Article information
This article is an academic review of the application in children of the measurement of fractional exhaled nitric oxide (FENO). We outline the joint American Thoracic Society/European Respiratory Society recommendations for online measurement of FENO in both cooperating children and children unable to cooperate, offline measurement with uncontrolled exhalation flow rate, offline measurement with controlled exhalation flow rate using a dynamic flow restrictor, and offline measurement during tidal breathing in children unable to cooperate.
This is followed by a review of the normal range of values for single-breath online measurements obtained with a chemiluminescence FENO analyzer (geometric mean, 9.7 parts per billion [ppb]; upper limit of the 95% confidence interval, 25.2 ppb). FENO values above 17 ppb have a sensitivity of 81% and a specificity of 80% for predicting asthma of an eosinophilic phenotype. We discuss the response of FENO values to anti-inflammatory treatment and the use of this marker in the management of asthma.
Results obtained with chemiluminescence and portable electrochemical analyzers are compared. The portable devices offer the possibility—in children over 5 years of age—of accurate and universal monitoring of exhaled nitric oxide concentrations, an emerging marker of eosinophilic inflammation in asthma that facilitates diagnosis, monitoring of disease progression, and assessment of response to therapy.
Key words:
Exhaled nitric oxide
Methodology
Portable analyzers
Children
Asthma
En este artículo se presenta una revisión académica sobre la aplicabilidad de la medida de la fracción exhalada de óxido nítrico (FENO) en niños. De acuerdo con las normas conjuntas de la American Thoracic Society/European Respiratory Society, se describen los métodos de medida on-line en niños colaboradores y no colaboradores, los registros off-line sin control de flujo de exhalación y con control de flujo de exhalación mediante restrictor de flujo dinámico, y el registro off-line a respiración corriente en niños no colaboradores.
Se revisan los valores de normalidad, fundamentalmente con los analizadores de la FENO por quimioluminiscencia, mediante registro on-line de una única respiración (media geométrica: 9,7 ppb -partes por mil millones-; límite superior del intervalo de confianza del 95%: 25,2 ppb). Los valores de la FENO superiores a 17 ppb aportan un 81% de sensibilidad y un 80% de especificidad para predecir asma de fenotipo eosinofílico. Se analiza la respuesta de la FENO al tratamiento antiinflamatorio y al seguimiento del asma.
Por último, se comparan los resultados entre los analizadores por quimioluminiscencia y los electroquímicos, portátiles. Estos últimos ofrecen la posibilidad, en niños mayores de 5 años, de un seguimiento adecuado y universal del óxido nítrico exhalado como indicador emergente de la inflamación eosinofílica en la enfermedad asmática, de modo que facilitan el diagnóstico, el control evolutivo y el seguimiento terapéutico.
Palabras clave:
Óxido nítrico exhalado
Metodología
Medidores portátiles
Niños
Asma
Full text is only aviable in PDF
References
[1]
LJ Ignarro, GM Buga, KS Word, RE Byrns, G Chaudhuri.
Proc Natl Acad Sci U S A, 84 (1987), pp. 9265-9269
[3]
O Smith.
Nobel Prize for NO research.
Nat Med, 4 (1998), pp. 1215
[4]
JB Guillén, EA Fiallos, AB Castillo, GA Vallejo.
Protest at Nobel omission of Moncada.
Nature, 396 (1998), pp. 614
[5]
K Alving, E Weitzberg, JM Lundberg.
Increased amount of nitric oxide in exhaled air of asthmatics.
Eur Respir J, 6 (1993), pp. 1368-1370
[6]
SA Kharitonov, D Yates, RA Robbins, R Longar-Sinclair, EA Shinebourne, PJ Barnes.
Increased nitric oxide in exhaled air of asthmatic patients.
Lancet, 343 (1994), pp. 133-135
[7]
SA Kharitonov, D Yates, PJ Barnes.
Inhaled glucocorticoids decrease nitric oxide in exhaled air of asthmatic patients.
Am J Respir Crit Care Med, 153 (1996), pp. 454-457
[8]
EL van Rensen, KC Straathof, MA Veselic-Charvat, AH Zwinderman, EH Bel, PJ Sterk.
Effect of inhaled steroids on airway hyperresponsiveness, sputum eosinophils, and exhaled nitric oxide levels in patients with asthma.
