Medical Progress
Airway nitrogen oxide measurements in asthma and other pediatric respiratory diseases,☆☆

https://doi.org/10.1067/mpd.2000.107526Get rights and content

Abstract

Markers for airway inflammation that can be measured noninvasively in expired air may be helpful in treating patients with asthma. For example, levels of nitric oxide are high in the breath of children with asthma exacerbations and decrease with anti-inflammatory therapy. Expired nitric oxide testing has now been standardized and may be useful for children with recurring wheezing that is diagnostically or therapeutically challenging. However, the results may be influenced by several biochemical and anatomic variables and must therefore be interpreted with caution. (J Pediatr 2000;137:14-20)

Section snippets

Airway nitrogen oxides

Noninvasive lung function tests have recently been developed for airway inflammation. Most of these tests involve measurement of nitrogen oxides. In 1991, Gustafsson et al16 reported the presence of nitric oxide in human breath, and several investigators subsequently observed high levels of NO in the breath of adults with asthma. Exhaled NO levels are now known also to be elevated in pediatric asthma and to decrease with anti-inflammatory therapy17, 18, 19, 20 (Fig 1).

. Individual (open squares)

Clinical measurement of nitric oxide

Gas-phase NO is most accurately measured in the clinical setting with the use of a chemiluminescent reaction between NO and ozone to form nitrogen dioxide, oxygen, and a photon.27 The machinery required is sensitive to <1 part per billion but is relatively expensive (over $10,000). This type of equipment has been used for decades to monitor environmental air pollution.

To measure airway NO levels, children begin by breathing NO-free air from a reservoir or filtering system. They may then perform

Exhaled NO and asthmatic airway inflammation

No matter which technique is used, differences in exhaled NO concentration between patients with asthma and healthy control subjects are robust. Mixed expired vital capacity NO concentrations are ~6 ppb in health but 2 to 3 times higher in asthma.18, 31, 36 Similar differences are observed in mixed tidal breathing measurements of NO19 and with on-line measurements.33 For perspective, these parts-per-billion levels of NO produced endogenously in the airway are 3 orders of magnitude less than

Expired NO in disease states other than asthma

Expired NO values are normal or lower than normal in all non-asthmatic pediatric obstructive pulmonary diseases. In particular, values are low in cystic fibrosis,47 possibly because of quenching by neutrophil-derived superoxide and/or prokaryotic denitrification, and in ciliary dyskinesia,48 perhaps reflecting decreased activity of NOS 3.49 Further, expired NO measurements have been used successfully to distinguish preschool children with isolated virus-induced wheezing (low values) from those

Additional factors to consider when interpreting an expired nitric oxide value

Expired NO concentrations do not always exclusively and directly reflect NOS expression or activity. Complete pharmacologic inhibition of NOS does not eliminate NO from expired air,45, 56 and hypernitrosopnea in the asthmatic guinea pig is not associated with NOS upregulation.56 Several additional determinants of exhaled NO values should be borne in mind when interpreting the results of clinical tests.

Other noninvasive markers for airway inflammation

Gas-phase NO is not the only compound that can be measured noninvasively in expired air and used to differentiate normal from inflamed lungs. For example, concentrations of nitrite are elevated in exhaled breath condensate from asthmatic subjects.68 Of note, levels fall somewhat during exacerbations in parallel with falling pH and increasing expired NO, suggesting that NO evolution from nitrite protonation contributes to hypernitrosopnea.57 Further, elevations of expired carbon monoxide

Conclusions and applications

Nitrogen oxides are endogenously produced compounds with a variety of roles in pediatric lung physiology and pathology. They are produced by three isoforms of NOS, all of which have been identified in the lung. The nitrogen oxide products of these enzymes can be measured by noninvasive techniques, which have already proven useful in the management of pediatric lung inflammation. Equipment for measuring expired NO is now available at many centers around the world. Both the European Respiratory

References (69)

  • J Hunt et al.

    Condensed expirate nitrite as a home marker for acute asthma [letter]

    Lancet

    (1995)
  • V Gemou-Engesaeth et al.

    Inhaled glucocorticoid therapy of childhood asthma is associated with reduced peripheral blood T cell activation and ‘Th2-type’ cytokine mRNA expression

    Pediatrics

    (1997)
  • AB Kay et al.

