Download PDF
Semin Respir Crit Care Med 2007; 28(3): 264-271
DOI: 10.1055/s-2007-981647
Copyright © 2007 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Exhaled Nitric Oxide in Infants-What Is a Nice Test Like FENO Doing in a Place Like This?

Esther van Mastrigt1 , Carmelo Gabriele1 , J. C. de Jongste1
  • 1Department of Pediatrics-Respiratory Medicine, Erasmus University Medical Centre-Sophia Children's Hospital, Rotterdam, The Netherlands
Further Information

Publication History

Publication Date:
22 August 2007 (online)

    Permissions and Reprints

ABSTRACT

In adults and older children the measurement of fractional exhaled nitric oxide (FENO) has been shown to be useful as a tool to diagnose and monitor eosinophilic airway inflammation. However, the recommended method to measure FENO in school-age children is not suited for use in preschool children and infants. This article reviews the data on FENO measurements in infants. In the first year of life, measurement of FENO can be done during tidal breathing or during a single forced passive expiration. Several technical factors, including contamination with nasal and ambient NO, and the influence of expiratory flow influence FENO levels in infants. Because asthma is uncommon in infants and wheezing is often related to viral infections, considerable differences in clinical utility of FENO between older children and infants could be expected. From the available data FENO could potentially be useful to identify early-onset asthma, to diagnose primary ciliary dyskinesia (PCD), and to monitor the effect of various treatments. In conclusion, there is still much uncertainty about the potential clinical utility of FENO in infants. There is a need for clinical studies showing the merits and limitations of different methodologies, to standardize FENO measurements in infants, and to obtain normal reference values for this age group.

KEYWORDS

Eosinophilic airway inflammation - early childhood wheezing - asthma - inflammometry - lung function

