Exhaled nitric oxide: A biomarker integrating both lung function and airway inflammation changes

doi:10.1016/j.jaci.2013.12.1070

Journal of Allergy and Clinical Immunology

Volume 134, Issue 3, September 2014, Pages 554-559

https://doi.org/10.1016/j.jaci.2013.12.1070 Get rights and content

Background

The increased fraction of exhaled nitric oxide (Feno) values observed in asthmatic patients are thought to reflect increased airway inflammation. However, Feno values can be affected by airway caliber reduction, representing a bias when using Feno values to assess asthma control.

Objective

We sought to determine the effect of changes in both airway caliber and inflammation on Feno values using the allergen challenge model.

Methods

FEV₁ and Feno values were measured during early airway responses (EARs) and late airway responses after challenge with house dust mite allergens in 15 patients with mild allergic asthma. Helium and sulfur hexafluoride (SF₆) phase III expired concentration slopes (S_He and S_SF6, respectively) from single-breath washout tests were measured to identify sites of airway constriction.

Results

In EARs, FEV₁ and Feno value decreases reached 36.8% and 22%, respectively (P < .001). ΔS_He was greater than ΔS_SF6 (+189.4% vs +82.2%, P = .001). In late airway responses FEV₁ and Feno value decreases reached 31.7% and 28.7%, respectively (P < .001), with the same ΔS_He and ΔS_SF6 pattern (+155.8% vs +76%, P = .001). Eight hours after the EAR, FEV₁ was still decreased (P < .001), whereas Feno values had returned to baseline. At 24 hours, FEV₁ had returned to baseline, with Feno values increased by 38.7% (P = .04).

Conclusion

In patients with mild allergic asthma, airway caliber changes modulate changes in Feno values resulting from airway inflammation. Therefore Feno should no longer be considered solely an inflammation biomarker but rather a biomarker that integrates both airway inflammation and lung function changes. Furthermore, early and late phases resulting from allergen exposure were shown to involve similar lung regions.

Section snippets

Subjects

Patients with intermittent or mild persistent asthma associated with house dust mite allergy were recruited from the outpatient asthma clinic (CUB Erasme University Hospital, Brussels, Belgium). Asthma was diagnosed according to standard criteria,¹ and sensitivity to house dust mite was evaluated by using skin prick tests or RASTs with commercially available extracts. Patients had no recent history of smoking or upper airway infection. At least 2 weeks before the challenge procedure, asthma

Patients' characteristics

Fifteen patients (mean age, 26 years; 11 men and 4 women) were included, with 13 exhibiting both EARs and LARs (dual responders). Baseline mean FEV₁ was 94.9% of predicted value.

Lung function and Feno values

For Feno values, spirometric values (FEV₁), S_He, and S_SF6, 5 time points after the allergen challenge were taken into account: EAR, recovery phase, LAR, and 8 and 24 hours after challenge. Fig 1 shows the mean changes in percentage from baseline of FEV₁ (Fig 1, black line and circles) and Feno (Fig 1, blue line and

Discussion

This study showed that in patients with mild allergic asthma, airway caliber changes significantly modulated Feno changes resulting from concomitant airway inflammatory reactions.

Feno is generally accepted as an airway inflammation marker because Feno values have been reported to reflect the eosinophilic inflammatory process that occurs in the airways of asthmatic patients.⁴ However, airway caliber appears to be another relevant determinant of Feno values. FEV₁ reduction induced by airway

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We used spirometry as an objective parameter to improve the accuracy of the diagnosis of asthma. FeNO, a type 2 inflammatory marker of asthma and atopic diseases,38 were also included as another outcome. In conclusion, higher cord blood soluble FasL levels at birth have a potentially long-term effect on atopic diseases, allergen sensitization, and lung function.
Serum or cord blood soluble Fas ligand (FasL) has been related to asthma, allergic rhinitis, and atopic dermatitis in cross-sectional and short-term follow-up studies. However, the association of cord blood soluble FasL with long-term allergic outcomes has seldom been investigated.
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This revision could be useful to summarize the role of FeNO in relation to asthma characteristics and help in the use of FeNO in different clinical settings particularly in low income countries.
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: Chiesi provided a grant for the Immunobiology of Asthma Unit.

: Disclosure of potential conflict of interest: A. Haccuria has received research support from and has a board membership with Chiesi. A. Michils has received research support from Chiesi, Novartis, and AstraZeneca; is on advisory boards for Chiesi, Novartis, and AstraZeneca; has received payment for lectures from AstraZeneca, Stallergenes, and Chiesi; and has received travel support from Novartis and Chiesi. A. Van Muylem has received research support and payment for lectures from Chiesi. S. Michiels declares that he has no relevant conflicts of interest.

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Asthma and lower airway diseaseExhaled nitric oxide: A biomarker integrating both lung function and airway inflammation changes

Background

Objective

Methods

Results

Conclusion

Section snippets

Subjects

Patients' characteristics

Lung function and Feno values

Discussion

Lancet

Respir Physiol Neurobiol

J Allergy Clin Immunol

Lancet

Global strategy for asthma management and prevention: GINA executive summary

Eur Respir J

Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long-term treatment. The AMPUL Study Group

Am J Respir Crit Care Med

Increased amount of nitric oxide in exhaled air of asthmatics

Eur Respir J

The use of exhaled nitric oxide concentration to identify eosinophilic airway inflammation: an observational study in adults with asthma

Clin Exp Allergy

The L-arginine-nitric oxide pathway

N Engl J Med

An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications

Am J Respir Crit Care Med

The current single exhalation method of measuring exhales nitric oxide is affected by airway calibre

Eur Respir J

Exhaled nitric oxide (NO) is reduced shortly after bronchoconstriction to direct and indirect stimuli in asthma

Am J Respir Crit Care Med

Effect of airways constriction on exhaled nitric oxide

J Appl Physiol

Airway responsiveness. Standardized challenge testing with pharmacological, physical and sensitizing stimuli in adults. Report Working Party Standardization of Lung Function Tests, European Community for Steel and Coal. Official Statement of the European Respiratory Society

Eur Respir J Suppl

Simultaneous measurement of nitric oxide production by conducting and alveolar airways of humans

J Appl Physiol

Airway contribution to alveolar nitric oxide in healthy subjects and stable asthma patients

J Appl Physiol

Lung volumes and forced ventilatory flows. Report Working Party. Standardization of Lung Function Tests. European Community for Steel and Coal. Official Statement of the European Respiratory Society

Eur Respir J

Adenosine 5′-monophosphate challenge elicits a more peripheral airway response than methacholine challenge

J Appl Physiol

A simple sequentially rejective multiple test procedure

Scand J Stat

Asthma and lower airway disease
Exhaled nitric oxide: A biomarker integrating both lung function and airway inflammation changes