Thorax, 54 (1999), pp. 403-408
[9]
C Lane, D Knight, S Burgess, P Franklin, F Horak, J Legg, et al.
Epithelial inducible nitric oxide synthase activity is the major determinant of nitric oxide concentration in exhaled breath.
Thorax, 59 (2004), pp. 757-760
[10]
PJ Franklin, SW Turner, PN Le Souef, SM Stick.
Exhaled nitric oxide and asthma: complex interactions between atopy, airway responsiveness, and symptoms in a community population of children.
Thorax, 58 (2003), pp. 1048-1052
[11]
J Batra, TP Singh, U Mabalirajan, A Sinha, R Prasad, B Ghosh, et al.
Association of inducible nitric oxide synthase with asthma severity, total serum immunoglobulin E and blood eosinophil levels.
Thorax, 62 (2007), pp. 16-22
[12]
PJ Franklin, R Taplin, SM Stick.
A community study of exhaled nitric oxide in healthy children.
Am J Respir Crit Care Med, 159 (1999), pp. 69-73
[13]
C Pedroletti, M Hogman, P Merilainen, LS Nordavall, G Hedlin, K Alving.
Nitric oxide airway diffusing capacity and mucosal concentration in asthmatic school children.
Pediatr Res, 54 (2003), pp. 496-501
[14]
LP Malmberg, T Petays, T Haahtela, T Laatikainen, P Jousilahti, E Vartiainen, et al.
Exhaled nitric oxide in healthy nonatopic school-age children.
Pediatr Pulmonol, 41 (2006), pp. 635-642
[15]
A Avital, K Uwyyed, N Berkman, E Bar-Yishay, S Godfrey, C Springer.
Exhaled nitric oxide is age-dependent in asthma.
Pediatr Pulmonol, 36 (2003), pp. 433-438
[16]
N Kissoon, LJ Duckworth, KV Blake, SP Murphy, CL Taylor, LR DeNicola, et al.
Exhaled nitric oxide concentrations: online versus offline values in healthy children.
Pediatr Pulmonol, 33 (2002), pp. 283-292
[17]
FL Ricciardolo, PJ Sterk, B Gaston, G Folkerts.
Nitric oxide in health and disease of the respiratory system.
Physiol Rev, 84 (2004), pp. 731-765
[18]
S Kharitonov, K Alving, PJ Barnes.
Exhaled and nasal nitric oxide measurements: recommendations. The European Respiratory Society Task Force.
Eur Respir J, 10 (1997), pp. 1683-1693
[19]
American Thoracic Society.
Recommendations for standardized procedures for the on-line and off-line measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide in adults and children-1999.
Am J Respir Crit Care Med, 160 (1999), pp. 2104-2117
[20]
E Baraldi, JC Jongste, B Gaston, K Alving, PJ Barnes, H Bisgaard, et al.
Measurement of exhaled nitric oxide in children.
Eur Respir J, 20 (2002), pp. 223-237
[21]
ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005.
Am J Respir Crit Care Med, 171 (2005), pp. 912-930
[22]
N Kissoon, L Duckworth, K Blake, S Murphy, PE Silkoff.
Exhaled nitric oxide measurements in childhood asthma: techniques and interpretation.
Pediatr Pulmonol, 28 (1999), pp. 282-296
[23]
N Kissoon, LJ Duckworth, KV Blake, SP Murphy, CL Taylor, PE Silkoff.
FE (NO): relationship to exhalation rates and online versus bag collection in healthy adolescents.
Am J Respir Crit Care Med, 162 (2000), pp. 539-545
[24]
SA Kharitonov, F Gonio, C Kelly, S Meah, PJ Barnes.
Reproducibility of exhaled nitric oxide measurements in healthy and asthmatic adults and children.
Eur Respir J, 21 (2003), pp. 433-438
[25]
GL Piacentini, A Bodini, S Costella, L Vicentini, Y Suzuki, AL Boner.
Exhaled nitric oxide is reduced after sputum induction in asthmatic children.
Pediatr Pulmonol, 29 (2002), pp. 430-433
[26]
LP Ho, FT Wood, A Robson, JA Innes, AP Greening.
The current single exhalation method of measuring exhales nitric oxide is affected by air calibre.
Eur Respir J, 15 (2000), pp. 1009-1013
[27]
F Buchvald, H Bisgaard.