REFERENCES

  • 1 Alving K, Weitzberg E, Lundberg J M. Increased amount of nitric oxide in exhaled air of asthmatics.  Eur Respir J. 1993;  6 1368-1370
    PubMedGoogle Scholar
  • 2 Nathan C, Xie Q W. Regulation of biosynthesis of nitric oxide.  J Biol Chem. 1994;  269 13725-13728
    PubMedGoogle Scholar
  • 3 ATS/ERS. Recommendations for Standardized Procedures for the Online and Offline Measurement of Exhaled Lower Respiratory Nitric Oxide and Nasal Nitric Oxide.  Am J Respir Crit Care Med. 2005;  171 912-930
    CrossrefPubMedGoogle Scholar
  • 4 GINA .Global Initiative for Asthma Management and Prevention, 2002. http://www.ginasthma.com
    Google Scholar
  • 5 Agertoft L, Pedersen S. Effects of long-term treatment with an inhaled corticosteroid on growth and pulmonary function in asthmatic children.  Respir Med. 1994;  88 373-381
    PubMedGoogle Scholar
  • 6 Baraldi E, de Jongste J C. Measurement of exhaled nitric oxide in children, 2001.  Eur Respir J. 2002;  20 223-237
    CrossrefPubMedGoogle Scholar
  • 7 Gabriele C, van der Wiel E C, Nieuwhof E M, Moll H, Merkus P JFM, de Jongste J C. Methodological aspects of exhaled nitric oxide measurements in infants.  Pediatr Allergy Immunol. 2007;  18 36-41
    CrossrefPubMedGoogle Scholar
  • 8 Franklin P J, Turner S W, Mutch R C, Stick S M. Measuring exhaled nitric oxide in infants during tidal breathing: methodological issues.  Pediatr Pulmonol. 2004;  37 24-30
    CrossrefPubMedGoogle Scholar
  • 9 Ratjen F, Kavuk I, Gartig S, Wiesemann H G, Grasemann H. Airway nitric oxide in infants with acute wheezy bronchitis.  Pediatr Allergy Immunol. 2000;  11 230-235
    CrossrefPubMedGoogle Scholar
  • 10 Frey U, Kuehni C, Roiha H et al.. Maternal atopic disease modifies effects of prenatal risk factors on exhaled nitric oxide in infants.  Am J Respir Crit Care Med. 2004;  170 260-265
    CrossrefPubMedGoogle Scholar
  • 11 Wildhaber J H, Hall G L, Stick S M. Measurements of exhaled nitric oxide with the single-breath technique and positive expiratory pressure in infants.  Am J Respir Crit Care Med. 1999;  159 74-78
    PubMedGoogle Scholar
  • 12 Franklin P J, Turner S W, Mutch R C, Stick S M. Comparison of single-breath and tidal breathing exhaled nitric oxide levels in infants.  Eur Respir J. 2004;  23 369-372
    CrossrefPubMedGoogle Scholar
  • 13 Artlich A, Busch T, Lewandowski K, Jonas S, Gortner L, Falke K J. Childhood asthma: exhaled nitric oxide in relation to clinical symptoms.  Eur Respir J. 1999;  13 1396-1401
    CrossrefPubMedGoogle Scholar
  • 14 Rutgers S R, Meijer R J, Kerstjens H A, van der Mark T W, Koeter G H, Postma D S. Nitric oxide measured with single-breath and tidal-breathing methods in asthma and COPD.  Eur Respir J. 1998;  12 816-819
    CrossrefPubMedGoogle Scholar
  • 15 Baraldi E, Azzolin N M, Dario C et al.. Effect of atmospheric nitric oxide (NO) on measurements of exhaled NO in asthmatic children.  Pediatr Pulmonol. 1998;  26 30-34
    CrossrefPubMedGoogle Scholar
  • 16 Stark H, Purokivi M, Kiviranta J, Randell J, Tukiainen H. Short-term and seasonal variations of exhaled and nasal NO in healthy subjects.  Respir Med. 2007;  101 265-271
    PubMedGoogle Scholar
  • 17 Schedin U, Norman M, Gustafsson L E, Jonsson B, Frostell C. Endogenous nitric oxide in the upper airways of premature and term infants.  Acta Paediatr. 1997;  86 1229-1235
    PubMedGoogle Scholar
  • 18 Schedin U, Norman M, Gustafsson L E, Herin P, Frostell C. Endogenous nitric oxide in the upper airways of healthy newborn infants.  Pediatr Res. 1996;  40 148-151
    PubMedGoogle Scholar
  • 19 Artlich A, Jonsson B, Bhiladvala M, Lonnqvist P A, Gustafsson L E. Single breath analysis of endogenous nitric oxide in the newborn.  Biol Neonate. 2001;  79 21-26
    CrossrefPubMedGoogle Scholar
  • 20 Baraldi E, Dario C, Ongaro R et al.. Exhaled nitric oxide concentrations during treatment of wheezing exacerbation in infants and young children.  Am J Respir Crit Care Med. 1999;  159(4 Pt 1) 1284-1288
    PubMedGoogle Scholar
  • 21 Olivieri M, Talamini G, Corradi M et al.. Reference values for exhaled nitric oxide (reveno) study.  Respir Res. 2006;  7 94
    CrossrefPubMedGoogle Scholar
  • 22 Deykin A, Massaro A F, Drazen J M, Israel E. Exhaled nitric oxide as a diagnostic test for asthma; online versus offline techniques and effect of flow rate.  Am J Respir Crit Care Med. 2002;  165 1597-1601
    CrossrefPubMedGoogle Scholar
  • 23 Martinez T, Weist A, Williams T, Clem C, Silkoff P, Tepper R S. Assessment of exhaled nitric oxide kinetics in healthy infants.  J Appl Physiol. 2003;  94 2384-2390
    PubMedGoogle Scholar
  • 24 Hall G L, Reinmann B, Wildhaber J H, Frey U. Tidal exhaled nitric oxide in healthy, unsedated newborn infants with prenatal tobacco exposure.  J Appl Physiol. 2002;  92 59-66
    PubMedGoogle Scholar
  • 25 Deykin A, Massaro A F, Coulston E, Drazen J M, Israel E. Exhaled nitric oxide following repeated spirometry or repeated plethysmography in healthy individuals.  Am J Respir Crit Care Med. 2000;  161(4 Pt 1) 1237-1240
    PubMedGoogle Scholar