    The role of cellular immunology in asthma

    Eur Respir J Suppl

    (1991)
  • J Bousquet et al.

    Eosinophilic inflammation in asthma

    N Engl J Med

    (1990)
  • T Haahtela et al.

    Comparison of a beta 2-agonist, terbutaline, with an inhaled corticosteroid, budesonide, in newly detected asthma

    N Engl J Med

    (1991)
  • WO Spitzer et al.

    The use of beta-agonists and the risk of death and near death from asthma

    N Engl J Med

    (1992)
  • P Ernst et al.

    Is the association between inhaled beta-agonist use and life-threatening asthma because of confounding by severity?

    Am Rev Respir Dis

    (1993)
  • T Haahtela et al.

    Effects of reducing or discontinuing inhaled budesonide in patients with mild asthma

    N Engl J Med

    (1994)
  • PJ Barnes

    Inhaled glucocorticoids for asthma

    N Engl J Med

    (1995)
  • J Garrett et al.

    Major reduction in asthma morbidity and continued reduction in asthma mortality in New Zealand: What lessons have been learned?

    Thorax

    (1995)
  • National Asthma Education Program

    Expert Panel 2: Guidelines for the diagnosis and management of asthma

    (1997)
  • T Hashimoto et al.

    Correlation between respiratory function and airway inflammation in asthma

    Int Arch Allergy Immunol

    (1999)
  • R Beasley et al.

    Cellular events in the bronchi in mild asthma and after bronchial provocation

    Am Rev Respir Dis

    (1989)
  • IJ Doull et al.

    Growth of prepubertal children with mild asthma treated with inhaled beclomethasone dipropionate

    Am J Respir Crit Care Med

    (1995)
  • RB Klein et al.

    Spirometric patterns in childhood asthma: peak flow compared with other indices

    Pediatr Pulmonol

    (1995)
  • A Artlich et al.

    Exhaled nitric oxide in childhood asthma

    Eur J Pediatr

    (1996)
  • CA Byrnes et al.

    Exhaled nitric oxide measurements in normal and asthmatic children

    Pediatr Pulmonol

    (1997)
  • C Nathan

    Nitric oxide as a secretol product of mammalian cells

    FASEB J

    (1992)
  • L Kobzik et al.

    Nitric oxide synthase in human and rat lung: immunocytochemical and histochemical localization

    Am J Respir Cell Mol Biol

    (1993)
  • GT De Sanctis et al.

    Contribution of nitric oxide synthases 1, 2, and 3 to airway hyperresponsiveness and inflammation in a murine model of asthma

    J Exp Med

    (1999)
  • WH Koppenol et al.

    Peroxynitrite, a cloaked oxidant formed by nitric oxide and superoxide

    Chem Res Toxicol

    (1992)
  • JS Stamler et al.

    Biochemistry of nitric oxide and its redox-activated forms

    Science

    (1992)
  • B Gaston et al.

    Endogenous nitrogen oxides and bronchodilator S-nitrosothiols in human airways

    Proc Natl Acad Sci USA

    (1993)
  • AJ Gow et al.

    The oxyhemoglobin reaction of nitric oxide

    Proc Natl Acad Sci USA

    (1999)
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      Citation Excerpt :

      The role of exhaled NO in pulmonary disease has also been reviewed by others (Bernareggi & Cremona, 1999; Ashutosh, 2000; Berlyne & Barnes, 2000; Hunt & Gaston, 2000; Marshall & Stamler, 2000; Kharitonov & Barnes, 2001; Yates, 2001).

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    Supported by National Institutes of Health grant RO1 BL59337 (B.G.), Virginia Thoracic Society (J.H.), National Institutes of Health Asthma Center Grant 1U19-A134607 (B.G. and J.H.), Cystic Fibrosis Foundation Grant No. GASTON95GO (B.G.), American Lung Association Grant No. RG-110-N (B.G.), and the University of Virginia Children’s Medical Center (B.G.).

    ☆☆

    Reprint requests: Benjamin Gaston, MD, Department of Pediatrics, Box 386, The University of Virginia Health System, Charlottesville VA, 22951.

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