FeNO measured at fixed exhalation flow rate during controlled tidal breathing in children from the age of 2 yr.
Am J Respir Crit Care Med, 163 (2001), pp. 699-704
[28]
PE Silkoff, CA Bates, JB Meiser, DL Bratton.
Single-breath exhaled nitric oxide in preschool children facilitated by a servo-controlled device maintaining constant flow.
Pediatr Pulmonol, 37 (2004), pp. 554-558
[29]
PF Daniel, B Klug, NH Valerius.
Measurement of exhaled nitric oxide in young children during tidal breathing through a face mask.
Pediatr Allergy Immunol, 16 (2005), pp. 248-253
[30]
Q Jöbsis, SL Schellekens, A Kroesbergen, WC Hop, JC de Jongste.
Off-line sampling of exhaled air for nitric oxide measurement in children: methodological aspects.
Eur Respir J, 17 (2001), pp. 898-903
[31]
E Baraldi, M Scollo, C Zaramella, S Zanconato, F Zacchello.
A simple flow-driven method for online measurement of exhaled NO starting at the age of 4 to 5 years.
Am J Respir Crit Care Med, 162 (2000), pp. 1828-1832
[32]
PG Djupesland, W Qian, JS Haight.
A new method for the remote collection of nasal and exhaled nitric oxide.
Chest, 120 (2001), pp. 1645-1650
[33]
MW Pijnenburg, ET Lissenberg, W Hofhuis, L Ghiro, WC Ho, WP Holland, et al.
Exhaled nitric oxide measurements with dynamic flow restriction in children aged 4-8 years.
Eur Respir J, 20 (2002), pp. 919-924
[34]
Q Jöbsis, HC Raatgeep, WC Hop, JC de Jongste.
Controlled low flow off line sampling of exhaled nitric oxide in children.
Thorax, 56 (2001), pp. 285-289
[35]
E Baraldi, C Dario, R Ongaro, M Scollo, NM Azzolin, N Panza, et al.
Exhaled nitric oxide concentrations during treatment of wheezing exacerbation in infants and young children.
Am J Respir Crit Care Med, 159 (1999), pp. 1284-1288
[36]
I Meyts, M Proesmans, V Van Gerven, K Hoppenbrouwers, K de Boeck.
Tidal off-line exhaled nitric oxide measurements in a pre-school population.
Eur J Pediatr, 162 (2003), pp. 506-510
[37]
PE Silkoff, M Carlson, T Bourke, R Katial, E Ogren, SJ Szefler.
The Aerocrine exhaled nitric oxide monitoring system NIOX is cleared by the US Food and Drug Administration for monitoring therapy in asthma.
J Allergy Clin Immunol, 114 (2004), pp. 1241-1256
[38]
E Napier, SW Turner.
Methodological issues related to exhaled nitric oxide measurement in children aged four to six years.
Pediatr Pulmonol, 40 (2005), pp. 97-104
[39]
F Buchvald, E Baraldi, S Carraro, B Gaston, J de Jongste, MW Pijnenburg, et al.
Measurements of exhaled nitric oxide in healthy subjects age 4 to 17 years.
J Allergy Clin Immunol, 115 (2005), pp. 1130-1136
[40]
C McGill, G Malik, SW Turner.
Validation of a hand-held exhaled nitric oxide analyzer for use in children.
Pediatr Pulmonol, 41 (2006), pp. 1053-1057
[41]
K Alving, C Janson, L Nordvall.
Performance of a new hand-held device for exhaled nitric oxide measurement in adults and children.
Respir Res, 7 (2006), pp. 67
[42]
S Vahlkvist, M Sinding, K Skamstrup, H Bisgaard.
Daily home measurements of exhaled nitric oxide in asthmatic children during natural birch pollen exposure.
J Allergy Clin Immunol, 17 (2006), pp. 1272-1276
[43]
D Menzies, A Nair, BJ Lipworth.
Portable exhaled nitric oxide measurements. Comparison with the “gold standard” technique.
Chest, 131 (2007), pp. 410-414
[44]
AM for tuna, T Feixas, P Casan.
Determinación de óxido nítrico en aire espirado (FENO) mediante un equipo portátil (NIOX-MINO® Aerocrine) en población sana.