  • 26 Gabriele C, Pijnenburg M W, Monti F, Hop W, Bakker M E, de Jongste J C. The effect of spirometry and exercise on exhaled nitric oxide in asthmatic children.  Pediatr Allergy Immunol. 2005;  16 243-247
    CrossrefPubMedGoogle Scholar
  • 27 Vints A M, Oostveen E, Eeckhaut G, Smolders M, De Backer W A. Time-dependent effect of nitrate-rich meals on exhaled nitric oxide in healthy subjects.  Chest. 2005;  128 2465-2470
    CrossrefPubMedGoogle Scholar
  • 28 Buchvald F, Baraldi E, Carraro S et al.. Measurements of exhaled nitric oxide in healthy subjects age 4 to 17 years.  J Allergy Clin Immunol. 2005;  115 1130-1136
    CrossrefPubMedGoogle Scholar
  • 29 Pijnenburg M W, Lissenberg E T, Hofhuis W et al.. Exhaled nitric oxide measurements with dynamic flow restriction in children aged 4-8 yrs.  Eur Respir J. 2002;  20 919-924
    CrossrefPubMedGoogle Scholar
  • 30 Biban P, Zangardi T, Baraldi E, Dussini N, Chiandetti L, Zacchello F. Mixed exhaled nitric oxide and plasma nitrites and nitrates in newborn infants.  Life Sci. 2001;  68 2789-2797
    CrossrefPubMedGoogle Scholar
  • 31 Colnaghi M, Condo V, Pugni L, Fumagalli M, Mosca F. Endogenous nitric oxide production in the airways of preterm and term infants.  Biol Neonate. 2003;  83 113-116
    CrossrefPubMedGoogle Scholar
  • 32 Gabriele C, Nieuwhof E M, van der Wiel E C et al.. Exhaled nitric oxide differentiates airway diseases in the first 2 years of life.  Pediatr Res. 2006;  60 461-465
    CrossrefPubMedGoogle Scholar
  • 33 Saglani S, Malmstrom K, Pelkonen A S et al.. Airway remodelling and inflammation in symptomatic infants with reversible airflow obstruction.  Am J Respir Crit Care Med. 2005;  171 722-727
    CrossrefPubMedGoogle Scholar
  • 34 Latzin P, Kuehni C E, Baldwin D N et al.. Elevated exhaled nitric oxide in newborns of atopic mothers precedes subsequent respiratory symptoms.  Am J Respir Crit Care Med. 2006;  174 1292-1298
    CrossrefPubMedGoogle Scholar
  • 35 Dinakar C, Craff M, Laskowski D. Infants and toddlers without asthma with eczema have elevated exhaled nitric oxide levels.  J Allergy Clin Immunol. 2006;  117 212-213
    CrossrefPubMedGoogle Scholar
  • 36 Franklin P J, Turner S W, Hall G L, Moeller A, Stick S M. Exhaled nitric oxide is reduced in infants with rhinorrhea.  Pediatr Pulmonol. 2005;  39 117-119
    CrossrefPubMedGoogle Scholar
  • 37 Moeller A, Franklin P, Hall G L et al.. Inhaled fluticasone dipropionate decreases levels of nitric oxide in recurrently wheezy infants.  Pediatr Pulmonol. 2004;  38 250-255
    CrossrefPubMedGoogle Scholar
  • 38 Straub D A, Moeller A, Minocchieri S et al.. The effect of montelukast on lung function and exhaled nitric oxide in infants with early childhood asthma.  Eur Respir J. 2005;  25 289-294
    CrossrefPubMedGoogle Scholar
  • 39 Guilbert T W, Morgan W J, Zeiger R S et al.. Long-term inhaled corticosteroids in preschool children at high risk for asthma.  N Engl J Med. 2006;  354 1985-1997
    CrossrefPubMedGoogle Scholar
  • 40 Saglani S, Nicholson A G, Scallan M et al.. Investigation of young children with severe recurrent wheeze: any clinical benefit?.  Eur Respir J. 2006;  27 29-35
    CrossrefPubMedGoogle Scholar
  • 41 Mahut B, Escudier E, de Blic J et al.. Impairment of nitric oxide output of conducting airways in primary ciliary dyskinesia.  Pediatr Pulmonol. 2006;  41 158-163
    CrossrefPubMedGoogle Scholar
  • 42 Corbelli R, Bringolf-Isler B, Amacher A et al.. Nasal nitric oxide measurement to screen children for primary ciliary dyskinesia.  Chest. 2004;  126 1054-1059
    CrossrefPubMedGoogle Scholar
  • 43 Baraldi E, Bonetto G, Zacchello F, Filippone M. Low exhaled nitric oxide in school-age children with bronchopulmonary dysplasia and airflow limitation.  Am J Respir Crit Care Med. 2005;  171 68-72
    CrossrefPubMedGoogle Scholar
  • 44 Abman S H. Bronchopulmonary dysplasia: a vascular hypothesis.  Am J Respir Crit Care Med. 2001;  164(10 Pt 1) 1755-1756
    CrossrefPubMedGoogle Scholar
  • 45 Leipala J A, Williams O, Sreekumar S et al.. Exhaled nitric oxide levels in infants with chronic lung disease.  Eur J Pediatr. 2004;  163 555-558
    PubMedGoogle Scholar
  • 46 Roiha H L, Kuehni C E, Zanolari M et al.. Alterations of exhaled nitric oxide in preterm infants with chronic lung disease.  Eur Respir J. 2007;  29 251-258
    PubMedGoogle Scholar
  • 47 Dotsch J, Demirakca S, Terbrack H G, Huls G, Rascher W, Kuhl P G. Airway nitric oxide in asthmatic children and patients with cystic fibrosis.  Eur Respir J. 1996;  9 2537-2540
    CrossrefPubMedGoogle Scholar
  • 48 Grasemann H, Michler E, Wallot M, Ratjen F. Decreased concentration of exhaled nitric oxide (NO) in patients with cystic fibrosis.  Pediatr Pulmonol. 1997;  24 173-177
    CrossrefPubMedGoogle Scholar
  • 49 Moeller A, Horak Jr F, Lane C et al.. Inducible NO synthase expression is low in airway epithelium from young children with cystic fibrosis.  Thorax. 2006;  61 514-520
    CrossrefPubMedGoogle Scholar

J. C de JongsteM.D. Ph.D. 

Erasmus MC-Sophia Children's Hospital/University Medical Centre, Department of Pediatrics

P.O. Box 2060, 3000 CB Rotterdam, The Netherlands

Email: j.c.dejongste@erasmusmc.nl

      >