclusion, the measurement of nitric oxide in exhaled air was one of the most promising methods for monitoring inflammation in the respiratory system. However, at this point available structured data only give it a limited utility, and it seems to be for now a substitute investigation which should be performed in situations when standard tests are not eloquent.
From the point of view of the pediatrician, the low com-pliance of young children should be added to the multitude of factors that may influence the measurement, leading to an even more relative nature of the obtained result. Other study-based evidence are awaited from a pneumological point of view; however, it should be noted that this method is in the focus of the attention of other medical specialties, still making it worthy of the attention of clinicians.
- https://en.wikipedia.org/wiki/Humphry_Davy - accessed in July 2017
- SoRelle R. Nobel prize awarded to scientists for nitric oxide discoveries. Circulation. 1998;98:2365-2366.
- L. E. Gustafsson, A. M. Leone, M. G. Persson, 1, N. P. Wiklund, and S. Moncada Endogenous nitric oxide is present in the exhaled air of rabbits, guinea pigs and humans. Biochemical and Biophysical Research Communications Volume 181, Issue 2, 16 December 1991, Pages 852-857
- Dweik RA, Comhair SA, Gaston B, Thunnissen FB, Farver C, Thomassen MJ, Kavuru M, Hammel J, Abu-Soud HM, Erzurum SC. NO chemical events in the human airway during the immediate and late antigen-induced asthmatic response. Proc Natl Acad Sci USA 2001;98:2622–2627
- Ricciardolo FL. Multiple roles of nitric oxide in the airways. Thorax 2003;58:175-182.
- Dweik RA, Boggs PB, Erzurum SC, Irvin CG, Leigh MW, Lundberg JO, et al. An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications. Am J Respir Crit Care Med 2011;184:602-15.
- Schneider A, Tilemann L, Schermer T, Gindner L, Laux G, Szecsenyi J, Meyer Diagnosing asthma in general practice with portable exhaled nitric oxide measurement--results of a prospective diagnostic study. FJ.Respir Res. 2009 Mar 3; 10:15. Epub 2009 Mar 3.
- Van der Heijden HH, Brouwer ML, Hoekstra F, van der Pol P, Merkus PJ.: Reference values of exhaled nitric oxide in healthy children 1-5 years using off-line tidal breathing. Pediatr Pulmonol. 2014 Mar;49(3):291-5
- Heijkenskjöld-Rentzhog C, Kalm-Stephens P, Nordvall L, Malinovschi A, Alving K. New method for single-breath fraction of exhaled nitric oxide measurement with improved feasibility in preschool children with asthma. Pediatr Allergy Immunol. 2015 Nov;26(7):662-7. doi: 10.1111/pai.12447. Epub 2015 Aug 13.
- Cho HJ, Jung YH, Yang SI, Lee E, Kim HY, Seo JH, et al. Reference values and determinants of fractional concentration of exhaled nitric oxide in healthy children. Allergy Asthma Immunol Res 2014;6: 169-74.
- Kippelen P, Caillaud C, Robert E, Masmoudi K, Préfaut C. Exhaled nitric oxide level during and after heavy exercise in athletes with exercise- induced hypoxaemia. Pflugers Arch 2002;444:397-404
- Kim HB, Eckel SP, Kim JH, Gilliland FD Exhaled NO: Determinants and Clinical Application in Children With Allergic Airway Disease. Allergy Asthma Immunol Res. 2016 Jan;8(1):12-21
- Petsky HL, Kew KM, Chang AB. Exhaled nitric oxide levels to guide treatment for children with asthma. Cochrane Database of Systematic Reviews 2016, Issue 11. Art. No.: CD011439. DOI: 10.1002/14651858. CD011439.pub2.
- Radu Diaconu, Carmen Diaconu, Gindrovel Dumitra – Exhaled nitric oxide and serum IgE în children admitted to a pediatric department – rez. P4577 in ERS Congress Viena 2012 Eur Respir J 2012; 40: Suppl. 56.
- R. Diaconu, L. Stănescu, L. Șelaru, M. Mateescu, D. Vâlceanu, A. Ciucu, A. Roșca. Exhaled nitric oxide and the therapeutic regimens in childhood asthma rez P 1119 in Vol. de rezumate ERS Congress Barcelona 2013
- R. Diaconu, L. Stănescu, C. Diaconu, C. Niculescu. Exhaled nitric oxide in pediatric patients admitted to a sports medicine department rez 3648 in Vol. de rezumate ERS Congress Amsterdam 2015
- http://ginasthma.org/2017-gina-report-global-strategy-for-asthma- management-and-prevention - accessed in July 2017
- Petsky HL, Kew KM, Chang AB. Exhaled nitric oxide levels to guide treatment for children with asthma. Cochrane Database of Systematic Reviews 2016, Issue 11. Art. No.: CD011439. DOI: 10.1002/14651858. CD011439.pub2
- Doğruel D, Yılmaz M, Bingöl G, Altıntaș DU, Güneșer Kendirli SFraction of exhaled nitric oxide as a predictor in juvenile idiopathic arthritis progression. Clin Rheumatol. 2017 Mar;36(3):541-546. doi: 10.1007/s10067- 016-3371-1. Epub 2016 Aug 10.
- Bica BE 1 , Gomes NM, Fernandes PD, Luiz RR, Koatz VL. Nitric oxide levels and the severity of juvenile idiopathic arthritis. Rheumatol Int. 2007 Jul;27(9):819-25. Epub 2007 Feb 8.
- Torretta S, Marchisio P, Drago L, Capaccio P, Baggi E, Pignataro L. The presence of biofilm-producing bacteria on tonsils is associated with increased exhaled nitric oxide levels: preliminary data in children who experience recurrent exacerbations of chronic tonsillitis. J Laryngol Otol. 2015 Mar;129(3):267-72. doi: 10.1017/S0022215115000031. Epub 2015 Feb 6.
- Oświęcimska J, Ziora K, Ziora D, Machura E, Smerdziński S, Pyś-Spychała M, Kasperski J, Zamłyński J, Kasperska-Zajac A. Elevated levels of exhaled nitric oxide in patients with anorexia nervosa. Eur Child Adolesc Psychiatry. 2014 Sep;23(9):845-50. doi: 10.1007/s00787-013-0467-x. Epub 2013 Nov 26.
- Rodrigues Pereira N, Bandeira Moss M, Assumpção CR, Cardoso CB, Mann GE, Brunini TM, Mendes-Ribeiro AC. Oxidative stress, l-arginine-nitric oxide and arginase pathways in platelets from adolescents with anorexia nervosa. Blood Cells Mol Dis. 2010 Mar 15;44(3):164-8. doi: 10.1016/j. bcmd.2009.12.003. Epub 2010 Jan 13.