Arch Bronconeumol, 43 (2007), pp. 176-179
[45]
Kharitonov S. NIOX-MINO®; a new handheld exhaled NO device. Proceedings of the European Respiratory Society 15th Annual Congress; 2005, September 17-21; Copenhagen. Copenhagen: European Respiratory Society; 2005.
[46]
Z Pedroletti, W Zetterquist, SL Nordval, K Alving.
Evaluation of different exhalation flow rates in exhaled nitric oxide (ENO) measurements in school children.
Eur Respir J, 16 (2000), pp. 22
[47]
M Scollo, C Zaramella, S Zanconato, E Baraldi.
Exhaled carbon monoxide (eCO) and exhaled nitric oxide (eNO) in children with acute asthma.
Eur Respir J, 16 (2000), pp. 23
[48]
LP Malmberg, AS Pelkonen, T Haahtela, M Turpeinen.
Exhaled nitric oxide rather than lung function distinguishes preschool children with probable asthma.
Thorax, 58 (2003), pp. 494-499
[49]
PF Daniel, B Klug, NH Valerius.
Exhaled nitric oxide in healthy young children during tidal breathing through a face mask.
Pediatr Allergy Immunol, 18 (2007), pp. 42-46
[50]
N Cobos Barroso, C Reverté Bober, S Gartner, S Liñán Cortés, L Quintó Domech.
Óxido nítrico exhalado y nasal en niños normales y asmáticos.
An Esp Pediatr, 49 (1998), pp. 241-247
[51]
F Balboa de Paz, S Rueda Esteban, E Aleo Luján, G Rodríguez Tauriz.
Óxido nítrico exhalado en niños sanos y asmáticos.
An Esp Pediatr, 57 (2002), pp. 12-17
[52]
TJ Warke, PS Fitch, V Brown, R Taylor, JD Lyons, M Ennis, et al.
Exhaled nitric oxide correlates with airway eosinophils in childhood asthma.
Thorax, 57 (2002), pp. 383-387
[53]
MW Pijnenburg, EM Bakker, WC Hop, JC de Jongste.
Titrating steroids on exhaled nitric oxide in children with asthma: a randomized controlled trial.
Am J Respir Crit Care Med, 172 (2005), pp. 831-836
[54]
LP Malmberg, H Turpeinen, P Rytila, S Sarna, T Haahtela.
Determinants of increased exhaled nitric oxide in patients with suspected asthma.
Allergy, 60 (2005), pp. 464-468
[55]
AD Smith, JO Cowan, S Filsell, C McLachlan, G Monti-Sheehan, P Jackson, et al.
Diagnosing asthma: comparisons between exhaled nitric oxide measurements and conventional tests.
Am J Respir Crit Care Med, 169 (2004), pp. 473-478
[56]
DR Taylor, MW Pijnenburg, AD Smith, JC De Jongste.
Exhaled nitric oxide measurements: clinical application and interpretation.
Thorax, 61 (2006), pp. 817-827
[57]
AM Fitzpatrick, MG Benjamin, SC Erzurum, WG Teague.
Features of severe asthma in school-age children: atopy and increased exhaled nitric oxide.
J Allergy Clin Immunol, 118 (2006), pp. 1218-1225
[58]
ENFUMOSA.
The ENFUMOSA cross-sectional European multicentre study of the clinical phenotype of chronic severe asthma. European Network for Understanding Mechanisms of Severe Asthma.
Eur Respir J, 22 (2003), pp. 470-477
[59]
SL Jones, J Kittelson, JO Cowan, EM Flannery, RJ Hancox, CR McLachlan, et al.
The predictive value of exhaled nitric oxide measurements in assessing changes in asthma control.
Am J Respir Crit Care Med, 164 (2001), pp. 738-743
[60]
AD Smith, JO Cowan, KP Brassett, GP Herbison, DR Taylor.
Use of exhaled nitric oxide measurements to guide treatment in chronic asthma.
N Engl J Med, 352 (2005), pp. 2163-2173
[61]
AD Smith, JO Cowan, JP Brassett, S Filsell, C McLachlan, G Monti-Sheehan, et al.
Exhaled nitric oxide: a predictor of steroid response.
Am J Respir Crit Care Med, 172 (2005), pp. 453-459
[62]
SJ Szefler, BR Phillips, FD Martínez, VM Chinchilli, RF Lemanske, RC Strunk.
Characterization of within-subject responses to fluticasone and montelukast in childhood asthma.
J Allergy Clin Immunol, 115 (2005), pp. 233-242
[63]
DA Straub, S Minocchieri, A Moeller, J Hamacher, JH Wildhaber.
The effect of montelukast on exhaled nitric oxide and lung function in asthmatic children 2 to 5 years old.
Chest, 127 (2005), pp. 509-514
[64]
MW Pijnenburg, W Hofhuis, WC Hop, JC de Jonste.
Exhaled nitric oxide predicts asthma relapse in children with clinical asthma remission.
Thorax, 60 (2005), pp. 215-218
[65]
A Moeller, P Franklin, GL Hall, S Turner, D Straub, JH Wildhaber.
Inhaled fluticasone dipropionate decreases levels of nitric oxide in recurrently wheezy infants.
Pediatr Pulmonol, 38 (2004), pp. 250-255
[66]
C Gabriele, EM Nieuwhof, EC van der Wiel, W Hofhuis, HA Moll, PJ Merkus, et al.
Exhaled nitric oxide differentiates airway diseases in the first two years of life.
Pediatr Res, 60 (2006), pp. 461-465
[67]
DA Straub, A Moeller, S Minocchieri, J Hamacher, FH Sennhauser, GJ Hall, et al.
The effect of montelukast on lung function and exhaled nitric oxide in infants with early childhood asthma.
Eur Respir J, 25 (2005), pp. 289-294
[68]
P Latzin, CE Kuehni, DN Baldwin, HL Roiha, C Casaulta, U Frey.
Elevated exhaled nitric oxide in newborns of atopic mothers precedes respiratory symptoms.
Am J Respir Crit Care Med, 174 (2006), pp. 1292-1298
[69]
JC de Jonste.
To wheeze or not to wheeze. Prospective FENO-typing in early infancy.
Am J Respir Crit Care Med, 174 (2006), pp. 1281-1285
[70]
LF Jouaville, I Annesi-Maesano, LT Nguyen, AS Bocage, M Bedu, D Caillaud.
Interrelationships among asthma, atopy, rhinitis and exhaled nitric oxide in a population-based sample of children.
Clin Exp Allergy, 33 (2003), pp. 1506-1511
[71]
O Williams, G Dimitriou, S Hannam, GF Rafferty, A Greenouhgh.
Lung function and exhaled nitric oxide levels in infants developing chronic lung disease.
Pediatr Pulmonol, 42 (2007), pp. 107-113
[72]
HE Elphick, EA Demoncheaux, S Ritson, TW Higenbottam, mL Everard.
Exhaled nitric oxide is reduced in infants with cystic fibrosis.
Thorax, 56 (2001), pp. 151-152
[73]
B Mahut, C Delacourt, F Zerah-Lancner, J de Blic, A Harf, C Delclaux.
Increase in alveolar nitric oxide in the presence of symptoms in childhood asthma.
Chest, 125 (2004), pp. 1012-1018
[74]
R Corbelli, B Bringolf-Isler, A Amacher, B Sasse, M Spycher, J Hammer.
Nasal nitric oxide measurements to screen children for primary ciliary dyskinesia.
Chest, 126 (2004), pp. 1054-1059
[75]
SA Kharitonov, PJ Barnes.
Clinical aspects of exhaled nitric oxide.
Eur Respir J, 16 (2000), pp. 781-792
[76]
SC Foley, NO Hopkins, MX Fitzgerald, SC Donnelly, P McLouhglin.
Airway nitric oxide output is reduced in bronchiectasis.
Respir Med, 101 (2007), pp. 1549-1555
[77]
N Cobos Barroso.
Óxido nítrico exhalado: aplicaciones el pediatría.
Arch Bronconeumol, 34 (1998), pp. 371-373
[78]
PA Steerenberg, NA Janssen, G De Meer, PH Fischer, S Nierkens, H van Loveren, et al.
Relationship between exhaled NO, respiratory synptoms, lung function, bronchial hyperresponsiveness, and blood eosinophilia in school children.
Thorax, 58 (2003), pp. 242-245
[79]
P Casan.
Novedades en el diagnóstico del asma.
Rev Patol Respir, 9 (2006), pp. 108-109
Copyright © 2008. Sociedad Española de Neumología y Cirugía Torácica (SEPAR)
